Comparisons of Prognosis between Surgically and Clinically Diagnosed Idiopathic Pulmonary Fibrosis Using Gap Model: A Korean National Cohort Study.

PubMed

Lee, Sang Hoon; Kim, Song Yee; Kim, Dong Soon; Kim, Young Whan; Chung, Man Pyo; Uh, Soo Taek; Park, Choon Sik; Jeong, Sung Hwan; Park, Yong Bum; Lee, Hong Lyeol; Shin, Jong Wook; Lee, Eun Joo; Lee, Jin Hwa; Jegal, Yangin; Lee, Hyun Kyung; Kim, Yong Hyun; Song, Jin Woo; Park, Moo Suk

2016-03-01

Although a multidisciplinary approach has become an important criterion for an idiopathic pulmonary fibrosis (IPF) diagnosis, lung biopsies remain crucial. However, the prognosis of patients with surgically diagnosed IPF (sIPF) is uncertain. We aimed to investigate the prognosis of patients with clinically diagnosed IPF (cIPF) and sIPF. In this retrospective observational study, the Korean Interstitial Lung Disease Study Group conducted a national survey to evaluate the clinical, physiological, radiological, and survival characteristics of patients with IPF from January 1, 2003 to December 31, 2007. Patients were recruited from 54 universities and teaching hospitals across the Republic of Korea. IPF diagnoses were established according to the 2002 American Thoracic Society (ATS)/European Respiratory Society criteria (ERS) guideline. A total of 1685 patients with IPF (1027 cIPF and 658 sIPF) were enrolled. Patients with sIPF were significantly younger, predominantly female, and nonsmokers (all P < 0.001). sIPF group had significantly better initial pulmonary function. The proportion of computed tomography-based honeycomb findings of patients with cIPF was higher than in those with sIPF (P < 0.001). A Kaplan-Meier analysis showed that the sIPF group had a better prognosis (P = 0.001). A survival analysis showed that age, pulmonary function parameters, pulmonary oxygen tension, honeycombing change, and combined lung cancer had a significant influence on patient prognosis. However, there was no significant difference in prognosis between the cIPF and sIPF groups after adjusting for GAP (gender, age, physiology) stage. The patients with sIPF had better clinical features than those with cIPF. However, after adjusting for GAP stage, the sIPF group showed similar prognoses as the cIPF group. This study showed that after adjusting for GAP stage, the prognosis of patients with IPF is the same regardless of the diagnostic method used.

Immature platelet fraction (IPF) as a predictive value for thrombopoietic recovery after allogeneic stem cell transplantation.

PubMed

Sakuragi, Mikiko; Hayashi, Satoru; Maruyama, Miho; Kiyokawa, Tomoko; Nagamine, Keisuke; Fujita, Jiro; Maeda, Tetsuo; Kato, Hisashi; Kashiwagi, Hirokazu; Kanakura, Yuzuru; Tomiyama, Yoshiaki

2018-03-01

We consecutively examined the utility of measurements of percentage of immature platelet fraction (IPF%) and absolute IPF number (A-IPF) in predicting thrombopoietic recovery in 15 adult patients who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT). Four patients were excluded from the evaluation due to insufficient data. Platelet count and IPF were measured by Sysmex XN-1000 (XN), a newer generation analyzer. First, we confirmed that platelet count measured by XN was more accurate than by XE-2100 (XE). IPF measurement was effective to predict the recovery in 7 of the 11 patients examined. Moreover, IPF measurement, especially IPF% measurement, suggested accelerated platelet turnover in two patients who failed to achieve platelet recovery by day 60. In addition to IPF%, A-IPF showed a complementary role on the prediction of thrombopoietic recovery. The increase in IPF% was only transient, while A-IPF values showed lasting increase during platelet recovery. In two patients (cases 6 and 7) an increase in A-IPF, but not in IPF%, was observed during platelet recovery. Our data suggest that IPF% and A-IPF measured by XN are useful for the prediction of thrombopoietic recovery and the assessment of pathogenesis of thrombocytopenia in patients after allo-SCT.

A novel genomic signature with translational significance for human idiopathic pulmonary fibrosis.

PubMed

Bauer, Yasmina; Tedrow, John; de Bernard, Simon; Birker-Robaczewska, Magdalena; Gibson, Kevin F; Guardela, Brenda Juan; Hess, Patrick; Klenk, Axel; Lindell, Kathleen O; Poirey, Sylvie; Renault, Bérengère; Rey, Markus; Weber, Edgar; Nayler, Oliver; Kaminski, Naftali

2015-02-01

The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions, despite the well recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study, we sought to identify genomic commonalities between the gene expression profiles from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium, and rat lungs harvested at Days 3, 7, 14, 21, 28, 42, and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at Day 7. At this point of maximal rat-human commonality, we identified a novel set of 12 disease-relevant translational gene markers (C6, CTHRC1, CTSE, FHL2, GAL, GREM1, LCN2, MMP7, NELL1, PCSK1, PLA2G2A, and SLC2A5) that was able to separate almost all patients with IPF from control subjects in our cohort and in two additional IPF/control cohorts (GSE10667 and GSE24206). Furthermore, in combination with diffusing capacity of carbon monoxide measurements, four members of the translational gene marker set contributed to stratify patients with IPF according to disease severity. Significantly, pirfenidone attenuated the expression change of one (CTHRC1) translational gene marker in the bleomycin-induced lung fibrosis model, in transforming growth factor-β1-treated primary human lung fibroblasts and transforming growth factor-β1-treated human epithelial A549 cells. Our results suggest that a strategy focused on rodent model-human disease commonalities may identify genes that could be used to predict the pharmacological impact of therapeutic interventions, and thus facilitate the development of novel treatments for this devastating lung disease.

Impact of Transcriptomics on Our Understanding of Pulmonary Fibrosis

PubMed Central

Vukmirovic, Milica; Kaminski, Naftali

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease characterized by aberrant remodeling of the lung parenchyma with extensive changes to the phenotypes of all lung resident cells. The introduction of transcriptomics, genome scale profiling of thousands of RNA transcripts, caused a significant inversion in IPF research. Instead of generating hypotheses based on animal models of disease, or biological plausibility, with limited validation in humans, investigators were able to generate hypotheses based on unbiased molecular analysis of human samples and then use animal models of disease to test their hypotheses. In this review, we describe the insights made from transcriptomic analysis of human IPF samples. We describe how transcriptomic studies led to identification of novel genes and pathways involved in the human IPF lung such as: matrix metalloproteinases, WNT pathway, epithelial genes, role of microRNAs among others, as well as conceptual insights such as the involvement of developmental pathways and deep shifts in epithelial and fibroblast phenotypes. The impact of lung and transcriptomic studies on disease classification, endotype discovery, and reproducible biomarkers is also described in detail. Despite these impressive achievements, the impact of transcriptomic studies has been limited because they analyzed bulk tissue and did not address the cellular and spatial heterogeneity of the IPF lung. We discuss new emerging technologies and applications, such as single-cell RNAseq and microenvironment analysis that may address cellular and spatial heterogeneity. We end by making the point that most current tissue collections and resources are not amenable to analysis using the novel technologies. To take advantage of the new opportunities, we need new efforts of sample collections, this time focused on access to all the microenvironments and cells in the IPF lung. PMID:29670881

A Novel Genomic Signature with Translational Significance for Human Idiopathic Pulmonary Fibrosis

PubMed Central

Tedrow, John; de Bernard, Simon; Birker-Robaczewska, Magdalena; Gibson, Kevin F.; Guardela, Brenda Juan; Hess, Patrick; Klenk, Axel; Lindell, Kathleen O.; Poirey, Sylvie; Renault, Bérengère; Rey, Markus; Weber, Edgar; Nayler, Oliver; Kaminski, Naftali

2015-01-01

The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions, despite the well recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study, we sought to identify genomic commonalities between the gene expression profiles from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium, and rat lungs harvested at Days 3, 7, 14, 21, 28, 42, and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at Day 7. At this point of maximal rat–human commonality, we identified a novel set of 12 disease-relevant translational gene markers (C6, CTHRC1, CTSE, FHL2, GAL, GREM1, LCN2, MMP7, NELL1, PCSK1, PLA2G2A, and SLC2A5) that was able to separate almost all patients with IPF from control subjects in our cohort and in two additional IPF/control cohorts (GSE10667 and GSE24206). Furthermore, in combination with diffusing capacity of carbon monoxide measurements, four members of the translational gene marker set contributed to stratify patients with IPF according to disease severity. Significantly, pirfenidone attenuated the expression change of one (CTHRC1) translational gene marker in the bleomycin-induced lung fibrosis model, in transforming growth factor-β1–treated primary human lung fibroblasts and transforming growth factor-β1–treated human epithelial A549 cells. Our results suggest that a strategy focused on rodent model–human disease commonalities may identify genes that could be used to predict the pharmacological impact of therapeutic interventions, and thus facilitate the development of novel treatments for this devastating lung disease. PMID:25029475

Femicide in Turkey between 2000 and 2010

PubMed Central

Toprak, Sadik; Ersoy, Gokhan

2017-01-01

Although intimate partner violence (IPV) is an important problem that threatens women’s health, very few studies focus on the victim—perpetrator relationship or examine this relationship across Turkey. The aim of this study is to contribute to a better understanding of femicide cases in Turkey and to describe the socio-demographic, clinical, forensic, and criminological characteristics of femicide victims and offenders. This study analysed 162 femicide cases that occurred in 12 cities in Turkey from 1 January 2000 to 31 December 2010. Eighty women were killed by their partners (classified as intimate partner femicide, IPF), and 81 women were killed by one of their relatives, friends, or strangers (classified as non-intimate partner femicide, non-IPF). According to our results, the typical IPF victim is of child-bearing age, does not have a paid job, is married or divorced, is killed in a domestic setting due to injuries to the thorax or abdomen produced by an edged/pointed weapon or firearm, and is possibly a victim of overkill. The typical IPF perpetrator is close to his victim’s age, has a paid job, has no mental disability, owns a gun, and has threatened his partner or ex-partner previously because of jealousy/infidelity/honour or separation. The typical non-IPF victim is very similar to the IPF victim; however, her marital status can be single, married or divorced, and she is commonly killed by a relative. The surveillance and screening of femicide and IPV is an important step when analysing and attempting to prevent femicide. Second, the training and sensitization of health professionals are important. Moreover, health staff should be encouraged to participate in advocacy interventions. Third, gun ownership must be brought under control. PMID:28832596

New treatment directions for IPF: current status of ongoing and upcoming clinical trials.

PubMed

Macagno, Francesco; Varone, Francesco; Leone, Paolo Maria; Mari, Pier-Valerio; Panico, Loredana; Berardini, Ludovica; Richeldi, Luca

2017-07-01

The main objective of this review is to explore the wide and expanding field of new clinical trials in IPF. Recent trials have confirmed the efficacy of the approved drugs pirfenidone and nintedanib; nonetheless, the discovery of new biological pathways has opened new horizons in this field. Areas covered: New strategies against matrix deposition are under study and so is for the role of immunity and autoimmunity. Recent advances in the use of stem cells are opening new possibilities for the recovery of damaged lung tissues. The role of microbioma is under investigation in order to evaluate the use of antibiotics in IPF treatment. Analysing all the new and the upcoming clinical trials, we are trying to offer a comprehensive view of the emerging new frontiers in the treatment of IPF. Expert commentary: The key points for the ongoing and upcoming clinical trials will be to avoid previous mistakes and to choose carefully both study populations and efficacy endpoints. The exciting possibility to enrol patients with progressive lung fibrosis, both idiopathic and not, could be a next step forward. How the existing therapies will fit in a futurist scenario of personalized medicine is still a challenge.

Experience with perioperative pirfenidone for lung cancer surgery in patients with idiopathic pulmonary fibrosis.

PubMed

Iwata, Takekazu; Yoshida, Shigetoshi; Nagato, Kaoru; Nakajima, Takahiro; Suzuki, Hidemi; Tagawa, Tetsuzo; Mizobuchi, Teruaki; Ota, Satoshi; Nakatani, Yukio; Yoshino, Ichiro

2015-10-01

Idiopathic pulmonary fibrosis (IPF) is a progressive diffuse lung disease associated with an increased risk of lung cancer. Patients with IPF sometimes develop a life-threatening acute exacerbation of IPF (AE-IPF) after lung cancer surgery. In this retrospective study, pirfenidone, an antifibrotic agent, was perioperatively administered to IPF patients with lung cancer with the aim of preventing postoperative AE-IPF, and the feasibility and clinical outcomes were investigated. Twelve IPF patients with concomitant lung cancer who received perioperative pirfenidone treatment (PPT) for lung cancer surgery were retrospectively investigated. Sixteen IPF patients undergoing lung cancer surgery without PPT were analyzed as historical controls. Compared to the controls, the PPT patients had a more severely impaired preoperative pulmonary function and a larger number of limited pulmonary resections. There was a significant preoperative decrease in the serum KL-6 levels of the PPT patients. No severe pirfenidone-related complications or IPF-related events occurred in the PPT patients, while six control patients developed AE-IPF (P = 0.0167). A quantitative histopathological evaluation of resected lung specimens found that tissue changes associated with IPF were significantly fewer in the PPT patients (P = 0.021). PPT is a feasible perioperative treatment for IPF patients with lung cancer. Its effectiveness in preventing postoperative AE-IPF thus warrants prospective verification.

Code-based Diagnostic Algorithms for Idiopathic Pulmonary Fibrosis. Case Validation and Improvement.

PubMed

Ley, Brett; Urbania, Thomas; Husson, Gail; Vittinghoff, Eric; Brush, David R; Eisner, Mark D; Iribarren, Carlos; Collard, Harold R

2017-06-01

Population-based studies of idiopathic pulmonary fibrosis (IPF) in the United States have been limited by reliance on diagnostic code-based algorithms that lack clinical validation. To validate a well-accepted International Classification of Diseases, Ninth Revision, code-based algorithm for IPF using patient-level information and to develop a modified algorithm for IPF with enhanced predictive value. The traditional IPF algorithm was used to identify potential cases of IPF in the Kaiser Permanente Northern California adult population from 2000 to 2014. Incidence and prevalence were determined overall and by age, sex, and race/ethnicity. A validation subset of cases (n = 150) underwent expert medical record and chest computed tomography review. A modified IPF algorithm was then derived and validated to optimize positive predictive value. From 2000 to 2014, the traditional IPF algorithm identified 2,608 cases among 5,389,627 at-risk adults in the Kaiser Permanente Northern California population. Annual incidence was 6.8/100,000 person-years (95% confidence interval [CI], 6.1-7.7) and was higher in patients with older age, male sex, and white race. The positive predictive value of the IPF algorithm was only 42.2% (95% CI, 30.6 to 54.6%); sensitivity was 55.6% (95% CI, 21.2 to 86.3%). The corrected incidence was estimated at 5.6/100,000 person-years (95% CI, 2.6-10.3). A modified IPF algorithm had improved positive predictive value but reduced sensitivity compared with the traditional algorithm. A well-accepted International Classification of Diseases, Ninth Revision, code-based IPF algorithm performs poorly, falsely classifying many non-IPF cases as IPF and missing a substantial proportion of IPF cases. A modification of the IPF algorithm may be useful for future population-based studies of IPF.

The prevalence of gastro-esophageal reflux disease and esophageal dysmotility in Chinese patients with idiopathic pulmonary fibrosis.

PubMed

Gao, Feng; Hobson, Anthony Robert; Shang, Zhan Min; Pei, Yan Xiang; Gao, Yan; Wang, Jian Xin; Huang, Wan Nong

2015-02-19

The cause of idiopathic pulmonary fibrosis (IPF) remains unknown, yet gastro-esophageal reflux disease (GERD) is highly prevalent in this population. GERD prevalence was studied, and esophageal function tests (EFT) were assessed in Chinese IPF patients. We prospectively studied 69 IPF patients who undertook both stationary High Resolution esophageal Manometry/Impedance (HRiM) and 24-hour esophageal Multi-Channel Intraluminal Impedance with pH Recordings (MII/pH). Patients were divided into GERD+ and GERD- groups according to pH results. Controls were HRiM treated healthy volunteers, and patients without IPF received HRiM and MII/pH diagnosed with GERD. 69 IPF patients, 62 healthy volunteers, and 88 IPF negative GERD patients were selected. GERD prevalence in IPF was 43/69 (62.3%), and 58.1% of patients presented with at least one typical symptom. Symptoms had a sensitivity of 58.1%, a specificity of 61.6%, a positive predictive value of 71.4% and a negative predictive of 47.1%. Compared with healthy volunteers, IPF patients had significantly decreased lower esophageal sphincter pressure (LESP), upper esophageal sphincter pressure (UESP) and complete bolus transit rate (CBTR). By contrast, IPF patients had increased total bolus transit time and prevalence of weak peristalsis. MII/pH showed that one third of IPF patients had abnormal distal and proximal reflux, especially non-acid reflux. Compared with GERD patients without IPF, GERD patients with IPF had significantly decreased CBTR and UESP with increased bolus exposure time. GERD prevalence in IPF was high, but symptoms alone were an unreliable predictor of reflux. IPF patients had lower LESP and UESP, impaired esophageal peristalsis and bolus clearance function with more proximal reflux events.

Medicare Program; Inpatient Psychiatric Facilities Prospective Payment System--Update for Fiscal Year Beginning October 1, 2015 (FY 2016). Final rule.

PubMed

2015-08-05

This final rule updates the prospective payment rates for Medicare inpatient hospital services provided by inpatient psychiatric facilities (IPFs) (which are freestanding IPFs and psychiatric units of an acute care hospital or critical access hospital). These changes are applicable to IPF discharges occurring during fiscal year (FY) 2016 (October 1, 2015 through September 30, 2016). This final rule also implements: a new 2012-based IPF market basket; an updated IPF labor-related share; a transition to new Core Based Statistical Area (CBSA) designations in the FY 2016 IPF Prospective Payment System (PPS) wage index; a phase-out of the rural adjustment for IPF providers whose status changes from rural to urban as a result of the wage index CBSA changes; and new quality measures and reporting requirements under the IPF quality reporting program. This final rule also reminds IPFs of the October 1, 2015 implementation of the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), and updates providers on the status of IPF PPS refinements.

Etiology and treatment of cough in idiopathic pulmonary fibrosis.

PubMed

Vigeland, Christine L; Hughes, Andrew H; Horton, Maureen R

2017-02-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of dysregulated wound healing leading to unremitting scarring and loss of lung function. The predominant symptoms are dyspnea on exertion and a persistent dry cough. For patients with IPF, cough is more than just bothersome; it has a significant negative impact on quality of life and is a marker of disease severity and progression. The etiology of cough in IPF is unclear but may be due to architectural distortion of the lungs, increased sensitivity of the cough reflex, airway inflammation, or changes in mucus production and clearance. There also may be an overlap between IPF cough and cough due to other common etiologies such as asthma, gastroesophageal reflux disease, upper airway cough syndrome, and medications. There are no approved therapies to specifically treat IPF cough, and recently approved medications for IPF have not been evaluated in cough. Few clinical trials have focused on treatments for IPF cough. To date, there is only one randomized, placebo control therapeutic study for IPF cough with thalidomide, which significantly reduced IPF cough and improved quality of life. Two additional cohort studies report that interferon-α and prednisolone also decrease IPF cough. However, no medication is approved to treat IPF cough. Currently, the mainstay of therapy for IPF cough is standard cough suppressants, which have limited efficacy and often intolerable side effects. Future studies are needed to determine an effective therapy to alleviate this particularly debilitating symptom and improve overall quality of life for patients suffering with IPF. Copyright © 2016 Elsevier Ltd. All rights reserved.

What's in a name? That which we call IPF, by any other name would act the same.

PubMed

Wells, Athol U; Brown, Kevin K; Flaherty, Kevin R; Kolb, Martin; Thannickal, Victor J

2018-05-01

Idiopathic pulmonary fibrosis (IPF) remains a truly idiopathic fibrotic disease, with a modest genetic predilection and candidate triggers but no overall explanation for the development of disease in non-familial cases. Agreement on terminology has contributed to major clinical and translational advances since the millennium. It is likely that the entity currently captured by the term "IPF" will be radically reclassified over the next decade, either through "splitting" (into IPF subgroups responding selectively to individual disease-modifying agents) or through "lumping" of IPF with other forms of progressive fibrotic lung disease (with shared pathogenetic mechanisms and IPF-like disease behaviour). In this perspective, we summarise the clinical and pathogenetic justification for a focus on "the progressive fibrotic phenotype" in future clinical and translational research. By this means, we can hope to address the needs of non-IPF patients with inexorably progressive fibrotic disease, currently disenfranchised by lack of access to agents that are efficacious in IPF. In this regard, ongoing trials of anti-fibrotic therapies in non-IPF patients with progressive fibrosis may be highly influential. Future revision of IPF nomenclature may be warranted if there are major conceptual changes but without compelling justification, the benefits of renaming IPF are likely to be outweighed by the resulting confusion. Copyright ©ERS 2018.

Implementation of the Iterative Proportion Fitting Algorithm for Geostatistical Facies Modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Yupeng, E-mail: yupeng@ualberta.ca; Deutsch, Clayton V.

2012-06-15

In geostatistics, most stochastic algorithm for simulation of categorical variables such as facies or rock types require a conditional probability distribution. The multivariate probability distribution of all the grouped locations including the unsampled location permits calculation of the conditional probability directly based on its definition. In this article, the iterative proportion fitting (IPF) algorithm is implemented to infer this multivariate probability. Using the IPF algorithm, the multivariate probability is obtained by iterative modification to an initial estimated multivariate probability using lower order bivariate probabilities as constraints. The imposed bivariate marginal probabilities are inferred from profiles along drill holes or wells.more » In the IPF process, a sparse matrix is used to calculate the marginal probabilities from the multivariate probability, which makes the iterative fitting more tractable and practical. This algorithm can be extended to higher order marginal probability constraints as used in multiple point statistics. The theoretical framework is developed and illustrated with estimation and simulation example.« less

Serum metalloproteinases 1 and 7 in the diagnosis of idiopathic pulmonary fibrosis and other interstitial pneumonias.

PubMed

Morais, António; Beltrão, Marília; Sokhatska, Oksana; Costa, Diogo; Melo, Natalia; Mota, Patricia; Marques, Agostinho; Delgado, Luís

2015-08-01

Accurate diagnosis of idiopathic pulmonary fibrosis (IPF) has important therapeutic and prognostic implications and would be greatly aided by reliable diagnostic biomarkers as IPF has sometimes overlapping features with other interstitial lung diseases (ILD). To explore the value of serum metalloproteinases (MMP) 1 and 7 levels in the differential diagnosis of IPF with other ILD. MMP-1/7 serum levels were measured using Luminex xMAP technology in 139 patients- 47 IPF, 36 non-IPF Usual Interstitial Pneumonia (UIP), 14 idiopathic Nonspecific Interstitial Pneumonia (iNSIP), 29 secondary NSIP (secNSIP), 13 stage IV sarcoidosis- and 20 healthy controls, and compared using the Mann-Whitney U test. MMP-1 was significantly higher in IPF than non-IPF UIP (P = .042) and sarcoidosis (P = .027). MMP-7 was significantly higher in IPF than controls (P < .001), non-IPF UIP (P = .003), secNSIP (P < .001), and sarcoidosis (P < .001). The Area Under the Curve for IPF versus other ILD was 0.63 (95%CI, 0.53-0.73) for MMP-1, 0.73 (95%CI, 0.65-0.81) for MMP-7, and 0.74 (95%CI, 0.66-0.82) for MMP-1/MMP-7 combined. Sensitivity and specificity for MMP-7 cutoff = 3.91 ng/mL was 72.3% and 66.3%, respectively, Positive Predictive Values = 52.3% and Negative Predictive Values = 82.4%. MMP-1 and particularly MMP-7 serum levels were significantly higher in IPF than in non-IPF UIP, the main entity in differential diagnosis. The value of these biomarkers as additional tools in a multidisciplinary approach to IPF diagnosis needs to be considered and further explored. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Role of Neighborhood Environment and Risk of Intimate Partner Femicide in a Large Urban Area

PubMed Central

Frye, Victoria; Galea, Sandro; Tracy, Melissa; Bucciarelli, Angela; Putnam, Sara; Wilt, Susan

2008-01-01

Objectives. We evaluated the contribution of neighborhood-level factors indicative of social disorganization, including educational and occupational attainment, immigrant concentration, physical disorder, and social cohesion, to the likelihood of intimate partner femicide (IPF) while taking into account known neighborhood- and individual-level IPF risk factors. Methods. We used medical examiner data on 1861 femicide victims between 1990 and 1999 and archival information on 59 neighborhoods in New York City to conduct a multilevel case–control analysis. Results. After controlling for neighborhood-level income, we found that no neighborhood factors were significantly associated with IPF risk, as compared with risk of non–IPF and risk of femicide from unknown perpetrators, above and beyond the contributions of individual-level factors. The strongest predictors of IPF were foreign country of birth and young age. Conclusions. IPF victims were nearly twice as likely as non-IPF victims to be foreign born; by contrast, there was little neighborhood-level heterogeneity with respect to IPF risk. Further research is needed to identify neighborhood characteristics that uniquely influence risk of IPF to guide community-level interventions. PMID:18556618

[Clinical value of angiogenin in predicting the prognosis of patients with idiopathic pulmonary fibrosis].

PubMed

Bai, Yanling; Zhu, Haiyan; Sun, Qiyu; Gu, Guozhong; Zhang, Lingyu; Li, Ying; Yang, Baofeng

2017-09-01

To explore the relationship between angiogenin-1/2 (Ang-1/2) and clinical parameters of idiopathic pulmonary fibrosis (IPF), and to assess the value of Ang-1/2 in predicting the prognosis of patients with IPF. A retrospective analysis was conducted. Ninety-one patients diagnosed as IPF by high resolution CT (HRCT) and lung biopsy admitted to Daqing Oil Field General Hospital from March 2014 to January 2015 were enrolled. The general data, serum parameters and pulmonary function parameters of all patients were collected. After treatment, all of the 91 patients were followed-up to 2 years. The patients were divided into favorable prognosis group and unfavorable prognosis group according to follow-up results. The differences in all parameters between the two groups were compared. The relationship between Ang-1, Ang-2 and lung function parameters was analyzed by Pearson correlation analysis. Cox proportional hazard regression model was used to evaluate the effect of clinical parameters on the prognosis of patients with IPF. The effect of Ang-2 in predicting prognosis of patients with IPF was analyzed by receiver operating characteristic (ROC) curve. During the 2-year follow-up period, 30 of 91 patients showed a favorable prognosis, and 55 showed an unfavorable prognosis with a poor prognosis rate of 64.71%, and 6 patients withdrew from the study due to loss of follow-up and death. Compared with the favorable prognosis group, Ang-2 level in the unfavorable prognosis group was significantly increased (μg/L: 2.88±1.63 vs. 1.89±1.22, t = 2.909, P = 0.005), but Ang-1 only showed a slight increase (μg/L: 28.70±14.26 vs. 25.62±11.95, t = 1.005, P = 0.318). The results of Pearson correlation analysis showed that Ang-2 level was negatively correlated with forced expiratory volume in 1 second (FVC1) and the percentage of carbon monoxide diffusing capacity accounting for the expected value (DLCO%: r value was -0.227 and -0.206, and P value was 0.147 and 0.253, respectively), but no significant correlation between the level of Ang-1 and FVC1 as well as DLCO% was found (r value was -0.153 and -0.121, and P value was 0.147 and 0.253, respectively). Cox proportional hazard regression model analysis showed that the prognosis of patients with IPF was significantly affected by smoking time and Ang-2 (both P < 0.05), and the influence of Ang-2 was greater [relative risk (RR): 1.236 vs. 1.006, P = 0.037]. Age, gender, smoking and the levels of FVC1, DLCO% and Ang-1 had no significant effect on the prognosis of IPF patients (all P > 0.05). Prognostic analysis showed that the area under ROC curve (AUC) of Ang-2 for predicting prognosis of patients with IPF was 0.692, and the best diagnostic point was 0.35 μg/L, the sensitivity was 61.8%, the specificity was 73.3%, the positive predictive value was 69.8%, and the negative predictive value was 65.7% which indicated that Ang-2 could predict the prognosis of patients with IPF. Ang-2 could assess the prognosis of patients with IPF, which is expected to be used as an indicator of predicting the prognosis of patients with IPF.

Sensitivity Analyses of the Change in FVC in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis.

PubMed

Lederer, David J; Bradford, Williamson Z; Fagan, Elizabeth A; Glaspole, Ian; Glassberg, Marilyn K; Glasscock, Kenneth F; Kardatzke, David; King, Talmadge E; Lancaster, Lisa H; Nathan, Steven D; Pereira, Carlos A; Sahn, Steven A; Swigris, Jeffrey J; Noble, Paul W

2015-07-01

FVC outcomes in clinical trials on idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary end point of FVC change in a phase 3 trial evaluating pirfenidone in adults with IPF. Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary end point of change from baseline to week 52 in FVC. The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis. Our results confirm the robustness of the statistical finding on the primary end point of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF. ClinicalTrials.gov; No.: NCT01366209; URL: www.clinicaltrials.gov.

A phase II trial evaluating the efficacy and safety of perioperative pirfenidone for prevention of acute exacerbation of idiopathic pulmonary fibrosis in lung cancer patients undergoing pulmonary resection: West Japan Oncology Group 6711 L (PEOPLE Study).

PubMed

Iwata, Takekazu; Yoshino, Ichiro; Yoshida, Shigetoshi; Ikeda, Norihiko; Tsuboi, Masahiro; Asato, Yuji; Katakami, Nobuyuki; Sakamoto, Kazuhiro; Yamashita, Yoshinori; Okami, Jiro; Mitsudomi, Tetsuya; Yamashita, Motohiro; Yokouchi, Hiroshi; Okubo, Kenichi; Okada, Morihito; Takenoyama, Mitsuhiro; Chida, Masayuki; Tomii, Keisuke; Matsuura, Motoki; Azuma, Arata; Iwasawa, Tae; Kuwano, Kazuyoshi; Sakai, Shuji; Hiroshima, Kenzo; Fukuoka, Junya; Yoshimura, Kenichi; Tada, Hirohito; Nakagawa, Kazuhiko; Nakanishi, Yoichi

2016-07-22

Idiopathic pulmonary fibrosis (IPF) often accompanies lung cancer, and life-threatening acute exacerbation (AE) of IPF (AE-IPF) is reported to occur in 20 % of IPF patients who undergo lung cancer surgery. Pirfenidone is an anti-fibrotic agent known to reduce disease progression in IPF patients. A phase II study was conducted to evaluate whether perioperative pirfenidone treatment could reduce the incidence of postoperative AE-IPF patients with lung cancer. Pirfenidone was orally administered to IPF patients who were candidates for lung cancer surgery; pirfenidone was dosed at 600 mg/day for the first 2 weeks, followed by 1200 mg/day. Surgery was performed after at least 2 weeks of 1200-mg/day administration. The primary endpoint was non-AE-IPF rate during postoperative days 0-30, compared to the null value of 80 %, and the secondary endpoint was safety. Radiologic and pathologic diagnoses of IPF and AE-IPF were confirmed by an independent review committee. From June 2012 to January 2014, 43 cases were enrolled, and 39 were eligible (full analysis set [FAS]). Both pirfenidone treatment and surgery were performed in 36 patients (per protocol set [PPS]). AE-IPF did not occur in 37/39 patients (94.9 % [95 % confidential interval: 82.7-99.4 %, p = 0.01]) in the FAS, and in 38/39 patients (97.2 % [95 % confidential interval: 85.5-99.9 %, p = 0.004] in the PPS. A grade 5 adverse event (death) occurred in 1 patient, after AE-IPF; no other grade 3-5 adverse events were observed. Perioperative pirfenidone treatment is safe, and is promising for reducing AE-IPF after lung cancer surgery in IPF patients. This clinical trial was registered with the University Hospital Medical Information Network (UMIN) on April 16th, 2012 (REGISTRATION NUMBER: UMIN000007774 ).

Idiopathic pulmonary fibrosis fibroblasts become resistant to Fas ligand-dependent apoptosis via the alteration of decoy receptor 3.

PubMed

Im, Jintaek; Kim, Kyutae; Hergert, Polla; Nho, Richard Seonghun

2016-09-01

Idiopathic pulmonary fibrosis (IPF) is an irreversible lethal lung disease with an unknown etiology. IPF patients' lung fibroblasts express inappropriately high Akt activity, protecting them in response to an apoptosis-inducing type I collagen matrix. FasL, a ligand for Fas, is known to be increased in the lung tissues of patients with IPF, implicated with the progression of IPF. Expression of Decoy Receptor3 (DcR3), which binds to FasL, thereby subsequently suppressing the FasL-Fas-dependent apoptotic pathway, is frequently altered in various human disease. However, the role of DcR3 in IPF fibroblasts in regulating their viability has not been examined. We found that enhanced DcR3 expression exists in the majority of IPF fibroblasts on collagen matrices, resulting in the protection of IPF fibroblasts from FasL-induced apoptosis. Abnormally high Akt activity suppresses GSK-3β function, thereby accumulating the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) in the nucleus, increasing DcR3 expression in IPF fibroblasts. This alteration protects IPF cells from FasL-induced apoptosis on collagen. However, the inhibition of Akt or NFATc1 decreases DcR3 mRNA and protein levels, which sensitizes IPF fibroblasts to FasL-mediated apoptosis. Furthermore, enhanced DcR3 and NFATc1 expression is mainly present in myofibroblasts in the fibroblastic foci of lung tissues derived from IPF patients. Our results showed that when IPF cells interact with collagen matrix, aberrantly activated Akt increases DcR3 expression via GSK-3β-NFATc1 and protects IPF cells from the FasL-dependent apoptotic pathway. These findings suggest that the inhibition of DcR3 function may be an effective approach for sensitizing IPF fibroblasts in response to FasL, limiting the progression of lung fibrosis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Pretreatment rate of decay in forced vital capacity predicts long-term response to pirfenidone in patients with idiopathic pulmonary fibrosis.

PubMed

Biondini, Davide; Balestro, Elisabetta; Lacedonia, Donato; Cerri, Stefania; Milaneschi, Rosanna; Luppi, Fabrizio; Cocconcelli, Elisabetta; Bazzan, Erica; Clini, Enrico; Foschino Barbaro, Maria Pia; Gregori, Dario; Cosio, Manuel G; Saetta, Marina; Spagnolo, Paolo

2018-04-13

Pirfenidone reduces functional decline in patients with Idiopathic Pulmonary Fibrosis (IPF). However, response to treatment is highly heterogeneous. We sought to evaluate whether response to pirfenidone is influenced by the pretreatment rate of forced vital capacity (FVC) decline. Fifty-six IPF patients were categorized as rapid (RP) or slow progressors (SP) based on whether their FVC decline in the year preceding pirfenidone treatment was > or ≤ 10% predicted. Following pirfenidone treatment patients were followed-up every 6 months and up to 24 months. In the entire population, pirfenidone reduced significantly FVC decline from 231 to 49 ml/year at 6 months (T6) (p = 0.003) and this effect was maintained at the 12-, 18- and 24-month time points (p value for trend n.s.). In RP, the reduction of FVC decline was evident at 6 months (36 vs 706 ml/year pretreatment; p = 0.002) and maintained, though to a lesser degree, at 12 (106 ml/year), 18 (176 ml/year) and 24 months (162 ml/year; p value for trend n.s). Among SP, the reduction in FVC decline was not significant at any of the time points analyzed. In conclusion, pirfenidone reduces FVC decline in IPF patients. However, its beneficial effect is more pronounced in patients with rapidly progressive disease.

Comparative proteomic analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and lung transplant donor lungs.

PubMed

Korfei, Martina; Schmitt, Sigrid; Ruppert, Clemens; Henneke, Ingrid; Markart, Philipp; Loeh, Benjamin; Mahavadi, Poornima; Wygrecka, Malgorzata; Klepetko, Walter; Fink, Ludger; Bonniaud, Philippe; Preissner, Klaus T; Lochnit, Günter; Schaefer, Liliana; Seeger, Werner; Guenther, Andreas

2011-05-06

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which no effective therapy exists to date. To identify the molecular mechanisms underlying IPF, we performed comparative proteome analysis of lung tissue from patients with sporadic IPF (n = 14) and human donor lungs (controls, n = 10) using two-dimensional gel electrophoresis and MALDI-TOF-MS. Eighty-nine differentially expressed proteins were identified, from which 51 were up-regulated and 38 down-regulated in IPF. Increased expression of markers for the unfolded protein response (UPR), heat-shock proteins, and DNA damage stress markers indicated a chronic cell stress-response in IPF lungs. By means of immunohistochemistry, induction of UPR markers was encountered in type-II alveolar epithelial cells of IPF but not of control lungs. In contrast, up-regulation of heat-shock protein 27 (Hsp27) was exclusively observed in proliferating bronchiolar basal cells and associated with aberrant re-epithelialization at the bronchiolo-alveolar junctions. Among the down-regulated proteins in IPF were antioxidants, members of the annexin family, and structural epithelial proteins. In summary, our results indicate that IPF is characterized by epithelial cell injury, apoptosis, and aberrant epithelial proliferation.

Breathing pattern and breathlessness in idiopathic pulmonary fibrosis: An observational study.

PubMed

Olukogbon, Kasope L; Thomas, Paul; Colasanti, Ricardo; Hope-Gill, Ben; Williams, Edgar Mark

2016-02-01

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive decline in lung function and increasing dyspnoea. The aim of this study was to investigate the relationship among IPF, pulmonary function, resting tidal breathing patterns and level of breathlessness. Thirty-one participants with IPF and 17 matched healthy controls underwent lung function testing, followed by a 2-min period of resting tidal breathing. The IPF cohort was stratified according to disease severity, based on their forced vital capacity and diffusion capacity for carbon monoxide. In comparison to the healthy controls, the IPF cohort showed a higher tidal volume, VT , of 0.22 L (P = 0.026) and a raised minute ventilation in the severest IPF group, while no differences in the timing of inspiration or expiration were observed. In the IPF cohort, the ratio of VT to forced vital capacity was around 15% higher. These changes corresponded with an increase in the self-reported sensation of breathlessness. Those with IPF increased their depth of breathing with worsening disease severity, with IPF-induced changes in pulmonary function and breathlessness associated with an altered tidal breathing pattern. © 2015 Asian Pacific Society of Respirology.

The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes.

PubMed

O'Dwyer, David N; Norman, Katy C; Xia, Meng; Huang, Yong; Gurczynski, Stephen J; Ashley, Shanna L; White, Eric S; Flaherty, Kevin R; Martinez, Fernando J; Murray, Susan; Noth, Imre; Arnold, Kelly B; Moore, Bethany B

2017-04-25

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial pneumonia. The disease pathophysiology is poorly understood and the etiology remains unclear. Recent advances have generated new therapies and improved knowledge of the natural history of IPF. These gains have been brokered by advances in technology and improved insight into the role of various genes in mediating disease, but gene expression and protein levels do not always correlate. Thus, in this paper we apply a novel large scale high throughput aptamer approach to identify more than 1100 proteins in the peripheral blood of well-characterized IPF patients and normal volunteers. We use systems biology approaches to identify a unique IPF proteome signature and give insight into biological processes driving IPF. We found IPF plasma to be altered and enriched for proteins involved in defense response, wound healing and protein phosphorylation when compared to normal human plasma. Analysis also revealed a minimal protein signature that differentiated IPF patients from normal controls, which may allow for accurate diagnosis of IPF based on easily-accessible peripheral blood. This report introduces large scale unbiased protein discovery analysis to IPF and describes distinct biological processes that further inform disease biology.

CYFRA 21.1 in bronchoalveolar lavage of idiopathic pulmonary fibrosis patients.

PubMed

Vercauteren, Inge M; Verleden, Stijn E; McDonough, John E; Vandermeulen, Elly; Ruttens, David; Lammertyn, Elise J; Bellon, Hannelore; De Dycker, Els; Dooms, Christophe; Yserbyt, Jonas; Verleden, Geert M; Vanaudenaerde, Bart M; Wuyts, Wim A

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of interstitial lung diseases, however, clinically relevant biomarkers of diagnosis or prognosis are lacking. In this study, we investigated the levels of a fragment of Cytokeratin 19 (CYFRA 21.1) in bronchoalveolar lavage (BAL) of IPF patients at time of diagnosis. We further evaluated associations between CYFRA 21.1, pulmonary function evolution, mortality, and BAL cell count. Using the Lumipulse® G1200, CYFRA 21.1 was measured in BAL samples of 81 IPF patients and 9 controls. Based upon the median detected level (1.2 ng/mL) of CYFRA 21.1 in IPF patients, they were subdivided into an IPF CYFRA 21.1 low group (≤ 1.2 ng/mL) and IPF CYFRA 21.1 high group (> 1.2 ng/mL). The CYFRA 21.1 levels were significantly higher in BAL of IPF patients compared to controls (P = .0015).Worse survival was observed, but no changes in pulmonary function, for IPF patients with high CYFRA 21.1 levels versus patients with low CYFRA 21.1 levels [P = .030, HR: 0.41, (0.18-0.92)[. The CYFRA 21.1 level correlated with both neutrophils (%: R = 0.60, P < .0001; #: R = 0.47, P < .0001) and eosinophils (%: R = 0.38, P = .0005; #: R = 0.30, P < .0072). CYFRA 21.1 is increased in BAL of IPF patients. IPF patients with a high CYFRA 21.1 concentration have a worse survival. CYFRA 21.1 levels correlate with eosinophils and neutrophils. Further studies are warranted in using CYFRA 21.1 as a biomarker for IPF prognosis.

Epigenomics of idiopathic pulmonary fibrosis

PubMed Central

Yang, Ivana V

2012-01-01

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease of unknown etiology. Development of IPF is influenced by both genetic and environmental factors. Gene-expression profiling studies have taught us quite a bit about the biology of this fatal disease, but epigenetic marks may be the missing link that connects the environmental exposure in genetically predisposed individuals to transcriptome changes associated with the development of IPF. This review will begin with an introduction to the disease, followed by brief summaries of studies of gene expression in IPF and epigenetic marks associated with exposures relevant to IPF. The majority of the discussion will focus on epigenetic studies conducted so far in IPF, the limitations, challenges and future directions in this field. PMID:22449190

Epigenomics of idiopathic pulmonary fibrosis.

PubMed

Yang, Ivana V

2012-04-01

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease of unknown etiology. Development of IPF is influenced by both genetic and environmental factors. Gene-expression profiling studies have taught us quite a bit about the biology of this fatal disease, but epigenetic marks may be the missing link that connects the environmental exposure in genetically predisposed individuals to transcriptome changes associated with the development of IPF. This review will begin with an introduction to the disease, followed by brief summaries of studies of gene expression in IPF and epigenetic marks associated with exposures relevant to IPF. The majority of the discussion will focus on epigenetic studies conducted so far in IPF, the limitations, challenges nd future directions in this field.

Acute exacerbation of idiopathic pulmonary fibrosis triggered by Aspergillus empyema.

PubMed

Suzuki, Atsushi; Kimura, Tomoki; Kataoka, Kensuke; Matsuda, Toshiaki; Yokoyama, Toshiki; Mori, Yuta; Kondoh, Yasuhiro

2018-01-01

Acute exacerbation (AE) is a severe and life-threatening complication of idiopathic pulmonary fibrosis (IPF). In 2016, the definition and diagnostic criteria for AE-IPF were updated by an international working group. The new definition includes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events) characterized by evidence of new widespread alveolar abnormality in patients with IPF. There are no currently proven beneficial management strategies for idiopathic and triggered AE-IPF. This is the first report describing AE-IPF triggered by Aspergillus empyema, which was improved by a combination of corticosteroid, systemic antifungal therapy, local antifungal therapy, and additional pharmacological therapies. Future research may reveal optimal strategies for both idiopathic and triggered AE-IPF.

Fibroblast-matrix interplay: Nintedanib and pirfenidone modulate the effect of IPF fibroblast-conditioned matrix on normal fibroblast phenotype.

PubMed

Epstein Shochet, Gali; Wollin, Lutz; Shitrit, David

2018-03-12

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. Activated fibroblasts are the key effector cells in fibrosis, producing excessive amounts of collagen and extracellular matrix (ECM) proteins. Whether the ECM conditioned by IPF fibroblasts determines the phenotype of naïve fibroblasts is difficult to explore. IPF-derived primary fibroblasts were cultured on Matrigel and then cleared using ammonium hydroxide, creating an IPF-conditioned matrix (CM). Normal fibroblast CM served as control. Normal fibroblasts were cultured on both types of CM, and cell count, cell distribution and markers of myofibroblast differentiation; transforming growth factor beta (TGFβ) signalling; and ECM expression were assessed. The effects of the anti-fibrotic drugs nintedanib and pirfenidone at physiologically relevant concentrations were also explored. Normal fibroblasts cultured on IPF-CM arranged in large aggregates as a result of increased proliferation and migration. Moreover, increased levels of pSmad3, pSTAT3 (phospho signal transducer and activator of transcription 3), alpha smooth muscle actin (αSMA) and Collagen1a were found, suggesting a differentiation towards a myofibroblast-like phenotype. SB505124 (10 μmol/L) partially reversed these alterations, suggesting a TGFβ contribution. Furthermore, nintedanib at 100 nmol/L and, to a lesser extent, pirfenidone at 100 μmol/L prevented the IPF-CM-induced fibroblast phenotype alterations, suggesting an attenuation of the ECM-fibroblast interplay. IPF fibroblasts alter the ECM, thus creating a CM that further propagates an IPF-like phenotype in normal fibroblasts. This assay demonstrated differences in drug activities for approved IPF drugs at clinically relevant concentrations. Thus, the matrix-fibroblast phenotype interplay might be a relevant assay to explore drug candidates for IPF treatment. © 2018 Asian Pacific Society of Respirology.

Expression of RXFP1 Is Decreased in Idiopathic Pulmonary Fibrosis. Implications for Relaxin-based Therapies

PubMed Central

Tan, Jiangning; Tedrow, John R.; Dutta, Justin A.; Juan-Guardela, Brenda; Nouraie, Mehdi; Chu, Yanxia; Trejo Bittar, Humberto; Ramani, Kritika; Biswas, Partha S.; Veraldi, Kristen L.; Kaminski, Naftali; Zhang, Yingze

2016-01-01

Rationale: Relaxin is a hormone that has been considered as a potential therapy for patients with fibrotic diseases. Objectives: To gauge the potential efficacy of relaxin-based therapies in idiopathic pulmonary fibrosis (IPF), we studied gene expression for relaxin/insulin-like family peptide receptor 1 (RXFP1) in IPF lungs and controls. Methods: We analyzed gene expression data obtained from the Lung Tissue Research Consortium and correlated RXFP1 gene expression data with cross-sectional clinical and demographic data. We also employed ex vivo donor and IPF lung fibroblasts to test RXFP1 expression in vitro. We tested CGEN25009, a relaxin-like peptide, in lung fibroblasts and in bleomycin injury. Measurements and Main Results: We found that RXFP1 is significantly decreased in IPF. In patients with IPF, the magnitude of RXFP1 gene expression correlated directly with diffusing capacity of the lung for carbon monoxide (P < 0.0001). Significantly less RXFP1 was detected in vitro in IPF fibroblasts than in donor controls. Transforming growth factor-β decreased RXFP1 in both donor and IPF lung fibroblasts. CGEN25009 was effective at decreasing bleomycin-induced, acid-soluble collagen deposition in vivo. The relaxin-like actions of CGEN25009 were abrogated by RXFP1 silencing in vitro, and, in comparison with donor lung fibroblasts, IPF lung fibroblasts exhibited decreased sensitivity to the relaxin-like effects of CGEN25009. Conclusions: IPF is characterized by the loss of RXFP1 expression. RXFP1 expression is directly associated with pulmonary function in patients with IPF. The relaxin-like effects of CGEN25009 in vitro are dependent on expression of RXFP1. Our data suggest that patients with IPF with the highest RXFP1 expression would be predicted to be most sensitive to relaxin-based therapies. PMID:27310652

Expression of RXFP1 Is Decreased in Idiopathic Pulmonary Fibrosis. Implications for Relaxin-based Therapies.

PubMed

Tan, Jiangning; Tedrow, John R; Dutta, Justin A; Juan-Guardela, Brenda; Nouraie, Mehdi; Chu, Yanxia; Trejo Bittar, Humberto; Ramani, Kritika; Biswas, Partha S; Veraldi, Kristen L; Kaminski, Naftali; Zhang, Yingze; Kass, Daniel J

2016-12-01

Relaxin is a hormone that has been considered as a potential therapy for patients with fibrotic diseases. To gauge the potential efficacy of relaxin-based therapies in idiopathic pulmonary fibrosis (IPF), we studied gene expression for relaxin/insulin-like family peptide receptor 1 (RXFP1) in IPF lungs and controls. We analyzed gene expression data obtained from the Lung Tissue Research Consortium and correlated RXFP1 gene expression data with cross-sectional clinical and demographic data. We also employed ex vivo donor and IPF lung fibroblasts to test RXFP1 expression in vitro. We tested CGEN25009, a relaxin-like peptide, in lung fibroblasts and in bleomycin injury. We found that RXFP1 is significantly decreased in IPF. In patients with IPF, the magnitude of RXFP1 gene expression correlated directly with diffusing capacity of the lung for carbon monoxide (P < 0.0001). Significantly less RXFP1 was detected in vitro in IPF fibroblasts than in donor controls. Transforming growth factor-β decreased RXFP1 in both donor and IPF lung fibroblasts. CGEN25009 was effective at decreasing bleomycin-induced, acid-soluble collagen deposition in vivo. The relaxin-like actions of CGEN25009 were abrogated by RXFP1 silencing in vitro, and, in comparison with donor lung fibroblasts, IPF lung fibroblasts exhibited decreased sensitivity to the relaxin-like effects of CGEN25009. IPF is characterized by the loss of RXFP1 expression. RXFP1 expression is directly associated with pulmonary function in patients with IPF. The relaxin-like effects of CGEN25009 in vitro are dependent on expression of RXFP1. Our data suggest that patients with IPF with the highest RXFP1 expression would be predicted to be most sensitive to relaxin-based therapies.

Incidence, Prevalence, and Clinical Course of Idiopathic Pulmonary Fibrosis

PubMed Central

Daniels, Craig E.; Schroeder, Darrell R.; St. Sauver, Jennifer; Hartman, Thomas E.; Bartholmai, Brian J.; Yi, Eunhee S.; Ryu, Jay H.

2010-01-01

Background: Limited data exist regarding the population-based epidemiology of idiopathic pulmonary fibrosis (IPF). The objective of the study was to describe the trends in the incidence, prevalence, and clinical course of IPF in the community. Methods: We conducted a population-based study of adult patients with IPF in Olmsted County, Minnesota, from 1997 to 2005. Two methods were used to identify IPF cases, as defined by the 2002 American Thoracic Society/European Respiratory Society consensus statement: (1) usual interstitial pneumonia (UIP) on a surgical lung biopsy specimen or a definite UIP pattern on a high-resolution CT image (narrow criteria) and (2) UIP on a surgical lung biopsy specimen or a definite or possible UIP pattern on CT image (broad criteria). Results: Of 596 patients screened for the possibility of pulmonary disease or pulmonary fibrosis over 9 years of follow-up, 47 cases had IPF. Of these, 24 met the narrow criteria. The age- and sex-adjusted incidence was 8.8/100,000 and 17.4/100,000 person-years, for narrow and broad criteria, respectively. The age-adjusted incidence was higher in men than in women, and among patients aged 70-79 years. During the study period, the incidence of IPF decreased (P < .001). On December 31, 2005, the age- and sex-adjusted prevalence was 27.9/100,000 and 63/100,000 persons by narrow and broad criteria, respectively. Thirty-seven patients experienced a total of 53 respiratory exacerbations (26 IPF related, 27 non-IPF related), and 34 (72%) patients died. The primary cause of death was IPF related in 16 (47%) patients. Median survival for narrow-criteria and broad-criteria incidence cases was 3.5 and 4.4 years, respectively. Conclusions: The incidence of IPF in Olmsted County decreased over the study period. Nonprimary IPF respiratory exacerbations are as frequent as primary IPF respiratory exacerbations and an important cause of death. PMID:19749005

Alveolar epithelial cells in idiopathic pulmonary fibrosis display upregulation of TRAIL, DR4 and DR5 expression with simultaneous preferential over-expression of pro-apoptotic marker p53.

PubMed

Akram, Khondoker M; Lomas, Nicola J; Forsyth, Nicholas R; Spiteri, Monica A

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating, and fatal lung disease of unknown aetiology with no current cure. The pathogenesis of IPF remains unclear but repeated alveolar epithelial cell (AEC) injuries and subsequent apoptosis are believed to be among the initiating/ongoing triggers. However, the precise mechanism of apoptotic induction is hitherto elusive. In this study, we investigated expression of a panel of pro-apoptotic and cell cycle regulatory proteins in 21 IPF and 19 control lung tissue samples. We reveal significant upregulation of the apoptosis-inducing ligand TRAIL and its cognate receptors DR4 and DR5 in AEC within active lesions of IPF lungs. This upregulation was accompanied by pro-apoptotic protein p53 overexpression. In contrast, myofibroblasts within the fibroblastic foci of IPF lungs exhibited high TRAIL, DR4 and DR5 expression but negligible p53 expression. Similarly, p53 expression was absent or negligible in IPF and control alveolar macrophages and lymphocytes. No significant differences in TRAIL expression were noted in these cell types between IPF and control lungs. However, DR4 and DR5 upregulation was detected in IPF alveolar macrophages and lymphocytes. The marker of cellular senescence p21(WAF1) was upregulated within affected AEC in IPF lungs. Cell cycle regulatory proteins Cyclin D1 and SOCS3 were significantly enhanced in AEC within the remodelled fibrotic areas of IPF lungs but expression was negligible in myofibroblasts. Taken together these findings suggest that, within the remodelled fibrotic areas of IPF, AEC can display markers associated with proliferation, senescence, and apoptotosis, where TRAIL could drive the apoptotic response. Clear understanding of disease processes and identification of therapeutic targets will direct us to develop effective therapies for IPF.

Lung transplantation in idiopathic pulmonary fibrosis: a systematic review of the literature

PubMed Central

2014-01-01

Background Idiopathic pulmonary fibrosis (IPF) is a distinct form of interstitial pneumonia with unknown origin and poor prognosis. Current pharmacologic treatments are limited and lung transplantation is a viable option for appropriate patients. The aim of this review was to summarize lung transplantation survival in IPF patients overall, between single (SLT) vs. bilateral lung transplantation (BLT), pre- and post Lung Allocation Score (LAS), and summarize wait-list survival. Methods A systematic review of English-language studies published in Medline or Embase between 1990 and 2013 was performed. Eligible studies were those of observational design reporting survival post-lung transplantation or while on the wait list among IPF patients. Results Median survival post-transplantation among IPF patients is estimated at 4.5 years. From ISHLT and OPTN data, one year survival ranged from 75% - 81%; 3-year: 59% - 64%; and 5-year: 47% - 53%. Post-transplant survival is lower for IPF vs. other underlying pre-transplant diagnoses. The proportion of IPF patients receiving BLT has steadily increased over the last decade and a half. Unadjusted analyses suggest improved long-term survival for BLT vs. SLT; after adjustment for patient characteristics, the differences tend to disappear. IPF patients account for the largest proportion of patients on the wait list and while wait list time has decreased, the number of transplants for IPF patients has increased over time. OPTN data show that wait list mortality is higher for IPF patients vs. other diagnoses. The proportion of IPF patients who died while awaiting transplantation ranged from 14% to 67%. While later transplant year was associated with increased survival, no significant differences were noted pre vs. post LAS implementation; however a high LAS vs low LAS was associated with decreased one-year survival. Conclusions IPF accounts for the largest proportion of patients awaiting lung transplants, and IPF is associated with higher wait-list and post-transplant mortality vs. other diagnoses. Improved BLT vs. SLT survival may be the result of selection bias. Survival pre- vs. post LAS appears to be similar except for IPF patients with high LAS, who have lower survival compared to pre-LAS. Data on post-transplant morbidity outcomes are sparse. PMID:25127540

Myositis-associated usual interstitial pneumonia has a better survival than idiopathic pulmonary fibrosis.

PubMed

Aggarwal, Rohit; McBurney, Christine; Schneider, Frank; Yousem, Samuel A; Gibson, Kevin F; Lindell, Kathleen; Fuhrman, Carl R; Oddis, Chester V

2017-03-01

To compare the survival outcomes between myositis-associated usual interstitial pneumonia (MA-UIP) and idiopathic pulmonary fibrosis (IPF-UIP). Adult MA-UIP and IPF-UIP patients were identified using CTD and IPF registries. The MA-UIP cohort included myositis or anti-synthetase syndrome patients with interstitial lung disease while manifesting UIP on high-resolution CT chest and/or a lung biopsy revealing UIP histology. IPF subjects met American Thoracic Society criteria and similarly had UIP histopathology. Kaplan-Meier survival curves compared cumulative and pulmonary event-free survival (event = transplant or death) between (i) all MA-UIP and IPF-UIP subjects, (ii) MA-UIP with biopsy proven UIP (n = 25) vs IPF-UIP subjects matched for age, gender and baseline forced vital capacity (±10%). Cox proportional hazards ratios compared the survival controlling for co-variates. Eighty-one IPF-UIP and 43 MA-UIP subjects were identified. The median cumulative and event-free survival time in IPF vs MA-UIP was 5.25/1.8 years vs 16.2/10.8 years, respectively. Cumulative and event-free survival was significantly worse in IPF-UIP vs MA-UIP [hazards ratio of IPF-UIP was 2.9 (95% CI: 1.5, 5.6) and 5.0 (95% CI: 2.8, 8.7) (P < 0.001), respectively]. IPF-UIP event-free survival (but not cumulative) remained significantly worse than MA-UIP with a hazards ratio of 6.4 (95% CI: 3.0, 13.8) after controlling for age at interstitial lung disease diagnosis, gender, ethnicity and baseline forced vital capacity%. Respiratory failure was the most common cause of death in both groups. A sub-analysis of 25 biopsy-proven MA-UIP subjects showed similar results. MA-UIP patients demonstrated a significant survival advantage over a matched IPF cohort, suggesting that despite similar histological and radiographic findings at presentation, the prognosis of MA-UIP is superior to that of IPF-UIP. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial.

PubMed

Raghu, Ganesh; Behr, Juergen; Brown, Kevin K; Egan, Jim J; Kawut, Steven M; Flaherty, Kevin R; Martinez, Fernando J; Nathan, Steven D; Wells, Athol U; Collard, Harold R; Costabel, Ulrich; Richeldi, Luca; de Andrade, Joao; Khalil, Nasreen; Morrison, Lake D; Lederer, David J; Shao, Lixin; Li, Xiaoming; Pedersen, Patty S; Montgomery, A Bruce; Chien, Jason W; O'Riordan, Thomas G

2013-05-07

Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). Academic and private hospitals. Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. Ambrisentan, 10 mg/d, or placebo. Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. The study was terminated early. Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. Gilead Sciences.

Acute exacerbation of idiopathic pulmonary fibrosis: lessons learned from acute respiratory distress syndrome?

PubMed

Marchioni, Alessandro; Tonelli, Roberto; Ball, Lorenzo; Fantini, Riccardo; Castaniere, Ivana; Cerri, Stefania; Luppi, Fabrizio; Malerba, Mario; Pelosi, Paolo; Clini, Enrico

2018-03-23

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease characterized by progressive loss of lung function and poor prognosis. The so-called acute exacerbation of IPF (AE-IPF) may lead to severe hypoxemia requiring mechanical ventilation in the intensive care unit (ICU). AE-IPF shares several pathophysiological features with acute respiratory distress syndrome (ARDS), a very severe condition commonly treated in this setting.A review of the literature has been conducted to underline similarities and differences in the management of patients with AE-IPF and ARDS.During AE-IPF, diffuse alveolar damage and massive loss of aeration occurs, similar to what is observed in patients with ARDS. Differently from ARDS, no studies have yet concluded on the optimal ventilatory strategy and management in AE-IPF patients admitted to the ICU. Notwithstanding, a protective ventilation strategy with low tidal volume and low driving pressure could be recommended similarly to ARDS. The beneficial effect of high levels of positive end-expiratory pressure and prone positioning has still to be elucidated in AE-IPF patients, as well as the precise role of other types of respiratory assistance (e.g., extracorporeal membrane oxygenation) or innovative therapies (e.g., polymyxin-B direct hemoperfusion). The use of systemic drugs such as steroids or immunosuppressive agents in AE-IPF is controversial and potentially associated with an increased risk of serious adverse reactions.Common pathophysiological abnormalities and similar clinical needs suggest translating to AE-IPF the lessons learned from the management of ARDS patients. Studies focused on specific therapeutic strategies during AE-IPF are warranted.

Modified GAP index for prediction of acute exacerbation of idiopathic pulmonary fibrosis in non-small cell lung cancer.

PubMed

Kobayashi, Haruki; Omori, Shota; Nakashima, Kazuhisa; Wakuda, Kazushige; Ono, Akira; Kenmotsu, Hirotsugu; Naito, Tateaki; Murakami, Haruyasu; Endo, Masahiro; Takahashi, Toshiaki

2017-10-01

Predicting the incidence rate of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) and its prognosis in patients with non-small cell lung cancer (NSCLC) and IPF is difficult. The aim was to study the incidence of IPF-AE during the clinical course of the disease and its prognosis in patients with both NSCLC and IPF. In this retrospective study, we compared the incidence rate of AE during the clinical course of the disease as well as the 1-year survival rate and overall survival (OS) of patients with NSCLC and IPF using a modified gender, age and physiology (mGAP) staging system based on gender, age and percent predicted forced vital capacity. Of 43 patients with NSCLC and IPF included in the final analysis, 17 patients (40%; 95% CI: 26-54%) experienced AE during the clinical course of the disease. One-year survival and median OS were 41.9% (95% CI: 28-57%) and 9.4 months, respectively. Further analysis showed that the incidence of IPF-AE gradually increased and that the 1-year survival rate and median OS gradually decreased with increasing mGAP index score and stage. Our study suggested that mGAP index score and cancer stage may predict IPF-AE and its prognosis in patients with NSCLC and IPF. © 2017 Asian Pacific Society of Respirology.

Sensitivity Analyses of the Change in FVC in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis

PubMed Central

Bradford, Williamson Z.; Fagan, Elizabeth A.; Glaspole, Ian; Glassberg, Marilyn K.; Glasscock, Kenneth F.; King, Talmadge E.; Lancaster, Lisa H.; Nathan, Steven D.; Pereira, Carlos A.; Sahn, Steven A.; Swigris, Jeffrey J.; Noble, Paul W.

2015-01-01

BACKGROUND: FVC outcomes in clinical trials on idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary end point of FVC change in a phase 3 trial evaluating pirfenidone in adults with IPF. METHODS: Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary end point of change from baseline to week 52 in FVC. RESULTS: The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis. CONCLUSIONS: Our results confirm the robustness of the statistical finding on the primary end point of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01366209; URL: www.clinicaltrials.gov PMID:25856121

Effect of telomere length on survival in idiopathic pulmonary fibrosis: an observational study with independent validation

PubMed Central

Stuart, Bridget D.; Lee, Joyce S.; Kozlitina, Julia; Noth, Imre; Devine, Megan S.; Glazer, Craig S.; Torres, Fernando; Kaza, Vaidehi; Girod, Carlos E.; Jones, Kirk D.; Elicker, Brett M.; Ma, Shwu-Fan; Vij, Rekha; Collard, Harold R.; Wolters, Paul J.; Garcia, Christine Kim

2014-01-01

Background Short telomere lengths are found in a subset of idiopathic pulmonary fibrosis (IPF) patients, but their clinical significance is unknown. The aim of this study was to investigate whether patients with various blood leukocyte telomere lengths had different overall survival. Methods Telomere lengths were measured in 370 genomic DNA samples isolated from peripheral blood collected from patients with interstitial lung disease (149 with IPF) at the time of their initial evaluation. Associations of telomere length with transplant-free survival were determined. Findings were validated in two independent IPF cohorts. Findings Patients with IPF had shorter telomere lengths than controls, but similar telomere lengths when compared to patients with other interstitial lung disease diagnoses after adjusting for age, male sex and ethnicity. Telomere length was independently associated with transplant-free survival time for patients with IPF (HR 0·22 [0·08–0·63], P-value = 0·0048), but not for patients with interstitial lung disease diagnoses other than IPF (HR 0·73 [0·16–3·41], P-value = 0·69). The association between telomere length and IPF survival was independent of age, male sex, forced vital capacity or diffusing capacity of carbon monoxide (and was replicated in two independent IPF cohorts (HR 0·11 [0·03–0·39], P-value 0·00066; HR 0·25 [0·07–0·87], P-value = 0·029). Addition of telomere length to clinical prediction models improved the integrative discrimination index, especially for IPF cohorts with milder disease. Interpretation These findings suggest that shorter leukocyte telomere lengths are associated with worse survival in IPF. Additional studies will be needed to determine clinically relevant thresholds for telomere length and how this biomarker may influence future risk stratification of IPF patients. Furthermore, this study offers mechanistic insight as disease progression in certain IPF patients may be related to aberrant signaling from short telomeres. Funding US National Heart, Lung, and Blood Institute; the National Center for Advancing Translational Science, the Harroun Family Foundation and the Nina Ireland Lung Disease Program. PMID:24948432

Right Ventricular Structure and Function in Idiopathic Pulmonary Fibrosis with or without Pulmonary Hypertension.

PubMed

D'Andrea, Antonello; Stanziola, Anna; Di Palma, Enza; Martino, Maria; D'Alto, Michele; Dellegrottaglie, Santo; Cocchia, Rosangela; Riegler, Lucia; Betancourt Cordido, Meredyth Vanessa; Lanza, Maurizia; Maglione, Marco; Diana, Veronica; Calabrò, Raffaele; Russo, Maria Giovanna; Vannan, Mani; Bossone, Eduardo

2016-01-01

To elucidate right ventricular (RV) function in patients with idiopathic pulmonary fibrosis (IPF) with and without pulmonary hypertension (PH) and its relation to other features of the disease. Clinical evaluation, standard Doppler echo, Doppler myocardial imaging (DMI), and 2D strain echocardiography (STE) of RV septal and lateral walls were performed in 52 IPF patients (66.5 ± 8.5 years; 27 males) and in 45 age- and sex-comparable controls using a commercial US system (MyLab Alpha, Esaote). Pulmonary artery mean pressure (mPAP) was estimated by standard echo Doppler. RV global longitudinal strain (RV GLS) was calculated by averaging RV local strains. The IPF patients were divided into 2 groups by noninvasive assessment of PH: no PH (mPAP<25 mmHg; 36 pts) and PH (mPAP ≥25 mmHg; 16 pts). Left ventricular diameters and ejection fraction were comparable between controls and IPF, while GLS was impaired in IPF (P < 0.01). RV end-diastolic diameters, wall thickness andmPAP were increased in IPF patients with PH. In addition, pulsed DMI detected in PH IPF impaired myocardial RV early diastolic (Em) peak velocity. Also peak systolic RV strain was reduced in basal and middle RV lateral free walls in IPF, as well as RV GLS (P < 0.0001). The impairment in RV wall strain was more evident when comparing controls with the no PH group than comparing the no PH group with the PH group. By multivariate analysis, independent association of RV strain with both six-minute walking test distance (P < 0.001), mPAP (P < 0.0001), as well as with forced vital capacity (FVC) % (P < 0.005) in IPF patients were observed. Impaired RV diastolic and systolic myocardial function were present even in IPF patients without PH, which indicates an early impact on RV function and structure in patients with IPF. © 2015, Wiley Periodicals, Inc.

Plasma Soluble Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

PubMed Central

Manichaikul, Ani; Sun, Li; Borczuk, Alain C.; Onengut-Gumuscu, Suna; Farber, Emily A.; Mathai, Susan K.; Zhang, Weiming; Raghu, Ganesh; Kaufman, Joel D.; Hinckley-Stukovsky, Karen D.; Kawut, Steven M.; Jelic, Sanja; Liu, Wen; Fingerlin, Tasha E.; Schwartz, David A.; Sell, Jessica L.; Rich, Stephen S.; Barr, R. Graham

2017-01-01

Rationale: The receptor for advanced glycation end products (RAGE) is underexpressed in idiopathic pulmonary fibrosis (IPF) lung, but the role of RAGE in human lung fibrosis remains uncertain. Objectives: To examine (1) the association between IPF risk and variation at rs2070600, a functional missense variant in AGER (the gene that codes for RAGE), and (2) the associations between plasma-soluble RAGE (sRAGE) levels with disease severity and time to death or lung transplant in IPF. Methods: We genotyped the rs2070600 single-nucleotide polymorphism in 108 adults with IPF and 324 race-/ethnicity-matched control subjects. We measured plasma sRAGE by ELISA in 103 adults with IPF. We used generalized linear and additive models as well as Cox models to control for potential confounders. We repeated our analyses in 168 (genetic analyses) and 177 (sRAGE analyses) adults with other forms of interstitial lung disease (ILD). Results: There was no association between rs2070600 variation among adults with IPF (P = 0.31). Plasma sRAGE levels were lower among adults with IPF and other forms of ILD than in control subjects (P < 0.001). The rs2070600 allele A was associated with a 49% lower sRAGE level (95% confidence interval [CI], 11 to 71%; P = 0.02) among adults with IPF. In adjusted analyses, lower sRAGE levels were associated with greater disease severity (14% sRAGE decrement per 10% FVC decrement; 95% CI, 5 to 22%) and a higher rate of death or lung transplant at 1 year (adjusted hazard ratio, 1.9 per logarithmic unit of sRAGE decrement; 95% CI, 1.2–3.3) in IPF. Similar findings were observed in a heterogeneous group of adults with other forms of ILD. Conclusions: Lower plasma sRAGE levels may be a biological measure of disease severity in IPF. Variation at the rs2070600 single-nucleotide polymorphism was not associated with IPF risk. PMID:28248552

Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis.

PubMed

Tjin, Gavin; White, Eric S; Faiz, Alen; Sicard, Delphine; Tschumperlin, Daniel J; Mahar, Annabelle; Kable, Eleanor P W; Burgess, Janette K

2017-11-01

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with few effective therapeutic options. Structural remodelling of the extracellular matrix [i.e. collagen cross-linking mediated by the lysyl oxidase (LO) family of enzymes (LOX, LOXL1-4)] might contribute to disease pathogenesis and represent a therapeutic target. This study aimed to further our understanding of the mechanisms by which LO inhibitors might improve lung fibrosis. Lung tissues from IPF and non-IPF subjects were examined for collagen structure (second harmonic generation imaging) and LO gene (microarray analysis) and protein (immunohistochemistry and western blotting) levels. Functional effects (collagen structure and tissue stiffness using atomic force microscopy) of LO inhibitors on collagen remodelling were examined in two models, collagen hydrogels and decellularized human lung matrices. LOXL1 / LOXL2 gene expression and protein levels were increased in IPF versus non-IPF. Increased collagen fibril thickness in IPF versus non-IPF lung tissues correlated with increased LOXL1/LOXL2, and decreased LOX, protein expression. β-Aminoproprionitrile (β-APN; pan-LO inhibitor) but not Compound A (LOXL2-specific inhibitor) interfered with transforming growth factor-β-induced collagen remodelling in both models. The β-APN treatment group was tested further, and β-APN was found to interfere with stiffening in the decellularized matrix model. LOXL1 activity might drive collagen remodelling in IPF lungs. The interrelationship between collagen structural remodelling and LOs is disrupted in IPF lungs. Inhibition of LO activity alleviates fibrosis by limiting fibrillar collagen cross-linking, thereby potentially impeding the formation of a pathological microenvironment in IPF. © 2017. Published by The Company of Biologists Ltd.

Fibulin-1 Predicts Disease Progression in Patients With Idiopathic Pulmonary Fibrosis

PubMed Central

Unger, Sofia; Corte, Tamera J.; Keller, Michael; Wolters, Paul J.; Richeldi, Luca; Cerri, Stefania; Prêle, Cecilia M.; Hansbro, Philip M.; Argraves, William Scott; Oliver, Rema A.; Oliver, Brian G.; Black, Judith L.; Burgess, Janette K.

2014-01-01

BACKGROUND: The underlying mechanisms of idiopathic pulmonary fibrosis (IPF) are unknown. This progressive disease has high mortality rates, and current models for prediction of mortality have limited value in identifying which patients will progress. We previously showed that the glycoprotein fibulin-1 is involved in enhanced proliferation and wound repair by mesenchymal cells and, thus, may contribute to lung fibrosis in IPF. METHODS: Serum, lung tissue, and lung function values were obtained from four independent locations (Sydney, NSW, and Perth, WA, Australia; San Francisco, CA; and Modena, Italy). Patients with IPF were followed for a minimum of 1 year and progression was defined as a significant decline in lung function or death. Primary parenchymal lung fibroblasts of 15 patients with and without IPF were cultured under nonstimulatory conditions. Fibulin-1 levels in serum, and secreted or deposited by fibroblasts, were measured by western blot and in lung tissue by immunohistochemistry. RESULTS: Serum fibulin-1 levels were increased in patients with IPF compared with subjects without lung disease (P = .006). Furthermore, tissue fibulin-1 levels were increased in patients with IPF (P = .02) and correlated negatively with lung function (r = −0.9, P < .05). Primary parenchymal fibroblasts from patients with IPF produced more fibulin-1 than those from subjects without IPF (P < .05). Finally, serum fibulin-1 levels at first blood draw predicted disease progression in IPF within 1 year (area under the curve , 0.71; 95% CI, 0.57-0.86; P = .012). CONCLUSIONS: Fibulin-1 is a novel potential biomarker for disease progression in IPF and raises the possibility that it could be used as a target for the development of new treatments. PMID:24832167

Comorbid Conditions in Idiopathic Pulmonary Fibrosis: Recognition and Management

PubMed Central

Oldham, Justin M.; Collard, Harold R.

2017-01-01

Idiopathic pulmonary fibrosis (IPF), a fibrosing interstitial pneumonia of unknown etiology, primarily affects older adults and leads to a progressive decline in lung function and quality of life. With a median survival of 3–5 years, IPF is the most common and deadly of the idiopathic interstitial pneumonias. Despite the poor survivorship, there exists substantial variation in disease progression, making accurate prognostication difficult. Lung transplantation remains the sole curative intervention in IPF, but two anti-fibrotic therapies were recently shown to slow pulmonary function decline and are now approved for the treatment of IPF in many countries around the world. While the approval of these therapies represents an important first step in combatting of this devastating disease, a comprehensive approach to diagnosing and treating patients with IPF remains critically important. Included in this comprehensive assessment is the recognition and appropriate management of comorbid conditions. Though IPF is characterized by single organ involvement, many comorbid conditions occur within other organ systems. Common cardiovascular processes include coronary artery disease and pulmonary hypertension (PH), while gastroesophageal reflux and hiatal hernia are the most commonly encountered gastrointestinal disorders. Hematologic abnormalities appear to place patients with IPF at increased risk of venous thromboembolism, while diabetes mellitus (DM) and hypothyroidism are prevalent metabolic disorders. Several pulmonary comorbidities have also been linked to IPF, and include emphysema, lung cancer, and obstructive sleep apnea. While the treatment of some comorbid conditions, such as CAD, DM, and hypothyroidism is recommended irrespective of IPF, the benefit of treating others, such as gastroesophageal reflux and PH, remains unclear. In this review, we highlight common comorbid conditions encountered in IPF, discuss disease-specific diagnostic modalities, and review the current state of treatment data for several key comorbidities. PMID:28824912

Fibulin-1 predicts disease progression in patients with idiopathic pulmonary fibrosis.

PubMed

Jaffar, Jade; Unger, Sofia; Corte, Tamera J; Keller, Michael; Wolters, Paul J; Richeldi, Luca; Cerri, Stefania; Prêle, Cecilia M; Hansbro, Philip M; Argraves, William Scott; Oliver, Rema A; Oliver, Brian G; Black, Judith L; Burgess, Janette K

2014-10-01

The underlying mechanisms of idiopathic pulmonary fibrosis (IPF) are unknown. This progressive disease has high mortality rates, and current models for prediction of mortality have limited value in identifying which patients will progress. We previously showed that the glycoprotein fibulin-1 is involved in enhanced proliferation and wound repair by mesenchymal cells and, thus, may contribute to lung fibrosis in IPF. Serum, lung tissue, and lung function values were obtained from four independent locations (Sydney, NSW, and Perth, WA, Australia; San Francisco, CA; and Modena, Italy). Patients with IPF were followed for a minimum of 1 year and progression was defined as a significant decline in lung function or death. Primary parenchymal lung fibroblasts of 15 patients with and without IPF were cultured under nonstimulatory conditions. Fibulin-1 levels in serum, and secreted or deposited by fibroblasts, were measured by western blot and in lung tissue by immunohistochemistry. Serum fibulin-1 levels were increased in patients with IPF compared with subjects without lung disease (P = .006). Furthermore, tissue fibulin-1 levels were increased in patients with IPF (P = .02) and correlated negatively with lung function (r = -0.9, P < .05). Primary parenchymal fibroblasts from patients with IPF produced more fibulin-1 than those from subjects without IPF (P < .05). Finally, serum fibulin-1 levels at first blood draw predicted disease progression in IPF within 1 year (area under the curve , 0.71; 95% CI, 0.57-0.86; P = .012). Fibulin-1 is a novel potential biomarker for disease progression in IPF and raises the possibility that it could be used as a target for the development of new treatments.

Managing comorbidities in idiopathic pulmonary fibrosis

PubMed Central

Fulton, Blair G; Ryerson, Christopher J

2015-01-01

Major risk factors for idiopathic pulmonary fibrosis (IPF) include older age and a history of smoking, which predispose to several pulmonary and extra-pulmonary diseases. IPF can be associated with additional comorbidities through other mechanisms as either a cause or a consequence of these diseases. We review the literature regarding the management of common pulmonary and extra-pulmonary comorbidities, including chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, venous thromboembolism, sleep-disordered breathing, gastroesophageal reflux disease, coronary artery disease, depression and anxiety, and deconditioning. Recent studies have provided some guidance on the management of these diseases in IPF; however, most treatment recommendations are extrapolated from studies of non-IPF patients. Additional studies are required to more accurately determine the clinical features of these comorbidities in patients with IPF and to evaluate conventional treatments and management strategies that are beneficial in non-IPF populations. PMID:26451121

Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis.

PubMed

Molyneaux, Philip L; Cox, Michael J; Wells, Athol U; Kim, Ho Cheol; Ji, Wonjun; Cookson, William O C; Moffatt, Miriam F; Kim, Dong Soon; Maher, Toby M

2017-02-01

Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) have been defined as events of clinically significant respiratory deterioration with an unidentifiable cause. They carry a significant mortality and morbidity and while their exact pathogenesis remains unclear, the possibility remains that hidden infection may play a role. The aim of this pilot study was to determine whether changes in the respiratory microbiota occur during an AE-IPF. Bacterial DNA was extracted from bronchoalveolar lavage from patients with stable IPF and those experiencing an AE-IPF. A hyper-variable region of the 16S ribosomal RNA gene (16S rRNA) was amplified, quantified and pyrosequenced. Culture independent techniques demonstrate AE-IPF is associated with an increased BAL bacterial burden compared to stable disease and highlight shifts in the composition of the respiratory microbiota during an AE-IPF.

CXCL14 is a candidate biomarker for Hedgehog signalling in idiopathic pulmonary fibrosis.

PubMed

Jia, Guiquan; Chandriani, Sanjay; Abbas, Alexander R; DePianto, Daryle J; N'Diaye, Elsa N; Yaylaoglu, Murat B; Moore, Heather M; Peng, Ivan; DeVoss, Jason; Collard, Harold R; Wolters, Paul J; Egen, Jackson G; Arron, Joseph R

2017-09-01

Idiopathic pulmonary fibrosis (IPF) is associated with aberrant expression of developmental pathways, including Hedgehog (Hh). As Hh signalling contributes to multiple pro-fibrotic processes, Hh inhibition may represent a therapeutic option for IPF. However, no non-invasive biomarkers are available to monitor lung Hh activity. We assessed gene and protein expression in IPF and control lung biopsies, mouse lung, fibroblasts stimulated in vitro with sonic hedgehog (SHh), and plasma in IPF patients versus controls, and cancer patients before and after treatment with vismodegib, a Hh inhibitor. Lung tissue from IPF patients exhibited significantly greater expression of Hh-related genes versus controls. The gene most significantly upregulated in both IPF lung biopsies and fibroblasts stimulated in vitro with SHh was CXCL14 , which encodes a soluble secreted chemokine whose expression is inhibited in vitro by the addition of vismodegib. CXCL14 expression was induced by SHh overexpression in mouse lung. Circulating CXCL14 protein levels were significantly higher in plasma from IPF patients than controls. In cancer patients, circulating CXCL14 levels were significantly reduced upon vismodegib treatment. CXCL14 is a systemic biomarker that could be used to identify IPF patients with increased Hh pathway activity and monitor the pharmacodynamic effects of Hh antagonist therapy in IPF. Post-results, NCT00968981. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Association Between Lung Microbiome and Disease Progression in IPF: A Prospective Cohort Study

PubMed Central

Han, MeiLan K.; Zhou, Yueren; Murray, Susan; Tayob, Nabihah; Noth, Imre; Lama, Vibha N.; Moore, Bethany B.; White, Eric S.; Flaherty, Kevin R.; Huffnagle, Gary B.; Martinez, Fernando J.

2014-01-01

Background The lung microbiome’s contribution to IPF pathogenesisis unknown. Using COMET-IPF (Correlating Outcomes with biochemical Markers to Estimate Time-progression in Idiopathic Pulmonary Fibrosis), the goal of this study was to determine whether unique microbial signatures would associate with disease progression. Methods IPF subjects within four years of diagnosis aged 35–80 were eligible for inclusion. Subjects were followed for up to a maximum of 80 weeks. This completed observational study is registered with ClinicalTrials.gov, number NCT01071707. Progression-free survival was defined as death, acute exacerbation, lung transplant, or decline in FVC of 10% or DLCO of 15%.DNA was isolated from 55 bronchoscopic alveolar lavage (BAL) samples. 454 pyrosequencing was used to assign operational taxonomic units (OTUs) based on a 3% sequence divergence. Adjusted Cox models identified OTUs significantly associated with progression-free survival at a p<0·10 level. These OTUs were then used in principal components (PC) analysis. The association between PCs and microbes with high factor loadings from the PC analysis and progression-free survival were examined via Cox regression analyses. Findings Mean FVC was 70·1% and mean DLCO 42·3 %predicted. Significant associations with disease progression were noted with increased % relative abundance of two OTUs identified by PC analysis, a Streptococcus OTU. (p<0·0009) and a Staphylococcus OTU(p=0·01). Strength of associations using PCs versus two OTUs alone was similar. Threshold analysis helped define a cut point for % relative abundance for each OTU associated with progression-free survival, >3·9% for the Streptococcus OTU, HR 10·19 (95% CI 2·94, 35·35; p=0·0002) and >1·8% for the Staphylococcus OTU, HR 5·06 (1·71, 14·93; p=0·003). Interpretation These preliminary data suggest IPF disease progression is associated with presence of specific members within the Staphylococcus and Streptococcus genera. PMID:24767767

Workshop on Idiopathic Pulmonary Fibrosis in Older Adults

PubMed Central

Castriotta, Richard J.; Eldadah, Basil A.; Foster, W. Michael; Halter, Jeffrey B.; Hazzard, William R.; Kiley, James P.; King, Talmadge E.; Horne, Frances McFarland; Nayfield, Susan G.; Reynolds, Herbert Y.; Schmader, Kenneth E.; Toews, Galen B.

2010-01-01

Idiopathic pulmonary fibrosis (IPF), a heterogeneous disease with respect to clinical presentation and rates of progression, disproportionately affects older adults. The diagnosis of IPF is descriptive, based on clinical, radiologic, and histopathologic examination, and definitive diagnosis is hampered by poor interobserver agreement and lack of a consensus definition. There are no effective treatments. Cellular, molecular, genetic, and environmental risk factors have been identified for IPF, but the initiating event and the characteristics of preclinical stages are not known. IPF is predominantly a disease of older adults, and the processes underlying normal aging might significantly influence the development of IPF. Yet, the biology of aging and the principles of medical care for this population have been typically ignored in basic, translational, or clinical IPF research. In August 2009, the Association of Specialty Professors, in collaboration with the American College of Chest Physicians, the American Geriatrics Society, the National Institute on Aging, and the National Heart, Lung, and Blood Institute, held a workshop, summarized herein, to review what is known, to identify research gaps at the interface of aging and IPF, and to suggest priority areas for future research. Efforts to answer the questions identified will require the integration of geriatrics, gerontology, and pulmonary research, but these efforts have great potential to improve care for patients with IPF. PMID:20822991

Decreased Apoptotic Rate of Alveolar Macrophages of Patients with Idiopathic Pulmonary Fibrosis

PubMed Central

Drakopanagiotakis, Fotios; Xifteri, Areti; Tsiambas, Evaggelos; Karameris, Andreas; Tsakanika, Konstantina; Karagiannidis, Napoleon; Mermigkis, Demetrios; Polychronopoulos, Vlasis; Bouros, Demosthenes

2012-01-01

Introduction. Increased apoptosis of epithelial cells and decreased apoptosis of myofibroblasts are involved in the pathogenesis of IPF. The apoptotic profile of alveolar macrophages (AMs) in IPF is unclear. Aim. To investigate whether AMs of patients with IPF exhibit a different apoptotic profile compared to normal subjects. Methods. We analyzed, by immunohistochemistry, the expression of the apoptotic markers fas, fas ligand , bcl-2, and bax in AM obtained from bronchoalveolar lavage fluid (BALF) of 20 newly diagnosed, treatment-naive IPF patients and of 16 controls. Apoptosis of AM was evaluated by Apoptag immunohistochemistry. IPF patients received either interferon-g and corticosteroids or azathioprine and corticosteroids for six months. Results. BALF AMs undergoing apoptosis were significantly less in IPF patients. No difference was found in the expression of fas or fas ligand, bcl-2 and bax between IPF and control group. No difference was found between the respiratory function parameters of the two treatment groups after six months. A positive correlation was found between the number of bcl-2 positive stained macrophages and DLCO after treatment. Conclusions. The decreased apoptotic rate of AM of patients with IPF is not associated with decreased expression of apoptosis mediators involved in the external or internal apoptotic pathway. PMID:22792456

Idiopathic Pulmonary Fibrosis: Diagnosis and Clinical Manifestations

PubMed Central

Nakamura, Yutaro; Suda, Takafumi

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a parenchymal lung disease characterized by progressive interstitial fibrosis. The clinical course of IPF can be unpredictable and may be punctuated by acute exacerbations. Although much progress is being made in unraveling the mechanisms underlying IPF, effective therapy for improving survival remains elusive. Longitudinal disease profiling, especially in terms of clinical manifestations in a large cohort of patients, should lead to proper management of the patients and development of new treatments for IPF. Appropriate multidisciplinary assessment in ongoing registries is required to achieve this. This review summarizes the current status of the diagnosis and clinical manifestations of IPF. PMID:27625576

Idiopathic pulmonary fibrosis in BRIC countries: the cases of Brazil, Russia, India, and China.

PubMed

Richeldi, Luca; Rubin, Adalberto Sperb; Avdeev, Sergey; Udwadia, Zarir F; Xu, Zuo Jun

2015-09-24

Idiopathic pulmonary fibrosis (IPF), the prototype of interstitial lung diseases, has the worst prognosis and is the only interstitial lung disease for which approved pharmacological treatments are available. Despite being considered a rare disease, IPF patients pose major challenges to both physicians and healthcare systems. It is estimated that a large number of IPF patients reside in BRIC countries (Brazil, Russia, India, and China) given their overall total population of approximately 3 billion inhabitants. Nevertheless, the limited availability of chest imaging in BRIC countries is considered a chief obstacle to diagnosis, since high-resolution computed tomography of the chest is the key diagnostic test for IPF. Further, obtaining reliable lung function tests and providing treatment access is difficult in the more rural areas of these countries. However, IPF might represent an opportunity for BRIC countries: the exponentially increasing demand for the enrollment of IPF patients in clinical trials of new drugs is predicted to face a shortage of patients - BRIC countries may thus play a crucial role in advancing towards a cure for IPF.

Using learning theory, interprofessional facilitation competencies, and behavioral indicators to evaluate facilitator training.

PubMed

LeGros, Theresa A; Amerongen, Helen M; Cooley, Janet H; Schloss, Ernest P

2015-01-01

Despite the increasing need for faculty and preceptors skilled in interprofessional facilitation (IPF), the relative novelty of the field poses a challenge to the development and evaluation of IPF programs. We use learning theory and IPF competencies with associated behavioral indicators to develop and evaluate six key messages in IPF training and experience. Our mixed methods approach included two phases: quantitative data collection with embedded qualitative data, followed by qualitative data collection in explanatory sequential fashion. This enabled triangulated analyses of both data types and of facilitation behaviors from facilitator and student perspectives. Results indicate the competency-based training was effective. Facilitators felt comfortable performing behaviors associated with IPF competencies; student observations of those behaviors supported facilitator self-reported performance. Overall, students perceived more facilitation opportunities than facilitators. Findings corroborate the importance of recruiting seasoned facilitators and establishing IPF guidelines that acknowledge variable team dynamics and help facilitators recognize teachable moments.

Assessing idiopathic pulmonary fibrosis (IPF) with bronchoscopic OCT (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hariri, Lida P.; Adams, David C.; Colby, Thomas V.; Tager, Andrew M.; Suter, Melissa J.

2016-03-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal form of fibrotic lung disease, with a significantly worse prognosis than other forms of pulmonary fibrosis (3-year survival rate of 50%). Distinguishing IPF from other fibrotic diseases is essential to patient care because it stratifies prognosis and therapeutic decision-making. However, making the diagnosis often requires invasive, high-risk surgical procedures to look for microscopic features not seen on chest CT, such as characteristic cystic honeycombing in the peripheral lung. Optical coherence tomography (OCT) provides rapid 3D visualization of large tissue volumes with microscopic resolutions well beyond the capabilities of CT. We aim to determine whether bronchoscopic OCT can provide a low-risk, non-surgical method for IPF diagnosis. We have developed bronchoscopic OCT catheters that access the peripheral lung and conducted in vivo peripheral lung imaging in patients, including those with pulmonary fibrosis. We also conducted bronchoscopic OCT in ex vivo lung from pulmonary fibrosis patients, including IPF, to determine if OCT could successfully visualize features of IPF through the peripheral airways. Our results demonstrate that OCT is able to visualize characteristic features of IPF through the airway, including microscopic honeycombing (< 1 mm diameter) not visible by CT, dense peripheral fibrosis, and spatial disease heterogeneity. We also found that OCT has potential to distinguish mimickers of IPF honeycombing, such as traction bronchiectasis and emphysema, from true honeycombing. These findings support the potential of bronchoscopic OCT as a minimally-invasive method for in vivo IPF diagnosis. However, future clinical studies are needed to validate these findings.

Innovative haematological parameters for early diagnosis of sepsis in adult patients admitted in intensive care unit.

PubMed

Buoro, Sabrina; Manenti, Barbara; Seghezzi, Michela; Dominoni, Paola; Barbui, Tiziano; Ghirardi, Arianna; Carobbio, Alessandra; Marchesi, Gianmariano; Riva, Ivano; Nasi, Alessandra; Ottomano, Cosimo; Lippi, Giuseppe

2018-04-01

This study was aimed to investigate the role of erythrocyte, platelet and reticulocyte (RET) parameters, measured by new haematological analyser Sysmex XN and C reactive protein (CRP), for early diagnosis of sepsis during intensive care unit (ICU) stay. The study population consisted of 62 ICU patients, 21 of whom developed sepsis during ICU stay and 41 who did not. The performance for early diagnosing of sepsis was calculated as area under the curve (AUC) of receiver operating characteristics curves analysis. Compared with CRP (AUC 0.81), immature platelet fraction (IPF) (AUC 0.82) showed comparable efficiency for identifying the onset of sepsis. The association with the risk of developing sepsis during ICU stay was also assessed. One day before the onset of sepsis, a decreased of RET% was significantly associated with the risk of developing sepsis (OR=0.35, 95% CI 0.14 to 0.87), whereas an increased of IPF absolute value (IPF#) was significantly associated with the risk of developing sepsis (OR=1.13, 95% CI 1.03 to 1.24) 2 days before the onset of sepsis. The value of CRP was not predictive of sepsis at either time points. IPF# and RET% may provide valuable clinical information for predicting the risk of developing sepsis, thus allowing early management of patients before the onset of clinically evident systemic infections. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Lung cancer in patients with idiopathic pulmonary fibrosis.

PubMed

Karampitsakos, Theodoros; Tzilas, Vasilios; Tringidou, Rodoula; Steiropoulos, Paschalis; Aidinis, Vasilis; Papiris, Spyros A; Bouros, Demosthenes; Tzouvelekis, Argyris

2017-08-01

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease of unknown etiology. With a gradually increasing worldwide prevalence and a mortality rate exceeding that of many cancers, IPF diagnosis and management are critically important and require a comprehensive multidisciplinary approach. This approach also involves assessment of comorbid conditions, such as lung cancer, that exerts a dramatic impact on disease survival. Emerging evidence suggests that progressive lung scarring in the context of IPF represents a risk factor for lung carcinogenesis. Both disease entities present with major similarities in terms of pathogenetic pathways, as well as potential causative factors, such as smoking and viral infections. Besides disease pathogenesis, anti-cancer agents, including nintedanib, have been successfully applied in the treatment of patients with IPF while an oncologic approach with a cocktail of several pleiotropic anti-fibrotic agents is currently in the therapeutic pipeline of IPF. Nevertheless, epidemiologic association between IPF and lung cancer does not prove causality. Currently there is significant lack of knowledge supporting a direct association between lung fibrosis and cancer reflecting to disappointing therapeutic algorithms. An optimal therapeutic strategy for patients with both IPF and lung cancer represents an amenable need. This review article synthesizes the current state of knowledge regarding pathogenetic commonalities between IPF and lung cancer and focuses on clinical and therapeutic data that involve both disease entities. Copyright © 2017. Published by Elsevier Ltd.

Lung fibrosis-associated soluble mediators and bronchoalveolar lavage from idiopathic pulmonary fibrosis patients promote the expression of fibrogenic factors in subepithelial lung myofibroblasts.

PubMed

Bouros, Evangelos; Filidou, Eirini; Arvanitidis, Konstantinos; Mikroulis, Dimitrios; Steiropoulos, Paschalis; Bamias, George; Bouros, Demosthenes; Kolios, George

2017-10-01

Idiopathic pulmonary fibrosis (IPF) is characterized by infiltration of inflammatory cells, excessive collagen production and accumulation of myofibroblasts. We explored the possible role of subepithelial lung myofibroblasts (SELMs) in the development of fibrosis in IPF. SELMs, isolated from surgical specimens of healthy lung tissue, were cultured with pro-inflammatory factors or bronchoalveolar lavage fluid (BALF) from patients with IPF or idiopathic non-specific interstitial pneumonia (iNSIP) and their fibrotic activity was assessed. Stimulation of SELMs with pro-inflammatory factors induced a significant increase of Tissue Factor (TF) and Tumor necrosis factor-Like cytokine 1 A (TL1A) expression and collagen production in culture supernatants. Stimulation with BALF from IPF patients with mild to moderate, but not severe disease, and from iNSIP patients induced a significant increase of TF expression. BALF from all IPF patients induced a significant increase of TL1A expression and collagen production, while BALF from iNSIP patients induced a significant increase of TL1A, but not of collagen production. Interestingly, TGF-β1 and BALF from all IPF, but not iNSIP patients, induced a significant increase in SELMs migration. In conclusion, BALF from IPF patients induces fibrotic activity in lung myofibroblasts, similar to mediators associated with lung fibrosis, indicating a key role of SELMs in IPF. Copyright © 2017 Elsevier Ltd. All rights reserved.

Idiopathic pulmonary fibrosis is associated with increased impedance measures of reflux compared to non-fibrotic disease among pre-lung transplant patients.

PubMed

Gavini, S; Finn, R T; Lo, W-K; Goldberg, H J; Burakoff, R; Feldman, N; Chan, W W

2015-09-01

Gastroesophageal reflux (GER) has been associated with idiopathic pulmonary fibrosis (IPF), although the mechanism remains unclear. Gastroesophageal reflux/microaspiration may lead to lung fibrosis, while increased pulmonary workload may also worsen GER. Comparing the GER profile of IPF patients to chronic obstructive pulmonary disease (COPD) patients with similar lung function may help delineate the role of GER in IPF pathogenesis. This was a retrospective cohort study of IPF and COPD patients undergoing pre-lung transplant multichannel intraluminal impedance and pH study (MII-pH) off acid suppression at a tertiary center in 2008-2014. Patients with prior fundoplication were excluded. Baseline demographics, pulmonary function test, and MII-pH results were recorded. Univariate analyses were performed using Fisher's exact (binary variables) and Student's t (continuous variables) tests. Logistic regression was performed to adjust for potential confounders. A total of 90 subjects (54 IPF, 36 COPD) met inclusion criteria. Compared to COPD, IPF patients had increased total reflux episodes (65.9 vs 46.1, p = 0.02), proximal reflux episodes (30.3 vs 20.3, p = 0.04), and prevalence of abnormal total reflux episodes (38.9% vs 16.7%, p = 0.02). On multivariate analyses, abnormal total reflux episodes (OR: 4.9, p = 0.05) and bolus reflux exposure time (OR: 4, p = 0.04) remained significantly associated with IPF. Abnormal reflux was significantly more prevalent among IPF patients after controlling for lung disease severity. Gastroesophageal reflux/microaspiration likely plays a role in fibrosis in IPF. A significant portion of IPF patients had increased non-acid reflux. Therapies aiming to prevent reflux of gastric contents may be more beneficial than antisecretory medications alone in these patients. © 2015 John Wiley & Sons Ltd.

Ten-Year Survival in Patients with Idiopathic Pulmonary Fibrosis After Lung Transplantation.

PubMed

ten Klooster, Liesbeth; Nossent, George D; Kwakkel-van Erp, Johanna M; van Kessel, Diana A; Oudijk, Erik J; van de Graaf, Ed A; Luijk, Bart; Hoek, Rogier A; van den Blink, Bernt; van Hal, Peter Th; Verschuuren, Erik A; van der Bij, Wim; van Moorsel, Coline H; Grutters, Jan C

2015-12-01

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal fibrosing lung disease with a median survival of approximately 3 years after diagnosis. The only medical option to improve survival in IPF is lung transplantation (LTX). The purpose of this study was to evaluate trajectory data of IPF patients listed for LTX and to investigate the survival after LTX. Data were retrospectively collected from September 1989 until July 2011 of all IPF patients registered for LTX in the Netherlands. Patients were included after revision of the diagnosis based on the criteria set by the ATS/ERS/JRS/ALAT. Trajectory data, clinical data at time of screening, and donor data were collected. In total, 98 IPF patients were listed for LTX. During the waiting list period, 30 % of the patients died. Mean pulmonary artery pressure, 6-min walking distance, and the use of supplemental oxygen were significant predictors of mortality on the waiting list. Fifty-two patients received LTX with a median overall survival after transplantation of 10 years. This study demonstrated a 10-year survival time after LTX in IPF. Furthermore, our study demonstrated a significantly better survival after bilateral LTX in IPF compared to single LTX although bilateral LTX patients were significantly younger.

Genetics and Early Detection in Idiopathic Pulmonary Fibrosis

PubMed Central

Putman, Rachel K.; Rosas, Ivan O.

2014-01-01

Genetic studies hold promise in helping to identify patients with early idiopathic pulmonary fibrosis (IPF). Recent studies using chest computed tomograms (CTs) in smokers and in the general population have demonstrated that imaging abnormalities suggestive of an early stage of pulmonary fibrosis are not uncommon and are associated with respiratory symptoms, physical examination abnormalities, and physiologic decrements expected, but less severe than those noted in patients with IPF. Similarly, recent genetic studies have demonstrated strong and replicable associations between a common promoter polymorphism in the mucin 5B gene (MUC5B) and both IPF and the presence of abnormal imaging findings in the general population. Despite these findings, it is important to note that the definition of early-stage IPF remains unclear, limited data exist to definitively connect abnormal imaging findings to IPF, and genetic studies assessing early-stage pulmonary fibrosis remain in their infancy. In this perspective we provide updated information on interstitial lung abnormalities and their connection to IPF. We summarize information on the genetics of pulmonary fibrosis by focusing on the recent genetic findings of MUC5B. Finally, we discuss the implications of these findings and suggest a roadmap for the use of genetics in the detection of early IPF. PMID:24547893

Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.

PubMed

Allen, Richard J; Porte, Joanne; Braybrooke, Rebecca; Flores, Carlos; Fingerlin, Tasha E; Oldham, Justin M; Guillen-Guio, Beatriz; Ma, Shwu-Fan; Okamoto, Tsukasa; John, Alison E; Obeidat, Ma'en; Yang, Ivana V; Henry, Amanda; Hubbard, Richard B; Navaratnam, Vidya; Saini, Gauri; Thompson, Norma; Booth, Helen L; Hart, Simon P; Hill, Mike R; Hirani, Nik; Maher, Toby M; McAnulty, Robin J; Millar, Ann B; Molyneaux, Philip L; Parfrey, Helen; Rassl, Doris M; Whyte, Moira K B; Fahy, William A; Marshall, Richard P; Oballa, Eunice; Bossé, Yohan; Nickle, David C; Sin, Don D; Timens, Wim; Shrine, Nick; Sayers, Ian; Hall, Ian P; Noth, Imre; Schwartz, David A; Tobin, Martin D; Wain, Louise V; Jenkins, R Gisli

2017-11-01

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses. We used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2). We investigated the effect of novel signals on gene expression in large transcriptomic and genomic data resources, and examined expression using lung tissue samples from patients with IPF and controls. 602 patients with IPF and 3366 controls were selected for stage 1. For stage 2, 2158 patients with IPF and 5195 controls were selected. We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18-1·37], p=1·32 × 10 -9 ) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56-3·26], p=1·12 × 10 -66 ) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35-1·54], p=7·81 × 10 -28 ). For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue from patients who had lung resection procedures (n=1111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF, and AKAP13 mRNA expression was 1·42-times higher in lung tissue from patients with IPF (n=46) than that in lung tissue from controls (n=51). AKAP13 is a Rho guanine nucleotide exchange factor regulating activation of RhoA, which is known to be involved in profibrotic signalling pathways. The identification of AKAP13 as a susceptibility gene for IPF increases the prospect of successfully targeting RhoA pathway inhibitors in patients with IPF. UK Medical Research Council, National Heart, Lung, and Blood Institute of the US National Institutes of Health, Agencia Canaria de Investigación, Innovación y Sociedad de la Información, Spain, UK National Institute for Health Research, and the British Lung Foundation. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis: an international case–cohort study

PubMed Central

Maher, Toby M.; Kolb, Martin; Poletti, Venerino; Nusser, Richard; Richeldi, Luca; Vancheri, Carlo; Wilsher, Margaret L.; Antoniou, Katerina M.; Behr, Jüergen; Bendstrup, Elisabeth; Brown, Kevin; Calandriello, Lucio; Corte, Tamera J.; Crestani, Bruno; Flaherty, Kevin; Glaspole, Ian; Grutters, Jan; Inoue, Yoshikazu; Kokosi, Maria; Kondoh, Yasuhiro; Kouranos, Vasileios; Kreuter, Michael; Johannson, Kerri; Judge, Eoin; Ley, Brett; Margaritopoulos, George; Martinez, Fernando J.; Molina-Molina, Maria; Morais, António; Nunes, Hilario; Raghu, Ganesh; Ryerson, Christopher J.; Selman, Moises; Spagnolo, Paolo; Taniguchi, Hiroyuki; Tomassetti, Sara; Valeyre, Dominique; Wijsenbeek, Marlies; Wuyts, Wim; Hansell, David; Wells, Athol

2017-01-01

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts. A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (κw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the C-index. A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (κw=0.65, IQR 0.53–0.72, p<0.0001) than academic physicians (κw=0.56, IQR 0.45–0.65, p<0.0001) or physicians with access to multidisciplinary team (MDT) meetings (κw=0.54, IQR 0.45–0.64, p<0.0001). The prognostic accuracy of academic physicians with >20 years of experience (C-index=0.72, IQR 0.0–0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70–0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72–0.75). Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts. PMID:28860269

Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis.

PubMed

DePianto, Daryle J; Chandriani, Sanjay; Abbas, Alexander R; Jia, Guiquan; N'Diaye, Elsa N; Caplazi, Patrick; Kauder, Steven E; Biswas, Sabyasachi; Karnik, Satyajit K; Ha, Connie; Modrusan, Zora; Matthay, Michael A; Kukreja, Jasleen; Collard, Harold R; Egen, Jackson G; Wolters, Paul J; Arron, Joseph R

2015-01-01

There is microscopic spatial and temporal heterogeneity of pathological changes in idiopathic pulmonary fibrosis (IPF) lung tissue, which may relate to heterogeneity in pathophysiological mediators of disease and clinical progression. We assessed relationships between gene expression patterns, pathological features, and systemic biomarkers to identify biomarkers that reflect the aggregate disease burden in patients with IPF. Gene expression microarrays (N=40 IPF; 8 controls) and immunohistochemical analyses (N=22 IPF; 8 controls) of lung biopsies. Clinical characterisation and blood biomarker levels of MMP3 and CXCL13 in a separate cohort of patients with IPF (N=80). 2940 genes were significantly differentially expressed between IPF and control samples (|fold change| >1.5, p<0.05). Two clusters of co-regulated genes related to bronchiolar epithelium or lymphoid aggregates exhibited substantial heterogeneity within the IPF population. Gene expression in bronchiolar and lymphoid clusters corresponded to the extent of bronchiolisation and lymphoid aggregates determined by immunohistochemistry in adjacent tissue sections. Elevated serum levels of MMP3, encoded in the bronchiolar cluster, and CXCL13, encoded in the lymphoid cluster, corresponded to disease severity and shortened survival time (p<10(-7) for MMP3 and p<10(-5) for CXCL13; Cox proportional hazards model). Microscopic pathological heterogeneity in IPF lung tissue corresponds to specific gene expression patterns related to bronchiolisation and lymphoid aggregates. MMP3 and CXCL13 are systemic biomarkers that reflect the aggregate burden of these pathological features across total lung tissue. These biomarkers may have clinical utility as prognostic and/or surrogate biomarkers of disease activity in interventional studies in IPF. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension.

PubMed

Chen, Ning-Yuan; D Collum, Scott; Luo, Fayong; Weng, Tingting; Le, Thuy-Trahn; M Hernandez, Adriana; Philip, Kemly; Molina, Jose G; Garcia-Morales, Luis J; Cao, Yanna; Ko, Tien C; Amione-Guerra, Javier; Al-Jabbari, Odeaa; Bunge, Raquel R; Youker, Keith; Bruckner, Brian A; Hamid, Rizwan; Davies, Jonathan; Sinha, Neeraj; Karmouty-Quintana, Harry

2016-08-01

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. The development of pulmonary hypertension (PH) is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced BMPR2 expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3, demonstrating reduced BMPR2 signaling and elevated TGF-β activity in IPF. In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 expression compared with control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2. We also demonstrate that isolated bone marrow-derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with immunohistochemistry showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of BMPR2 mediated by a collection of miRs induced by IL6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF. Copyright © 2016 the American Physiological Society.

Evaluation of a respiratory symptom diary for clinical studies of idiopathic pulmonary fibrosis.

PubMed

Bacci, Elizabeth Dansie; O'Quinn, Sean; Leidy, Nancy Kline; Murray, Lindsey; Vernon, Margaret

2018-01-01

There are no validated patient diaries for evaluating respiratory symptoms in idiopathic pulmonary fibrosis (IPF). To evaluate the performance properties of the chronic obstructive pulmonary disease (COPD) Evaluating Respiratory Symptoms™ (E-RS™: COPD) measure in patients with IPF. Concept elicitation and cognitive interviews were conducted with IPF patients to evaluate content validity, including comprehensiveness, relevance, and interpretability of E-RS™ items in this patient population. Secondary analyses of IPF clinical study data were performed to evaluate the scoring structure of the tool. With modifications, reliability, validity, and responsiveness of the instrument (E-RS™: IPF) were evaluated. Qualitative interviews (n = 30) were conducted. During the elicitation interviews (n = 20), concept saturation for IPF respiratory symptoms was achieved; all respiratory symptoms covered by the E-RS™ were endorsed by ≥ 30% of the sample. During cognitive interviews (n = 10), all participants found the items interpretable and relevant. Factor analyses conducted via secondary analysis of IPF clinical study data identified no total score and four symptom scales: Chest, Breathlessness, Cough, and Sputum. Reliability of each scale was high (internal consistency [α] >0.85); 2-day reproducibility (ICC >0.88). Validity was supported through significant (P < 0.0001) relationships with the St. George's Respiratory Questionnaire (SGRQ), the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ), and other variables. The scales were responsive to change when evaluated using SGRQ Symptoms, UCSD-SOBQ, and Patient Global Impression of Change as anchors (P < 0.01 to P < 0.0001). The E-RS™: IPF is a valid, reliable, and responsive tool for evaluating respiratory symptoms in patients with IPF. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

PubMed Central

Mora, Ana L.; Rojas, Mauricio

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a chronic age-related lung disease with high mortality that is characterized by abnormal scarring of the lung parenchyma. There has been a recent attempt to define the age-associated changes predisposing individuals to develop IPF. Age-related perturbations that are increasingly found in epithelial cells and fibroblasts from IPF lungs compared with age-matched cells from normal lungs include defective autophagy, telomere attrition, altered proteostasis, and cell senescence. These divergent processes seem to converge in mitochondrial dysfunction and metabolic distress, which potentiate maladaptation to stress and susceptibility to age-related diseases such as IPF. Therapeutic approaches that target aging processes may be beneficial for halting the progression of disease and improving quality of life in IPF patients. PMID:28145905

Pathogenesis of Idiopathic Pulmonary Fibrosis

PubMed Central

Wolters, Paul J.; Collard, Harold R.; Jones, Kirk D.

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated. PMID:24050627

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

PubMed Central

Mora, Ana L.; Rojas, Mauricio; Pardo, Annie; Selman, Moises

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches. PMID:29081515

iTRAQ-Based Proteomics Reveals Novel Biomarkers for Idiopathic Pulmonary Fibrosis

PubMed Central

Niu, Rui; Liu, Ying; Zhang, Ying; Zhang, Yuan; Wang, Hui; Wang, Yongbin; Wang, Wei; Li, Xiaohui

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a gradual lung disease with a survival of less than 5 years post-diagnosis for most patients. Poor molecular description of IPF has led to unsatisfactory interpretation of the pathogenesis of this disease, resulting in the lack of successful treatments. The objective of this study was to discover novel noninvasive biomarkers for the diagnosis of IPF. We employed a coupled isobaric tag for relative and absolute quantitation (iTRAQ)-liquid chromatography–tandem mass spectrometry (LC–MS/MS) approach to examine protein expression in patients with IPF. A total of 97 differentially expressed proteins (38 upregulated proteins and 59 downregulated proteins) were identified in the serum of IPF patients. Using String software, a regulatory network containing 87 nodes and 244 edges was built, and the functional enrichment showed that differentially expressed proteins were predominantly involved in protein activation cascade, regulation of response to wounding and extracellular components. A set of three most significantly upregulated proteins (HBB, CRP and SERPINA1) and four most significantly downregulated proteins (APOA2, AHSG, KNG1 and AMBP) were selected for validation in an independent cohort of IPF and other lung diseases using ELISA test. The results confirmed the iTRAQ profiling results and AHSG, AMBP, CRP and KNG1 were found as specific IPF biomarkers. ROC analysis indicated the diagnosis potential of the validated biomarkers. The findings of this study will contribute in understanding the pathogenesis of IPF and facilitate the development of therapeutic targets. PMID:28122020

Clinical Impact of Emphysema Evaluated by High-Resolution Computed Tomography on Idiopathic Pulmonary Fibrosis Diagnosed by Surgical Lung Biopsy.

PubMed

Kohashi, Yasuo; Arai, Toru; Sugimoto, Chikatoshi; Tachibana, Kazunobu; Akira, Masanori; Kitaichi, Masanori; Hayashi, Seiji; Inoue, Yoshikazu

2016-01-01

The prognosis of combined cases of pulmonary fibrosis and emphysema is unresolved partially because radiological differentiation between usual interstitial pneumonia and nonspecific interstitial pneumonia is difficult in coexisting emphysema cases. The purpose of this study was to clarify the clinical impact of emphysema on the survival of patients with idiopathic pulmonary fibrosis (IPF). One hundred and seven patients with interstitial lung diseases were diagnosed by surgical lung biopsies between 2006 and 2012, and 47 patients were diagnosed with IPF through multidisciplinary discussion. Emphysema on high-resolution computed tomography scans was evaluated semiquantitatively by visual scoring. Eight out of the 47 IPF patients showed a higher emphysema score (>3) and were diagnosed to have IPF-emphysema. The median survival time of patients with IPF-emphysema (1,734 days) from the initial diagnosis was significantly shorter than that of patients with IPF alone (2,229 days) by Kaplan-Meier analysis (p = 0.007, log-rank test). Univariate Cox proportional hazard regression analyses revealed that a higher total emphysema score (>3.0) was a significantly poor prognostic factor in addition to Krebs von den Lungen-6, surfactant protein-D, arterial oxygen tension, percent forced vital capacity, and percent diffusing capacity of carbon monoxide (%DLCO). Multivariate Cox proportional hazard regression analyses with the stepwise method showed that higher total emphysema score (>3) and %DLCO were significantly poor prognostic factors. The prognosis of IPF-emphysema was significantly worse than that of IPF alone. © 2016 S. Karger AG, Basel.

iTRAQ-Based Proteomics Reveals Novel Biomarkers for Idiopathic Pulmonary Fibrosis.

PubMed

Niu, Rui; Liu, Ying; Zhang, Ying; Zhang, Yuan; Wang, Hui; Wang, Yongbin; Wang, Wei; Li, Xiaohui

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a gradual lung disease with a survival of less than 5 years post-diagnosis for most patients. Poor molecular description of IPF has led to unsatisfactory interpretation of the pathogenesis of this disease, resulting in the lack of successful treatments. The objective of this study was to discover novel noninvasive biomarkers for the diagnosis of IPF. We employed a coupled isobaric tag for relative and absolute quantitation (iTRAQ)-liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach to examine protein expression in patients with IPF. A total of 97 differentially expressed proteins (38 upregulated proteins and 59 downregulated proteins) were identified in the serum of IPF patients. Using String software, a regulatory network containing 87 nodes and 244 edges was built, and the functional enrichment showed that differentially expressed proteins were predominantly involved in protein activation cascade, regulation of response to wounding and extracellular components. A set of three most significantly upregulated proteins (HBB, CRP and SERPINA1) and four most significantly downregulated proteins (APOA2, AHSG, KNG1 and AMBP) were selected for validation in an independent cohort of IPF and other lung diseases using ELISA test. The results confirmed the iTRAQ profiling results and AHSG, AMBP, CRP and KNG1 were found as specific IPF biomarkers. ROC analysis indicated the diagnosis potential of the validated biomarkers. The findings of this study will contribute in understanding the pathogenesis of IPF and facilitate the development of therapeutic targets.

Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts.

PubMed

Newman, Donna R; Sills, W Shane; Hanrahan, Katherine; Ziegler, Amanda; Tidd, Kathleen McGinnis; Cook, Elizabeth; Sannes, Philip L

2016-02-01

The wingless (Wnt) family of signaling ligands contributes significantly to lung development and is highly expressed in patients with usual interstitial pneumonia (UIP). We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF) and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or UIP were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with TGF-β1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without TGF-β1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and TGF-β1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF. © 2016 The Histochemical Society.

Epidemiology of Idiopathic Pulmonary Fibrosis in Northern Italy.

PubMed

Harari, Sergio; Madotto, Fabiana; Caminati, Antonella; Conti, Sara; Cesana, Giancarlo

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of idiopathic interstitial pneumonia. Despite its clinical relevance, few studies have examined the epidemiology of IPF and temporal variation in disease incidence and prevalence. Aim of the study was to investigate the prevalence, incidence and trends of IPF in Lombardy, a region with nearly 10 million inhabitants, during 2005-2010. For the identification of IPF patients, we used healthcare administrative databases of Lombardy Healthcare System and adopted three algorithms: generic, broad and narrow case definition (GCD, BCD, NCD). IPF cases were identified according to diagnoses reported in inpatient and outpatient claims occurred during 2000-2010. We estimated age- and sex-adjusted annual prevalence and incidence rates from 2005 to 2010, thus allowing for a 5-year washout period. The mean annual incidence rate was estimated at 2.3 and 5.3 per 100,000 person-years using NCD and GCD, respectively. IPF incidence was higher among males, and increased with age. Trend remained stable over the years. The estimated annual prevalence rate was 35.5, 22.4, and 12.6 per 100,000 person-years using GCD, BCD and NCD, respectively, and increased with age. Moreover, we observed a positive trend over the years. Using BCD and NCD, prevalence was higher among males. The results of this study, which is one of the largest population-based survey ever conducted according to strict criteria, indicated that prevalence of IPF increased across the years while incidence remained stable, thus suggesting that survival with IPF has improved.

Detection of Alveolar Fibrocytes in Idiopathic Pulmonary Fibrosis and Systemic Sclerosis

PubMed Central

Phin, Sophie; Debray, Marie-Pierre; Marchal-Somme, Joelle; Tiev, Kiet; Bonay, Marcel; Fabre, Aurélie; Soler, Paul; Dehoux, Monique; Crestani, Bruno

2013-01-01

Background Fibrocytes are circulating precursors for fibroblasts. Blood fibrocytes are increased in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to determine whether alveolar fibrocytes are detected in broncho-alveolar lavage (BAL), to identify their prognostic value, and their potential association with culture of fibroblasts from BAL. Methods We quantified fibrocytes in BAL from 26 patients with IPF, 9 patients with Systemic Sclerosis(SSc)-interstitial lung disease (ILD), and 11 controls. BAL cells were cultured to isolate alveolar fibroblasts. Results Fibrocytes were detected in BAL in 14/26 IPF (54%) and 5/9 SSc patients (55%), and never in controls. Fibrocytes were in median 2.5% [0.4–19.7] and 3.0% [2.7–3.7] of BAL cells in IPF and SSc-ILD patients respectively. In IPF patients, the number of alveolar fibrocytes was correlated with the number of alveolar macrophages and was associated with a less severe disease but not with a better outcome. Fibroblasts were cultured from BAL in 12/26 IPF (46%), 5/9 SSc-ILD (65%) and never in controls. The detection of BAL fibrocytes did not predict a positive culture of fibroblasts. Conclusion Fibrocytes were detected in BAL fluid in about half of the patients with IPF and SSc-ILD. Their number was associated with less severe disease in IPF patients and did not associate with the capacity to grow fibroblasts from BAL fluid. PMID:23341987

Lung Fibroblasts, Aging, and Idiopathic Pulmonary Fibrosis.

PubMed

Pardo, Annie; Selman, Moisés

2016-12-01

Idiopathic pulmonary fibrosis (IPF) is an aging-associated, progressive, and irreversible lung disease of unknown etiology, elusive pathogenesis, and very limited therapeutic options. The hallmarks of IPF are aberrant activation of alveolar epithelial cells and accumulation of fibroblasts and myofibroblasts along with excessive production of extracellular matrix. The linkage of aging with this disorder is uncertain, but a number of changes associated with aging, including telomere attrition, cell senescence, and mitochondrial dysfunction, have been revealed in IPF lungs. Also, aging seems to confer a profibrotic phenotype upon fibroblasts and to increase the severity of the fibrogenic response in non-IPF fibrotic lung disorders. Better knowledge of the pathophysiological mechanisms linking aging to IPF will advance understanding of its pathogenesis and may provide new therapeutic windows to treatment of this devastating disease.

Severity of cough in idiopathic pulmonary fibrosis is associated with MUC5 B genotype

PubMed Central

2014-01-01

Background A polymorphism (rs35705950) in the promoter region of the mucin MUC5B is associated with both familial and sporadic forms of idiopathic pulmonary fibrosis. (IPF) We hypothesize that this common MUC5B variant will impact the expression of cough, a frequent disabling symptom seen in subjects with IPF. Methods We genotyped 136 subjects with IPF. All living subjects were provided with a Leicester Cough Questionnaire (LCQ) to measure cough severity. We assessed allele effects of the MUC5B polymorphism on the LCQ scores using SAS General Linear Models (GLM) in the patients with IPF. Results In the 68 of the total 136 IPF patients who returned the LCQ, MUC5B minor allele frequency (T) is consistent with prior published studies (31%). We found a significant independent effect of the T allele on the LCQ score (p = 0.002 for subjects with IPF). This effect is independent of other common causes of cough, including gastroesophogeal reflux disease and upper airway cough syndrome. Conclusions Cough severity, a common disabling phenotypic component of IPF, is significantly associated with the presence of the minor allele of a MUC5B promoter polymorphism. This study highlights a possible genetic mechanism for phenotypic heterogeneity in pulmonary fibrosis. PMID:24667072

Surgical Outcomes of Lung Cancer Patients with Combined Pulmonary Fibrosis and Emphysema and Those with Idiopathic Pulmonary Fibrosis without Emphysema.

PubMed

Sato, Seijiro; Koike, Terumoto; Hashimoto, Takehisa; Ishikawa, Hiroyuki; Okada, Akira; Watanabe, Takehiro; Tsuchida, Masanori

2016-08-23

Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder. The aim of this study was to compare the surgical outcomes of lung cancer patients with CPFE and those with idiopathic pulmonary fibrosis (IPF) without emphysema. A total of 1548 patients who underwent surgery for primary lung cancer between January 2001 and December 2012 were retrospectively reviewed. Of the 1548 patients, 55 (3.6%) had CPFE on computed tomography (CT), and 45 (2.9%) had IPF without emphysema. The overall and disease-free 5-year survival rates for patients with CPFE were not significantly worse than those for patients with IPF without emphysema (24.9% vs. 36.8%, p = 0.814; 39.8% vs. 39.3%, p = 0.653, respectively). Overall, 21 (38.1%) patients with CPFE and nine patients (20.0%) with IPF without emphysema developed postoperative cardiopulmonary complications. Patients with CPFE had significantly more postoperative cardiopulmonary complications involving pulmonary air leakage for >6 days, hypoxemia, and arrhythmia than patients with IPF without emphysema (p = 0.048). There was no significant difference in survival after surgical treatment between CPFE patients and IPF patients without emphysema, but CPFE patients had significantly higher morbidity than IPF patients without emphysema.

Quantitative analysis of lung elastic fibers in idiopathic pleuroparenchymal fibroelastosis (IPPFE): comparison of clinical, radiological, and pathological findings with those of idiopathic pulmonary fibrosis (IPF).

PubMed

Enomoto, Noriyuki; Kusagaya, Hideki; Oyama, Yoshiyuki; Kono, Masato; Kaida, Yusuke; Kuroishi, Shigeki; Hashimoto, Dai; Fujisawa, Tomoyuki; Yokomura, Koshi; Inui, Naoki; Nakamura, Yutaro; Suda, Takafumi

2014-05-28

The pathological appearance of idiopathic pleuroparenchymal fibroelastosis (IPPFE) with hematoxylin-eosin staining is similar to that of usual interstitial pneumonia (UIP) in patients with idiopathic pulmonary fibrosis (IPF). The amount of elastic fibers (EF) and detailed differences between IPPFE and IPF have not been fully elucidated. The aim of this study was to quantify the EF and identify the differences between IPPFE and IPF. We evaluated six patients with IPPFE and 28 patients with IPF who underwent surgical lung biopsy or autopsy. The patients' clinical history, physical findings, chest high-resolution computed tomography (HRCT) findings, and pathological features of lung specimens were retrospectively evaluated. The amounts of EF in lung specimens were quantified with Weigert's staining using a camera with a charge-coupled device and analytic software in both groups. Fewer patients with IPPFE than IPF had fine crackles (50.0% vs. 96.4%, p = 0.012). Patients with IPPFE had a lower forced vital capacity (62.7 ± 10.9% vs. 88.6 ± 21.9% predicted, p = 0.009), higher consolidation scores on HRCT (1.7 ± 0.8 vs. 0.3 ± 0.5, p < 0.0001), lower body mass indices (17.9 ± 0.9 vs. 24.3 ± 2.8, p < 0.0001), and more pneumothoraces than did patients with IPF (66.7 vs. 3.6%, p = 0.002). Lung specimens from patients with IPPFE had more than twice the amount of EF than did those from patients with IPF (28.5 ± 3.3% vs. 12.1 ± 4.4%, p < 0.0001). The amount of EF in the lower lobes was significantly lower than that in the upper lobes, even in the same patient with IPPFE (23.6 ± 2.4% vs. 32.4 ± 5.5%, p = 0.048). However, the amount of EF in the lower lobes of patients with IPPFE was still higher than that of patients with IPF (23.6 ± 2.4% vs. 12.2 ± 4.4%, p < 0.0001). More than twice the amount of EF was found in patients with IPPFE than in those with IPF. Even in the lower lobes, the amount of EF was higher in patients with IPPFE than in those with IPF, although the distribution of lung EF was heterogeneous in IPPFE specimens.

Evaluation of recently validated non-invasive formula using basic lung functions as new screening tool for pulmonary hypertension in idiopathic pulmonary fibrosis patients

PubMed Central

Ghanem, Maha K.; Makhlouf, Hoda A.; Agmy, Gamal R.; Imam, Hisham M. K.; Fouad, Doaa A.

2009-01-01

BACKGROUND: A prediction formula for mean pulmonary artery pressure (MPAP) using standard lung function measurement has been recently validated to screen for pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) patients. OBJECTIVE: To test the usefulness of this formula as a new non invasive screening tool for PH in IPF patients. Also, to study its correlation with patients' clinical data, pulmonary function tests, arterial blood gases (ABGs) and other commonly used screening methods for PH including electrocardiogram (ECG), chest X ray (CXR), trans-thoracic echocardiography (TTE) and computerized tomography pulmonary angiography (CTPA). MATERIALS AND METHODS: Cross-sectional study of 37 IPF patients from tertiary hospital. The accuracy of MPAP estimation was assessed by examining the correlation between the predicted MPAP using the formula and PH diagnosed by other screening tools and patients' clinical signs of PH. RESULTS: There was no statistically significant difference in the prediction of PH using cut off point of 21 or 25 mm Hg (P = 0.24). The formula-predicted MPAP greater than 25 mm Hg strongly correlated in the expected direction with O2 saturation (r = −0.95, P < 0.000), partial arterial O2 tension (r = −0.71, P < 0.000), right ventricular systolic pressure measured by TTE (r = 0.6, P < 0.000) and hilar width on CXR (r = 0.31, P = 0.03). Chest symptoms, ECG and CTPA signs of PH poorly correlated with the same formula (P > 0.05). CONCLUSIONS: The prediction formula for MPAP using standard lung function measurements is a simple non invasive tool that can be used as TTE to screen for PH in IPF patients and select those who need right heart catheterization. PMID:19881164

Identification of the lipid biomarkers from plasma in idiopathic pulmonary fibrosis by Lipidomics.

PubMed

Yan, Feng; Wen, Zhensong; Wang, Rui; Luo, Wenling; Du, Yufeng; Wang, Wenjun; Chen, Xianyang

2017-12-06

Idiopathic pulmonary fibrosis (IPF) is an irreversible interstitial pulmonary disease featured by high mortality, chronic and progressive course, and poor prognosis with unclear etiology. Currently, more studies have been focusing on identifying biomarkers to predict the progression of IPF, such as genes, proteins, and lipids. Lipids comprise diverse classes of molecules and play a critical role in cellular energy storage, structure, and signaling. The role of lipids in respiratory diseases, including cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD) has been investigated intensely in the recent years. The human serum lipid profiles in IPF patients however, have not been thoroughly understood and it will be very helpful if there are available molecular biomarkers, which can be used to monitor the disease progression or provide prognostic information for IPF disease. In this study, we performed the ultraperformance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-QTOF/MS) to detect the lipid variation and identify biomarker in plasma of IPF patients. The plasma were from 22 IPF patients before received treatment and 18 controls. A total of 507 individual blood lipid species were determined with lipidomics from the 40 plasma samples including 20 types of fatty acid, 159 types of glycerolipids, 221 types of glycerophospholipids, 47 types of sphingolipids, 46 types of sterol lipids, 7 types of prenol lipids, 3 types of saccharolipids, and 4 types of polyketides. By comparing the variations in the lipid metabolite levels in IPF patients, a total of 62 unique lipids were identified by statistical analysis including 24 kinds of glycerophoslipids, 30 kinds of glycerolipids, 3 kinds of sterol lipids, 4 kinds of sphingolipids and 1 kind of fatty acids. Finally, 6 out of 62 discriminating lipids were selected as the potential biomarkers, which are able to differentiate between IPF disease and controls with ROC analysis. Our results provided vital information regarding lipid metabolism in IPF patients and more importantly, a few potentially promising biomarkers were firstly identified which may have a predictive role in monitoring and diagnosing IPF disease.

Qualitative European survey of patients with idiopathic pulmonary fibrosis: patients' perspectives of the disease and treatment.

PubMed

Russell, Anne-Marie; Ripamonti, Elena; Vancheri, Carlo

2016-01-14

'Living with IPF and an exploration of Esbriet® - a new treatment' was an exploratory, qualitative, real-world survey of European patients with idiopathic pulmonary fibrosis (IPF) who were receiving treatment with pirfenidone prior to its commercial availability. The aim of the survey was to probe the impact of IPF on patients' quality of life; the role of healthcare professionals and caregivers; the information needs of both patients and their caregivers; and patients' perceptions of pirfenidone as a new treatment option for IPF. Patients from the UK, Germany and Italy, with a diagnosis of IPF (duration >3 months), who were being treated with pirfenidone, were recruited from patient support groups, specialist centres and advocacy groups. Semi-structured, qualitative, in-depth patient interviews of 1-h duration were conducted by an independent researcher. Patients were initially asked about their experiences of living with IPF and then prompted to describe their experiences of taking pirfenidone. Techniques utilised included: the bubble-speech technique; the icon cards projective exercise; and the free association exercise. All interviews were transcribed and analysed by an independent researcher. Forty-five patients (71% male) were interviewed (mean age 68.5 years; mean time since diagnosis 3.5 years); 87% of patients reported that diagnosis took >1 year. Patients reported that IPF had a significant physical and emotional impact on their quality of life. The beneficial role played by caregivers and interstitial lung disease specialist nurses (where available) was specifically highlighted. Although most patients were keen for information on IPF, this was often of poor quality, out of date, or in English only. Patients' perceptions of pirfenidone were largely positive and associated with 'hope' but were also influenced by the level of side effects experienced. This survey highlights the impact of IPF on patients' lives, and the need to adequately support both patients and their caregivers. These findings demonstrate the value of seeking patients' perspectives of a chronic disease such as IPF and how this information can be used to guide improvements in care, to best support the needs of patients with this devastating condition.

Mechanical induction of cough in Idiopathic Pulmonary Fibrosis

PubMed Central

2011-01-01

Background Patients with idiopathic pulmonary fibrosis (IPF) frequently develop a dry, irritating cough which often proves refractory to anti-tussive therapies. The precise pathogenetic mechanisms responsible for this cough are unknown. We hypothesised that changes in nerves modulating mechanical sensitivity in areas of interstitial fibrosis might lead to enhanced cough response to mechanical stimulation of the chest in IPF. Methods We studied 27 non-smoking subjects with IPF (63% male), mean (SD) age 71.7 (7) years and 30 healthy non-smokers. Quality of life (Leicester Cough Questionnaire), cough symptom scores and cough severity scores (visual analog scales) were recorded. Percussion stimulation was applied over the posterior lung base, upper anterior chest and manubrium sternum at sequential frequencies (20 Hertz (Hz), 40 Hz and 60 Hz) for up to 60 seconds and repeated twice at two minute intervals. The number of subjects achieving two and five-cough responses, total cough counts and cough latency were recorded. In separate experiments, the effect of mechanical stimulation on the pattern of breathing was determined in eight IPF subjects and five control subjects. Results In patients with IPF, we demonstrated strong correlations between subjective cough measurements, particularly the cough symptom score and Leicester Cough Questionnaire (r = -0.86; p < 0.001). Mechanical percussion induced a true cough reflex in 23/27 (85%) IPF subjects, but only 5/30 (17%) controls (p < 0.001). More patients with IPF reached the two-cough response at a lower frequency (20 Hz) posteriorly than at other positions. Highest mean cough totals were seen with stimulation at or above 40 Hz. Mechanical stimulation had no effect on respiratory rate but increased tidal volume in four (50%) subjects with IPF, particularly at higher frequencies. It was associated with increased urge to cough followed by a true cough reflex. Conclusions This study demonstrates that patients with IPF show enhanced cough reflex sensitivity to mechanical stimulation of the chest wall whilst normal individuals show little or no response. The observation that low frequency stimulation over the lung base, where fibrosis is most extensive, induces cough in more patients than at other sites supports the hypothesis that lung distortion contributes to the pathogenesis of cough in IPF. PMID:21477349

Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis

PubMed Central

Xia, Hong; Gilbertsen, Adam; Herrera, Jeremy; Racila, Emilian; Peterson, Mark; Griffin, Timothy; Benyumov, Alexey; Yang, Libang; Bitterman, Peter B.; Henke, Craig A.

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a prevalence of 1 million persons worldwide. The fibrosis spreads from affected alveoli into contiguous alveoli and leads to death by asphyxiation. We previously discovered that the IPF lung harbors fibrogenic mesenchymal progenitor cells (MPCs) that serve as a cell of origin for disease-mediating myofibroblasts. In a prior genomewide transcriptional analysis, we found that IPF MPCs displayed increased expression of S100 calcium-binding A4 (S100A4), a protein linked to cancer cell proliferation and invasiveness. Here, we have examined whether S100A4 mediates MPC fibrogenicity. Ex vivo analysis revealed that IPF MPCs had increased levels of nuclear S100A4, which interacts with L-isoaspartyl methyltransferase to promote p53 degradation and MPC self-renewal. In vivo, injection of human IPF MPCs converted a self-limited bleomycin-induced mouse model of lung fibrosis to a model of persistent fibrosis in an S100A4-dependent manner. S100A4 gain of function was sufficient to confer fibrotic properties to non-IPF MPCs. In IPF tissue, fibroblastic foci contained cells expressing Ki67 and the MPC markers SSEA4 and S100A4. The expression colocalized in an interface region between myofibroblasts in the focus core and normal alveolar structures, defining this region as an active fibrotic front. Our findings indicate that IPF MPCs are intrinsically fibrogenic and that S100A4 confers MPCs with fibrogenicity. PMID:28530639

Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis.

PubMed

Rogliani, Paola; Calzetta, Luigino; Cavalli, Francesco; Matera, Maria Gabriella; Cazzola, Mario

2016-10-01

The prevalence of idiopathic pulmonary fibrosis (IPF) is increasing every year. Pirfenidone and nintedanib were approved for treatment of IPF in 2014, but they received only a conditional recommendation for use and, thus, to date no drugs are strongly recommended for IPF. The aim of this study was to assess the effectiveness and safety of the currently approved drugs for IPF and N-acetylcysteine (NAC), the most debated drug in the last update of guidelines for IPF treatment. RCTs in IPF were identified searching from databases of published and unpublished studies. The influence of pirfenidone, nintedanib and NAC on clinical outcomes, safety, and mortality was assessed via pair-wise meta-analysis. Ten papers (3847 IPF patients; 2254 treated; 1593 placebo) were included in this study. Our results showed that both pirfenidone and nintedanib, but not NAC, were significantly effective in reducing FVC decline and the risk of FVC ≥10% decline in percent predicted over 12 months. Nintenadib significantly protected against the risk of acute exacerbation and mortality. Pirfenidone and nintedanib showed a similar and good safety profile, whereas NAC provided a signal for increased adverse events. The rank of effectiveness emerging from this meta-analysis represents an indirect indicator of potential differences between currently approved doses of pirfenidone and nintedanib. Direct comparisons are necessary to assess this matter, and well designed bench-to-bedside studies would permit to understand the potential of combined, sequential, or adjunctive treatment regimens in which perhaps NAC may have a role for specific clusters of IPF patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Protein kinase D is increased and activated in lung epithelial cells and macrophages in idiopathic pulmonary fibrosis.

PubMed

Gan, Huachen; McKenzie, Raymond; Hao, Qin; Idell, Steven; Tang, Hua

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and usually fatal lung disease of unknown etiology for which no effective treatments currently exist. Hence, there is a profound need for the identification of novel drugable targets to develop more specific and efficacious therapeutic intervention in IPF. In this study, we performed immunohistochemical analyses to assess the cell type-specific expression and activation of protein kinase D (PKD) family kinases in normal and IPF lung tissue sections. We also analyzed PKD activation and function in human lung epithelial cells. We found that PKD family kinases (PKD1, PKD2 and PKD3) were increased and activated in the hyperplastic and regenerative alveolar epithelial cells lining remodeled fibrotic alveolar septa and/or fibroblast foci in IPF lungs compared with normal controls. We also found that PKD family kinases were increased and activated in alveolar macrophages, bronchiolar epithelium, and honeycomb cysts in IPF lungs. Interestingly, PKD1 was highly expressed and activated in the cilia of IPF bronchiolar epithelial cells, while PKD2 and PKD3 were expressed in the cell cytoplasm and nuclei. In contrast, PKD family kinases were not apparently increased and activated in IPF fibroblasts or myofibroblasts. We lastly found that PKD was predominantly activated by poly-L-arginine, lysophosphatidic acid and thrombin in human lung epithelial cells and that PKD promoted epithelial barrier dysfunction. These findings suggest that PKD may participate in the pathogenesis of IPF and may be a novel target for therapeutic intervention in this disease.

Fatigue in sarcoidosis and idiopathic pulmonary fibrosis: differences in character and severity between diseases.

PubMed

Atkins, Christopher Peter; Gilbert, Daniel; Brockwell, Claire; Robinson, Sue; Wilson, Andrew Malcolm

2016-08-01

Sarcoidosis and idiopathic pulmonary fibrosis (IPF) are two common forms of interstitial lung disease. Fatigue is a recognised feature of sarcoidosis but an association between IPF and fatigue has not been investigated. To investigate the frequency and severity of fatigue in these groups, and variables affecting fatigue scores. A cross-sectional questionnaire study of patients with sarcoidosis and IPF followed-up at a single hospital was undertaken. Questionnaire data included validated measures of fatigue, anxiety, depression, sleepiness and dyspnoea, plus measures of disease severity including spirometry data. Questionnaires were administered to 232 patients (82 healthy volunteers, 73 sarcoidosis patients and 77 IPF patients). Sarcoidosis patients had statistically higher sleepiness scores but no significant difference was seen between overall measures of fatigue, anxiety or depression. Stratification by severity revealed a non-statistically significant tendency towards more severe fatigue scores in sarcoidosis. Regression analysis failed to identify any significant predictor variables measured in the sarcoidosis cohort, though in the IPF group both dyspnoea and sleepiness scores were significant predictors of fatigue (R2=0.74). Both sarcoidosis and IPF patients suffer with fatigue, although sarcoidosis patients tended towards reporting more severe fatigue scores, suggesting a subgroup with severe fatigue. The fatigue experienced by the two groups appears to be different; sarcoidosis patients report greater frequency of mental fatigue whereas IPF patients appear to suffer exhaustion, potentially related to dyspnoea. Dyspnoea and sleepiness scores modeled the majority of fatigue in the IPF group, whereas no single factor was able to predict fatigue in sarcoidosis.

Epidemiology of Idiopathic Pulmonary Fibrosis in Northern Italy

PubMed Central

Caminati, Antonella; Conti, Sara; Cesana, Giancarlo

2016-01-01

Background Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of idiopathic interstitial pneumonia. Despite its clinical relevance, few studies have examined the epidemiology of IPF and temporal variation in disease incidence and prevalence. Aim of the study was to investigate the prevalence, incidence and trends of IPF in Lombardy, a region with nearly 10 million inhabitants, during 2005–2010. Methods For the identification of IPF patients, we used healthcare administrative databases of Lombardy Healthcare System and adopted three algorithms: generic, broad and narrow case definition (GCD, BCD, NCD). IPF cases were identified according to diagnoses reported in inpatient and outpatient claims occurred during 2000–2010. We estimated age- and sex-adjusted annual prevalence and incidence rates from 2005 to 2010, thus allowing for a 5-year washout period. Results The mean annual incidence rate was estimated at 2.3 and 5.3 per 100,000 person-years using NCD and GCD, respectively. IPF incidence was higher among males, and increased with age. Trend remained stable over the years. The estimated annual prevalence rate was 35.5, 22.4, and 12.6 per 100,000 person-years using GCD, BCD and NCD, respectively, and increased with age. Moreover, we observed a positive trend over the years. Using BCD and NCD, prevalence was higher among males. Conclusions The results of this study, which is one of the largest population-based survey ever conducted according to strict criteria, indicated that prevalence of IPF increased across the years while incidence remained stable, thus suggesting that survival with IPF has improved. PMID:26841042

Involvement of Alveolar Epithelial Cell Necroptosis in IPF Pathogenesis.

PubMed

Lee, Ji-Min; Yoshida, Masahiro; Kim, Mi-So; Lee, June-Hyuk; Baek, Ae-Rin; Jang, An Soo; Kim, Do Jin; Minagawa, Shunsuke; Chin, Su Sie; Park, Choon-Sik; Araya, Jun; Kuwano, Kazuyoshi; Park, Sung Woo

2018-02-14

Alveolar epithelial cell (AEC) injury leading to cell death is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF). Among regulated/programmed cell death, the excessive apoptosis of AECs has been widely implicated in IPF pathogenesis. Necroptosis is a type of regulated/programmed necrosis. A multiprotein complex composed of receptor-interacting protein kinase-1 and -3 (RIPK1/3) plays a key regulatory role in initiating necroptosis. Although necroptosis participates in disease pathogeneses through the release of damage-associated molecular patterns (DAMPs), its association with IPF progression remains elusive. In this study, we attempted to illuminate the involvement of RIPK3-regulated necroptosis in IPF pathogenesis. IPF lung tissues were used to detect necroptosis, and the role of RIPK3 was determined using cell culturing models of AECs. Lung fibrosis models of bleomycin (BLM) treatment were also used. RIPK3 expression levels were increased in IPF lungs and both apoptosis and necroptosis were detected mainly in AECs. Necrostatin-1 and RIPK3 knockdown experiments in AECs revealed the participation of necroptosis in BLM and hydrogen peroxide-induced cell death. BLM treatment induced RIPK3 expression in AECs and increased High Mobility Group Box 1 (HMGB1) and interleukin 1β (IL-1β) levels in mouse lungs. The efficient attenuation of BLM-induced lung inflammation and fibrosis was determined in RIPK3 knockout mice and by necrostatin-1 with a concomitant reduction in HMGB1 and IL-1β. RIPK3-regulated necroptosis in AECs is involved in the mechanism of lung fibrosis development through the release of DAMPs as part of the pathogenic sequence of IPF.

Impact of Intimate Partner Forced Sex on HIV Risk Factors in Physically Abused African American and African Caribbean Women.

PubMed

Draughon, Jessica E; Lucea, Marguerite B; Campbell, Jacquelyn C; Paterno, Mary T; Bertrand, Desiree R; Sharps, Phyllis W; Campbell, Doris W; Stockman, Jamila K

2015-10-01

We examined associations between intimate partner forced sex (IPFS) and HIV sexual risk behaviors among physically abused Black women. Women aged 18-55 in intimate relationships were interviewed in health clinics in Baltimore, MD and St. Thomas and St. Croix, US Virgin Islands (USVI). Of 426 physically abused women, 38% experienced IPFS; (Baltimore = 44 and USVI = 116). USVI women experiencing IPFS were more likely to have 3+ past-year sex partners (AOR 2.06, 95% CI 1.03-4.14), casual sex partners (AOR 2.71, 95% CI 1.42-5.17), and concurrent sex partners (AOR 1.94, 95% CI 1.01-3.73) compared to their counterparts. Baltimore women reporting IPFS were more likely to have exchanged sex (AOR 3.57, 95% CI 1.19-10.75). Women experiencing IPFS were more likely to report their abuser having other sexual partners in Baltimore (AOR 3.30, 95% CI 1.22-8.88) and USVI (AOR 2.03, 95% CI 1.20-3.44). Clinicians should consider the influence of IPFS on individual and partnership HIV sexual risk behaviors.

Long-term effects of a 12-week exercise training program on clinical outcomes in idiopathic pulmonary fibrosis.

PubMed

Vainshelboim, Baruch; Oliveira, Jose; Fox, Benjamin Daniel; Soreck, Yafit; Fruchter, Oren; Kramer, Mordechai Reuven

2015-06-01

Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating, lung disease, with few therapeutic options. Data are limited with respect to the long-term effect of exercise training (ET) in IPF. This study sought to evaluate the long-term effects of a 12-week ET program on clinical outcomes in IPF patients. Thirty-four IPF patients were randomly allocated to ET or control groups. ET group participated in a 12-week supervised exercise program, while the control group continued with regular medical treatment alone. Exercise capacity, 30 s-chair-stand test for leg strength, dyspnea, and Saint George's Respiratory Questionnaire (SGRQ) for quality of life (QOL) were assessed at baseline and re-evaluated at 11 months from baseline. In addition, at 30-month time point from baseline, the impact of the 12-week intervention was analyzed with respect to survival and cardio-respiratory-related hospitalizations. Thirty-two patients completed the 12-week intervention and 28 patients (14 in each group) were re-evaluated. At 11-month follow-up, no significant differences between the groups and time effect were demonstrated for most outcomes. ET group showed preserved values at the baseline level while the control group showed a trend of deterioration. Only the 30 s-chair-stand test (mean difference 3 stands, p = 0.01) and SGRQ (mean difference -6 units, p = 0.037) were significantly different between the groups. At 30 months, the survival analysis showed three deaths, eight hospitalizations occurred in the control group versus one death, one lung transplantation and seven hospitalizations in the ET group, with no significant differences between groups. At 11-month follow-up, the 12-week ET program showed clinical outcomes were preserved at baseline levels with some maintenance of improvements in leg strength and QOL in the ET group. The control group showed a trend of deterioration in the outcomes. At 30 months, the 12-week ET program did not show benefits in prognosis although the study was underpowered to detect such differences. We suggest including ET as a long-term continued treatment and as a core component of pulmonary rehabilitation programs for IPF patients.

ENA-78 is an important angiogenic factor in idiopathic pulmonary fibrosis.

PubMed

Keane, M P; Belperio, J A; Burdick, M D; Lynch, J P; Fishbein, M C; Strieter, R M

2001-12-15

Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal disorder. Fibroplasia and deposition of extracellular matrix are dependent, in part, on angiogenesis and vascular remodeling. We obtained open lung biopsies from patients undergoing thoracic surgery for reasons other than interstitial lung disease (control) (n = 78) and from patients with IPF (n = 91). We found that levels of epithelial neutrophil-activating peptide 78 (ENA-78) were greater from tissue specimens of IPF patients, as compared with control subjects. When ENA-78 was depleted from IPF tissue specimens, tissue-derived angiogenic activity was markedly reduced. Immunolocalization of ENA-78 demonstrated that hyperplastic Type II pneumocytes and macrophages were the predominant cellular sources of ENA-78. These findings support the notion that ENA-78 may be an important additional factor that regulates angiogenic activity in IPF.

Molecular biomarkers in idiopathic pulmonary fibrosis

PubMed Central

Ley, Brett; Brown, Kevin K.

2014-01-01

Molecular biomarkers are highly desired in idiopathic pulmonary fibrosis (IPF), where they hold the potential to elucidate underlying disease mechanisms, accelerated drug development, and advance clinical management. Currently, there are no molecular biomarkers in widespread clinical use for IPF, and the search for potential markers remains in its infancy. Proposed core mechanisms in the pathogenesis of IPF for which candidate markers have been offered include alveolar epithelial cell dysfunction, immune dysregulation, and fibrogenesis. Useful markers reflect important pathological pathways, are practically and accurately measured, have undergone extensive validation, and are an improvement upon the current approach for their intended use. The successful development of useful molecular biomarkers is a central challenge for the future of translational research in IPF and will require collaborative efforts among those parties invested in advancing the care of patients with IPF. PMID:25260757

Molecular Phenotypes Distinguish Patients with Relatively Stable from Progressive Idiopathic Pulmonary Fibrosis (IPF)

PubMed Central

Boon, Kathy; Bailey, Nathaniel W.; Yang, Jun; Steel, Mark P.; Groshong, Steve; Kervitsky, Dolly; Brown, Kevin K.; Schwarz, Marvin I.; Schwartz, David A.

2009-01-01

Background Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic interstitial lung disease that is unresponsive to current therapy and often leads to death. However, the rate of disease progression differs among patients. We hypothesized that comparing the gene expression profiles between patients with stable disease and those in which the disease progressed rapidly will lead to biomarker discovery and contribute to the understanding of disease pathogenesis. Methodology and Principal Findings To begin to address this hypothesis, we applied Serial Analysis of Gene Expression (SAGE) to generate lung expression profiles from diagnostic surgical lung biopsies in 6 individuals with relatively stable (or slowly progressive) IPF and 6 individuals with progressive IPF (based on changes in DLCO and FVC over 12 months). Our results indicate that this comprehensive lung IPF SAGE transcriptome is distinct from normal lung tissue and other chronic lung diseases. To identify candidate markers of disease progression, we compared the IPF SAGE profiles in stable and progressive disease, and identified a set of 102 transcripts that were at least 5-fold up regulated and a set of 89 transcripts that were at least 5-fold down regulated in the progressive group (P-value≤0.05). The over expressed genes included surfactant protein A1, two members of the MAPK-EGR-1-HSP70 pathway that regulate cigarette-smoke induced inflammation, and Plunc (palate, lung and nasal epithelium associated), a gene not previously implicated in IPF. Interestingly, 26 of the up regulated genes are also increased in lung adenocarcinomas and have low or no expression in normal lung tissue. More importantly, we defined a SAGE molecular expression signature of 134 transcripts that sufficiently distinguished relatively stable from progressive IPF. Conclusions These findings indicate that molecular signatures from lung parenchyma at the time of diagnosis could prove helpful in predicting the likelihood of disease progression or possibly understanding the biological activity of IPF. PMID:19347046

Killing the mother of one's child: psychiatric risk factors among male perpetrators and offspring health consequences.

PubMed

Lysell, Henrik; Dahlin, Marie; Långström, Niklas; Lichtenstein, Paul; Runeson, Bo

2016-03-01

To study possible psychiatric and criminological risk factors of intimate partner femicide (IPF) as well as the bereaved offspring's psychiatric morbidity and premature death. We conducted a nested case-control study, based on Swedish national registries, including all perpetrators of IPF. We computed risk estimates relative to matched population controls, which were compared to those of non-IPF homicide offenders. Exposed children were matched to population controls and followed longitudinally up to 37 years. Offspring outcomes were psychiatric and substance use disorders (according to ICD) self-harm; violent crime; suicide; and premature, all-cause death. We identified 261 male IPF perpetrators and 494 bereaved children from 1973 through 2009. Multivariable logistic regression suggested that major mental disorder (adjusted odds ratio [OR] = 5.9; 95% CI, 3.3-10.6) and violent crime convictions (adjusted OR = 4.4; 95% CI, 2.7-7.2) were independent risk factors of IPF, but substance use disorders were not (aOR = 0.4; 95% CI, 0.2-1.0). Children exposed to IPF before age 18 years had elevated risks of major mental disorder (adjusted hazard ratio [HR] = 5.7; 95% Cl, 3.0-10.6), substance use disorders (adjusted HR = 5.8; 95% CI, 2.8-11.9) and self-harm (adjusted HR = 5.7; 95% CI, 3.0-11.1). Offspring 18 years or older at the IPF had an increased risk of completed suicide (adjusted HR = 4.3; 95% CI, 1.3-14.5). Previous major mental disorder and violent behavior were strong independent risk factors for IPF. Bereavement caused by IPF had significant associations with the offspring's future life, especially for those below 18 years of age at exposure. Our findings demonstrate the need of direct support to the exposed offspring by health care providers and social services. © Copyright 2016 Physicians Postgraduate Press, Inc.

Identification of a Cell-of-Origin for Fibroblasts Comprising the Fibrotic Reticulum in Idiopathic Pulmonary Fibrosis

PubMed Central

Xia, Hong; Bodempudi, Vidya; Benyumov, Alexey; Hergert, Polla; Tank, Damien; Herrera, Jeremy; Braziunas, Jeff; Larsson, Ola; Parker, Matthew; Rossi, Daniel; Smith, Karen; Peterson, Mark; Limper, Andrew; Jessurun, Jose; Connett, John; Ingbar, David; Phan, Sem; Bitterman, Peter B.; Henke, Craig A.

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the middle aged and elderly with a prevalence of one million persons worldwide. The fibrosis spreads from affected alveoli into contiguous alveoli, creating a reticular network that leads to death by asphyxiation. Lung fibroblasts from patients with IPF have phenotypic hallmarks, distinguishing them from their normal counterparts: pathologically activated Akt signaling axis, increased collagen and α-smooth muscle actin expression, distinct gene expression profile, and ability to form fibrotic lesions in model organisms. Despite the centrality of these fibroblasts in disease pathogenesis, their origin remains uncertain. Here, we report the identification of cells in the lungs of patients with IPF with the properties of mesenchymal progenitors. In contrast to progenitors isolated from nonfibrotic lungs, IPF mesenchymal progenitor cells produce daughter cells manifesting the full spectrum of IPF hallmarks, including the ability to form fibrotic lesions in zebrafish embryos and mouse lungs, and a transcriptional profile reflecting these properties. Morphological analysis of IPF lung tissue revealed that mesenchymal progenitor cells and cells with the characteristics of their progeny comprised the fibrotic reticulum. These data establish that the lungs of patients with IPF contain pathological mesenchymal progenitor cells that are cells of origin for fibrosis-mediating fibroblasts. These fibrogenic mesenchymal progenitors and their progeny represent an unexplored target for novel therapies to interdict fibrosis. PMID:24631025

IPF: new insight on pathogenesis and treatment.

PubMed

Harari, S; Caminati, A

2010-05-01

Recent years have seen a robust influx of exciting new observations regarding the mechanisms that regulate the initiation and progression of pulmonary fibrosis but the pathogenesis remains poorly understood. The search for an alternative hypothesis to unremitting, chronic inflammation as the primary explanation for the pathophysiology of idiopathic pulmonary fibrosis (IPF) derives, in part, from the lack of therapeutic efficacy of high-dose immunosuppressive therapy in patients with IPF. The inflammatory hypothesis of IPF has since been challenged by the epithelial injury hypothesis, in which fibrosis is believed to result from epithelial injury, activation, and/or apoptosis with abnormal wound healing. This hypothesis suggests that recurrent unknown injury to distal pulmonary parenchyma causes repeated epithelial injury and apoptosis. The resultant loss of alveolar epithelium exposes the underlying basement membrane to oxidative damage and degradation. Emerging concepts suggest that IPF is the result of epithelial-mesenchymal interaction. The initiation of this fibrotic response may depend upon genetic factors and environmental triggers; the role of Th1 or Th2 cell-derived cytokines may also be important. This process appears to be unique to usual interstitial pneumonia/IPF. It is clear that IPF is a heterogeneous disease with variations in pathology, high-resolution computed tomography findings, and patterns of progression. Idiopathic pulmonary fibrosis is a complex disorder, and no unifying hypothesis has been identified at present that explains all the abnormalities.

Assessing idiopathic pulmonary fibrosis (IPF) with bronchoscopic OCT (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hariri, Lida P.; Adams, David C.; Colby, Thomas V.; Tager, Andrew M.; Suter, Melissa J.

2016-03-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal form of fibrotic lung disease, with a 3 year survival rate of 50%. Diagnostic certainty of IPF is essential to determine the most effective therapy for patients, but often requires surgery to resect lung tissue and look for microscopic honeycombing not seen on chest computed tomography (CT). Unfortunately, surgical lung resection has high risks of associated morbidity and mortality in this patient population. We aim to determine whether bronchoscopic optical coherence tomography (OCT) can serve as a novel, low-risk paradigm for in vivo IPF diagnosis without surgery or tissue removal. OCT provides rapid 3D visualization of large tissue volumes with microscopic resolutions well beyond the capabilities of CT. We have designed bronchoscopic OCT catheters to effectively and safely access the peripheral lung, and conducted in vivo peripheral lung imaging in patients, including those with pulmonary fibrosis. We utilized these OCT catheters to perform bronchoscopic imaging in lung tissue from patients with pulmonary fibrosis to determine if bronchoscopic OCT could successfully visualize features of IPF through the peripheral airways. OCT was able to visualize characteristic features of IPF through the airway, including microscopic honeycombing (< 1 mm diameter) not visible by CT, dense peripheral fibrosis, and spatial disease heterogeneity. These findings support the potential of bronchoscopic OCT as a minimally-invasive method for in vivo IPF diagnosis. However, future clinical studies are needed to validate these findings.

Induction with Infliximab and a Plant-Based Diet as First-Line (IPF) Therapy for Crohn Disease: A Single-Group Trial

PubMed Central

Chiba, Mitsuro; Tsuji, Tsuyotoshi; Nakane, Kunio; Tsuda, Satoko; Ishii, Hajime; Ohno, Hideo; Watanabe, Kenta; Ito, Mai; Komatsu, Masafumi; Sugawara, Takeshi

2017-01-01

Background Approximately 30% of patients with Crohn disease (CD) are unresponsive to biologics. No previous study has focused on a plant-based diet in an induction phase of CD treatment. Objective To investigate the remission rate of infliximab combined with a plant-based diet as first-line (IPF) therapy for CD. Methods This was a prospective single-group trial conducted at tertiary hospitals. Subjects included consecutive adults with a new diagnosis (n = 26), children with a new diagnosis (n = 11), and relapsing adults (n = 9) with CD who were naïve to treatment with biologics. Patients were admitted and administered a standard induction therapy with infliximab (5 mg/kg; 3 infusions at 0, 2, and 6 weeks). Additionally, they received a lacto-ovo-semivegetarian diet. The primary end point was remission, defined as the disappearance of active CD symptoms at week 6. Secondary end points were Crohn Disease Activity Index (CDAI) score, C-reactive protein (CRP) concentration, and mucosal healing. Results Two adults with a new diagnosis were withdrawn from the treatment protocol because of intestinal obstruction. The remission rates by the intention-to-treat and per-protocol analyses were 96% (44/46) and 100% (44/44), respectively. Mean CDAI score (314) on admission decreased to 63 at week 6 (p < 0.0001). Mean CRP level on admission (5.3 mg/dL) decreased to 0.2 (p < 0.0001). Mucosal healing was achieved in 46% (19/41) of cases. Conclusion IPF therapy can induce remission in most patients with CD who are naïve to biologics regardless of age or whether they have a new diagnosis or relapse. PMID:29035182

Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis: role of transmembrane SCF and the PAR-2/PKC-α/Raf-1/p44/42 signaling pathway.

PubMed

Wygrecka, Malgorzata; Dahal, Bhola K; Kosanovic, Djuro; Petersen, Frank; Taborski, Brigitte; von Gerlach, Susanne; Didiasova, Miroslava; Zakrzewicz, Dariusz; Preissner, Klaus T; Schermuly, Ralph T; Markart, Philipp

2013-06-01

Mast cell (MC) accumulation has been demonstrated in the lungs of idiopathic pulmonary fibrosis (IPF) patients. Mediators released from MCs may regulate tissue remodeling processes, thereby contributing to IPF pathogenesis. We investigated the role of MC-fibroblast interaction in the progression of lung fibrosis. Increased numbers of activated MCs, in close proximity to fibroblast foci and alveolar type II cells, were observed in IPF lungs. Correspondingly elevated tryptase levels were detected in IPF lung tissue samples. Coculture of human lung MCs with human lung fibroblasts (HLFs) induced MC activation, as evinced by tryptase release, and stimulated HLF proliferation; IPF HLFs exhibited a significantly higher growth rate, compared with control. Tryptase stimulated HLF growth in a PAR-2/PKC-α/Raf-1/p44/42-dependent manner and potentiated extracellular matrix production, but independent of PKC-α, Raf-1, and p44/42 activities. Proproliferative properties of tryptase were attenuated by knockdown or pharmacological inhibition of PAR-2, PKC-α, Raf-1, or p44/42. Expression of transmembrane SCF, but not soluble SCF, was elevated in IPF lung tissue and in fibroblasts isolated from IPF lungs. Coculture of IPF HLFs with MCs enhanced MC survival and proliferation. These effects were cell-contact dependent and could be inhibited by application of anti-SCF antibody or CD117 inhibitor. Thus, fibroblasts and MCs appear to work in concert to perpetuate fibrotic processes and so contribute to lung fibrosis progression. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Effect of Single vs Bilateral Lung Transplantation on Plasma Surfactant Protein D Levels in Idiopathic Pulmonary Fibrosis

PubMed Central

Beers, Michael F.; Ahya, Vivek N.; Kawut, Steven M.; Sims, Karen D.; Lederer, David J.; Palmer, Scott M.; Wille, Keith; Lama, Vibha N.; Shah, Pali D.; Orens, Jonathan B.; Bhorade, Sangeeta; Crespo, Maria; Weinacker, Ann; Demissie, Ejigayehu; Bellamy, Scarlett; Christie, Jason D.; Ware, Lorraine B.

2011-01-01

Background: Serum levels of surfactant protein D (SP-D) have been suggested as reflecting epithelial damage in acute lung injury, COPD, and idiopathic pulmonary fibrosis (IPF). However, little is known about SP-D levels in the setting of lung transplantation. Methods: We examined plasma SP-D levels in 104 subjects from a prospective, multicenter cohort study of lung allograft recipients. Plasma SP-D was measured by enzyme-linked immunosorbent assay prior to transplant and daily for 3 days after transplant. Results: Subjects undergoing transplant for IPF had higher baseline SP-D levels (median, 325 ng/mL) compared with subjects with cystic fibrosis, COPD, and pulmonary hypertension (median, 100, 80, and 82 ng/mL, respectively; P = .0001). Among subjects with IPF undergoing bilateral transplant, SP-D levels declined rapidly postoperatively. In contrast, SP-D levels in subjects undergoing single lung transplant for IPF remained significantly higher than those of bilateral allograft recipients. Among subjects undergoing single lung transplant for IPF, the development of primary graft dysfunction (PGD) was associated with a subsequent rise in SP-D levels, whereas SP-D levels in IPF subjects undergoing bilateral transplant declined, even in the presence of grade 3 PGD. Importantly, single lung allograft recipients without PGD had higher postoperative SP-D levels than bilateral allograft recipients with PGD. Conclusions: Subjects undergoing lung transplant for IPF have significantly higher baseline plasma SP-D levels compared with those with other diagnoses. Plasma SP-D is likely a biomarker of the air-blood barrier integrity in the native IPF lung, but may be less useful as a biomarker of PGD after transplant. PMID:21349925

Pirfenidone for Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis

PubMed Central

Venegas, Carmen; Arenas, Alex; Rada, Gabriel

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. In the last decades pirfenidone an anti-inflammatory and anti-fibrotic agent has shown benefit in inhibit collagen production and has also demonstrated benefit in decline progression in IPF in physiological outcomes as Forced vital capacity (FVC), in clinical outcomes such as progression free survival (PFS) and a benefit in mortality but no in clinically relevant outcomes as exacerbations or worsening of IPF. Methods: We conducted a systematic review to evaluate the effectiveness of physiological and clinical outcomes of pirfenidone compared to placebo in IPF. We performed a search with no language restriction. Two researchers performed literature search, quality assessment, data extraction and analysis. And was performed a summary of findings table following the GRADE approach. Results: We included 5 RCTs (Randomized controlled trials) in analysis. The meta-analysis resulted in a decrease in all cause-mortality (RR 0.52 IC 0.32–0.88) and IPF related mortality (RR 0.32 IC 0.14–0.75); other outcomes evaluated were worsening of IPF (RR 0.64 IC 0.50–0.83) and acute exacerbation (RR: 0.72 IC 0.30–1.66 respectively). Also there was a decrease in progression free survival (PFS) (RR 0.83 IC 0.74–0.92) compared to placebo. Conclusions: We observed significant differences in physiologic and clinically relevant outcomes such as reduction in all-cause mortality, IPF related mortality, worsening and exacerbation of IPF and PFS. So pirfenidone treatment should be considered not only for its benefits in pulmonary function tests but also by its clinically relevant outcomes. PMID:26308723

Validation of the facial assessment by computer evaluation (FACE) program for software-aided eyelid measurements.

PubMed

Choi, Catherine J; Lefebvre, Daniel R; Yoon, Michael K

2016-06-01

The aim of this article is to validate the accuracy of Facial Assessment by Computer Evaluation (FACE) program in eyelid measurements. Sixteen subjects between the ages of 27 and 65 were included with IRB approval. Clinical measurements of upper eyelid margin reflex distance (MRD1) and inter-palpebral fissure (IPF) were obtained. Photographs were then taken with a digital single lens reflex camera with built-in pop-up flash (dSLR-pop) and a dSLR with lens-mounted ring flash (dSLR-ring) with the cameras upright, rotated 90, 180, and 270 degrees. The images were analyzed using both the FACE and ImageJ software to measure MRD1 and IPF.Thirty-two eyes of sixteen subjects were included. Comparison of clinical measurement of MRD1 and IPF with FACE measurements of photos in upright position showed no statistically significant differences for dSLR-pop (MRD1: p = 0.0912, IPF: p = 0.334) and for dSLR-ring (MRD1: p = 0.105, IPF: p = 0.538). One-to-one comparison of MRD1 and IPF measurements in four positions obtained with FACE versus ImageJ for dSLR-pop showed moderate to substantial agreement for MRD1 (intraclass correlation coefficient = 0.534 upright, 0.731 in 90 degree rotation, 0.627 in 180 degree rotation, 0.477 in 270 degree rotation) and substantial to excellent agreement in IPF (ICC = 0.740, 0.859, 0.849, 0.805). In photos taken with dSLR-ring, there was excellent agreement of all MRD1 (ICC = 0.916, 0.932, 0.845, 0.812) and IPF (ICC = 0.937, 0.938, 0.917, 0.888) values. The FACE program is a valid method for measuring margin reflex distance and inter-palpebral fissure.

Cough is less common and less severe in systemic sclerosis-associated interstitial lung disease compared to other fibrotic interstitial lung diseases.

PubMed

Cheng, Jasmine Z; Wilcox, Pearce G; Glaspole, Ian; Corte, Tamera J; Murphy, Darra; Hague, Cameron J; Ryerson, Christopher J

2017-11-01

The objectives of this study were to determine the prevalence and characteristics of cough in idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP) and systemic sclerosis-associated interstitial lung disease (SSc-ILD). Cough severity was measured in consecutive patients with IPF (n = 77), HP (n = 32) and SSc-ILD (n = 67) using a 10-cm visual analogue scale (VAS). Dyspnoea and quality of life were measured using established questionnaires. Cough severity was compared across ILD subtypes and predictors of cough severity were determined using multivariate analysis. Cough was more common in IPF and chronic HP compared to SSc-ILD (87% and 83% vs 68%, P = 0.02). The median (interquartile range) VAS score was 39 (17-65) in the IPF cohort, 29 (11-48) in HP and 18 (0-33) in SSc-ILD (P < 0.0001). Cough was more often productive in chronic HP and IPF (63% and 43% vs 21%, P < 0.001). Cough severity was independently predicted only by ILD diagnosis and higher dyspnoea score. Cough severity was not associated with other common causes of cough. Cough was a significant predictor of quality of life in IPF and SSc-ILD with adjustment for age, sex, dyspnoea and ILD severity; however, cough was not associated with quality of life in chronic HP. Cough is more frequent, more severe and more often productive in IPF and chronic HP compared to SSc-ILD, despite similar ILD severity in these cohorts. Cough severity is strongly and independently associated with dyspnoea and pulmonary function, and is a significant contributor to reduced quality of life in both IPF and SSc-ILD. © 2017 Asian Pacific Society of Respirology.

No effect of unemployment on intimate partner-related femicide during the financial crisis: a longitudinal ecological study in Spain.

PubMed

Torrubiano-Domínguez, J; Vives-Cases, C; San-Sebastián, M; Sanz-Barbero, B; Goicolea, I; Álvarez-Dardet, C

2015-09-30

Spain's financial crisis has been characterized by an increase in unemployment. This increase could have produced an increase in deaths of women due to intimate partner-related femicides (IPF). This study aims to determine whether the increase in unemployment among both sexes in different regions in Spain is related to an increase in the rates of IPF during the current financial crisis period. An ecological longitudinal study was carried out in Spain's 17 regions. Two study periods were defined: pre-crisis period (2005-2007) and crisis period (2008-2013). IPF rates adjusted by age and unemployment rates for men and women were calculated. We fitted multilevel linear regression models in which observations at level 1 were nested within regions according to a repeated measurements design. Rates of unemployment have progressively increased in Spain, rising above 20 % from 2008 to 2013 in some regions. IPF rates decreased in some regions during crisis period with respect to pre-crisis period. The multilevel analysis does not support the existence of a significant relationship between the increase in unemployment in men and women and the decrease in IPF since 2008. The increase in unemployment in men and women in Spain does not appear to have an effect on IPF. The results of the multilevel analysis discard the hypothesis that the increase in the rates of unemployment in women and men are related to an increase in IPF rates. The decline in IPF since 2008 might be interpreted as the result of exposure to other factors such as the lower frequency of divorces in recent years or the medium term effects of the integral protection measures of the law on gender violence that began in 2005.

Respiratory comorbidities and risk of mortality in hospitalized patients with idiopathic pulmonary fibrosis.

PubMed

Oda, Keishi; Yatera, Kazuhiro; Fujino, Yoshihisa; Kido, Takashi; Hanaka, Tetsuya; Sennari, Konomi; Fushimi, Kiyohide; Matsuda, Shinya; Mukae, Hiroshi

2018-01-01

Respiratory comorbidities are frequently associated with idiopathic pulmonary fibrosis (IPF). However, little is known about their prognostic impact in hospitalized patients with IPF. We examined the impact of respiratory comorbidities on the mortality rates of hospitalized patients with IPF using a Japanese nationwide database. We identified 5665 hospitalized patients diagnosed with IPF between April 2010 and March 2013. The primary outcome was defined as the in-hospital mortality at 30 days after admission. The impact of respiratory comorbidities was assessed using a Cox proportional hazards model that incorporated clinically relevant factors. In hospitalized patients with IPF, the prevalence of bacterial pneumonia, pulmonary hypertension, and lung cancer were 9.5%, 4.6%, and 3.7%, respectively. Among patients with bacterial pneumonia, the four most common pathogens were Streptococcus pneumoniae (31.6%), methicillin-resistant Streptococcus aureus (18.4%), Klebsiella pneumoniae (9.2%), and Pseudomonas aeruginosa (9.2%). Lung cancer was more commonly found in the lower lobes (60.1%) than in other lobes. The survival at 30 days from admission was 78.4% in all patients and significantly lower in IPF patients with bacterial pneumonia (adjusted hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.04-1.63; p < 0.023) and patients with lung cancer (adjusted HR, 1.99; 95% CI, 1.47-2.69; p < 0.001) than in others. Pulmonary hypertension was not associated with mortality. IPF patients with one or more of these three respiratory comorbidities had a poorer survival than others (p < 0.05). Respiratory comorbidities, especially bacterial pneumonia and lung cancer, influence mortality in hospitalized patients with IPF. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Idiopathic pulmonary fibrosis: a holistic approach to disease management in the antifibrotic age.

PubMed

Shaw, Jonathon; Marshall, Tracey; Morris, Helen; Hayton, Conal; Chaudhuri, Nazia

2017-11-01

Idiopathic pulmonary fibrosis (IPF) is the most common cause of interstitial lung disease (ILD) and carries a worse prognosis than many cancers. Until recently, there were no active treatment options available for patients with IPF, meaning palliation or lung transplantation in selected patients were the only options. The management of IPF has changed dramatically over the last decade with the advent of two antifibrotic agents; pirfenidone and nintedanib. These new agents have been shown to reduce decline in lung function and pirfenidone has been shown to reduce mortality. The changing landscape of IPF diagnosis and management present a number of issues that may be encountered including management of side effects related to antifibrotic therapy. This article aims to give an overview of the holistic approach to the management of patients with IPF, including antifibrotic management, symptom management and the invaluable role of the ILD specialist nurse.

Idiopathic pulmonary fibrosis: a holistic approach to disease management in the antifibrotic age

PubMed Central

Shaw, Jonathon; Marshall, Tracey; Morris, Helen; Chaudhuri, Nazia

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is the most common cause of interstitial lung disease (ILD) and carries a worse prognosis than many cancers. Until recently, there were no active treatment options available for patients with IPF, meaning palliation or lung transplantation in selected patients were the only options. The management of IPF has changed dramatically over the last decade with the advent of two antifibrotic agents; pirfenidone and nintedanib. These new agents have been shown to reduce decline in lung function and pirfenidone has been shown to reduce mortality. The changing landscape of IPF diagnosis and management present a number of issues that may be encountered including management of side effects related to antifibrotic therapy. This article aims to give an overview of the holistic approach to the management of patients with IPF, including antifibrotic management, symptom management and the invaluable role of the ILD specialist nurse. PMID:29268540

A review of current and novel therapies for idiopathic pulmonary fibrosis

PubMed Central

Rafii, Rokhsara; Juarez, Maya M.; Albertson, Timothy E.

2013-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic interstitial lung disease that is associated with a median survival of 2-3 years from initial diagnosis. To date, there is no treatment approved for IPF in the United States, and only one pharmacological agent has been approved outside of the United States. Nevertheless, research over the past 10 years has provided us with a wealth of information on its histopathology, diagnostic work-up, and a greater understanding of its pathophysiology. Specifically, IPF is no longer thought to be a predominantly pro-inflammatory disorder. Rather, the fibrosis in IPF is increasingly understood to be the result of a fibroproliferative and aberrant wound healing cascade. The development of therapeutic targets has shifted in accord with this paradigm change. This review highlights the current understanding of IPF, and the recent as well as novel therapeutics being explored in clinical trials for the treatment of this devastating disease. PMID:23372951

Lung Cancer in Patients with Severe Idiopathic Pulmonary Fibrosis: Critical Aspects.

PubMed

Bargagli, Elena; Bonti, Viola; Ferrari, Katia; Rosi, Elisabetta; Bindi, Alessandra; Bartolucci, Maurizio; Chiara, Moroni; Voltolini, Luca

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease limited to the lung with an undefined etiopathogenesis and a very short life expectancy (less than 5 years). IPF susceptibility has been associated with several genetic and environmental risk factors and the prognosis is conditioned by comorbidities such as gastro-esophageal reflux, depression, venous thromboembolism, pulmonary hypertension and lung cancer. At 5 years follow-up, 15% of IPF patients develop lung cancer, which can significantly reduce their survival. Because diagnostic or therapeutic procedures such as surgical, radiation or pharmacological treatments may induce acute exacerbations and increase mortality, the management of lung cancer in IPF patients is a very difficult task. This study discusses advantages and disadvantages of lung cancer treatments in patients with severe IPF, highlighting several controversial aspects on this topic, including potential nintedanib treatment. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

DOES NEIGHBORHOOD ENVIRONMENT DIFFERENTIATE INTIMATE PARTNER FEMICIDES FROM OTHER FEMICIDES?

PubMed Central

Beyer, Kirsten M. M.; Layde, Peter M.; Hamberger, L. Kevin; Laud, Purushottam W.

2015-01-01

We examined the association between neighborhood-level factors and intimate partner femicide (IPF) using Wisconsin Violent Death Reporting System (WVDRS) data and Wisconsin Coalition Against Domestic Violence (WCADV) reports, in concert with neighborhood-level information. After controlling for individual characteristics, neighborhood-level disadvantage was associated with a decreased likelihood of IPF status, as compared to other femicides, while neighborhood-level residential instability was associated with an increased likelihood of IPF status. Neighborhood plays a role in differentiating IPFs from other femicides in our study area. Our findings demonstrate the importance of multilevel strategies for understanding and reducing the burden of intimate partner violence. PMID:25540251

Optimizing quality of life in patients with idiopathic pulmonary fibrosis

PubMed Central

van Manen, Mirjam J. G.; Geelhoed, J. J. Miranda.; Tak, Nelleke C.; Wijsenbeek, Marlies S.

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive and ultimately fatal lung disease. The combination of poor prognosis, uncertainty of disease course and severe symptom burden heavily impacts patients’ and their families’ quality of life. Though new antifibrotic drugs have been shown to decrease disease progression, the effect on health-related quality of life (HRQOL) has not been convincingly demonstrated. In a relentless disease such as IPF, striving to optimize HRQOL should complement the endeavour to prolong life. Unfortunately, there is a paucity of interventions improving symptoms and functionality for patients with IPF, and research focusing on symptom improvement, and assessing and optimizing HRQOL, is limited. This review summarizes the most recent insights into measuring and improving quality of life for patients with IPF, and discusses challenges in the management of this devastating disease. Moreover, we postulate a new model for continuous care in IPF – ‘the ABCDE of IPF care’: Assessing patients’ needs; Backing patients by giving information and support; delivering Comfort care by focusing on treating symptoms and taking into account Comorbidities; striving to prolong life by Disease modification; helping and preparing patients and their caregivers for the eventual End-of-life events that are likely to occur. PMID:28134007

Role of pirfenidone in the management of pulmonary fibrosis.

PubMed

Meyer, Keith C; Decker, Catherine A

2017-01-01

Pulmonary fibrosis is associated with a number of specific forms of interstitial lung disease (ILD) and can lead to progressive decline in lung function, poor quality of life, and, ultimately, early death. Idiopathic pulmonary fibrosis (IPF), the most common fibrotic ILD, affects up to 1 in 200 elderly individuals and has a median survival that ranges from 3 to 5 years following initial diagnosis. IPF has not been shown to respond to immunomodulatory therapies, but recent trials with novel antifibrotic agents have demonstrated lessening of lung function decline over time. Pirfenidone has been shown to significantly slow decline in forced vital capacity (FVC) over time and prolong progression-free survival, which led to its licensing by the United States Food and Drug Administration (FDA) in 2014 for the treatment of patients with IPF. However, pirfenidone has been associated with significant side effects, and patients treated with pirfenidone must be carefully monitored. We review recent and ongoing clinical research and experience with pirfenidone as a pharmacologic therapy for patients with IPF, provide a suggested approach to incorporate pirfenidone into a treatment algorithm for patients with IPF, and examine the potential of pirfenidone as a treatment for non-IPF forms of ILD accompanied by progressive pulmonary fibrosis.

Neglected evidence in idiopathic pulmonary fibrosis and the importance of early diagnosis and treatment.

PubMed

Cottin, Vincent; Richeldi, Luca

2014-03-01

In idiopathic pulmonary fibrosis (IPF), some facts or concepts based on substantial evidence, whilst implicit for learned subspecialists, have previously been neglected and/or not explicitly formulated or made accessible to a wider audience. IPF is strongly associated with cigarette smoking and is predominantly a disease of ageing. However, its cause(s) remain elusive and, thus, it is one of the most challenging diseases for the development of novel effective and safe therapies. With the approval of pirfenidone for patients with mild-to-moderate IPF, an earlier diagnosis of IPF is a prerequisite for earlier treatment and, potentially, improvement of the long-term clinical outcome of this progressive and ultimately fatal disease. An earlier diagnosis may be achieved in IPF by promoting thin-slice chest high-resolution computed tomography screening of interstitial lung disease as a "by-product" of large-scale lung cancer screening strategies in smokers, but other techniques, which have been neglected in the past, are now available. Lung auscultation and early identification of "velcro" crackles has been proposed as a key component of early diagnosis of IPF. An ongoing study is exploring correlations between lung sounds on auscultation obtained using electronic stethoscopes and high-resolution computed tomography patterns.

Long-term efficacy of macrolide treatment in idiopathic pulmonary fibrosis: a retrospective analysis.

PubMed

Kuse, Naoyuki; Abe, Shinji; Hayashi, Hiroki; Kamio, Koichiro; Saito, Yoshinobu; Usuki, Jiro; Azuma, Arata; Kudoh, Shoji; Gemma, Akihiko

2016-10-07

There is growing evidence for anti-inflammatory activities of macrolides in chronic respiratory diseases, such as diffuse panbronchiolitis, cystic fibrosis, or chronic bronchitis. The long-term effect of macrolides in idiopathic pulmonary fibrosis (IPF) is unknown. This study was aimed to investigate the effect of macrolide therapy on the frequency of acute exacerbation (AE) and the mortality in IPF. A total 52 IPF patients who were treated by combination of conventional agents with or without macrolides were retrospectively reviewed. The primary endpoint was the incidence of AE in IPF patients. We also observed survival rate after the treatment with or without macrolides. AE was observed in 4 of 29 cases (13.8%) treated with macrolides and 8 of 23 cases (34.8%) treated without macrolides, respectively during 36 months. AE free survival rate of macrolide group was significantly better than that of non-macrolide group (logrank p=0.027). Survival rate of IPF patients with macrolide therapy was significantly better than that of patients without macrolide therapy (p=0.047). Our results indicate the potential beneficial efficacy of macrolide therapy combined with oral corticosteroids, immunosuppressive or anti-fibrotic agents in IPF.

Idiopathic pulmonary fibrosis and lung cancer: a clinical and pathogenesis update.

PubMed

Antoniou, Katerina M; Tomassetti, Sara; Tsitoura, Eliza; Vancheri, Carlo

2015-11-01

About one out of 10 patients with idiopathic pulmonary fibrosis (IPF) develop lung cancer. This review provides an epidemiology and clinical update of the association of these two lethal diseases. In addition, we focus on the emerging overlapping epigenetic mechanisms in both diseases. In a vast majority of cases, lung cancer is diagnosed during the clinical and radiological follow-up for the fibrosis. The risk of development of lung cancer in IPF is higher for older male smokers and there is a significantly higher prevalence of lung cancer in the combined IPF and emphysema syndrome compared with fibrosis only. The association of two lethal diseases, such as IPF and lung cancer, carries a very poor outcome and the correct treatment strategy, particularly for advanced forms of lung cancer, is still unclear. The two novel drugs approved for IPF, pirfenidone and nintedanib, open a new scenario in which treated patients with fibrosis will live longer, and possibly have a lower incidence of lung cancer. However, prospective studies are urgently needed to definitively clarify the role of lung cancer treatment in the management of IPF patients. Furthermore, common epigenetic alterations may represent a promising target for therapeutic approaches in the near future.

Utilizing a Homecare Platform for Remote Monitoring of Patients with Idiopathic Pulmonary Fibrosis.

PubMed

Panagopoulos, Christos; Malli, Foteini; Menychtas, Andreas; Smyrli, Efstathia-Petrina; Georgountzou, Aikaterini; Daniil, Zoe; Gourgoulianis, Konstantinos I; Tsanakas, Panayiotis; Maglogiannis, Ilias

2017-01-01

Homecare and home telemonitoring are a focal point of emerging healthcare schemes, with proven benefits for both patients, caregivers and providers, including reduction of healthcare costs and improved patients' quality of life, especially in the case of chronic disease management. Studies have evaluated solutions for remote monitoring of chronic patients based on technologies that allow daily symptom and vital signs monitoring, tailored to the needs of specific diseases. In this work, we present an affordable home telemonitoring system for patients with idiopathic pulmonary fibrosis (IPF), based on an application for mobile devices and Bluetooth-enabled sensors for pulse oximetry and blood pressure measurements. Besides monitoring of vital signs, the system incorporates communication via videoconferencing and emergency response, with support from a helpdesk service. A pilot study was conducted, in order to verify the proposed solution's feasibility. The results support the utilization of the system for effective monitoring of patients with IPF.

Radiological characteristics, histological features and clinical outcomes of lung cancer patients with coexistent idiopathic pulmonary fibrosis.

PubMed

Khan, K A; Kennedy, M P; Moore, E; Crush, L; Prendeville, S; Maher, M M; Burke, L; Henry, M T

2015-02-01

Despite advances in diagnosis and management, the outcomes for both lung cancer and idiopathic pulmonary fibrosis (IPF) are still unfavourable. The pathophysiology and outcomes for patients with concomitant lung cancer and IPF remains unclear. A retrospective analysis was performed of all patients presenting with concomitant IPF and lung cancer to our centre over a 3-year period. Patients with connective tissue disease, asbestos exposure, sarcoidosis, previous thoracic radiation, radiological evidence of fibrosis but no histological confirmation of lung cancer, or the use of medications known to cause pulmonary fibrosis were excluded. We describe clinical, radiological and pathological characteristics of this group. We also report the response to standardized lung cancer therapy in this cohort. Of 637 lung cancer patients, 34 were identified with concomitant IPF (5.3 %) and all were smokers. 85 % had non-small cell lung cancer, 41 % were squamous cell cancers. The majority of tumours were located in the lower lobes, peripheral and present in an area of honeycombing. Despite the fact that approximately 2/3rds of the patients had localised or locally advanced lung cancer, the outcome of therapy for lung cancer was extremely poor regardless of tumour stage or severity of IPF. At our centre, 1/20 patients with lung cancer have concomitant IPF. The majority of these tumours are small in size, peripheral in location and squamous cell carcinoma; in an area of honey combing. The outcome for concomitant lung cancer and IPF regardless of stage or therapy is poor.

Reduced incidence of lung cancer in patients with idiopathic pulmonary fibrosis treated with pirfenidone.

PubMed

Miura, Yukiko; Saito, Takefumi; Tanaka, Toru; Takoi, Hiroyuki; Yatagai, Yohei; Inomata, Minoru; Nei, Takahito; Saito, Yoshinobu; Gemma, Akihiko; Azuma, Arata

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is a disease with a worse prognosis than some types of cancer. In patients with IPF, lung cancer is critical because of the associated high mortality rate from its progression and fatal complications from anticancer treatments. Therefore, preventing lung cancer in patients with IPF is primordial. Pirfenidone is an anti-fibrotic agent that reduces the decline in forced vital capacity. This study aimed to assess the effect of pirfenidone in the development of lung cancer in patients with IPF. Data from 261 patients with IPF with and without pirfenidone were retrospectively reviewed, and the incidence of lung cancer was analyzed. In the pirfenidone group, the incidence of lung cancer was significantly lower than in the non-pirfenidone group (2.4% vs. 22.0%, P < 0.0001). Multivariate Cox proportional hazards regression analysis demonstrated that pirfenidone decreased the risk of lung cancer (hazard ratio, 0.11; 95% confidence interval, 0.03 to 0.46; P = 0.003), whereas coexisting emphysema increased the incidence of lung cancer (hazard ratio, 3.22; 95% confidence interval, 1.35 to 7.70; P = 0.009). Pirfenidone might correlate with a decreased risk of lung cancer in patients with IPF. However, no definite conclusion can be drawn from this retrospective study, and a multicenter, prospective cohort study is still warranted to confirm the effect of pirfenidone on lung cancer in patients with IPF. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Clinical characteristics in patients with asymmetric idiopathic pulmonary fibrosis.

PubMed

Callahan, Sean J; Xia, Meng; Murray, Susan; Flaherty, Kevin R

2016-10-01

A group of patients with idiopathic pulmonary fibrosis (IPF) presents with disease affecting one lung markedly more than the other. At this time, it is unclear how this population differs from those who present with more symmetric disease. We sought to explain the characteristics of the asymmetric group and how their disease progresses. In this retrospective case-control study we accessed an interstitial lung disease (ILD) database and identified 14 asymmetric IPF cases via high-resolution computed tomography (HRCT) scoring of each lung lobe's disease severity. We identified 28 symmetric IPF controls from the same database using the same methods, and compared the clinical features of each group. Patients with asymmetric disease exhibited similar demographics as those in the general IPF population; they were predominantly male (64%), elderly (69 years old), and used tobacco (57%). We found a trend toward significantly increased all-cause mortality in the case population two years following diagnosis (p = 0.089). Pulmonary function tests were significantly lower in the case group at the time of diagnosis, then both groups experienced gradual decline. We found no statistically significant differences in number of IPF exacerbations (cases 43%, controls 39%, p = 0.824) and gastro-esophageal reflux (both groups 50%). Patients with asymmetric IPF resemble patients in the general IPF population but may have a lower overall survival rate. Further systemic factors may be studied to identify reasons for disease asymmetry and clinical decline in this population. Published by Elsevier Ltd.

Mortality on the Waiting List for Lung Transplantation in Patients with Idiopathic Pulmonary Fibrosis: A Single-Centre Experience.

PubMed

Bennett, David; Fossi, Antonella; Bargagli, Elena; Refini, Rosa Metella; Pieroni, Maria; Luzzi, Luca; Ghiribelli, Claudia; Paladini, Piero; Voltolini, Luca; Rottoli, Paola

2015-10-01

Lung transplantation (LTX) is nowadays accepted as a treatment option for selected patients with end-stage pulmonary disease. Idiopathic pulmonary fibrosis (IPF) is characterized by the radiological and histologic appearance of usual interstitial pneumonia. It is associated with a poor prognosis, and LTX is considered an effective treatment to significantly modify the natural history of this disease. The aim of the present study was to analyse mortality during the waiting list in IPF patients at a single institution. A retrospective analysis on IPF patients (n = 90) referred to our Lung Transplant Program in the period 2001-2014 was performed focusing on patients' characteristics and associated risk factors. Diagnosis of IPF was associated with high mortality on the waiting list with respect to other diagnosis (p < 0.05). No differences in demographic, clinical, radiological data and time spent on the waiting list were observed between IPF patients who underwent to LTX or lost on the waiting list. Patients who died showed significant higher levels of pCO2 and needed higher flows of O2-therapy on effort (p < 0.05). Pulmonary function tests failed to predict mortality and no other medical conditions were associated with survival. Patients newly diagnosed with IPF, especially in small to medium lung transplant volume centres and in Countries where a long waiting list is expected, should be immediately referred to transplantation, delay results in increased mortality. Early identification of IPF patients with a rapid progressive phenotype is strongly needed.

Crackle pitch and rate do not vary significantly during a single automated-auscultation session in patients with pneumonia, congestive heart failure, or interstitial pulmonary fibrosis.

PubMed

Vyshedskiy, Andrey; Ishikawa, Sadamu; Murphy, Raymond L H

2011-06-01

To determine the variability of crackle pitch and crackle rate during a single automated-auscultation session with a computerized 16-channel lung-sound analyzer. Forty-nine patients with pneumonia, 52 with congestive heart failure (CHF), and 18 with interstitial pulmonary fibrosis (IPF) performed breathing maneuvers in the following sequence: normal breathing, deep breathing, cough several times; deep breathing, vital-capacity maneuver, and deep breathing. From the auscultation recordings we measured the crackle pitch and crackle rate. Crackle pitch variability, expressed as a percentage of the average crackle pitch, was small in all patients and in all maneuvers: pneumonia 11%, CHF 11%, pulmonary fibrosis 7%. Crackle rate variability was also small: pneumonia 31%, CHF 32%, IPF 24%. Compared to the first deep-breathing maneuver (100%), the average crackle pitch did not significantly change following coughing (pneumonia 100%, CHF 103%, IPF 100%), the vital-capacity maneuver (pneumonia 100%, CHF 92%, IPF 104%), or during quiet breathing (pneumonia 97%, CHF 100%, IPF 104%). Similarly, the average crackle rate did not change significantly following coughing (pneumonia 105%, CHF 110%, IPF 90%) or the vital-capacity maneuver (pneumonia 102%, CHF 101%, IPF 99%). However, during normal breathing the crackle rate was significantly lower in the patients with pneumonia (74%, P < .001) and significantly higher in the patients with IPF (147%, P < .05) than it was during deep breathing. In patients with CHF the average crackle rate during normal breathing was not significantly different from that during the first deep-breathing maneuver (108%). Crackle pitch and rate were surprisingly stable in all 3 conditions. Neither crackle pitch nor crackle rate changed significantly from breath to breath or from one deep-breathing maneuver to another, even when the maneuvers were separated by cough or the vital-capacity maneuver. The observation that crackle rate is a reproducible measurement during one automated-auscultation session suggests that crackle rate can be used to follow the course of cardiopulmonary illnesses such as pneumonia, IPF, and CHF.

Influence of radiological emphysema on lung function test in idiopathic pulmonary fibrosis.

PubMed

Bodlet, Aline; Maury, Gisèle; Jamart, Jacques; Dahlqvist, Caroline

2013-11-01

Idiopathic pulmonary fibrosis (IPF) is one of the most frequent interstitial lung disease. Emphysema can be associated with IPF as described in the «Combined pulmonary fibrosis and emphysema» syndrome. The primary endpoint of this retrospective cohort study was to evaluate the impact of the association of IPF and emphysema on lung function tests parameters (FVC, TLC, FEV1, FEV1/FVC and DLCO). The secondary endpoint was to assess the impact of the associated radiological emphysema on lung function parameters used in the du Bois prognostic score recently developed by Ron du Bois et al. We retrospectively reviewed the medical files of 98 patients with lung fibrosis who were followed in our University Hospital with access to pharmacological studies and lung transplantation from 1981 to 2011. Fifty six patients were considered for analysis. The collected data included gender, age, smoking history and respiratory hospitalizations. We also analysed their pulmonary functional parameters along with radiological characteristics, in particular the presence of emphysema which was assessed on thoracic high resolution CT scan. The du Bois score was retrospectively calculated from these data. TLC and FVC at diagnosis were significantly higher in the IPF-E group compared to the IPF group (respectively 86.6 ± 17.2% pv versus 72.0 ± 15.0% pv; p: 0.004 and 86.8 ± 18.4% pv versus 72.6 ± 20.6% pv; p: 0.020). The [Formula: see text] used in the calculation of the du Bois prognostic score was significantly higher in the IPF-E group. By cons, [Formula: see text] was not statistically different between the two groups. Radiological emphysema associated with IPF had an impact on pulmonary function tests. Despite this difference, the du Bois score was not statistically different between these two groups. Nevertheless, after one year of follow up, the patients with emphysema were in a subclass with a lower mortality rate than those without emphysema. Copyright © 2013 Elsevier Ltd. All rights reserved.

Prognostic significance of surfactant protein A, surfactant protein D, Clara cell protein 16, S100 protein, trefoil factor 3, and prostatic secretory protein 94 in idiopathic pulmonary fibrosis, sarcoidosis, and chronic pulmonary obstructive disease.

PubMed

Doubková, Martina; Karpíšek, Michal; Mazoch, Jiri; Skřičková, Jana; Doubek, Michael

2016-10-07

Identification of serum and bronchoalveolar lavage fluid (BALF) biomarkers may facilitate diagnosis and prognostication in various lung disorders. Serum and BALF levels of surfactant protein A (SP-A), surfactant protein D (SP-D), Clara cell protein 16 (CC16), S100 protein, trefoil factor 3 (TFF3), and prostatic secretory protein 94 (PSP94) were evaluated in 94 consecutive patients (idiopathic pulmonary fibrosis (IPF; n=18), sarcoidosis (n=25), chronic obstructive pulmonary disease (COPD; n=51)), and in 155 healthy controls. Biomarkers were measured at diagnosis and compared with disease characteristics. Both uniparametric and multiparametric analyses were used. Seven significant correlations were found: 1) BALF PSP94 level correlated with prognosis of sarcoidosis (P=0.035); 2) BALF SP-D level with pulmonary functions in IPF (P=0.032); 3) BALF SP-D and TFF3 with IPF mortality (P=0.049 and 0.017, respectively); 4) serum TFF3 level with COPD mortality (P=0.006,); 5) serum SP-A with pulmonary functions impairment in IPF (P=0.011); 6) serum SP-D level was associated with HRCT interstitial score in IPF (P=0.0346); and 7) serum SP-A was associated with staging of COPD according to spirometry (P<0.001). Moreover, our analysis showed that some biomarker levels differed significantly among the diseases: 1) BALF SP-D level differed between sarcoidosis and IPF; 2) serum SP-A level differed among IPF, sarcoidosis, COPD and was also different from healthy controls; 3) serum S100A6, S100A11 levels differed among IPF, sarcoidosis, COPD from healthy controls 4) serum SP-D, CC16, TFF-3 levels distinguished IPF patients from healthy controls; and 5) serum CC16, TFF3, PSP94 distinguished COPD patients from healthy controls. Our study shows that some of selected biomarkers should have prognostic value in the analysed lung disorders. On the other hand, these biomarkers do not appear to be unequivocally suitable for differential diagnosis of these disorders.

Integrated Transitions of Care for Patients With Rare Pulmonary Diseases.

PubMed

Moreo, Kathleen; Lattimer, Cheri; Lett, James E; Heggen-Peay, Cherilyn L; Simone, Laura

Many continuing education (CE) resources are available to support case management professionals in developing competencies in transitions of care (TOC) that apply generally across disease areas. However, CE programs and tools are lacking for advanced TOC competencies in specific disease areas. This article describes 2 projects in which leading TOC, case management, and CE organizations collaborated to develop CE-accredited interdisciplinary pathways for promoting safe and effective TOC for patients with rare pulmonary diseases, including pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). The interdisciplinary pathways apply to PAH and IPF case management practice and TOC across settings that include community-based primary care and specialty care, PAH or IPF centers of expertise, acute care and post-acute settings, long-term care, rehabilitation and skilled nursing facilities, and patients' homes. Both PAH and IPF are chronic, progressive respiratory diseases that are associated with severe morbidity and mortality, along with high health care costs. Because they are relatively rare diseases with nonspecific symptoms and many comorbidities, PAH and IPF are difficult to diagnose. Early diagnosis, referral to centers of expertise, and aggressive treatment initiation are essential for slowing disease progression and maintaining quality of life and function. Both the rarity and complexity of PAH and IPF pose unique challenges to ensuring effective and safe TOC. Expert consensus and evidence-based approaches to meeting these challenges, and thereby improving PAH and IPF patient outcomes, are presented in the 2 interdisciplinary TOC pathways that are described in this article. In coordinating care for patients with complex pulmonary diseases such as PAH and IPF, case managers across practice settings can play key roles in improving workflow processes and communication, transition planning, coordinating TOC with centers of expertise, coordinating care and TOC for patients with comorbidities, providing patient and caregiver education, promoting engagement between patients and the team, advancing the care plan, and improving ongoing adherence to treatment in order to maximize the patient's pulmonary function. Details regarding these interprofessional roles and responsibilities are provided in the full interdisciplinary TOC pathways for PAH and IPF.

A home monitoring program including real-time wireless home spirometry in idiopathic pulmonary fibrosis: a pilot study on experiences and barriers.

PubMed

Moor, C C; Wapenaar, M; Miedema, J R; Geelhoed, J J M; Chandoesing, P P; Wijsenbeek, M S

2018-05-29

In idiopathic pulmonary fibrosis (IPF), home monitoring experiences are limited, not yet real-time available nor implemented in daily care. We evaluated feasibility and potential barriers of a new home monitoring program with real-time wireless home spirometry in IPF. Ten patients with IPF were asked to test this home monitoring program, including daily home spirometry, for four weeks. Measurements of home and hospital spirometry showed good agreement. All patients considered real-time wireless spirometry useful and highly feasible. Both patients and researchers suggested relatively easy solutions for the identified potential barriers regarding real-time home monitoring in IPF.

The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis.

PubMed

Williamson, James D; Sadofsky, Laura R; Hart, Simon P

2015-03-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti-neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. In this review, we compare the pathogenesis and histological features of human IPF and bleomycin-induced pulmonary fibrosis (BPF) induced in rodents by intratracheal delivery. We discuss the current understanding of IPF and BPF disease development, from the contribution of alveolar epithelial cells and inflammation to the role of fibroblasts and cytokines, and draw conclusions about what we have learned from the intratracheal bleomycin model of lung fibrosis.

Development of brain synchronisation within school-age--individual analysis of resting (α) coherence in a longitudinal data set.

PubMed

Gmehlin, Dennis; Thomas, Christine; Weisbrod, Matthias; Walther, Stephan; Resch, Franz; Oelkers-Ax, Rieke

2011-10-01

Given evidence that synchronisation of neuronal activity may be a correlate of cognition, we examined EEG coherence as function of age and inter-electrode distance in healthy children and adolescents in order to elucidate basic information for a better understanding of developmental disorders associated with deficits in cognitive functions. Based on a 64-channel eyes closed resting EEG we combined local and global coherence measures in order to reduce volume conduction and reference effects. We used a two point longitudinal design in order to analyze intraindividual change during school-age (n=40; 6-18 years). Coherence was analyzed within individually adjusted frequency bands and around iPF (= individual alpha peak frequency). Both local and global resting coherence was largest in the alpha range and particularly around iPF. Local synchronisation was larger in the left compared with the right hemisphere. Controlling for increases in iPF, synchronisation increased with age, with global changes being most pronounced in the alpha range. Moreover age-related changes suggest an earlier development in girls. Our data provides evidence that both local and global functional integration increases during normal development within school-age. This general pattern - combined with more specific effects of sex and frequency - may help to specify deviations in developmental disorders. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Measurement of the extreme ankle range of motion required by female ballet dancers.

PubMed

Russell, Jeffrey A; Kruse, David W; Nevill, Alan M; Koutedakis, Yiannis; Wyon, Matthew A

2010-12-01

Female ballet dancers require extreme ankle motion, especially plantar flexion, but research about measuring such motion is lacking. The purposes of this study were to determine in a sample of ballet dancers whether non-weight-bearing ankle range of motion is significantly different from the weight-bearing equivalent and whether inclinometric plantar flexion measurement is a suitable substitute for standard plantar flexion goniometry. Fifteen female ballet dancers (5 university, 5 vocational, and 5 professional dancers; age 21 ± 3.0 years) volunteered. Subjects received 5 assessments on 1 ankle: non-weight-bearing goniometry dorsiflexion (NDF) and plantar flexion (NPF), weight-bearing goniometry in the ballet positions demi-plié (WDF) and en pointe (WPF), and non-weight-bearing plantar flexion inclinometry (IPF). Mean NDF was significantly lower than WDF (17° ± 1.3° vs 30° ± 1.8°, P < .001). NPF (77° ± 2.5°) was significantly lower than both WPF (83° ± 2.2°, P = .01) and IPF (89° ± 1.6°, P < .001), and WPF was significantly lower than IPF (P = .013). Dorsiflexion tended to decrease and plantar flexion tended to increase with increasing ballet proficiency. The authors conclude that assessment of extreme ankle motion in female ballet dancers is challenging, and goniometry and inclinometry appear to measure plantar flexion differently.

Idiopathic pulmonary fibrosis (IPF) signaling pathways and protective roles of melatonin.

PubMed

Hosseinzadeh, Azam; Javad-Moosavi, Seyed Ali; Reiter, Russel J; Hemati, Karim; Ghaznavi, Habib; Mehrzadi, Saeed

2018-05-15

Idiopathic pulmonary fibrosis (IPF) is characterized by the progressive loss of lung function due to tissue scarring. A variety of pro-inflammatory and pro-fibrogenic factors including interleukin‑17A, transforming growth factor β, Wnt/β‑catenin, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factors, endotelin‑1, renin angiotensin system and impaired caveolin‑1 function are involved in the IPF pathogenesis. Current therapies for IPF have some limitations and this highlights the need for effective therapeutic agents to treat this fatal disease. Melatonin and its metabolites are broad-spectrum antioxidants that not only remove reactive oxygen and nitrogen species by radical scavenging but also up-regulate the expression and activity of endogenous antioxidants. Via these actions, melatonin and its metabolites modulate a variety of molecular pathways in different pathophysiological conditions. Herein, we review the signaling pathways involved in the pathophysiology of IPF and the potentially protective effects of melatonin on these pathways. Copyright © 2018 Elsevier Inc. All rights reserved.

A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

PubMed Central

Englert, Judson M.; Hanford, Lana E.; Kaminski, Naftali; Tobolewski, Jacob M.; Tan, Roderick J.; Fattman, Cheryl L.; Ramsgaard, Lasse; Richards, Thomas J.; Loutaev, Inna; Nawroth, Peter P.; Kasper, Michael; Bierhaus, Angelika; Oury, Tim D.

2008-01-01

Idiopathic pulmonary fibrosis (IPF) is a severely debilitating disease associated with a dismal prognosis. There are currently no effective therapies for IPF, thus the identification of novel therapeutic targets is greatly needed. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors whose activation has been linked to various pathologies. In healthy adult animals, RAGE is expressed at the highest levels in the lung compared to other tissues. To investigate the hypothesis that RAGE is involved in IPF pathogenesis, we have examined its expression in two mouse models of pulmonary fibrosis and in human tissue from IPF patients. In each instance we observed a depletion of membrane RAGE and its soluble (decoy) isoform, sRAGE, in fibrotic lungs. In contrast to other diseases in which RAGE signaling promotes pathology, immunohistochemical and hydroxyproline quantification studies on aged RAGE-null mice indicate that these mice spontaneously develop pulmonary fibrosis-like alterations. Furthermore, when subjected to a model of pulmonary fibrosis, RAGE-null mice developed more severe fibrosis, as measured by hydroxyproline assay and histological scoring, than wild-type controls. Combined with data from other studies on mouse models of pulmonary fibrosis and human IPF tissues indicate that loss of RAGE contributes to IPF pathogenesis. PMID:18245812

Should vitamin K be supplemented instead of antagonised in patients with idiopathic pulmonary fibrosis?

PubMed

De Brouwer, Bart; Piscaer, Ianthe; Von Der Thusen, Jan H; Grutters, Jan C; Schutgens, Roger Eg; Wouters, Emiel Fm; Janssen, Rob

2018-03-01

There is an ongoing need for additional interventions in idiopathic pulmonary fibrosis (IPF) as antifibrotic drugs currently available only inhibit and do not stall disease progression. Vitamin K is a co-factor for the activation of coagulation factors. However, it is also required to activate proteins with functions outside of the coagulation cascade, such as matrix Gla protein (MGP), a defender against soft tissue calcification. Vitamin K antagonists are anticoagulants that are, for unknown reasons, associated with increased mortality in IPF. Areas covered: We advance the hypothesis that modulation of vitamin K-dependent MGP activation in IPF patients by either vitamin K antagonism or administration may result in acceleration and deceleration of fibrosis progression, respectively. Furthermore, shortfall in vitamin K could be suspected in IPF based on the high prevalence of certain co-morbidities, such as vascular calcification and lung cancer. Expert commentary: We hypothesize that vitamin K status is reduced in IPF patients. This, in combination with studies suggesting that vitamin K may play a role in lung fibrosis pathogenesis, would provide a rationale for conducting a clinical trial assessing the potential mitigating effects of vitamin K administration on progression of lung fibrosis, prevention of co-morbidities and mortality in IPF.

Pattern uniformity control in integrated structures

NASA Astrophysics Data System (ADS)

Kobayashi, Shinji; Okada, Soichiro; Shimura, Satoru; Nafus, Kathleen; Fonseca, Carlos; Biesemans, Serge; Enomoto, Masashi

2017-03-01

In our previous paper dealing with multi-patterning, we proposed a new indicator to quantify the quality of final wafer pattern transfer, called interactive pattern fidelity error (IPFE). It detects patterning failures resulting from any source of variation in creating integrated patterns. IPFE is a function of overlay and edge placement error (EPE) of all layers comprising the final pattern (i.e. lower and upper layers). In this paper, we extend the use cases with Via in additional to the bridge case (Block on Spacer). We propose an IPFE budget and CD budget using simple geometric and statistical models with analysis of a variance (ANOVA). In addition, we validate the model with experimental data. From the experimental results, improvements in overlay, local-CDU (LCDU) of contact hole (CH) or pillar patterns (especially, stochastic pattern noise (SPN)) and pitch walking are all critical to meet budget requirements. We also provide a special note about the importance of the line length used in analyzing LWR. We find that IPFE and CD budget requirements are consistent to the table of the ITRS's technical requirement. Therefore the IPFE concept can be adopted for a variety of integrated structures comprising digital logic circuits. Finally, we suggest how to use IPFE for yield management and optimization requirements for each process.

Second harmonic generation microscopy analysis of extracellular matrix changes in human idiopathic pulmonary fibrosis

PubMed Central

Tilbury, Karissa; Hocker, James; Wen, Bruce L.; Sandbo, Nathan; Singh, Vikas; Campagnola, Paul J.

2014-01-01

Abstract. Patients with idiopathic fibrosis (IPF) have poor long-term survival as there are limited diagnostic/prognostic tools or successful therapies. Remodeling of the extracellular matrix (ECM) has been implicated in IPF progression; however, the structural consequences on the collagen architecture have not received considerable attention. Here, we demonstrate that second harmonic generation (SHG) and multiphoton fluorescence microscopy can quantitatively differentiate normal and IPF human tissues. For SHG analysis, we developed a classifier based on wavelet transforms, principle component analysis, and a K-nearest-neighbor algorithm to classify the specific alterations of the collagen structure observed in IPF tissues. The resulting ROC curves obtained by varying the numbers of principal components and nearest neighbors yielded accuracies of >95%. In contrast, simpler metrics based on SHG intensity and collagen coverage in the image provided little or no discrimination. We also characterized the change in the elastin/collagen balance by simultaneously measuring the elastin autofluorescence and SHG intensities and found that the IPF tissues were less elastic relative to collagen. This is consistent with known mechanical consequences of the disease. Understanding ECM remodeling in IPF via nonlinear optical microscopy may enhance our ability to differentiate patients with rapid and slow progression and, thus, provide better prognostic information. PMID:25134793

miR-185 and miR-29a are similarly expressed in the bronchoalveolar lavage cells in IPF and lung cancer but common targets DNMT1 and COL1A1 show disease specific patterns

PubMed Central

Bibaki, Eleni; Tsitoura, Eliza; Vasarmidi, Eirini; Margaritopoulos, George; Trachalaki, Athina; Koutoulaki, Chara; Georgopoulou, Theodora; Spandidos, Demetrios A.; Tzanakis, Nikos; Antoniou, Katerina M.

2018-01-01

Idiopathic pulmonary fibrosis (IPF) and lung cancer (LC) constitute two progressively devastating lung diseases with common risk factors including aging and smoking. There is an increasing interest in the investigation of common pathogenic mechanisms between IPF and LC with therapeutic implications. Several oncomirs, microRNAs associated with malignancy, are also linked with IPF. miR-29a and miR-185 downregulation is probably involved both in carcinogenesis and fibrogenesis. We have previously observed miR-29a and miR-185 downregulation in IPF cells from bronchoalveolar lavage (BAL) and in this study we investigated their expression in LC BAL cells. Common targets of miR-29a and miR-185 such as DNA methyltransferase (DNMT)1, DNMT3b, COL1A1, AKT1 and AKT2 were measured. Potential correlations with pulmonary function tests, smoking status and endobronchial findings were investigated. Similar levels of miR-29a and miR-185 were detected in IPF and LC while their common targets AKT1 and DNMT3b were not found to differ, suggesting potential pathogenetic similarities at the level of key epigenetic regulators. By conrast, COL1A1 mRNA levels were increased in IPF suggesting a disease-specific mRNA signature. Notably, DNMT1 was downregulated in the LC group and its expression was further reduced in the presence of increasing malignant burden as it was implied by the endobronchial findings. PMID:29568927

Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung.

PubMed

Sava, Parid; Ramanathan, Anand; Dobronyi, Amelia; Peng, Xueyan; Sun, Huanxing; Ledesma-Mendoza, Adrian; Herzog, Erica L; Gonzalez, Anjelica L

2017-12-21

Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown etiology characterized by a compositionally and mechanically altered extracellular matrix. Poor understanding of the origin of α-smooth muscle actin (α-SMA) expressing myofibroblasts has hindered curative therapies. Though proposed as a source of myofibroblasts in mammalian tissues, identification of microvascular pericytes (PC) as contributors to α-SMA-expressing populations in human IPF and the mechanisms driving this accumulation remain unexplored. Here, we demonstrate enhanced detection of α-SMA+ cells coexpressing the PC marker neural/glial antigen 2 in the human IPF lung. Isolated human PC cultured on decellularized IPF lung matrices adopt expression of α-SMA, demonstrating that these cells undergo phenotypic transition in response to direct contact with the extracellular matrix (ECM) of the fibrotic human lung. Using potentially novel human lung-conjugated hydrogels with tunable mechanical properties, we decoupled PC responses to matrix composition and stiffness to show that α-SMA+ PC accumulate in a mechanosensitive manner independent of matrix composition. PC activated with TGF-β1 remodel the normal lung matrix, increasing tissue stiffness to facilitate the emergence of α-SMA+ PC via MKL-1/MTRFA mechanotranduction. Nintedanib, a tyrosine-kinase inhibitor approved for IPF treatment, restores the elastic modulus of fibrotic lung matrices to reverse the α-SMA+ phenotype. This work furthers our understanding of the role that microvascular PC play in the evolution of IPF, describes the creation of an ex vivo platform that advances the study of fibrosis, and presents a potentially novel mode of action for a commonly used antifibrotic therapy that has great relevance for human disease.

Efficacy of pirfenidone and disease severity of idiopathic pulmonary fibrosis: Extended analysis of phase III trial in Japan.

PubMed

Taguchi, Yoshio; Ebina, Masahito; Hashimoto, Seishu; Ogura, Takashi; Azuma, Arata; Taniguchi, Hiroyuki; Kondoh, Yasuhiro; Suga, Moritaka; Takahashi, Hiroki; Nakata, Koichiro; Sugiyama, Yukihiko; Kudoh, Shoji; Nukiwa, Toshihiro

2015-11-01

A phase III clinical trial of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) in Japan has revealed that pirfenidone attenuated the decline in vital capacity (VC) and improved progression-free survival (PFS). We conducted an extended analysis of the pirfenidone trial to investigate its efficacy with respect to IPF severity in the trial population. Patients in the phase III trial were stratified by baseline pulmonary functions including %VC predicted, %diffusion capacity for carbon monoxide predicted, and oxygen saturation by pulse oximetry on exertion and were categorized into mild, moderate, and severe groups of functional impairment. The efficacy of pirfenidone for VC and PFS over 52 weeks was compared among the three sub-populations. Of 264 patients, 102 (39%), 90 (34%), and 72 patients (27%) were classified as having mild, moderate, and severe grades of functional impairment, respectively. This classification was associated with arterial oxygen partial pressure at rest and degree of dyspnea at baseline. While pirfenidone attenuated VC decline at all grades of severity, covariance analysis revealed pirfenidone to have better efficacy in the sub-population with mild-grade IPF. Mixed model repeated measures analysis confirmed that pirfenidone markedly attenuated VC decline in patients with mild-grade IPF compared to its effects in patients with moderate or severe IPF. Pirfenidone also improved PFS markedly in patients with mild-grade IPF. This extended analysis suggested that pirfenidone exerted better therapeutic effects in patients with milder IPF. Further analysis with a larger population is needed to confirm these results. Copyright © 2015. Published by Elsevier B.V.

Pirfenidone for acute exacerbation of idiopathic pulmonary fibrosis: A retrospective study.

PubMed

Furuya, Kenta; Sakamoto, Susumu; Shimizu, Hiroshige; Sekiya, Muneyuki; Kinoshita, Arisa; Isshiki, Takuma; Sugino, Keishi; Matsumoto, Keiko; Homma, Sakae

2017-05-01

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a rapid and ultimately fatal condition, and no effective treatment has been established. Pirfenidone has antifibrotic effects in IPF; however, its efficacy for AE-IPF is unclear. To evaluate the efficacy of pirfenidone for AE-IPF. We retrospectively reviewed the medical records of 135 IPF patients treated during the period from April 2008 to April 2015 and identified and extracted 47 AE-IPF patients (42 men, 5 women; mean age, 73.5 years). The clinical features and outcomes of the 20 patients treated with pirfenidone were compared with those of the 27 patients treated without pirfenidone. We then excluded the 25 patients who did not receive recombinant human soluble thrombomodulin (rhTM) and analyzed data from the remaining 22 patients (20 men, 2 women; mean age, 73.7 years). Clinical features and outcomes were compared between the 10 patients treated with pirfenidone and the 12 patients who did not receive pirfenidone. There were no significant differences between the two groups in baseline characteristics, except for pirfenidone use before onset. Three-month survival was significantly better in patients treated with pirfenidone than in the control group (55% vs 34%, p = 0.042). In univariate analysis, nonuse of pirfenidone was a potential risk factor for death at 3 months (hazard ratio, 6.993; p = 0.043) in patients treated with rhTM. A regimen of pirfenidone combined with corticosteroids and rhTM may improve survival in patients with AE-IPF. Copyright © 2017 Elsevier Ltd. All rights reserved.

Quantitative assessment of source contributions to PM2.5 on the west coast of Peninsular Malaysia to determine the burden of Indonesian peatland fire

NASA Astrophysics Data System (ADS)

Fujii, Yusuke; Tohno, Susumu; Amil, Norhaniza; Latif, Mohd Talib

2017-12-01

Almost every dry season, peatland fires occur in Sumatra and Kalimantan Inlands. Dense smoke haze from Indonesian peatland fires (IPFs) causes impacts on health, visibility, transport and regional climate in Southeast Asian countries such as Indonesia, Malaysia, and Singapore. Quantitative knowledge of IPF source contribution to ambient aerosols in Southeast Asia (SEA) is so useful to make appropriate suggestions to policy makers to mitigate IPF-induced haze pollution. However, its quantitative contribution to ambient aerosols in SEA remains unclarified. In this study, the source contributions to PM2.5 were determined by the Positive Matrix Factorization (PMF) model with annual comprehensive observation data at Petaling Jaya on the west coast of Peninsular Malaysia, which is downwind of the IPF areas in Sumatra Island, during the dry (southwest monsoon: June-September) season. The average PM2.5 mass concentration during the whole sampling periods (Aug 2011-Jul 2012) based on the PMF and chemical mass closure models was determined as 20-21 μg m-3. Throughout the sampling periods, IPF contributed (on average) 6.1-7.0 μg m-3 to the PM2.5, or ∼30% of the retrieved PM2.5 concentration. In particular, the PM2.5 was dominantly sourced from IPF during the southwest monsoon season (51-55% of the total PM2.5 concentration on average). Thus, reducing the IPF burden in the PM2.5 levels would drastically improve the air quality (especially during the southwest monsoon season) around the west coast of Peninsular Malaysia.

The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis.

PubMed

Kurowska-Stolarska, Mariola; Hasoo, Manhl K; Welsh, David J; Stewart, Lynn; McIntyre, Donna; Morton, Brian E; Johnstone, Steven; Miller, Ashley M; Asquith, Darren L; Millar, Neal L; Millar, Ann B; Feghali-Bostwick, Carol A; Hirani, Nikhil; Crick, Peter J; Wang, Yuqin; Griffiths, William J; McInnes, Iain B; McSharry, Charles

2017-06-01

Idiopathic pulmonary fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF; therefore, microRNAs may reveal novel pathogenic pathways. We sought to determine the regulatory role of microRNA (miR)-155 in the profibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts, and its contribution to experimental pulmonary fibrosis. Bleomycin-induced lung fibrosis in wild-type and miR-155 -/- mice was analyzed by histology, collagen, and profibrotic gene expression. Mechanisms were identified by in silico and molecular approaches and validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors. miR-155 -/- mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGF-β production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the profibrotic phenotype of IPF and miR-155 -/- fibroblasts. We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Recent advances in understanding idiopathic pulmonary fibrosis

PubMed Central

Daccord, Cécile; Maher, Toby M.

2016-01-01

Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF. PMID:27303645

Glucose Transporter-1 Distribution in Fibrotic Lung Disease

PubMed Central

Malide, Daniela; Yao, Jianhua; Nathan, Steven D.; Rosas, Ivan O.; Gahl, William A.; Moss, Joel; Gochuico, Bernadette R.

2013-01-01

Background: [18F]-2-fluoro-2-deoxyglucose (FDG)-PET scan uptake is increased in areas of fibrosis and honeycombing in patients with idiopathic pulmonary fibrosis (IPF). Glucose transporter-1 (Glut-1) is known to be the main transporter for FDG. There is a paucity of data regarding the distribution of Glut-1 and the cells responsible for FDG binding in fibrotic lung diseases. Methods: We applied immunofluorescence to localize Glut-1 in normal, IPF, and Hermansky-Pudlak syndrome (HPS) pulmonary fibrosis lung tissue specimens as well as an array of 19 different lung neoplasms. In addition, we investigated Glut-1 expression in inflammatory cells from BAL fluid (BALF) from healthy volunteers, subjects with IPF, and subjects with HPS pulmonary fibrosis. Results: In normal lung tissue, Glut-1 immunoreactivity was seen on the surface of erythrocytes. In tissue sections from fibrotic lung diseases (IPF and HPS pulmonary fibrosis), Glut-1 immunoreactivity was present on the surface of erythrocytes and inflammatory cells. BALF inflammatory cells from healthy control subjects showed no immunoreactivity; BALF cells from subjects with IPF and HPS pulmonary fibrosis showed Glut-1 immunoreactivity associated with neutrophils and alveolar macrophages. Conclusions: Glut-1 transporter expression in normal lung is limited to erythrocytes. In fibrotic lung, erythrocytes and inflammatory cells express Glut-1. Together, these data suggest that FDG-PET scan uptake in IPF could be explained by enhanced inflammatory and erythrocytes uptake due to neovascularization seen in IPF and not an upregulation of metabolic rate in pneumocytes. Thus, FDG-PET scan may detect inflammation and neovascularization in lung fibrosis. PMID:23699745

Integrated Genomics Reveals Convergent Transcriptomic Networks Underlying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis.

PubMed

Kusko, Rebecca L; Brothers, John F; Tedrow, John; Pandit, Kusum; Huleihel, Luai; Perdomo, Catalina; Liu, Gang; Juan-Guardela, Brenda; Kass, Daniel; Zhang, Sherry; Lenburg, Marc; Martinez, Fernando; Quackenbush, John; Sciurba, Frank; Limper, Andrew; Geraci, Mark; Yang, Ivana; Schwartz, David A; Beane, Jennifer; Spira, Avrum; Kaminski, Naftali

2016-10-15

Despite shared environmental exposures, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease are usually studied in isolation, and the presence of shared molecular mechanisms is unknown. We applied an integrative genomic approach to identify convergent transcriptomic pathways in emphysema and IPF. We defined the transcriptional repertoire of chronic obstructive pulmonary disease, IPF, or normal histology lungs using RNA-seq (n = 87). Genes increased in both emphysema and IPF relative to control were enriched for the p53/hypoxia pathway, a finding confirmed in an independent cohort using both gene expression arrays and the nCounter Analysis System (n = 193). Immunohistochemistry confirmed overexpression of HIF1A, MDM2, and NFKBIB members of this pathway in tissues from patients with emphysema or IPF. Using reads aligned across splice junctions, we determined that alternative splicing of p53/hypoxia pathway-associated molecules NUMB and PDGFA occurred more frequently in IPF or emphysema compared with control and validated these findings by quantitative polymerase chain reaction and the nCounter Analysis System on an independent sample set (n = 193). Finally, by integrating parallel microRNA and mRNA-Seq data on the same samples, we identified MIR96 as a key novel regulatory hub in the p53/hypoxia gene-expression network and confirmed that modulation of MIR96 in vitro recapitulates the disease-associated gene-expression network. Our results suggest convergent transcriptional regulatory hubs in diseases as varied phenotypically as chronic obstructive pulmonary disease and IPF and suggest that these hubs may represent shared key responses of the lung to environmental stresses.

Idiopathic Pulmonary Fibrosis and the Elderly: Diagnosis and Management Considerations.

PubMed

Jo, Helen E; Randhawa, Sharan; Corte, Tamera J; Moodley, Yuben

2016-05-01

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive fibrosing interstitial lung disease, which ultimately results in respiratory failure and death. The median age at diagnosis is 66 years, and the incidence increases with age, making this a disease that predominantly affects the elderly population. IPF can often be difficult to diagnose, as its symptoms--cough, dyspnoea and fatigue--are non-specific and can often be attributed to co-morbidities such as heart failure and chronic obstructive pulmonary disease. Making an accurate diagnosis of IPF is imperative, as new treatments that appear to slow the progression of IPF have recently become available. Pirfenidone and nintedanib are two such treatments, which have shown efficacy in randomised controlled trials. As with all new treatments, caution must be advocated in the elderly, as these patients often lie outside the narrow clinical trial cohorts that are studied, and the benefits of therapy must be weighed against potential toxicities. Both medications, while relatively safe, have been associated with adverse effects, particularly gastrointestinal symptoms such as nausea, diarrhoea and anorexia. In this review, we highlight measures to improve recognition and accurate diagnosis of IPF, as well as co-morbidities that often affect the diagnosis and disease course. The gold standard for IPF diagnosis is a multidisciplinary meeting whereby clinicians, radiologists and histopathologists reach a consensus after interactive discussion. In many cases, a lung biopsy may not be available because of high risk or patient choice, particularly in the elderly. In these cases, there is debate as to whether a biopsy is required, given the high rates of IPF in patients over the age of 70 years with interstitial changes on computed tomography. We also discuss the management of IPF, drawing particular attention to specific issues affecting the elderly population, especially with regard to polypharmacy and end-of-life care. Through this article, we endeavour to improve awareness of this devastating disease and thus improve recognition of the disease and its outcomes in elderly patients.

miR-34 miRNAs Regulate Cellular Senescence in Type II Alveolar Epithelial Cells of Patients with Idiopathic Pulmonary Fibrosis

PubMed Central

Disayabutr, Supparerk; Kim, Eun Kyung; Cha, Seung-Ick; Green, Gary; Naikawadi, Ram P.; Jones, Kirk D.; Golden, Jeffrey A.; Schroeder, Aaron; Matthay, Michael A.; Kukreja, Jasleen; Erle, David J.; Collard, Harold R.; Wolters, Paul J.

2016-01-01

Pathologic features of idiopathic pulmonary fibrosis (IPF) include genetic predisposition, activation of the unfolded protein response, telomere attrition, and cellular senescence. The mechanisms leading to alveolar epithelial cell (AEC) senescence are poorly understood. MicroRNAs (miRNAs) have been reported as regulators of cellular senescence. Senescence markers including p16, p21, p53, and senescence-associated β-galactosidase (SA-βgal) activity were measured in type II AECs from IPF lungs and unused donor lungs. miRNAs were quantified in type II AECs using gene expression arrays and quantitative RT-PCR. Molecular markers of senescence (p16, p21, and p53) were elevated in IPF type II AECs. SA-βgal activity was detected in a greater percentage in type II AECs isolated from IPF patients (23.1%) compared to patients with other interstitial lung diseases (1.2%) or normal controls (0.8%). The relative levels of senescence-associated miRNAs miR-34a, miR-34b, and miR-34c, but not miR-20a, miR-29c, or miR-let-7f were significantly higher in type II AECs from IPF patients. Overexpression of miR-34a, miR-34b, or miR-34c in lung epithelial cells was associated with higher SA-βgal activity (27.8%, 35.1%, and 38.2%, respectively) relative to control treated cells (8.8%). Targets of miR-34 miRNAs, including E2F1, c-Myc, and cyclin E2, were lower in IPF type II AECs. These results show that markers of senescence are uniquely elevated in IPF type II AECs and suggest that the miR-34 family of miRNAs regulate senescence in IPF type II AECs. PMID:27362652

Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis.

PubMed

Li, Fu Jun; Surolia, Ranu; Li, Huashi; Wang, Zheng; Kulkarni, Tejaswini; Liu, Gang; de Andrade, Joao A; Kass, Daniel J; Thannickal, Victor J; Duncan, Steven R; Antony, Veena B

2017-09-01

Autoimmunity has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the repertoire of autoantigens involved in this disease and the clinical relevance of these autoimmune responses are still being explored. Our initial discovery assays demonstrated that circulating and intrapulmonary vimentin levels are increased in IPF patients. Subsequent studies showed native vimentin induced HLA-DR-dependent in vitro proliferation of CD4 T cells from IPF patients and enhanced the production of IL-4, IL-17, and TGF-β1 by these lymphocytes in contrast to normal control specimens. Vimentin supplementation of IPF PBMC cultures also resulted in HLA-DR-dependent production of IgG with anti-vimentin specificities. Circulating anti-vimentin IgG autoantibody levels were much greater in IPF subjects from the University of Alabama at Birmingham ( n = 102) and the University of Pittsburgh (U. Pitt., n = 70) than in normal controls. Anti-vimentin autoantibody levels in IPF patients were HLA biased and inversely correlated with physiological measurements of lung function (i.e., forced expiratory volumes and diffusing capacities). Despite considerable intergroup differences in transplant-free survival between these two independent IPF cohorts, serious adverse outcomes were most frequent among the patients within each population that had the highest anti-vimentin autoantibody levels (University of Alabama at Birmingham: hazard ratio 2.5, 95% confidence interval 1.2-5.3, p = 0.012; University of Pittsburgh: hazard ratio 2.7, 95% confidence interval 1.3-5.5, p = 0.006). These data show that anti-vimentin autoreactivity is prevalent in IPF patients and is strongly associated with disease manifestations. These findings have implications with regard to the pathogenesis of this enigmatic disease and raise the possibility that therapies specifically directed at these autoimmune processes could have therapeutic efficacy. Copyright © 2017 by The American Association of Immunologists, Inc.

Pulmonary 18F-FDG uptake helps refine current risk stratification in idiopathic pulmonary fibrosis (IPF).

PubMed

Win, Thida; Screaton, Nicholas J; Porter, Joanna C; Ganeshan, Balaji; Maher, Toby M; Fraioli, Francesco; Endozo, Raymondo; Shortman, Robert I; Hurrell, Lynn; Holman, Beverley F; Thielemans, Kris; Rashidnasab, Alaleh; Hutton, Brian F; Lukey, Pauline T; Flynn, Aiden; Ell, Peter J; Groves, Ashley M

2018-05-01

There is a lack of prognostic biomarkers in idiopathic pulmonary fibrosis (IPF) patients. The objective of this study is to investigate the potential of 18 F-FDG-PET/ CT to predict mortality in IPF. A total of 113 IPF patients (93 males, 20 females, mean age ± SD: 70 ± 9 years) were prospectively recruited for 18 F-FDG-PET/CT. The overall maximum pulmonary uptake of 18 F-FDG (SUV max ), the minimum pulmonary uptake or background lung activity (SUV min ), and target-to-background (SUV max / SUV min ) ratio (TBR) were quantified using routine region-of-interest analysis. Kaplan-Meier analysis was used to identify associations of PET measurements with mortality. We also compared PET associations with IPF mortality with the established GAP (gender age and physiology) scoring system. Cox analysis assessed the independence of the significant PET measurement(s) from GAP score. We investigated synergisms between pulmonary 18 F-FDG-PET measurements and GAP score for risk stratification in IPF patients. During a mean follow-up of 29 months, there were 54 deaths. The mean TBR ± SD was 5.6 ± 2.7. Mortality was associated with high pulmonary TBR (p = 0.009), low forced vital capacity (FVC; p = 0.001), low transfer factor (TLCO; p < 0.001), high GAP index (p = 0.003), and high GAP stage (p = 0.003). Stepwise forward-Wald-Cox analysis revealed that the pulmonary TBR was independent of GAP classification (p = 0.010). The median survival in IPF patients with a TBR < 4.9 was 71 months, whilst in those with TBR > 4.9 was 24 months. Combining PET data with GAP data ("PET modified GAP score") refined the ability to predict mortality. A high pulmonary TBR is independently associated with increased risk of mortality in IPF patients.

Change in forced vital capacity and associated subsequent outcomes in patients with newly diagnosed idiopathic pulmonary fibrosis.

PubMed

Reichmann, William M; Yu, Yanni F; Macaulay, Dendy; Wu, Eric Q; Nathan, Steven D

2015-12-29

Idiopathic pulmonary fibrosis (IPF) is a rare and serious disease characterized by progressive lung-function loss. Limited evidence has been published on the impact of lung-function loss on subsequent patient outcomes. This study examined change in forced vital capacity (FVC) across IPF patients in the 6 months after diagnosis and its association with clinical and healthcare resource utilization (HRU) outcomes in a real-world setting in the U.S. A retrospective chart review was conducted of patients diagnosed with IPF by U.S. pulmonologists. Patient eligibility criteria included: 1) 40 years or older with a confirmed date of first IPF diagnosis with high-resolution computed tomography and/or lung biopsy between 01/2011 and 06/2013; 2) FVC results recorded at first diagnosis (±1 month) and at 6 months (±3 months) following diagnosis. Based on relative change in FVC percent predicted (FVC%), patients were categorized as stable (decline <5%), marginal decline (decline ≥5% and <10%), or significant decline (decline ≥10%). Physician-reported clinical and HRU outcomes were assessed from ~6 months post-diagnosis until the last contact date with the physician and compared between FVC% change groups. Multivariable Cox proportional-hazards models were constructed to assess risk of mortality, suspected acute exacerbation (AEx), and hospitalization post-FVC% change. Generalized estimating equations were used to account for multiple patients contributed by individual physicians. The sample included 490 IPF patients contributed by 168 pulmonologists. The mean (SD) age was 61 (11) years, 68% were male, and the mean (SD) baseline FVC% was 60% (26%). 250 (51%) patients were categorized as stable, 98 (20%) as marginal decline, and 142 (29%) as significant decline. The mean (SD) observation time was 583 (287) days. In both unadjusted analysis and multivariable models, significantly worse clinical outcomes and increased HRU were observed with greater lung-function decline. These findings suggest that nearly half of IPF patients experienced decline in FVC% within ~6 months following IPF diagnosis. Greater FVC% decline was associated with an increased risk of further IPF progression, suspected AEx, mortality, and higher rate of HRU. Management options that slow FVC decline may help improve future health outcomes in IPF.

Immunohistochemical and morphometric evaluation of COX-1 and COX-2 in the remodeled lung in idiopathic pulmonary fibrosis and systemic sclerosis* ,**

PubMed Central

Parra, Edwin Roger; Lin, Flavia; Martins, Vanessa; Rangel, Maristela Peres; Capelozzi, Vera Luiza

2013-01-01

OBJECTIVE: To study the expression of COX-1 and COX-2 in the remodeled lung in systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) patients, correlating that expression with patient survival. METHODS: We examined open lung biopsy specimens from 24 SSc patients and 30 IPF patients, using normal lung tissue as a control. The histological patterns included fibrotic nonspecific interstitial pneumonia (NSIP) in SSc patients and usual interstitial pneumonia (UIP) in IPF patients. We used immunohistochemistry and histomorphometry to evaluate the expression of COX-1 and COX-2 in alveolar septa, vessels, and bronchioles. We then correlated that expression with pulmonary function test results and evaluated its impact on patient survival. RESULTS: The expression of COX-1 and COX-2 in alveolar septa was significantly higher in IPF-UIP and SSc-NSIP lung tissue than in the control tissue. No difference was found between IPF-UIP and SSc-NSIP tissue regarding COX-1 and COX-2 expression. Multivariate analysis based on the Cox regression model showed that the factors associated with a low risk of death were younger age, high DLCO/alveolar volume, IPF, and high COX-1 expression in alveolar septa, whereas those associated with a high risk of death were advanced age, low DLCO/alveolar volume, SSc (with NSIP), and low COX-1 expression in alveolar septa. CONCLUSIONS: Our findings suggest that strategies aimed at preventing low COX-1 synthesis will have a greater impact on SSc, whereas those aimed at preventing high COX-2 synthesis will have a greater impact on IPF. However, prospective randomized clinical trials are needed in order to confirm that. PMID:24473763

Pulmonary Function and Survival in Idiopathic vs Secondary Usual Interstitial Pneumonia

PubMed Central

Strand, Matthew J.; Sprunger, David; Cosgrove, Gregory P.; Fernandez-Perez, Evans R.; Frankel, Stephen K.; Huie, Tristan J.; Olson, Amy L.; Solomon, Joshua; Brown, Kevin K.

2014-01-01

BACKGROUND: The usual interstitial pneumonia (UIP) pattern of lung injury may occur in the setting of connective tissue disease (CTD), but it is most commonly found in the absence of a known cause, in the clinical context of idiopathic pulmonary fibrosis (IPF). Our objective was to observe and compare longitudinal changes in pulmonary function and survival between patients with biopsy-proven UIP found in the clinical context of either CTD or IPF. METHODS: We used longitudinal data analytic models to compare groups (IPF [n = 321] and CTD-UIP [n = 56]) on % predicted FVC (FVC %) or % predicted diffusing capacity of the lung for carbon monoxide (Dlco %), and we used both unadjusted and multivariable techniques to compare survival between these groups. RESULTS: There were no significant differences between groups in longitudinal changes in FVC % or Dlco % up to diagnosis, or from diagnosis to 10 years beyond (over which time, the mean decrease in FVC % per year [95% CI] was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for CTD-UIP, P = .49 for difference; and the mean decrease in Dlco % per year was 4.7 [4.0, 5.3] for IPF and 4.3 [3.0, 5.6] for CTD-UIP, P = .60 for difference). Despite the lack of differences in pulmonary function, subjects with IPF had worse survival in unadjusted (log-rank P = .003) and certain multivariable analyses. CONCLUSIONS: Despite no significant differences in changes in pulmonary function over time, patients with CTD-UIP (at least those with certain classifiable CTDs) live longer than patients with IPF—an observation that we suspect is due to an increased rate of mortal acute exacerbations in patients with IPF. PMID:24700149

Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis

PubMed Central

Inomata, Minoru; Nishioka, Yasuhiko; Azuma, Arata

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. The molecular mechanisms involved in the progression of IPF are not fully understood; however, the platelet-derived growth factor (PDGF)/PDGF receptor pathway is thought to play a critical role in fibrogenesis of the lungs. Other growth factors, including fibroblast growth factor and vascular endothelial growth factor, are also thought to contribute to the pathogenesis of pulmonary fibrosis. Nintedanib is an inhibitor of multiple tyrosine kinases, including receptors for PDGF, fibroblast growth factor, and vascular endothelial growth factor. In the Phase II TOMORROW trial, treatment with 150 mg of nintedanib twice daily showed a trend to slow the decline in lung function and significantly decrease acute exacerbations in patients with IPF, while showing an acceptable safety profile. The Phase III INPULSIS trials demonstrated a significant decrease in the annual rate of decline in forced vital capacity in IPF patients treated with 150 mg nintedanib twice daily. In the INPULSIS-2 trial, the time to the first acute exacerbation significantly increased in IPF patients who were treated with 150 mg of nintedanib twice daily. Pirfenidone, another antifibrotic drug, was shown to limit the decline in pulmonary function in patients with IPF in the ASCEND trial. Combination therapy with nintedanib and pirfenidone is anticipated, although further evaluation of its long-term safety is needed. There is limited evidence for the safety of the combination therapy although a Phase II trial conducted in Japan demonstrated that combination therapy with nintedanib and pirfenidone was tolerable for 1 month. Available antifibrotic agents (ie, pirfenidone and N-acetylcysteine) have limited efficacy as single therapies for IPF; therefore, further study of combination therapy with antifibrotic agents is needed. PMID:26346347

Measurement of immature platelets with Abbott CD-Sapphire and Sysmex XE-5000 in haematology and oncology patients.

PubMed

Meintker, Lisa; Haimerl, Maria; Ringwald, Jürgen; Krause, Stefan W

2013-11-01

Measurement of immature platelets was introduced into routine diagnostics by Sysmex as immature platelet fraction (IPF) some years ago and recently by Abbott as reticulated platelet fraction (rPT). Here, we compare both methods. We evaluated the precision and agreement of these parameters between Sysmex XE-5000 and Abbott CD-Sapphire in three distinct thrombocytopaenic cohorts: 30 patients with beginning thrombocytopaenia and 64 patients with recovering platelets (PLT) after chemotherapy, 16 patients with immune thrombocytopaenia (ITP) or heparin-induced thrombocytopaenia type 2 (HIT) and 110 additional normal controls. Furthermore, we analysed, how IPF/rPT differed between these thrombocytopaenic cohorts and controls. Both analysers demonstrated acceptable overall precision (repeatability) of IPF/rPT with lower precision at low PLT counts. IPF/rPT artificially increased during storage of blood samples overnight. Inter-instrument comparison showed a moderate correlation (Pearson r²=0.38) and a systematic bias of 1.04 towards higher IPF-values with the XE-5000. IPF/rPT was highest in recovering thrombopoesis after chemotherapy and moderately increased in ITP/HIT. The normal range deduced from control samples was much narrower with CD-Sapphire (1.0%-3.8%, established here for the first time) in comparison to XE-5000 (0.8%-7.9%) leading to a smaller overlap of samples with increased PLT turnover and normal controls. IPF and rPT both give useful information on PLT turnover, although the two analysers only show a moderate inter-instrument correlation and have different reference ranges. A better separation of patient groups with high PLT turnover like ITP/HIT from normal controls is obtained by CD-Sapphire.

Smoking-related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung.

PubMed

Antoniou, Katerina M; Walsh, Simon L; Hansell, David M; Rubens, Michael R; Marten, Katharina; Tennant, Rachel; Hansel, Trevor; Desai, Sujal R; Siafakas, Nikolaos M; du Bois, Roland M; Wells, Athol U

2013-11-01

A combined pulmonary fibrosis/emphysema syndrome has been proposed, but the basis for this syndrome is currently uncertain. The aim was to evaluate the prevalence of emphysema in idiopathic pulmonary fibrosis (IPF) and rheumatoid lung (rheumatoid arthritis-interstitial lung disease (RA-ILD)), and to compare the morphological features of lung fibrosis between smokers and non-smokers. Using high-resolution computed tomography, the prevalence of emphysema and the pack-year smoking histories associated with emphysema were compared between current/ex-smokers with IPF (n = 186) or RA-ILD (n = 46), and non-chronic obstructive pulmonary disease (COPD) controls (n = 103) and COPD controls (n = 34). The coarseness of fibrosis was compared between smokers and non-smokers. Emphysema, present in 66/186 (35%) patients with IPF and 22/46 (48%) smokers with RA-ILD, was associated with lower pack-year smoking histories than in control groups (P < 0.05 for all comparisons). The presence of emphysema in IPF was positively linked to the pack-year smoking history (odds ratio 1.04, 95% confidence interval (CI) 1.02-1.06, P < 0.0005). In IPF, fibrosis was coarser in smokers than in non-smokers on univariate and multivariate analysis (P < 0.01 for all comparisons). In RA-ILD, fibrosis was coarser in patients with emphysema but did not differ significantly between smokers and non-smokers. In IPF and RA-ILD, a high prevalence of concurrent emphysema, in association with low pack-year smoking histories, and an association between coarser pulmonary fibrosis and a history of smoking in IPF together provide support for possible pathogenetic linkage to smoking in both diseases. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.

MicroRNA-29c regulates apoptosis sensitivity via modulation of the cell-surface death receptor, Fas, in lung fibroblasts.

PubMed

Matsushima, Shingo; Ishiyama, Junichi

2016-12-01

MicroRNAs play an important role in the development and progression of various diseases, such as idiopathic pulmonary fibrosis (IPF). Although the accumulation of aberrant fibroblasts resistant to apoptosis is a hallmark in IPF lungs, the mechanism regulating apoptosis susceptibility is not fully understood. Here, we investigated the role of miR-29, which is the most downregulated microRNA in IPF lungs and is also known as a regulator of extracellular matrix (ECM), in the mechanism of apoptosis resistance. We found that functional inhibition of miR-29c caused resistance to Fas-mediated apoptosis in lung fibroblasts. Furthermore, experiments using miR-29c inhibitor and miR-29c mimic revealed that miR-29c regulated expression of the death receptor, Fas, and formation of death-inducing signaling complex leading to extrinsic apoptosis. The representative profibrotic transforming growth factor (TGF)-β downregulated the expression of miR-29c as well as Fas receptor and conferred resistance to apoptosis. We also found that introduction of miR-29c mimic abrogated these TGF-β-induced phenotypes of Fas repression and apoptosis resistance. The results presented here suggest that downregulation of miR-29 observed in IPF lungs may be associated with the apoptosis-resistant phenotype of IPF lung fibroblasts via downregulation of Fas receptor. Therefore, restoration of miR-29 expression in IPF lungs could not only inhibit the accumulation of ECM but also normalize the sensitivity to apoptosis in lung fibroblasts, which may be an effective strategy for treatment of IPF. Copyright © 2016 the American Physiological Society.

Bronchoscopic Lung Cryobiopsy Increases Diagnostic Confidence in the Multidisciplinary Diagnosis of Idiopathic Pulmonary Fibrosis.

PubMed

Tomassetti, Sara; Wells, Athol U; Costabel, Ulrich; Cavazza, Alberto; Colby, Thomas V; Rossi, Giulio; Sverzellati, Nicola; Carloni, Angelo; Carretta, Elisa; Buccioli, Matteo; Tantalocco, Paola; Ravaglia, Claudia; Gurioli, Christian; Dubini, Alessandra; Piciucchi, Sara; Ryu, Jay H; Poletti, Venerino

2016-04-01

Surgical lung biopsy is often required for a confident multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF). Alternative, less-invasive biopsy methods, such as bronchoscopic lung cryobiopsy (BLC), are highly desirable. To address the impact of BLC on diagnostic confidence in the multidisciplinary diagnosis of IPF. In this cross-sectional study we selected 117 patients with fibrotic interstitial lung disease without a typical usual interstitial pneumonia pattern on high-resolution computed tomography. All cases underwent lung biopsies: 58 were BLC, and 59 were surgical lung biopsy (SLB). Two clinicians, two radiologists, and two pathologists sequentially reviewed clinical-radiologic findings and biopsy results, recording at each step in the process their diagnostic impressions and confidence levels. We observed a major increase in diagnostic confidence after the addition of BLC, similar to SLB (from 29 to 63%, P = 0.0003 and from 30 to 65%, P = 0.0016 of high confidence IPF diagnosis, in the BLC group and SLB group, respectively). The overall interobserver agreement in IPF diagnosis was similar for both approaches (BLC overall kappa, 0.96; SLB overall kappa, 0.93). IPF was the most frequent diagnosis (50 and 39% in the BLC and SLB group, respectively; P = 0.23). After the addition of histopathologic information, 17% of cases in the BLC group and 19% of cases in the SLB group, mostly idiopathic nonspecific interstitial pneumonia and hypersensitivity pneumonitis, were reclassified as IPF. BLC is a new biopsy method that has a meaningful impact on diagnostic confidence in the multidisciplinary diagnosis of interstitial lung disease and may prove useful in the diagnosis of IPF. This study provides a robust rationale for future studies investigating the diagnostic accuracy of BLC compared with SLB.

Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis.

PubMed

Espindola, Milena S; Habiel, David M; Narayanan, Rohan; Jones, Isabelle; Coelho, Ana L; Murray, Lynne A; Jiang, Dianhua; Noble, Paul W; Hogaboam, Cory M

2018-06-01

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling, which progressively abolishes lung function in an RTK (receptor tyrosine kinase)-dependent manner. Gas6 (growth arrest-specific 6) ligand, Tyro3 (TYRO3 protein tyrosine kinase 3), and Axl (anexelekto) RTK expression and activity are increased in IPF. To determine if targeting these RTK pathways would inhibit fibroblast activation and the development of pulmonary fibrosis. Quantitative genomic, proteomic, and functional analyses were used to determine Gas6/TAM (Tyro3, Axl, and Mertk [MER proto-oncogene, tyrosine kinase]) RTK expression and activation in tissues and fibroblasts from normal and IPF lungs. The profibrotic impact of these RTK pathways were also examined in bleomycin-induced pulmonary fibrosis and in SCID/Bg mice that developed pulmonary fibrosis after the intravenous administration of primary IPF fibroblasts. Gas6, Axl, and Tyro3 were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts. Targeting these pathways with either specific antibodies directed at Gas6 or Axl, or with small-molecule TAM inhibitors indicated that the small molecule-mediated targeting approach was more efficacious in both in vitro and in vivo studies. Specifically, the TAM receptor inhibitor R428 (also known as BGB324) significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6/TAM receptor targeting agents. Finally, loss of Gas6 expression decreased lung fibrotic responses to bleomycin and treatment with R428 inhibited pulmonary fibrosis in humanized SCID/Bg mice. Gas6/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF, suggesting that targeting this RTK pathway might be an effective antifibrotic strategy in this disease.

UK asbestos imports and mortality due to idiopathic pulmonary fibrosis.

PubMed

Barber, C M; Wiggans, R E; Young, C; Fishwick, D

2016-03-01

Previous studies have demonstrated that the rising mortality due to mesothelioma and asbestosis can be predicted from historic asbestos usage. Mortality due to idiopathic pulmonary fibrosis (IPF) is also rising, without any apparent explanation. To compare mortality due to these conditions and examine the relationship between mortality and national asbestos imports. Mortality data for IPF and asbestosis in England and Wales were available from the Office for National Statistics. Data for mesothelioma deaths in England and Wales and historic UK asbestos import data were available from the Health & Safety Executive. The numbers of annual deaths due to each condition were plotted separately by gender, against UK asbestos imports 48 years earlier. Linear regression models were constructed. For mesothelioma and IPF, there was a significant linear relationship between the number of male and female deaths each year and historic UK asbestos imports. For asbestosis mortality, a similar relationship was found for male but not female deaths. The annual numbers of deaths due to asbestosis in both sexes were lower than for IPF and mesothelioma. The strength of the association between IPF mortality and historic asbestos imports was similar to that seen in an established asbestos-related disease, i.e. mesothelioma. This finding could in part be explained by diagnostic difficulties in separating asbestosis from IPF and highlights the need for a more accurate method of assessing lifetime occupational asbestos exposure. © Crown copyright 2015.

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

PubMed Central

Mizuno, Takako; Sridharan, Anusha; Du, Yina; Guo, Minzhe; Wikenheiser-Brokamp, Kathryn A.; Perl, Anne-Karina T.; Funari, Vincent A.; Gokey, Jason J.; Stripp, Barry R.; Whitsett, Jeffrey A.

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease characterized by airway remodeling, inflammation, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing (scRNA-seq) to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 (AT2) cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in IPF. Individual IPF cells frequently coexpressed alveolar type 1 (AT1), AT2, and conducting airway selective markers, demonstrating “indeterminate” states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-β, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. The present study provides a rich data source to further explore lung health and disease. PMID:27942595

The hedgehog system machinery controls transforming growth factor-β-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis.

PubMed

Cigna, Natacha; Farrokhi Moshai, Elika; Brayer, Stéphanie; Marchal-Somme, Joëlle; Wémeau-Stervinou, Lidwine; Fabre, Aurélie; Mal, Hervé; Lesèche, Guy; Dehoux, Monique; Soler, Paul; Crestani, Bruno; Mailleux, Arnaud A

2012-12-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in IPF. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog (SHH) pathway members in normal and IPF human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor (TGF)-β1. We showed that the hedgehog pathway was reactivated in the IPF lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-β pathway in human lung fibroblasts. TGF-β1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-β1-induced myofibroblastic differentiation of control fibroblasts, but differentiation of IPF fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the TGF-β1 effects on normal and IPF fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Nintedanib (OFEV) in the treatment of idiopathic pulmonary fibrosis.

PubMed

Fukihara, Jun; Kondoh, Yasuhiro

2016-12-01

Nintedanib is a new anti-fibrosis agent that is an intracellular tyrosine kinase inhibitor targeting platelet derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor. Although nintedanib is attracting much attention as a new treatment option for patients with idiopathic pulmonary fibrosis (IPF), the clinical evidence is limited mainly to the results from the dose-deciding phase II TOMORROW trial and phase III INPULSIS trials, which evaluated efficacy and safety of nintedanib for patients with IPF, prespecified subgroup analyses, pooled analyses and meta-analyses derived from those trials. Areas covered: In this document, we mainly reviewed reports on working mechanisms of nintedanib, and efficacy and safety of nintedanib for patients with IPF. The literature search was undertaken using Pub Med. Expert commentary: It is unknown whether the efficacy of nintedanib in patients enrolled in the clinical trials will be the same for the entire spectrum of patients, including patients unfit for the clinical trials due to age, severity, timing of IPF diagnosis or diagnosis of interstitial pneumonias other than IPF. Sufficient consideration should be given when selecting candidates for nintedanib in the real world.

A safety evaluation of pirfenidone for the treatment of idiopathic pulmonary fibrosis.

PubMed

Anderson, Adam; Shifren, Adrian; Nathan, Steven D

2016-07-01

Pirfenidone is a novel oral anti-fibrotic agent approved for the treatment of idiopathic pulmonary fibrosis (IPF). Since IPF is a chronic and progressive disease most commonly encountered in an older population, therapeutic options should be not only effective, but also free from drug interactions and as safe and tolerable as possible. Comprehensive data from randomized controlled trials, meta-analyses, safety studies, and post-marketing data are available to assess the efficacy and safety of pirfenidone in the treatment of IPF. Information on efficacy, adverse events, drug tolerability and discontinuation rates both in clinical trials and real-world clinical experiences are reported. Pirfenidone has an abundance of data supporting its use in mild-to-moderate IPF. Observational evidence suggests a similar efficacy in severe IPF. In clinical trials, observational studies and real-world use, adverse events are frequent, though generally mild and well tolerated, especially with adequate patient education. Preventative strategies, along with timely and appropriate management of adverse events are critical in improving patient compliance, thereby ensuring the benefits of long-term treatment with pirfenidone.

Flexibility and fatigue evaluation of oblique as compared with anterior lumbar interbody cages with integrated endplate fixation.

PubMed

Freeman, Andrew L; Camisa, William J; Buttermann, Glenn R; Malcolm, James R

2016-01-01

This study was undertaken to quantify the in vitro range of motion (ROM) of oblique as compared with anterior lumbar interbody devices, pullout resistance, and subsidence in fatigue. Anterior and oblique cages with integrated plate fixation (IPF) were tested using lumbar motion segments. Flexibility tests were conducted on the intact segments, cage, cage + IPF, and cage + IPF + pedicle screws (6 anterior, 7 oblique). Pullout tests were then performed on the cage + IPF. Fatigue testing was conducted on the cage + IPF specimens for 30,000 cycles. No ROM differences were observed in any test group between anterior and oblique cage constructs. The greatest reduction in ROM was with supplemental pedicle screw fixation. Peak pullout forces were 637 ± 192 N and 651 ± 127 N for the anterior and oblique implants, respectively. The median cage subsidence was 0.8 mm and 1.4 mm for the anterior and oblique cages, respectively. Anterior and oblique cages similarly reduced ROM in flexibility testing, and the integrated fixation prevented device displacement. Subsidence was minimal during fatigue testing, most of which occurred in the first 2500 cycles.

Treatment of idiopathic pulmonary fibrosis in Australia and New Zealand: A position statement from the Thoracic Society of Australia and New Zealand and the Lung Foundation Australia.

PubMed

Jo, Helen E; Troy, Lauren K; Keir, Gregory; Chambers, Daniel C; Holland, Anne; Goh, Nicole; Wilsher, Margaret; de Boer, Sally; Moodley, Yuben; Grainge, Christopher; Whitford, Helen; Chapman, Sally; Reynolds, Paul N; Glaspole, Ian; Beatson, David; Jones, Leonie; Hopkins, Peter; Corte, Tamera J

2017-10-01

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease (ILD) of unknown aetiology with a median survival of only 2-5 years. It is characterized by progressive dyspnoea and worsening lung function, ultimately resulting in death. Until recently, there were no effective therapies for IPF; however, with the publication of two landmark clinical trials in 2014, the anti-fibrotic therapies, nintedanib and pirfenidone, have gained widespread approval. This position paper aims to highlight the current evidence for the treatment of IPF, with particular application to the Australian and New Zealand population. We also consider areas in which evidence is currently lacking, especially with regard to the broader IPF severity spectrum and treatment of co-morbid conditions. The utility of non-pharmacological therapies including pulmonary rehabilitation, oxygen as well as symptom management thought to be important in the holistic care of IPF patients are also discussed. © 2017 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.

Effects of hypoxia and hyperoxia on the differential expression of VEGF-A isoforms and receptors in Idiopathic Pulmonary Fibrosis (IPF).

PubMed

Barratt, Shaney L; Blythe, Thomas; Ourradi, Khadija; Jarrett, Caroline; Welsh, Gavin I; Bates, David O; Millar, Ann B

2018-01-15

Dysregulation of VEGF-A bioavailability has been implicated in the development of lung injury/fibrosis, exemplified by Idiopathic Pulmonary Fibrosis (IPF). VEGF-A is a target of the hypoxic response via its translational regulation by HIF-1α. The role of hypoxia and hyperoxia in the development and progression of IPF has not been explored. In normal lung (NF) and IPF-derived fibroblasts (FF) VEGF-A xxx a protein expression was upregulated by hypoxia, mediated through activation of VEGF-A xxx a gene transcription. VEGF-A receptors and co-receptors were differentially expressed by hypoxia and hyperoxia. Our data supports a potential role for hypoxia, hyperoxia and VEGF-A xxx a isoforms as drivers of fibrogenesis.

Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis.

PubMed

Borok, Z; Buhl, R; Grimes, G J; Bokser, A D; Hubbard, R C; Holroyd, K J; Roum, J H; Czerski, D B; Cantin, A M; Crystal, R G

1991-07-27

Idiopathic pulmonary fibrosis (IPF) is characterised by alveolar inflammation, exaggerated release of oxidants, and subnormal concentrations of the antioxidant glutathione in respiratory epithelial lining fluid (ELF). Glutathione (600 mg twice daily for 3 days) was given by aerosol to 10 patients with IPF. Total ELF glutathione rose transiently, ELF oxidised glutathione concentrations increased, and there was a decrease in spontaneous superoxide anion release by alveolar macrophages. Thus, glutathione by aerosol could be a means of reversing the oxidant-antioxidant imbalance in IPF.

The Expression of AQP1 IS Modified in Lung of Patients With Idiopathic Pulmonary Fibrosis: Addressing a Possible New Target.

PubMed

Galán-Cobo, Ana; Arellano-Orden, Elena; Sánchez Silva, Rocío; López-Campos, José Luis; Gutiérrez Rivera, César; Gómez Izquierdo, Lourdes; Suárez-Luna, Nela; Molina-Molina, María; Rodríguez Portal, José A; Echevarría, Miriam

2018-01-01

Activation of the epithelial-mesenchymal transition process (EMT) by which alveolar cells in human lung tissue undergo differentiation giving rise to a mesenchymal phenotype (fibroblast/miofibroblasts) has been well recognized as a key element in the origin of idiopathic pulmonary fibrosis (IPF). Here we analyzed expression of AQP1 in lung biopsies of patients diagnosed with IPF, and compared it to biopsies derived from patients with diverse lung pneumonies, such as hypersensitivity pneumonitis, sarcoidosis or normal lungs. Immunostaining for AQP1 showed a clear increment of AQP1 localized in the alveolar epithelium in biopsies from IPF patients alone. Moreover, to examine the possible participation of AQP1 in the pathophysiology of IPF, we evaluated its role in the pro-fibrotic transformation induced by transforming growth factor (TGF-β) in vitro . Human alveolar epithelial cells (A549), and fibroblasts derived from an IPF patient (LL29), or fibroblasts from healthy normal lung tissue (MRC-5), were treated with TGF-β, and levels of expression of AQP1, as well as those of E-cadherin, vimentin, α-SMA and collagen were analyzed by RT-qPCR, western blot and immunohistochemistry. An increase of AQP1 mRNA and protein after TGF-β treatment (4-72h) was observed either in A549 or IPF fibroblast-LL29 but not in MRC-5 fibroblasts. A gradual reduction of E-cadherin, and increased expression of vimentin, with no changes in α-SMA levels were observed in A549. Whereas in LL29 and MRC-5, TGF-β1 elicited a large production of collagen and α-SMA that was significantly greater in IPF fibroblast-LL29. Changes observed are consistent with activation of EMT by TGF-β, but whether modifications in AQP1 expression are responsible or independent events occurring at the same time is still unknown. Our results suggest that AQP1 plays a role in the pro-fibrotic TGF-β action and contributes to the etiology and pathophysiology of IPF. Understanding AQP1's role will help us comprehend the fate of this disease.

Interplay between EZH2 and G9a Regulates CXCL10 Gene Repression in Idiopathic Pulmonary Fibrosis.

PubMed

Coward, William R; Brand, Oliver J; Pasini, Alice; Jenkins, Gisli; Knox, Alan J; Pang, Linhua

2018-04-01

Selective repression of the antifibrotic gene CXCL10 contributes to tissue remodeling in idiopathic pulmonary fibrosis (IPF). We have previously reported that histone deacetylation and histone H3 lysine 9 (H3K9) methylation are involved in CXCL10 repression. In this study, we explored the role of H3K27 methylation and the interplay between the two histone lysine methyltransferases enhancer of zest homolog 2 (EZH2) and G9a in CXCL10 repression in IPF. By applying chromatin immunoprecipitation, Re-ChIP, and proximity ligation assays, we demonstrated that, like G9a-mediated H3K9 methylation, EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3) was significantly enriched at the CXCL10 promoter in fibroblasts from IPF lungs (F-IPF) compared with fibroblasts from nonfibrotic lungs, and we also found that EZH2 and G9a physically interacted with each other. EZH2 knockdown reduced not only EZH2 and H3K27me3 but also G9a and H3K9me3, and G9a knockdown reduced not only G9 and H3K9me3 but also EZH2 and H3K27me3. Depletion and inhibition of EZH2 and G9a also reversed histone deacetylation and restored CXCL10 expression in F-IPF. Furthermore, treatment of fibroblasts from nonfibrotic lungs with the profibrotic cytokine transforming growth factor-β1 increased EZH2, G9a, H3K27me3, H3K9me3, and histone deacetylation at the CXCL10 promoter, similar to that observed in F-IPF, which was correlated with CXCL10 repression and was prevented by EZH2 and G9a knockdown. These findings suggest that a novel and functionally interdependent interplay between EZH2 and G9a regulates histone methylation-mediated epigenetic repression of the antifibrotic CXCL10 gene in IPF. This interdependent interplay may prove to be a target for epigenetic intervention to restore the expression of CXCL10 and other antifibrotic genes in IPF.

Genomic profiles of lung cancer associated with idiopathic pulmonary fibrosis.

PubMed

Hwang, Ji An; Kim, Deokhoon; Chun, Sung-Min; Bae, SooHyun; Song, Joon Seon; Kim, Mi Young; Koo, Hyun Jung; Song, Jin Woo; Kim, Woo Sung; Lee, Jae Cheol; Kim, Hyeong Ryul; Choi, Chang-Min; Jang, Se Jin

2018-01-01

Little is known about the pathogenesis or molecular profiles of idiopathic pulmonary fibrosis-associated lung cancer (IPF-LC). This study was performed to investigate the genomic profiles of IPF-LC and to explore the possibility of defining potential therapeutic targets in IPF-LC. We assessed genomic profiles of IPF-LC by using targeted exome sequencing (OncoPanel version 2) in 35 matched tumour/normal pairs surgically resected between 2004 and 2014. Germline and somatic variant calling was performed with GATK HaplotypeCaller and MuTect with GATK SomaticIndelocator, respectively. Copy number analysis was conducted with CNVkit, with focal events determined by Genomic Identification of Significant Targets in Cancer 2.0, and pathway analysis (KEGG) with DAVID. Germline mutations in TERT (rs2736100, n = 33) and CDKN1A (rs2395655, n = 27) associated with idiopathic pulmonary fibrosis risk were detected in most samples. A total of 410 somatic mutations were identified, with an average of 11.7 per tumour, including 69 synonymous, 177 missense, 17 nonsense, 1 nonstop and 11 splice-site mutations, and 135 small coding indels. Spectra of the somatic mutations revealed predominant C > T transitions despite an extensive smoking history in most patients, suggesting a potential association between APOBEC-related mutagenesis and the development of IPF-LC. TP53 (22/35, 62.9%) and BRAF (6/35, 17.1%) were found to be significantly mutated in IPF-LC. Recurrent focal amplifications in three chromosomal loci (3q26.33, 7q31.2, and 12q14.3) and 9p21.3 deletion were identified, and genes associated with the JAK-STAT signalling pathway were significantly amplified in IPF-LC (P = 0.012). This study demonstrates that IPF-LC is genetically characterized by the presence of somatic mutations reflecting a variety of environmental exposures on the background of specific germline mutations, and is associated with potentially targetable alterations such as BRAF mutations. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study.

PubMed

Dressen, Amy; Abbas, Alexander R; Cabanski, Christopher; Reeder, Janina; Ramalingam, Thirumalai R; Neighbors, Margaret; Bhangale, Tushar R; Brauer, Matthew J; Hunkapiller, Julie; Reeder, Jens; Mukhyala, Kiran; Cuenco, Karen; Tom, Jennifer; Cowgill, Amy; Vogel, Jan; Forrest, William F; Collard, Harold R; Wolters, Paul J; Kropski, Jonathan A; Lancaster, Lisa H; Blackwell, Timothy S; Arron, Joseph R; Yaspan, Brian L

2018-06-08

Idiopathic pulmonary fibrosis (IPF) risk has a strong genetic component. Studies have implicated variations at several loci, including TERT, surfactant genes, and a single nucleotide polymorphism at chr11p15 (rs35705950) in the intergenic region between TOLLIP and MUC5B. Patients with IPF who have risk alleles at rs35705950 have longer survival from the time of IPF diagnosis than do patients homozygous for the non-risk allele, whereas patients with shorter telomeres have shorter survival times. We aimed to assess whether rare protein-altering variants in genes regulating telomere length are enriched in patients with IPF homozygous for the non-risk alleles at rs35705950. Between Nov 1, 2014, and Nov 1, 2016, we assessed blood samples from patients aged 40 years or older and of European ancestry with sporadic IPF from three international phase 3 clinical trials (INSPIRE, CAPACITY, ASCEND), one phase 2 study (RIFF), and US-based observational studies (Vanderbilt Clinical Interstitial Lung Disease Registry and the UCSF Interstitial Lung Disease Clinic registry cohorts) at the Broad Institute (Cambridge, MA, USA) and Human Longevity (San Diego, CA, USA). We also assessed blood samples from non-IPF controls in several clinical trials. We did whole-genome sequencing to assess telomere length and identify rare protein-altering variants, stratified by rs35705950 genotype. We also assessed rare functional variation in TERT exons and compared telomere length and disease progression across genotypes. We assessed samples from 1510 patients with IPF and 1874 non-IPF controls. 30 (3%) of 1046 patients with an rs35705950 risk allele had a rare protein-altering variant in TERT compared with 34 (7%) of 464 non-risk allele carriers (odds ratio 0·40 [95% CI 0·24-0·66], p=0·00039). Subsequent analyses identified enrichment of rare protein-altering variants in PARN and RTEL1, and rare variation in TERC in patients with IPF compared with controls. We expanded our study population to provide a more accurate estimation of rare variant frequency in these four loci, and to calculate telomere length. The proportion of patients with at least one rare variant in TERT, PARN, TERC, or RTEL1 was higher in patients with IPF than in controls (149 [9%] of 1739 patients vs 205 [2%] of 8645 controls, p=2·44 × 10 -8 ). Patients with IPF who had a variant in any of the four identified telomerase component genes had telomeres that were 3·69-16·10% shorter than patients without a variant in any of the four genes and had an earlier mean age of disease onset than patients without one or more variants (65·1 years [SD 7·8] vs 67·1 years [7·9], p=0·004). In the placebo arms of clinical trials, shorter telomeres were significantly associated with faster disease progression (1·7% predicted forced vital capacity per kb per year, p=0·002). Pirfenidone had treatment benefit regardless of telomere length (p=4·24 × 10 -8 for telomere length lower than the median, p=0·0044 for telomere length greater than the median). Rare protein-altering variants in TERT, PARN, TERC, and RTEL1 are enriched in patients with IPF compared with controls, and, in the case of TERT, particularly in individuals without a risk allele at the rs35705950 locus. This suggests that multiple genetic factors contribute to sporadic IPF, which might implicate distinct mechanisms of pathogenesis and disease progression. Genentech, National Institutes of Health, Francis Family Foundation, Pulmonary Fibrosis Foundation, Nina Ireland Program for Lung Health, US Department of Veterans Affairs. Copyright © 2018 Elsevier Ltd. All rights reserved.

Immature platelet fraction in bacterial sepsis severity assessment

NASA Astrophysics Data System (ADS)

Djuang, M. H.; Ginting, F.; Hariman, H.

2018-03-01

Sepsis is an infection-induced syndrome, mostly caused by bacteria, of organ dysfunctions that caused by host response dysregulations. One of the simplest sepsis-indicator is platelet and its indexes. A new platelet parameter called immature platelet count (IPF) became theinterest in this study. The study aims to see whether IPF could assess sepsis severity by procalcitonin (PCT).Sixty-four of seventy-one patients with increased PCT were included in this cross-sectional study and separated into three groups based on their PCT levels. IPF showed no significance among the three groups (p-value>0.05) while platelet count was significant (p-value<0.05). Mean Platelet Volume (MPV) and Platelet Distribution Width (PDW) showed a strongpositive correlation with IPF. Higher sepsis severity based on PCT showed larger platelet count, as the result of platelet destructions caused by pro-inflammatory cytokines and endotoxins.

IDIOPATHIC PULMONARY FIBROSIS: NEW CONCEPTS IN PATHOGENESIS AND IMPLICATIONS FOR DRUG THERAPY

PubMed Central

Horowitz, Jeffrey C.; Thannickal, Victor J.

2008-01-01

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal pulmonary disease for which there are no proven or approved drug therapies. Anti-inflammatory and immunosuppressive agents have been largely ineffective. The precise relationship of IPF to other idiopathic interstitial pneumonias (IIPs) is not known, despite the observation that different histopathological patterns of IIP may co-exist in the same patient. We propose that these different histopathological “reaction” patterns may be determined by complex interactions between host and environmental factors that alter the local alveolar milieu. Recent paradigms in IPF pathogenesis have focused on dysregulated epithelial-mesenchymal interactions, an imbalance in TH1/TH2 cytokines and potential roles for aberrant angiogenesis. In this review, we discuss these evolving concepts in disease pathogenesis and emerging therapies designed to target pro-fibrogenic pathways in IPF. PMID:16928146

Impaired diversity of the lung microbiome predicts progression of idiopathic pulmonary fibrosis.

PubMed

Takahashi, Youhei; Saito, Atsushi; Chiba, Hirofumi; Kuronuma, Koji; Ikeda, Kimiyuki; Kobayashi, Tomofumi; Ariki, Shigeru; Takahashi, Motoko; Sasaki, Yasushi; Takahashi, Hiroki

2018-02-27

Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe form of idiopathic interstitial pneumonias. Although IPF has not been thought to be associated with bacterial communities, recent papers reported the possible role of microbiome composition in IPF. The roles of microbiomes in respiratory functions and as clinical biomarkers for IPF remain unknown. In this study, we aim to identify the relationship between the microbial environment in the lung and clinical findings. Thirty-four subjects diagnosed with IPF were included in this analysis. The 16S rDNA was purified from bronchoalveolar lavage fluid obtained at the time of diagnosis and analyzed using next-generation sequencing techniques to characterize the bacterial communities. Furthermore, microbiomes from mice with bleomycin-induced lung fibrosis were analyzed. The most prevalent lung phyla were Firmicutes, Proteobacteria and Bacteroidetes. Decreased microbial diversity was found in patients with low forced vital capacity (FVC) and early mortality. Additionally, the diversity and relative abundance of Firmicutes, Streptococcaceae, and Veillonellaceae were significantly associated with FVC, 6-min walk distance, and serum surfactant protein D. Bleomycin-induced lung fibrosis resulted in decrease of diversity and alteration of microbiota in PCoA analysis. These results support the observations in human specimens. This study identified relationships between specific taxa in BALF and clinical findings, which were also supported by experiments in a mouse model. Our data suggest the possibility that loss of microbial diversity is associated with disease activities of IPF.

Nitrated fatty acids reverse pulmonary fibrosis by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages

PubMed Central

Reddy, Aravind T.; Lakshmi, Sowmya P.; Zhang, Yingze; Reddy, Raju C.

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease, thought to be largely transforming growth factor β (TGFβ) driven, for which there is no effective therapy. We assessed the potential benefits in IPF of nitrated fatty acids (NFAs), which are unique endogenous agonists of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor that exhibits wound-healing and antifibrotic properties potentially useful for IPF therapy. We found that pulmonary PPARγ is down-regulated in patients with IPF. In vitro, knockdown or knockout of PPARγ expression in isolated human and mouse lung fibroblasts induced a profibrotic phenotype, whereas treating human fibroblasts with NFAs up-regulated PPARγ and blocked TGFβ signaling and actions. NFAs also converted TGFβ to inactive monomers in cell-free solution, suggesting an additional mechanism through which they may inhibit TGFβ. In vivo, treating mice bearing experimental pulmonary fibrosis with NFAs reduced disease severity. Also, NFAs up-regulated the collagen-targeting factor milk fat globule-EGF factor 8 (MFG-E8), stimulated collagen uptake and degradation by alveolar macrophages, and promoted myofibroblast dedifferentiation. Moreover, treating mice with established pulmonary fibrosis using NFAs reversed their existing myofibroblast differentiation and collagen deposition. These findings raise the prospect of treating IPF with NFAs to halt and perhaps even reverse the progress of IPF.—Reddy, A. T., Lakshmi, S. P., Zhang, Y., Reddy, R. C. Nitrated fatty acids reverse pulmonary fibrosis by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages. PMID:25252739

Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old.

PubMed

Raghu, Ganesh; Chen, Shih-Yin; Hou, Qiang; Yeh, Wei-Shi; Collard, Harold R

2016-07-01

We sought to present the epidemiology of idiopathic pulmonary fibrosis (IPF) in adults 18-64 years old in the USA.From adults aged 18-64 years in a large administrative claims data in 2004-2010, patients with IPF were identified using diagnosis codes. We estimated annual incidence and cumulative prevalence of IPF over time, and examined potential risk factors for the IPF diagnosis.The annual cumulative prevalence increased steadily in the first few years (from 13.4 cases per 100 000 persons in 2005 to 18.2 cases in 2010 per 100 000 persons), which is likely due to a methodological reason, while the annual incidence of IPF decreased over time (from 7.9 cases per 100 000 person-years in 2005 to 5.8 cases in 2010 per 100 000 person-years). The overall decrease was mainly driven by a decreasing trend in the younger patients (aged 18-44 years), while the incidence in older patients remained stable. Consistent trends were observed in subgroups defined by previously published more restrictive algorithms for diagnosis. Older age and male sex were associated with a higher incidence of disease (p<0.05).In US adults younger than 65 years, we observed a decreasing incidence of IPF over time which may partially explain the plateau of cumulative prevalence in the last few years of our data. Copyright ©ERS 2016.

Synergistic role of HSP90α and HSP90β to promote myofibroblast persistence in lung fibrosis.

PubMed

Bellaye, Pierre-Simon; Shimbori, Chiko; Yanagihara, Toyoshi; Carlson, David A; Hughes, Philip; Upagupta, Chandak; Sato, Seidai; Wheildon, Nolan; Haystead, Timothy; Ask, Kjetil; Kolb, Martin

2018-02-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung parenchyma, causing significant morbidity through worsening dyspnoea and overall functional decline. IPF is characterised by apoptosis-resistant myofibroblasts, which are a major source for the excessive production of extracellular matrix (ECM) overtaking normal lung tissue. We sought to study the role of heat shock protein (HSP) isoforms HSP90α and HSP90β, whose distinct roles in lung fibrogenesis remain elusive.We determined the level of circulating HSP90α in IPF patients (n=31) and age-matched healthy controls (n=9) by ELISA. The release of HSP90α and HSP90β was evaluated in vitro in primary IPF and control lung fibroblasts and ex vivo after mechanical stretch on fibrotic lung slices from rats receiving adenovector-mediated transforming growth factor-β1.We demonstrate that circulating HSP90α is upregulated in IPF patients in correlation with disease severity. The release of HSP90α is enhanced by the increase in mechanical stress of the fibrotic ECM. This increase in extracellular HSP90α signals through low-density lipoprotein receptor-related protein 1 (LRP1) to promote myofibroblast differentiation and persistence. In parallel, we demonstrate that the intracellular form of HSP90β stabilises LRP1, thus amplifying HSP90α extracellular action.We believe that the specific inhibition of extracellular HSP90α is a promising therapeutic strategy to reduce pro-fibrotic signalling in IPF. Copyright ©ERS 2018.

Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.

PubMed

Peng, Ruoqi; Sridhar, Sriram; Tyagi, Gaurav; Phillips, Jonathan E; Garrido, Rosario; Harris, Paul; Burns, Lisa; Renteria, Lorena; Woods, John; Chen, Leena; Allard, John; Ravindran, Palanikumar; Bitter, Hans; Liang, Zhenmin; Hogaboam, Cory M; Kitson, Chris; Budd, David C; Fine, Jay S; Bauer, Carla M T; Stevenson, Christopher S

2013-01-01

The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.

Clinical features of usual interstitial pneumonia with anti-neutrophil cytoplasmic antibody in comparison with idiopathic pulmonary fibrosis.

PubMed

Hosoda, Chiaki; Baba, Tomohisa; Hagiwara, Eri; Ito, Hiroyuki; Matsuo, Norikazu; Kitamura, Hideya; Iwasawa, Tae; Okudela, Koji; Takemura, Tamiko; Ogura, Takashi

2016-07-01

Myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) is occasionally positive in patients with usual interstitial pneumonia (UIP). However, the differences from idiopathic pulmonary fibrosis (IPF/UIP) have not been well documented. We aimed to clarify the clinical, radiological and pathological features of UIP associated with MPO-ANCA (ANCA/UIP). We retrospectively reviewed the medical records of 12 consecutive ANCA/UIP patients not manifesting microscopic polyangiitis and 108 IPF/UIP patients with no autoantibodies, both diagnosed by surgical lung biopsy. There was no significant difference in clinical background, laboratory results and pulmonary function tests between ANCA/UIP patients and IPF/UIP patients except for the percentage of bronchoalveolar lavage neutrophils. HRCT showed subpleural reticulation in both groups. Increased attenuation around honeycombing and cysts was significantly observed in ANCA/UIP. Pathologically, ANCA/UIP had more prominent inflammatory cell infiltration, lymphoid follicles with germinal centres and cellular bronchiolitis. During the disease course, three of 12 patients (25%) developed microscopic polyangiitis. Immunosuppressive treatment tended to be more effective in ANCA/UIP patients, and the survival time in ANCA/UIP patients tended to be longer than those with IPF/UIP. ANCA/UIP may be distinguishable from IPF/UIP with a combination of HRCT findings of increased attenuation around honeycombing and cysts and some of the characteristic pathological findings. In contrast to IPF/UIP, immunosuppressive treatment could be a therapeutic option for ANCA/UIP. © 2016 Asian Pacific Society of Respirology.

Determinants of initiation and progression of idiopathic pulmonary fibrosis

PubMed Central

Kottmann, Robert Matthew; Hogan, Christopher M.; Phipps, Richard P.; Sime, Patricia J.

2013-01-01

IPF is a devastating disease with few therapeutic options. The precise aetiology of IPF remains elusive. However, our understanding of the pathologic processes involved in the initiation and progression of this disease is improving. Data on the mechanisms underlying IPF have been generated from epidemiologic investigations as well as cellular and molecular studies of human tissues. Although no perfect animal model of human IPF exists, pre-clinical animal studies have helped define pathways which are likely important in human disease. Epithelial injury, fibroblast activation and repetitive cycles of injury and abnormal repair are almost certainly key events. Factors which have been associated with initiation and/or progression of IPF include viral infections, abnormal cytokine, chemokine and growth factor production, oxidant stress, autoimmunity, inhalational of toxicants and gastro-oesophageal reflux disease. Furthermore, recent evidence identifies a role for a variety of genetic and epigenetic abnormalities ranging from mutations in surfactant protein C to abnormalities in telomere length and telomerase activity. The challenge remains to identify additional inciting agents and key dysregulated pathways that lead to disease progression so that we can develop targeted therapies to treat or prevent this serious disease. PMID:19740254

Quantification of idiopathic pulmonary fibrosis using computed tomography and histology.

PubMed

Coxson, H O; Hogg, J C; Mayo, J R; Behzad, H; Whittall, K P; Schwartz, D A; Hartley, P G; Galvin, J R; Wilson, J S; Hunninghake, G W

1997-05-01

We used computed tomography (CT) and histologic analysis to quantify lung structure in idiopathic pulmonary fibrosis (IPF). CT scans were obtained from IPF and control patients and lung volumes were estimated from measurements of voxel size, and X-ray attenuation values of each voxel. Quantitative estimates of lung structure were obtained from biopsies obtained from diseased and normal CT regions using stereologic methods. CT density was used to calculate the proportion of tissue and air, and this value was used to correct the biopsy specimens to the level of inflation during the CT scan. The data show that IPF is associated with a reduction in airspace volume with no change in tissue volume or weight compared with control lungs. Lung surface area decreased two-thirds (p < 0.001) and mean parenchymal thickness increased tenfold (p < 0.001). An exudate of fluid and cells was present in the airspace of the diseased lung regions and the number of inflammatory cells, collagen, and proteoglycans was increased per 100 g of tissue in IPF. We conclude that IPF reorganized lung tissue content causing a loss of airspace and surface area without increasing the total lung tissue.

Macrophage migration inhibitory factor in lung tissue of idiopathic pulmonary fibrosis patients.

PubMed

Olivieri, Carmela; Bargagli, Elena; Inghilleri, Simona; Campo, Ilaria; Cintorino, Marcella; Rottoli, Paola

2016-06-01

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disorder characterized by a pattern of Usual Interstitial Pneumonia where the presence of fibroblastic foci is the hallmark of the disease. In the present study, we analyzed the migration inhibitory factor (MIF) expression in lung tissue of IPF patients compared with healthy controls and organizing pneumonia (OP) patients focusing into MIF potential role in fibroblastic foci development. The immunohistochemical analysis was performed in 10 IPF patients (7 male), 3 OP patients (2 male), and 3 healthy controls (all male) using the streptavidin-biotin method (Dako). In IPF samples, MIF resulted overexpressed in the areas of active fibrosis and, in particular, in the alveolar epithelium, bronchiolar epithelium, and in the peripheral zones of fibroblastic foci. Bronchiolar epithelium from organizing pneumonia patients resulted only weakly positive for MIF while no evidence of MIF expression was reported for alveolar epithelium. In the control subject group, MIF was unexpressed except for a weak presence in the bronchiolar epithelium. In conclusion, MIF is a pleiotropic cytokine involved in the pathogenesis of IPF being mainly expressed in the areas of remodeling and active fibrosis, in bronchiolar and alveolar epithelium, and in the peripheral zone of fibroblastic foci.

Analysis of cellular and protein content of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis.

PubMed Central

Reynolds, H Y; Fulmer, J D; Kazmierowski, J A; Roberts, W C; Frank, M M; Crystal, R G

1977-01-01

To evaluate cellular and protein components in the lower respiratory tract of patients with idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (CHP), limited broncho-alveolar lavage was done in 58 patients (19 IPF, 7 CHP, and 32 controls). Analysis of the cells and protein in the lavage fluids from patients with IPF revealed an inflammatory and eosinophilic response and a significant elevation of IgG in the lungs. With corticosteroid therapy, inflammation diminished but eosinophils remained. Lavage fluid from patients with CHP also had eosinophils and elevated levels of IgG. However, in contrast to IPF, lavage fluid from CHP patients contained IgM, fewer inflammatory cells, and a strikingly increased number (38-74%) of lymphocytes. Identification of lavage lymphocytes in CHP showed that T lymphocytes were significantly elevated and B lymphocytes were decreased compared to peripheral blood. These studies suggest nthat the lung in IPF and CHP may function as a relatively independent immune organ, and that analysis of cells and proteins in broncho-alveolar lavage fluid may be of diagnostic, therapeutic, and investigative value in evaluating patients with fibrotic lung disease. PMID:830661

[Innovative therapeutics for idiopathic pulmonary fibrosis].

PubMed

Uzunhan, Yurdagül; Nunes, Hilario; Gille, Thomas; Bron, Camille; Planès, Carole; Valeyre, Dominique

2011-12-01

Idiopathic pulmonary fibrosis (IPF), the most common and severe interstitial lung disease, remains a great challenge for clinicians. The natural history of the disease is incompletely understood and its prognosis is as devastating as that of many cancers. The most recent international consensus conference on IPF does not recommend any specific medical treatment and underlines the role of symptomatic care and management of co-morbidities, as well as lung transplantation, which should be openly discussed with the patient, if applicable, without delay. The lack of efficacy observed with steroids and immunosuppressive agents argues the current pathogenic hypothesis consistent with an abnormal alveolar epithelium wound healing after repeated injury. Thus, a need for anti-fibrosing and epithelial protective drugs emerged. Considerable progress has been made regarding the validation of relevant endpoints for clinical trials on IPF and pathogenesis, these two aspects of research being a framework for the exploration of new therapeutic approaches. Pirfenidone is the first drug that has been approved by health-care system for IPF treatment in Japan and in Europe. Many novel and promising drugs based on recent targets are under investigation. Combined therapies targeting different pathogenic pathways may represent the future for the treatment of IPF. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis

PubMed Central

Wex, Eva; Pautsch, Alexander; Schnapp, Gisela; Hostettler, Katrin E.; Stowasser, Susanne; Kolb, Martin

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix (ECM) proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and transforming growth factor-β are believed to play important roles in the pathogenesis of IPF. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with IPF, which has recently been demonstrated in phase III clinical trials. PMID:25745043

Understanding the Determinants of Health-Related Quality of Life in Rheumatoid Arthritis-Associated Interstitial Lung Disease

PubMed Central

Natalini, Jake G.; Swigris, Jeff J.; Morisset, Julie; Elicker, Brett M.; Jones, Kirk D.; Fischer, Aryeh; Collard, Harold R.; Lee, Joyce S.

2017-01-01

Rationale Health-related quality of life (HRQL) is impaired among patients with interstitial lung disease (ILD). Little is understood about HRQL in specific subtypes of ILD. Objectives The aim of this study was to characterize and identify clinical determinants of HRQL among patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and compare them to patients with idiopathic pulmonary fibrosis (IPF). Methods We identified patients with a diagnosis of RA-ILD and IPF from an ongoing longitudinal cohort of ILD patients. HRQL was measured at their baseline visit using the Short Form Health Survey (SF-36), versions 1 and 2. Regression models were used to characterize and understand the relationship between selected baseline clinical covariates, the physical component score (PCS) and mental component score (MCS) of the SF-36. Measurements and Main Results RA-ILD patients (n=50) were more likely to be younger and female compared to IPF patients (n=50). After controlling for age and pulmonary function, RA-ILD patients had a lower HRQL compared to IPF patients, as measured by the PCS (P=0.03), with significant differences in two of four PCS domains – bodily pain (P<0.01) and general health (P=0.01). Clinical covariates most strongly associated with a lower PCS in RA-ILD patients compared to IPF patients were the presence of joint pain or stiffness and dyspnea severity (P<0.01). Mental and emotional health, as measured by the MCS, was similar between RA-ILD and IPF patients. Conclusion The physical components of HRQL appear worse in RA-ILD patients compared to IPF patients as measured by the PCS of the SF-36. Differences in the PCS of the SF-36 can be explained in part by dyspnea severity and joint symptoms among patients with RA-ILD. PMID:28502413

Normal Lung Quantification in Usual Interstitial Pneumonia Pattern: The Impact of Threshold-based Volumetric CT Analysis for the Staging of Idiopathic Pulmonary Fibrosis.

PubMed

Ohkubo, Hirotsugu; Kanemitsu, Yoshihiro; Uemura, Takehiro; Takakuwa, Osamu; Takemura, Masaya; Maeno, Ken; Ito, Yutaka; Oguri, Tetsuya; Kazawa, Nobutaka; Mikami, Ryuji; Niimi, Akio

2016-01-01

Although several computer-aided computed tomography (CT) analysis methods have been reported to objectively assess the disease severity and progression of idiopathic pulmonary fibrosis (IPF), it is unclear which method is most practical. A universal severity classification system has not yet been adopted for IPF. The purpose of this study was to test the correlation between quantitative-CT indices and lung physiology variables and to determine the ability of such indices to predict disease severity in IPF. A total of 27 IPF patients showing radiological UIP pattern on high-resolution (HR) CT were retrospectively enrolled. Staging of IPF was performed according to two classification systems: the Japanese and GAP (gender, age, and physiology) staging systems. CT images were assessed using a commercially available CT imaging analysis workstation, and the whole-lung mean CT value (MCT), the normally attenuated lung volume as defined from -950 HU to -701 Hounsfield unit (NL), the volume of the whole lung (WL), and the percentage of NL to WL (NL%), were calculated. CT indices (MCT, WL, and NL) closely correlated with lung physiology variables. Among them, NL strongly correlated with forced vital capacity (FVC) (r = 0.92, P <0.0001). NL% showed a large area under the receiver operating characteristic curve for detecting patients in the moderate or advanced stages of IPF. Multivariable logistic regression analyses showed that NL% is significantly more useful than the percentages of predicted FVC and predicted diffusing capacity of the lungs for carbon monoxide (Japanese stage II/III/IV [odds ratio, 0.73; 95% confidence intervals (CI), 0.48 to 0.92; P < 0.01]; III/IV [odds ratio. 0.80; 95% CI 0.59 to 0.96; P < 0.01]; GAP stage II/III [odds ratio, 0.79; 95% CI, 0.56 to 0.97; P < 0.05]). The measurement of NL% by threshold-based volumetric CT analysis may help improve IPF staging.

JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study.

PubMed

Milara, Javier; Ballester, Beatriz; Morell, Anselm; Ortiz, José L; Escrivá, Juan; Fernández, Estrella; Perez-Vizcaino, Francisco; Cogolludo, Angel; Pastor, Enrique; Artigues, Enrique; Morcillo, Esteban; Cortijo, Julio

2018-06-01

Pulmonary hypertension (PH) is a common disorder in patients with idiopathic pulmonary fibrosis (IPF) and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation ( V )/perfusion ( Q ) mismatching and oxygen desaturation. Janus kinase type 2 (JAK2) is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown. The study of JAK2 as potential target to treat PH in IPF. JAK2 expression was increased in pulmonary arteries (PAs) from IPF (n=10; 1.93-fold; P=0.0011) and IPF+PH (n=9; 2.65-fold; P<0.0001) compared with PA from control subjects (n=10). PA remodelling was evaluated in human pulmonary artery endothelial cells (HPAECs) and human pulmonary artery smooth muscle cells (HPASMCs) from patients with IPF in vitro treated with the JAK2 inhibitor JSI-124 or siRNA-JAK2 and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-JAK2 inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. JAK2 inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel (BK Ca ). JAK2 inhibition activated BK Ca channels and reduced intracellular Ca 2+ . JSI-124 1 mg/kg/day, reduced bleomycin-induced lung fibrosis, PA remodelling, right ventricular hypertrophy, PA hypertension and V / Q mismatching in rats. The animal studies followed the ARRIVE guidelines. JAK2 participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.

PubMed

Petrovski, Slavé; Todd, Jamie L; Durheim, Michael T; Wang, Quanli; Chien, Jason W; Kelly, Fran L; Frankel, Courtney; Mebane, Caroline M; Ren, Zhong; Bridgers, Joshua; Urban, Thomas J; Malone, Colin D; Finlen Copeland, Ashley; Brinkley, Christie; Allen, Andrew S; O'Riordan, Thomas; McHutchison, John G; Palmer, Scott M; Goldstein, David B

2017-07-01

Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology. The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis. We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis. We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10 -7 ) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10 -22 ). We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.

A cohort study of Danish patients with interstitial lung diseases: burden, severity, treatment and survival.

PubMed

Hyldgaard, Charlotte

2015-04-01

Interstitial lung diseases (ILDs) form a heterogeneous group of rare diseases characterised by varying degrees of pulmonary inflammation and fibrosis. We hypothesised that IPF and unclassifiable ILD were common in a Danish ILD cohort and that prognostic factors based on disease characteristics and comorbidities could be identified The aims of the PhD study were to describe the demographics of ILD in Central Denmark, to characterise the distribution of ILD diagnoses, and to assess prognostic factors in IPF and unclassifiable ILD. The study is based on a cohort of 431 ILD patients referred to our department during a 6-year period. All ILD diagnoses were re-evaluated according to current diagnostic criteria. Patients were followed from the time of first visit on suspicion of an ILD to the last visit to the centre, death, transplantation, or discharge from follow-up. The incidence of ILD was 4.1 per 100,000 inhabitants, and the incidence of IPF was 1.3 per 100,000 inhabitants in Central Den-mark. The most frequently occurring ILDs were IPF (28%), unclassifiable ILDs (extensive fibrotic disease and other unclassifiable ILDs) (24%), connective tissue disease-related ILD (14%), hyper-sensitivity pneumonitis (7%) and NSIP (7%). Cardiovascular dis-ease was present in 21% of the patients. The presence of cardio-vascular disease at the time of IPF diagnosis did not lead to increased mortality, whereas cardiovascular disease diagnosed during the course of IPF was a statistically significant predictor of mortality. Our study also showed that diabetes and concomitant anticoagulant therapy were associated with worse outcome in IPF, and that a simple HRCT scoring system could be used in the prediction of outcome in fibrotic ILDs. The study of unclassifiable ILD revealed two disease categories: one group characterised by extensive fibrotic disease and one characterised by more inflammatory features. The latter group was characterised by younger age and significantly better prognosis. We evaluated the pragmatic disease classification based on the clinical disease pattern included in the 2013 revision of the guidelines of diagnosis and treatment of interstitial lung diseases. We found that it was able to separate patients with unclassifiable ILD into categories with highly significant differences in survival. We also evaluated the ILD-GAP model, which is based on gender, age and pulmonary function (physiology), and found that it was a valuable predictor of survival in unclassifiable ILD. In a multivariate model, the two prediction scores showed significant individual contribution to the prognostic assessment. The present study has provided the first estimate of ILD and IPF incidence in the Danish population and has shown that demographics and survival of IPF in this cohort were comparable to what has been reported in other studies. Comorbidities were common among patients with IPF, and the results of the study have led us to believe that careful diagnosis and treatment of comorbidities are important in order to optimise outcome in patients with IPF, although our findings need to be confirmed in larger studies. Unclassifiable ILD is frequent in daily clinical practice but has not been characterised in detail. Our study showed that it was possible to identify predictors of outcome and to validate the ILD-GAP model in this cohort. The study also showed that the Disease Behaviour Classification can be used in the management of patients with unclassifiable ILD.

Host–Microbial Interactions in Idiopathic Pulmonary Fibrosis

PubMed Central

Willis-Owen, Saffron A. G.; Cox, Michael J.; James, Phillip; Cowman, Steven; Loebinger, Michael; Blanchard, Andrew; Edwards, Lindsay M.; Stock, Carmel; Daccord, Cécile; Renzoni, Elisabetta A.; Wells, Athol U.; Moffatt, Miriam F.; Cookson, William O. C.; Maher, Toby M.

2017-01-01

Rationale: Changes in the respiratory microbiome are associated with disease progression in idiopathic pulmonary fibrosis (IPF). The role of the host response to the respiratory microbiome remains unknown. Objectives: To explore the host–microbial interactions in IPF. Methods: Sixty patients diagnosed with IPF were prospectively enrolled together with 20 matched control subjects. Subjects underwent bronchoalveolar lavage (BAL), and peripheral whole blood was collected into PAXgene tubes for all subjects at baseline. For subjects with IPF, additional samples were taken at 1, 3, and 6 months and (if alive) 1 year. Gene expression profiles were generated using Affymetrix Human Gene 1.1 ST arrays. Measurements and Main Results: By network analysis of gene expression data, we identified two gene modules that strongly associated with a diagnosis of IPF, BAL bacterial burden (determined by 16S quantitative polymerase chain reaction), and specific microbial operational taxonomic units, as well as with lavage and peripheral blood neutrophilia. Genes within these modules that are involved in the host defense response include NLRC4, PGLYRP1, MMP9, and DEFA4. The modules also contain two genes encoding specific antimicrobial peptides (SLPI and CAMP). Many of these particular transcripts were associated with survival and showed longitudinal overexpression in subjects experiencing disease progression, further strengthening the relationship of the transcripts with disease. Conclusions: Integrated analysis of the host transcriptome and microbial signatures demonstrated an apparent host response to the presence of an altered or more abundant microbiome. These responses remained elevated in longitudinal follow-up, suggesting that the bacterial communities of the lower airways may act as persistent stimuli for repetitive alveolar injury in IPF. PMID:28085486

Lung Transplantation for Hypersensitivity Pneumonitis

PubMed Central

Singer, Jonathan P.; Koth, Laura; Mooney, Joshua; Golden, Jeff; Hays, Steven; Greenland, John; Wolters, Paul; Ghio, Emily; Jones, Kirk D.; Leard, Lorriana; Kukreja, Jasleen; Blanc, Paul D.

2015-01-01

BACKGROUND: Hypersensitivity pneumonitis (HP) is an inhaled antigen-mediated interstitial lung disease (ILD). Advanced disease may necessitate the need for lung transplantation. There are no published studies addressing lung transplant outcomes in HP. We characterized HP outcomes compared with referents undergoing lung transplantation for idiopathic pulmonary fibrosis (IPF). METHODS: To identify HP cases, we reviewed records for all ILD lung transplantation cases at our institution from 2000 to 2013. We compared clinical characteristics, survival, and acute and chronic rejection for lung transplant recipients with HP to referents with IPF. We also reviewed diagnoses of HP discovered only by explant pathology and looked for evidence of recurrent HP after transplant. Survival was compared using Kaplan-Meier methods and Cox proportional hazard modeling. RESULTS: We analyzed 31 subjects with HP and 91 with IPF among 183 cases undergoing lung transplantation for ILD. Survival at 1, 3, and 5 years after lung transplant in HP compared with IPF was 96%, 89%, and 89% vs 86%, 67%, and 49%, respectively. Subjects with HP manifested a reduced adjusted risk for death compared with subjects with IPF (hazard ratio, 0.25; 95% CI, 0.08-0.74; P = .013). Of the 31 cases, the diagnosis of HP was unexpectedly made at explant in five (16%). Two subjects developed recurrent HP in their allografts. CONCLUSIONS: Overall, subjects with HP have excellent medium-term survival after lung transplantation and, relative to IPF, a reduced risk for death. HP may be initially discovered only by review of the explant pathology. Notably, HP may recur in the allograft. PMID:25412059

Up-Regulation and Profibrotic Role of Osteopontin in Human Idiopathic Pulmonary Fibrosis

PubMed Central

Pardo, Annie; Gibson, Kevin; Cisneros, José; Richards, Thomas J; Yang, Yinke; Becerril, Carina; Yousem, Samueal; Herrera, Iliana; Ruiz, Victor; Selman, Moisés; Kaminski, Naftali

2005-01-01

Background Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung. Methods and Findings Using oligonucleotide arrays, we identified osteopontin as one of the genes that significantly distinguishes IPF from normal lungs. Osteopontin was localized to alveolar epithelial cells in IPF lungs and was also significantly elevated in bronchoalveolar lavage from IPF patients. To study the fibrosis-relevant effects of osteopontin we stimulated primary human lung fibroblasts and alveolar epithelial cells (A549) with recombinant osteopontin. Osteopontin induced a significant increase of migration and proliferation in both fibroblasts and epithelial cells. Epithelial growth was inhibited by the pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) and antibody to CD44, while fibroproliferation was inhibited by GRGDS and antibody to αvβ3 integrin. Fibroblast and epithelial cell migration were inhibited by GRGDS, anti-CD44, and anti-αvβ3. In fibroblasts, osteopontin up-regulated tissue inhibitor of metalloprotease-1 and type I collagen, and down-regulated matrix metalloprotease-1 (MMP-1) expression, while in A549 cells it caused up-regulation of MMP-7. In human IPF lungs, osteopontin colocalized with MMP-7 in alveolar epithelial cells, and application of weakest link statistical models to microarray data suggested a significant interaction between osteopontin and MMP-7. Conclusions Our results provide a potential mechanism by which osteopontin secreted from the alveolar epithelium may exert a profibrotic effect in IPF lungs and highlight osteopontin as a potential target for therapeutic intervention in this incurable disease. PMID:16128620

Effectiveness of combined therapy with pirfenidone and inhaled N-acetylcysteine for advanced idiopathic pulmonary fibrosis: a case-control study.

PubMed

Sakamoto, Susumu; Muramatsu, Yoko; Satoh, Keita; Ishida, Fumiaki; Kikuchi, Naoshi; Sano, Go; Sugino, Keishi; Isobe, Kazutoshi; Takai, Yujiro; Homma, Sakae

2015-04-01

Treatment with pirfenidone may slow the decline in vital capacity and increase progression-free survival (PFS) in idiopathic pulmonary fibrosis (IPF). The effects of combination therapy with inhaled N-acetylcysteine (NAC) and pirfenidone are unclear. We assessed the effects of this combination therapy in patients with advanced IPF. Patients with a diagnosis of advanced IPF (Japanese Respiratory Society stage III/IV IPF) and a relative decline in forced vital capacity (FVC) of ≥ 10% within the previous 6 (± 2) months were enrolled. Outcomes were evaluated in a 12-month follow-up pulmonary function test. Treatment was considered ineffective if the decline in FVC was ≥ 10% and effective if the decline was <10%. We compared clinical characteristics, effectiveness and PFS between patients receiving inhaled NAC plus pirfenidone (n = 24) and those receiving pirfenidone alone (control; n = 10). Data from 34 IPF patients (age range, 59-82 years) were analysed. At the 12-month follow-up examination, treatment was deemed effective in 8 of 17 (47%) patients receiving NAC plus pirfenidone and in 2 of 10 (20%) receiving pirfenidone alone. The annual rate of change in FVC was -610 mL in the NAC plus pirfenidone group and -1320 mL in the pirfenidone group (P < 0.01). PFS was longer (304 days) in the NAC plus pirfenidone group than in the pirfenidone group (168 days; P = 0.016). Combination treatment with inhaled NAC and oral pirfenidone reduced the rate of annual FVC decline and improved PFS in patients with advanced IPF. © 2015 Asian Pacific Society of Respirology.

Serum surfactant protein D predicts the outcome of patients with idiopathic pulmonary fibrosis treated with pirfenidone.

PubMed

Ikeda, Kimiyuki; Shiratori, Masanori; Chiba, Hirofumi; Nishikiori, Hirotaka; Yokoo, Keiki; Saito, Atsushi; Hasegawa, Yoshihiro; Kuronuma, Koji; Otsuka, Mitsuo; Yamada, Gen; Takahashi, Hiroki

2017-10-01

Idiopathic pulmonary fibrosis (IPF) is a fatal pulmonary disease with poor prognosis. Pirfenidone, the first antifibrotic drug, suppresses the decline in forced vital capacity (FVC) and improves prognosis in some, but not all, patients with IPF; therefore, an indicator for identifying improved outcomes in pirfenidone therapy is desirable. This study aims to clarify whether baseline parameters can be predictors of disease progression and prognosis in patients with IPF treated with pirfenidone. We retrospectively investigated patients with IPF who started treatment with pirfenidone between December 2008 and November 2014 at the Sapporo Medical University Hospital. Patients treated with pirfenidone for ≥6 months were enrolled in this study and were observed until November 2015. We investigated the association of clinical characteristics, pulmonary function test results, and blood examination results at the start of pirfenidone with the outcome of patients. Sixty patients were included in this study. In multivariate logistic regression analysis, % predicted FVC and serum surfactant protein (SP)-D levels were predictors of a ≥10% decline in FVC in the initial 12 months. In the Cox proportional hazards model, these two factors predicted progression-free survival. Pack-years, % predicted diffusing capacity for carbon monoxide, and SP-D levels predicted overall survival. The serum SP-D level was a predictor of disease progression and prognosis in patients with IPF treated with pirfenidone. In addition, this analysis describes the relative usefulness of other clinical parameters at baseline in estimating the prognosis of patients with IPF who are candidates for pirfenidone therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Content validity of CASA-Q cough domains and UCSD-SOBQ for use in patients with Idiopathic Pulmonary Fibrosis.

PubMed

Gries, Katharine Suzanne; Esser, Dirk; Wiklund, Ingela

2013-09-16

The study objective was to assess the content validity of the Cough and Sputum Assessment Questionnaire (CASA-Q) cough domains and the UCSD Shortness of Breath Questionnaire (SOBQ) for use in patients with Idiopathic Pulmonary Fibrosis (IPF). Cross-sectional, qualitative study with cognitive interviews in patients with IPF. Study outcomes included relevance, comprehension of item meaning, understanding of the instructions, recall period, response options, and concept saturation. Interviews were conducted with 18 IPF patients. The mean age was 68.9 years (SD 11.9), 77.8% were male, and 88.9% were Caucasian. The intended meaning of the CASA-Q cough domain items was clearly understood by most of the participants (89-100%). All participants understood the CASA-Q instructions; the correct recall period was reported by 89% of the patients, and the response options were understood by 76%. The intended meaning of the UCSD-SOBQ items was relevant and clearly understood by all participants. Participants understood the instructions (83%) and all patients understood the response options (100%). The reported recall period varied based on the type of activity performed. No concepts were missing, suggesting that saturation was demonstrated for both measures. This study provides evidence for content validity for the CASA-Q cough domains and the UCSD-SOBQ for patients with IPF. Items of both questionnaires were understood and perceived as relevant to measure the key symptoms of IPF. The results of this study support the use of these instruments in IPF clinical trials as well as further studies of their psychometric properties.

Update on therapeutic management of idiopathic pulmonary fibrosis

PubMed Central

Tzouvelekis, Argyris; Bonella, Francesco; Spagnolo, Paolo

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive diffuse parenchymal lung disease of unknown origin, with a mortality rate exceeding that of many cancers. The diagnostic process is complex and relies on the clinician integrating clinical, laboratory, radiological, and histological data. In the last decade, major advances in our understanding of the pathogenesis of IPF have shifted the paradigm from a primarily inflammatory process evolving to fibrosis to a condition driven by aberrant wound healing following alveolar epithelial cell injury that results in scarring of the lung, architectural distortion, and irreversible loss of function. Improved understanding of disease pathogenesis has led to the identification of several therapeutic targets and the design of high-quality clinical trials evaluating novel compounds. However, the results of these studies have been mostly disappointing, probably due to the plethora of mediators, growth factors, and signaling pathways involved in the fibrotic process. Most recently, pirfenidone and nintedanib, two compounds with pleiotropic anti-fibrotic properties, have been proven effective in reducing functional decline and disease progression in IPF. This is a major breakthrough. Nevertheless, we still have a long way to go. In fact, neither pirfenidone nor nintedanib is a cure for IPF, and most patients continue to progress despite treatment. As such, comprehensive care of patients with IPF, including management of concomitant conditions and physical debility, as well as timely referral for lung transplantation, remains essential. Several agents with a high potential are currently being tested, and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF. PMID:25767391

Idiopathic pulmonary fibrosis: evolving concepts.

PubMed

Ryu, Jay H; Moua, Teng; Daniels, Craig E; Hartman, Thomas E; Yi, Eunhee S; Utz, James P; Limper, Andrew H

2014-08-01

Idiopathic pulmonary fibrosis (IPF) occurs predominantly in middle-aged and older adults and accounts for 20% to 30% of interstitial lung diseases. It is usually progressive, resulting in respiratory failure and death. Diagnostic criteria for IPF have evolved over the years, and IPF is currently defined as a disease characterized by the histopathologic pattern of usual interstitial pneumonia occurring in the absence of an identifiable cause of lung injury. Understanding of the pathogenesis of IPF has shifted away from chronic inflammation and toward dysregulated fibroproliferative repair in response to alveolar epithelial injury. Idiopathic pulmonary fibrosis is likely a heterogeneous disorder caused by various interactions between genetic components and environmental exposures. High-resolution computed tomography can be diagnostic in the presence of typical findings such as bilateral reticular opacities associated with traction bronchiectasis/bronchiolectasis in a predominantly basal and subpleural distribution, along with subpleural honeycombing. In other circumstances, a surgical lung biopsy may be needed. The clinical course of IPF can be unpredictable and may be punctuated by acute deteriorations (acute exacerbation). Although progress continues in unraveling the mechanisms of IPF, effective therapy has remained elusive. Thus, clinicians and patients need to reach informed decisions regarding management options including lung transplant. The findings in this review were based on a literature search of PubMed using the search terms idiopathic pulmonary fibrosis and usual interstitial pneumonia, limited to human studies in the English language published from January 1, 2000, through December 31, 2013, and supplemented by key references published before the year 2000. Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Screening for Helicobacter pylori in Idiopathic Pulmonary Fibrosis Lung Biopsies.

PubMed

Kreuter, Michael; Kirsten, Detlef; Bahmer, Thomas; Penzel, Roland; Claussen, Martin; Ehlers-Tenenbaum, Svenja; Muley, Thomas; Palmowski, Karin; Eichinger, Monika; Leider, Marta; Herth, Felix J F; Rabe, Klaus F; Bittmann, Iris; Warth, Arne

2016-01-01

Increasing evidence suggests a role of gastro-oesophageal reflux (GER) in idiopathic pulmonary fibrosis (IPF) pathogenesis. Recently, an association between serum Helicobacter pylori (HP) antibody positivity and more severe disease was described, but HP has not been directly analysed in lung tissue so far. To investigate the presence of HP in the lung tissue of IPF patients. Two tertiary interstitial lung disease care centre databases were screened for available lung biopsy material from IPF patients. Clinical and radiological data, including presence of GER and antiacid medication, were evaluated. HP-specific PCR was carried out on the IPF lung biopsy specimens. A total of 39 IPF patients were included, of whom 85% were male. The patients' median age was 66 years, their vital capacity was 79% predicted, and their diffusing capacity for carbon monoxide was 53% predicted. In all, 82% of the lung biopsies were surgical and 18% transbronchial. Comorbidities were GER disease in 23% (n = 9), sleep apnoea in 13% (n = 5) and hiatal hernia in 38% of the cases (n = 15). Proton pump inhibitors were prescribed at the time of biopsy in 21% of the cases (n = 9). After a median follow-up of 25 months (range 6-69), there were 1 death, 1 lung transplantation and 8 acute exacerbations without relevant differences between the GER and non-GER subgroups. HP DNA was not detected in any of the lung tissue samples. The fact that no HP DNA was detected in the lung tissues calls into question the proposed relevance of HP to the direct pathogenesis of IPF. © 2015 S. Karger AG, Basel.

Cellular senescence and autophagy in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

PubMed

Kuwano, Kazuyoshi; Araya, Jun; Hara, Hiromichi; Minagawa, Shunsuke; Takasaka, Naoki; Ito, Saburo; Kobayashi, Kenji; Nakayama, Katsutoshi

2016-11-01

Aging is associated with impairments in homeostasis. Although aging and senescence are not equivalent, the number of senescent cells increases with aging. Cellular senescence plays important roles in tissue repair or remodeling, as well as embryonic development. Autophagy is a process of lysosomal self-degradation that maintains a homeostatic balance between the synthesis, degradation, and recycling of cellular proteins. Autophagy diminishes with aging; additionally, accelerated aging can be attributed to reduced autophagy. Cellular senescence has been widely implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), a disease of accelerated lung aging, presumably by impairing cell repopulation and by aberrant cytokine secretion in the senescence-associated secretory phenotype. The possible participation of autophagy in the pathogenic sequence of COPD has been extensively explored. Although it has been reported that increased autophagy may induce epithelial cell death, an insufficient reserve of autophagy can induce cellular senescence in bronchial epithelial cells of COPD. Furthermore, advanced age is one of the most important risk factors for the development of idiopathic pulmonary fibrosis (IPF). Telomere shortening is found in blood leukocytes and alveolar epithelial cells from patients with IPF. Accelerated senescence of epithelial cells plays a role in IPF pathogenesis by perpetuating abnormal epithelial-mesenchymal interactions. Insufficient autophagy may be an underlying mechanism of accelerated epithelial cell senescence and myofibroblast differentiation in IPF. Herein, we review the molecular mechanisms of cellular senescence and autophagy and summarize the role of cellular senescence and autophagy in both COPD and IPF. Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Identification and validation of differentially expressed transcripts by RNA-sequencing of formalin-fixed, paraffin-embedded (FFPE) lung tissue from patients with Idiopathic Pulmonary Fibrosis.

PubMed

Vukmirovic, Milica; Herazo-Maya, Jose D; Blackmon, John; Skodric-Trifunovic, Vesna; Jovanovic, Dragana; Pavlovic, Sonja; Stojsic, Jelena; Zeljkovic, Vesna; Yan, Xiting; Homer, Robert; Stefanovic, Branko; Kaminski, Naftali

2017-01-12

Idiopathic Pulmonary Fibrosis (IPF) is a lethal lung disease of unknown etiology. A major limitation in transcriptomic profiling of lung tissue in IPF has been a dependence on snap-frozen fresh tissues (FF). In this project we sought to determine whether genome scale transcript profiling using RNA Sequencing (RNA-Seq) could be applied to archived Formalin-Fixed Paraffin-Embedded (FFPE) IPF tissues. We isolated total RNA from 7 IPF and 5 control FFPE lung tissues and performed 50 base pair paired-end sequencing on Illumina 2000 HiSeq. TopHat2 was used to map sequencing reads to the human genome. On average ~62 million reads (53.4% of ~116 million reads) were mapped per sample. 4,131 genes were differentially expressed between IPF and controls (1,920 increased and 2,211 decreased (FDR < 0.05). We compared our results to differentially expressed genes calculated from a previously published dataset generated from FF tissues analyzed on Agilent microarrays (GSE47460). The overlap of differentially expressed genes was very high (760 increased and 1,413 decreased, FDR < 0.05). Only 92 differentially expressed genes changed in opposite directions. Pathway enrichment analysis performed using MetaCore confirmed numerous IPF relevant genes and pathways including extracellular remodeling, TGF-beta, and WNT. Gene network analysis of MMP7, a highly differentially expressed gene in both datasets, revealed the same canonical pathways and gene network candidates in RNA-Seq and microarray data. For validation by NanoString nCounter® we selected 35 genes that had a fold change of 2 in at least one dataset (10 discordant, 10 significantly differentially expressed in one dataset only and 15 concordant genes). High concordance of fold change and FDR was observed for each type of the samples (FF vs FFPE) with both microarrays (r = 0.92) and RNA-Seq (r = 0.90) and the number of discordant genes was reduced to four. Our results demonstrate that RNA sequencing of RNA obtained from archived FFPE lung tissues is feasible. The results obtained from FFPE tissue are highly comparable to FF tissues. The ability to perform RNA-Seq on archived FFPE IPF tissues should greatly enhance the availability of tissue biopsies for research in IPF.

Medicare program; inpatient psychiatric facilities prospective payment system--update for fiscal year beginning October 1, 2014 (FY 2015). Final rule.

PubMed

2014-08-06

This final rule will update the prospective payment rates for Medicare inpatient hospital services provided by inpatient psychiatric facilities (IPFs). These changes will be applicable to IPF discharges occurring during the fiscal year (FY) beginning October 1, 2014 through September 30, 2015. This final rule will also address implementation of ICD-10-CM and ICD-10-PCS codes; finalize a new methodology for updating the cost of living adjustment (COLA), and finalize new quality measures and reporting requirements under the IPF quality reporting program.

Reconciling healthcare professional and patient perspectives in the development of disease activity and response criteria in connective tissue disease-related interstitial lung diseases.

PubMed

Saketkoo, Lesley Ann; Mittoo, Shikha; Frankel, Sid; LeSage, Daphne; Sarver, Catherine; Phillips, Kristine; Strand, Vibeke; Matteson, Eric L

2014-04-01

Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.

Long-term management of IPF with pirfenidone - a clinical case study with 5 years follow-up.

PubMed

Richeldi, L; Sgalla, G; Cerri, S

2013-09-01

Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic interstitial lung disease that is associated with a median survival of 2-5 years from initial diagnosis. To date, the search for an effective treatment has involved numerous clinical trials of investigational agents but without significant success. Nevertheless, research over the past 10 years has provided us with a wealth of information on its histopathology, diagnostic work-up, and a greater understanding of its pathophysiology. Specifically, IPF is no longer thought to be a predominantly pro-inflammatory disorder. Rather, the fibrosis in IPF is increasingly understood to be the result of a fibroproliferative and aberrant wound healing cascade. The development of therapeutic targets has therefore shifted in accordance with this paradigm change. Emerging clinical data from recently published and ongoing trials investigating new potential pharmacological agents should be considered in the routine clinical management of these patients. Based upon encouraging results from randomised-controlled trials showing a positive effect in slowing decline in pulmonary function and reducing disease progression, pirfenidone was approved in 2011 as the first treatment in patients with IPF. This case study describes the clinical course of a patient enrolled into the Phase III and open-label extension studies of pirfenidone.

The lived experience with idiopathic pulmonary fibrosis: a qualitative study.

PubMed

Overgaard, Dorthe; Kaldan, Gudrun; Marsaa, Kristoffer; Nielsen, Thyge Lynghøj; Shaker, Saher Burhan; Egerod, Ingrid

2016-05-01

The disease course in idiopathic pulmonary fibrosis (IPF) is variable, but patients experience a progressive decline in lung function and increased symptom burden leading to death. Little is known about the patients' experience and their needs during the disease course or about the burden on family caregivers. Both patients and family caregivers face an altered life as the disease progresses. The aim of our study was to increase knowledge of life with IPF for patients and family caregivers.This study had a qualitative descriptive design using in-depth dyadic interviews with IPF patients (n=25) and family caregivers (n=24). We used the five-step analysis from the framework method and analysed the data on three levels: the patient, the family caregivers and couple level.The following six themes emerged as the main results: information and disclosure, reactional dyssynchrony, perpetual vigilance, emotional ambivalence, gradual and tacit role shift, and adapted coping strategies.Our findings suggest that IPF patients need information at the time of diagnosis, but some issues should be paced as the disease progresses. A palliation plan was demanded by patients and their caregivers. Further efforts are required to provide palliative care to IPF patients starting at the time of diagnosis. Copyright ©ERS 2016.

Initial Poor Function and Primary Nonfunction in Deceased-Donor Orthotopic Liver Transplantation Maintaining Short Cold Ischemic Time.

PubMed

Das, Somak; Swain, Sudeepta Kumar; Addala, Pavan Kumar; Balasubramaniam, Ramakrishnan; Gopakumar, C V; Zirpe, Dinesh; Renganathan, Kirubakaran; Kollu, Harsha; Patel, Darshan; Vibhute, Bipin B; Rao, Prashantha S; Krishnan, Elankumaran; Gopasetty, Mahesh; Khakhar, Anand K; Vaidya, Anil; Ramamurthy, Anand

2016-12-01

Nations with emerging deceased-donor liver transplantation programs, such as India, face problems associated with poor donor maintenance. Cold ischemic time (CIT) is typically maintained short by matching donor organ recovery and recipient hepatectomy to achieve maximum favorable outcome. We analyzed different extended criteria donor factors including donor acidosis, which may act as a surrogate marker of poor donor maintenance, to quantify the risk of primary nonfunction (PNF) or initial poor function (IPF). A single-center retrospective outcome analysis of prospectively collected data of patients undergoing deceased-donor liver transplantation over 2 years to determine the impact of different extended criteria donor factors on IPF and PNF. From March 2013 to February 2015, a total of 84 patients underwent deceased-donor liver transplantation. None developed PNF. Thirteen (15.5%) patients developed IPF. Graft macrosteatosis and donor acidosis were only related to IPF ( P = .002 and P = .032, respectively). Cold ischemic time was maintained short (81 cases ≤8 hours, maximum 11 hours) in all cases. Poor donor maintenance as evidenced by donor acidosis and graft macrosteatosis had significant impact in developing IPF when CIT is kept short. Similar study with larger sample size is required to establish extended criteria cutoff values.

Effects of pirfenidone on increased cough reflex sensitivity in guinea pigs.

PubMed

Okazaki, Akihito; Ohkura, Noriyuki; Fujimura, Masaki; Katayama, Nobuyuki; Kasahara, Kazuo

2013-10-01

Pirfenidone, an antifibrotic drug with anti-inflammatory and antioxidant effects, delays fibrosis in idiopathic pulmonary fibrosis (IPF). Patients with IPF have a greater cough reflex sensitivity to inhaled capsaicin than healthy people, and cough is an independent predictor of IPF disease progression; however, the effects of pirfenidone on cough reflex sensitivity are unknown. After challenge with an aerosolized antigen in actively sensitized guinea pigs, pirfenidone was administered intraperitoneally, and the cough reflex sensitivity was measured at 48 h after the challenge. Bronchoalveolar lavage (BAL) was performed, and the tracheal tissue was collected. Pirfenidone suppressed the capsaicin-induced increase in cough reflex sensitivity in a dose-dependent manner. Additionally, increased levels of prostaglandin E2, substance P, and leukotriene B4, but not histamine, in the BAL fluid were dose dependently suppressed by pirfenidone. The decrease in neutral endopeptidase activity in the tracheal tissue was also alleviated by pirfenidone treatment. The total number of cells and components in the BAL fluid was not influenced. These results suggest that pirfenidone ameliorates isolated cough based on increased cough reflex sensitivity associated with allergic airway diseases, and potentially relieve chronic cough in IPF patients who often have increased cough reflex sensitivity. Prospective studies on cough-relieving effects of pirfenidone in patients with IPF are therefore warranted. Copyright © 2013 Elsevier Ltd. All rights reserved.

Transcriptome of Cultured Lung Fibroblasts in Idiopathic Pulmonary Fibrosis: Meta-Analysis of Publically Available Microarray Datasets Reveals Repression of Inflammation and Immunity Pathways.

PubMed

Plantier, Laurent; Renaud, Hélène; Respaud, Renaud; Marchand-Adam, Sylvain; Crestani, Bruno

2016-12-13

Heritable profibrotic differentiation of lung fibroblasts is a key mechanism of idiopathic pulmonary fibrosis (IPF). Its mechanisms are yet to be fully understood. In this study, individual data from four independent microarray studies comparing the transcriptome of fibroblasts cultured in vitro from normal (total n = 20) and IPF (total n = 20) human lung were compiled for meta-analysis following normalization to z-scores. One hundred and thirteen transcripts were upregulated and 115 were downregulated in IPF fibroblasts using the Significance Analysis of Microrrays algorithm with a false discovery rate of 5%. Downregulated genes were highly enriched for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional classes related to inflammation and immunity such as Defense response to virus, Influenza A, tumor necrosis factor (TNF) mediated signaling pathway, interferon-inducible absent in melanoma2 (AIM2) inflammasome as well as Apoptosis. Although upregulated genes were not enriched for any functional class, select factors known to play key roles in lung fibrogenesis were overexpressed in IPF fibroblasts, most notably connective tissue growth factor ( CTGF ) and serum response factor ( SRF ), supporting their role as drivers of IPF. The full data table is available as a supplement.

Biopsy in idiopathic pulmonary fibrosis: back to the future.

PubMed

Rossi, Giulio; Spagnolo, Paolo

2017-09-01

Idiopathic Pulmonary Fibrosis (IPF) is a relentlessly progressive, fibrosing interstitial pneumonia characterized by a radiologic and/or histologic pattern of usual interstitial pneumonia (UIP). The availability of two effective anti-fibrotic drugs in IPF has encouraged the identification and treatment of patients in early stages in order to maximize clinical benefit. The ability of high-resolution computed tomography (HRCT) to identify a 'definite' UIP pattern is suboptimal, particularly in the absence of honeycombing. Therefore, radiologic criteria for UIP are currently being redefined. Histology represents the major source of information to define a UIP pattern. Novel and less invasive approaches (particularly cryobiopsy) to sample interstitial lung diseases have demonstrated high sensitivity and specificity. In parallel, researchers are focusing on molecular mechanisms underlying IPF with the aim to identify more specific druggable targets. Lung tissue is therefore essential for diagnostic, pathogenetic and therapeutic purposes. Areas covered: We identified and critically reviewed the most relevant recent literature related to the limitations of current radiologic criteria, new lung sampling procedures, and molecular pathways in support of the need of lung tissue to better understand IPF. Expert commentary: The development of truly effective treatments for IPF requires the identification of key pathogenetic molecules and pathways. To this end, the availability of lung tissue is vital.

New Therapeutic Targets in Idiopathic Pulmonary Fibrosis. Aiming to Rein in Runaway Wound-Healing Responses

PubMed Central

Ahluwalia, Neil; Shea, Barry S.

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, with a median survival as short as 3 years from the time of diagnosis and no pharmacological therapies yet approved by the U.S. Food and Drug Administration. To address the great unmet need for effective IPF therapy, a number of new drugs have recently been, or are now being, evaluated in clinical trials. The rationales for most of these therapeutic candidates are based on the current paradigm of IPF pathogenesis, in which recurrent injury to the alveolar epithelium is believed to drive aberrant wound healing responses, resulting in fibrosis rather than repair. Here we discuss drugs in recently completed or currently ongoing phase II and III IPF clinical trials in the context of their putative mechanisms of action and the aberrant repair processes they are believed to target: innate immune activation and polarization, fibroblast accumulation and myofibroblast differentiation, or extracellular matrix deposition and stiffening. Placed in this context, the positive results of recently completed trials of pirfenidone and nintedanib, and results that will come from ongoing trials of other agents, should provide valuable insights into the still-enigmatic pathogenesis of this disease, in addition to providing benefits to patients with IPF. PMID:25090037

Trace metals in fluids lining the respiratory system of patients with idiopathic pulmonary fibrosis and diffuse lung diseases.

PubMed

Bargagli, Elena; Lavorini, Federico; Pistolesi, Massimo; Rosi, Elisabetta; Prasse, Antje; Rota, Emilia; Voltolini, Luca

2017-07-01

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an undefined etiopathogenesis. Oxidative stress contributes to alveolar injury and fibrosis development and, because transition metals are essential to the functioning of most proteins involved in redox reactions, a better knowledge of metal concentrations and metabolism in the respiratory system of IPF patients may provide a valuable complementary approach to prevent and manage a disease which is often misdiagnosed or diagnosed in later stages. The present review summarizes and discusses literature data on the elemental composition of bronchoalveolar lavage (BAL), induced sputum and exhaled breath condensate (EBC) from patients affected by IPF and healthy subjects. Available data are scanty and the lack of consistent methods for the collection and analysis of lung and airways lining fluids makes it difficult to compare the results of different studies. However, the elemental composition of BAL samples from IPF patients seems to have a specific profile that can be distinguished from that of patients with other interstitial lung diseases (ILD) or control subjects. Suggestions are given towards standard sampling and analytical procedures of BAL samples, in the aim to assess typical element concentration patterns and their potential role as biomarkers of IPF. Copyright © 2017 Elsevier GmbH. All rights reserved.

Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis

PubMed Central

Tashiro, Jun; Rubio, Gustavo A.; Limper, Andrew H.; Williams, Kurt; Elliot, Sharon J.; Ninou, Ioanna; Aidinis, Vassilis; Tzouvelekis, Argyrios; Glassberg, Marilyn K.

2017-01-01

Large multicenter clinical trials have led to two recently approved drugs for patients with idiopathic pulmonary fibrosis (IPF); yet, both of these therapies only slow disease progression and do not provide a definitive cure. Traditionally, preclinical trials have utilized mouse models of bleomycin (BLM)-induced pulmonary fibrosis—though several limitations prevent direct translation to human IPF. Spontaneous pulmonary fibrosis occurs in other animal species, including dogs, horses, donkeys, and cats. While the fibrotic lungs of these animals share many characteristics with lungs of patients with IPF, current veterinary classifications of fibrotic lung disease are not entirely equivalent. Additional studies that profile these examples of spontaneous fibroses in animals for similarities to human IPF should prove useful for both human and animal investigators. In the meantime, studies of BLM-induced fibrosis in aged male mice remain the most clinically relevant model for preclinical study for human IPF. Addressing issues such as time course of treatment, animal size and characteristics, clinically irrelevant treatment endpoints, and reproducibility of therapeutic outcomes will improve the current status of preclinical studies. Elucidating the mechanisms responsible for the development of fibrosis and disrepair associated with aging through a collaborative approach between researchers will promote the development of models that more accurately represent the realm of interstitial lung diseases in humans. PMID:28804709

Directly data processing algorithm for multi-wavelength pyrometer (MWP).

PubMed

Xing, Jian; Peng, Bo; Ma, Zhao; Guo, Xin; Dai, Li; Gu, Weihong; Song, Wenlong

2017-11-27

Data processing of multi-wavelength pyrometer (MWP) is a difficult problem because unknown emissivity. So far some solutions developed generally assumed particular mathematical relations for emissivity versus wavelength or emissivity versus temperature. Due to the deviation between the hypothesis and actual situation, the inversion results can be seriously affected. So directly data processing algorithm of MWP that does not need to assume the spectral emissivity model in advance is main aim of the study. Two new data processing algorithms of MWP, Gradient Projection (GP) algorithm and Internal Penalty Function (IPF) algorithm, each of which does not require to fix emissivity model in advance, are proposed. The novelty core idea is that data processing problem of MWP is transformed into constraint optimization problem, then it can be solved by GP or IPF algorithms. By comparison of simulation results for some typical spectral emissivity models, it is found that IPF algorithm is superior to GP algorithm in terms of accuracy and efficiency. Rocket nozzle temperature experiment results show that true temperature inversion results from IPF algorithm agree well with the theoretical design temperature as well. So the proposed combination IPF algorithm with MWP is expected to be a directly data processing algorithm to clear up the unknown emissivity obstacle for MWP.

Prevalence of respiratory viruses in Iranian patients with idiopathic pulmonary fibrosis.

PubMed

Keyvani, Hossein; Moghoofei, Mohsen; Bokharaei-Salim, Farah; Mostafaei, Shayan; Javad Mousavi, Seyed-Ali; Monavari, Seyed Hamidreza; Esghaei, Maryam

2017-11-01

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal lung disease. One of the risk factors involved in the acquisition of IPF is viral infections, especially respiratory viruses. In the present study, we investigated the detection of respiratory viruses and the possible relationship between these viruses and IPF. This cross-sectional study was supported by the Iran University of Medical Sciences (IUMS), Tehran, Iran. A total of 40 respiratory samples (five nasopharyngeal and 35 bronchoalveolar lavage specimens) were obtained from IPF patients referred to IUMS hospitals between April 2015 and December 2016. Assays were performed using the CLART Pneumovir DNA array assay, which made it possible to detect five genera of respiratory viruses simultaneously.Results/Key findings. Altogether, 22 of the 40 participants were male. Respiratory syncytial virus (RSV), parainfluenza, rhino, corona and influenza viruses were found in 2.5 % (1/40), 7.5 % (3/40), 10 % (4/40), 2.5 % (1/40) and 0% (0/40) of cases, respectively. Determining a correlation between the viruses and IPF is not an easy task, and therefore, this will require more research. In addition, the CLART Pneumovir DNA array can be considered as a useful method for simultaneous detection of several viral respiratory infections.

Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis.

PubMed

Lutz, Dennis; Gazdhar, Amiq; Lopez-Rodriguez, Elena; Ruppert, Clemens; Mahavadi, Poornima; Günther, Andreas; Klepetko, Walter; Bates, Jason H; Smith, Bradford; Geiser, Thomas; Ochs, Matthias; Knudsen, Lars

2015-02-01

Idiopathic pulmonary fibrosis (IPF) and bleomycin-induced pulmonary fibrosis are associated with surfactant system dysfunction, alveolar collapse (derecruitment), and collapse induration (irreversible collapse). These events play undefined roles in the loss of lung function. The purpose of this study was to quantify how surfactant inactivation, alveolar collapse, and collapse induration lead to degradation of lung function. Design-based stereology and invasive pulmonary function tests were performed 1, 3, 7, and 14 days after intratracheal bleomycin-instillation in rats. The number and size of open alveoli was correlated to mechanical properties. Active surfactant subtypes declined by Day 1, associated with a progressive alveolar derecruitment and a decrease in compliance. Alveolar epithelial damage was more pronounced in closed alveoli compared with ventilated alveoli. Collapse induration occurred on Day 7 and Day 14 as indicated by collapsed alveoli overgrown by a hyperplastic alveolar epithelium. This pathophysiology was also observed for the first time in human IPF lung explants. Before the onset of collapse induration, distal airspaces were easily recruited, and lung elastance could be kept low after recruitment by positive end-expiratory pressure (PEEP). At later time points, the recruitable fraction of the lung was reduced by collapse induration, causing elastance to be elevated at high levels of PEEP. Surfactant inactivation leading to alveolar collapse and subsequent collapse induration might be the primary pathway for the loss of alveoli in this animal model. Loss of alveoli is highly correlated with the degradation of lung function. Our ultrastructural observations suggest that collapse induration is important in human IPF.

Visual vs Fully Automatic Histogram-Based Assessment of Idiopathic Pulmonary Fibrosis (IPF) Progression Using Sequential Multidetector Computed Tomography (MDCT)

PubMed Central

Colombi, Davide; Dinkel, Julien; Weinheimer, Oliver; Obermayer, Berenike; Buzan, Teodora; Nabers, Diana; Bauer, Claudia; Oltmanns, Ute; Palmowski, Karin; Herth, Felix; Kauczor, Hans Ulrich; Sverzellati, Nicola

2015-01-01

Objectives To describe changes over time in extent of idiopathic pulmonary fibrosis (IPF) at multidetector computed tomography (MDCT) assessed by semi-quantitative visual scores (VSs) and fully automatic histogram-based quantitative evaluation and to test the relationship between these two methods of quantification. Methods Forty IPF patients (median age: 70 y, interquartile: 62-75 years; M:F, 33:7) that underwent 2 MDCT at different time points with a median interval of 13 months (interquartile: 10-17 months) were retrospectively evaluated. In-house software YACTA quantified automatically lung density histogram (10th-90th percentile in 5th percentile steps). Longitudinal changes in VSs and in the percentiles of attenuation histogram were obtained in 20 untreated patients and 20 patients treated with pirfenidone. Pearson correlation analysis was used to test the relationship between VSs and selected percentiles. Results In follow-up MDCT, visual overall extent of parenchymal abnormalities (OE) increased in median by 5 %/year (interquartile: 0 %/y; +11 %/y). Substantial difference was found between treated and untreated patients in HU changes of the 40th and of the 80th percentiles of density histogram. Correlation analysis between VSs and selected percentiles showed higher correlation between the changes (Δ) in OE and Δ 40th percentile (r=0.69; p<0.001) as compared to Δ 80th percentile (r=0.58; p<0.001); closer correlation was found between Δ ground-glass extent and Δ 40th percentile (r=0.66, p<0.001) as compared to Δ 80th percentile (r=0.47, p=0.002), while the Δ reticulations correlated better with the Δ 80th percentile (r=0.56, p<0.001) in comparison to Δ 40th percentile (r=0.43, p=0.003). Conclusions There is a relevant and fully automatically measurable difference at MDCT in VSs and in histogram analysis at one year follow-up of IPF patients, whether treated or untreated: Δ 40th percentile might reflect the change in overall extent of lung abnormalities, notably of ground-glass pattern; furthermore Δ 80th percentile might reveal the course of reticular opacities. PMID:26110421

Greater endurance capacity and improved dyspnoea with acute oxygen supplementation in idiopathic pulmonary fibrosis patients without resting hypoxaemia.

PubMed

Dowman, Leona M; McDonald, Christine F; Bozinovski, Steven; Vlahos, Ross; Gillies, Rebecca; Pouniotis, Dodie; Hill, Catherine J; Goh, Nicole S L; Holland, Anne E

2017-07-01

Supplemental oxygen is commonly prescribed in patients with idiopathic pulmonary fibrosis (IPF), although its benefits have not been proven. The aims of this study were to investigate the effect of oxygen on oxidative stress, cytokine production, skeletal muscle metabolism and physiological response to exercise in IPF. Eleven participants with IPF received either oxygen, at an FiO 2 of 0.50, or compressed air for 1 h at rest and during a cycle endurance test at 85% of peak work rate. Blood samples collected at rest and during exercise were analysed for markers of oxidative stress, skeletal muscle metabolism and cytokines. The protocol was repeated a week later with the alternate intervention. Compared with air, oxygen did not adversely affect biomarker concentrations at rest and significantly improved endurance time (mean difference = 99 ± 81s, P = 0.002), dyspnoea (-1 ± 1 U, P = 0.02), systolic blood pressure (BP; -11 ± 11 mm Hg, P = 0.006), nadir oxyhaemoglobin saturation (SpO 2 ; 8 ± 6%, P = 0.001), SpO 2 at 2-min (7 ± 6%, P = 0.003) and 5-min isotimes (5 ± 3, P < 0.001) and peak exercise xanthine concentrations (-42 ± 73 µmol/L, P = 0.03). Air significantly increased IL-10 (5 ± 5 pg/mL, P = 0.04) at 2-min isotime. Thiobarbituric acid-reactive substances (TBARs), IL-6, TNF-α, creatine kinase, lactate, heart rate and fatigue did not differ between the two interventions at any time point. In patients with IPF, breathing oxygen at FiO 2 of 0.50 at rest seems safe. During exercise, oxygen improves exercise tolerance, alleviates exercise-induced hypoxaemia and reduces dyspnoea. A potential relationship between oxygen administration and improved skeletal muscle metabolism should be explored in future studies. © 2017 Asian Pacific Society of Respirology.

Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study.

PubMed

Morell, Ferran; Villar, Ana; Montero, María-Ángeles; Muñoz, Xavier; Colby, Thomas V; Pipvath, Sudhakar; Cruz, María-Jesús; Raghu, Ganesh

2013-11-01

The clinical features of idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis can be indistinguishable; the need to eliminate occult environmental factors known to cause pulmonary fibrosis in patients suspected to have IPF during diagnostic evaluation is evident. We aimed to investigate occult, putative causes in the environments of patients diagnosed with IPF using tests beyond those conventionally used. In this case-cohort study, 60 consecutive patients diagnosed with IPF on the basis of the 2000 American Thoracic Society (ATS) and the European Respiratory Society (ERS) criteria were prospectively followed up every 4 months for 6 years between Jan 1, 2004, and Dec 31, 2009. At each visit a uniformly applied questionnaire was administered to these 60 patients to identify occult antigen exposure known to cause hypersensitivity pneumonitis. Patients underwent specific IgG determination, bronchoalveolar lavage, bronchial challenge testing with suspected antigens, and re-review of histopathological features in existing and subsequently obtained surgical lung biopsy samples and from lung explants. Specimens obtained from suspected sources from the patient's environment were subjected to cultures in microbiology laboratory. These clinical data and discussions among pulmonologists and radiologists familiar with IPF were used to confirm the diagnosis in accordance with 2011 ATS, ERS, Japanese Respiratory Society, and Latin American Thoracic Association guidelines; 46 of the 60 patients had IPF according to the 2011 guidelines, and our analyses in this study were focused on these 46 patients. 20 of the 46 (43%, 95% CI 29-58) patients with IPF according to 2011 guidelines had a subsequent diagnosis of chronic hypersensitivity pneumonitis: nine patients had positive bronchial challenge testing (eight of whom were also IgG positive and six of these patients also had surgical lung biopsy showing a pattern consistent with chronic hypersensitivity pneumonitis); seven were IgG positive plus had histopathology on surgical lung biopsy that was consistent with hypersensitivity pneumonitis; one was IgG positive plus had greater than 20% lymphocytes in bronchoalveolar lavage fluid; and three had findings on surgical lung biopsy that were consistent with subacute hypersensitivity pneumonitis (and IgG positive). Altogether, 29 of 46 patients diagnosed with IPF who had met the 2011 criteria had lung tissue available for histopathology (surgical lung biopsy in 28 patients and explanted lung in two patients, one of whom also had surgical biopsy) during the study period, and 16 of the 20 patients with chronic hypersensitivity pneumonitis had histopathological features on surgical lung biopsy that were consistent with this diagnosis. 26 of the 46 patients remained with a diagnosis of IPF. Almost half of patients diagnosed with IPF on the basis of 2011 criteria were subsequently diagnosed with chronic hypersensitivity pneumonitis, and most of these cases were attributed to exposure of occult avian antigens from commonly used feather bedding. Our results reflect findings in one centre with recognised expertise in chronic hypersensitivity pneumonitis, and further research and studies at other centres are warranted. Fondo de Investigaciones Sanitarias; Fundació Privada Cellex; SEPAR 2010. Copyright © 2013 Elsevier Ltd. All rights reserved.

Grainyhead-like 2 (GRHL2) distribution reveals novel pathophysiological differences between human idiopathic pulmonary fibrosis and mouse models of pulmonary fibrosis

PubMed Central

Mahavadi, Poornima; Sasikumar, Satish; Cushing, Leah; Hyland, Tessa; Rosser, Ann E.; Riccardi, Daniela; Lu, Jining; Kalin, Tanya V.; Kalinichenko, Vladimir V.; Guenther, Andreas; Ramirez, Maria I.; Pardo, Annie; Selman, Moisés; Warburton, David

2013-01-01

Chronic injury of alveolar lung epithelium leads to epithelial disintegrity in idiopathic pulmonary fibrosis (IPF). We had reported earlier that Grhl2, a transcriptional factor, maintains alveolar epithelial cell integrity by directly regulating components of adherens and tight junctions and thus hypothesized an important role of GRHL2 in pathogenesis of IPF. Comparison of GRHL2 distribution at different stages of human lung development showed its abundance in developing lung epithelium and in adult lung epithelium. However, GRHL2 is detected in normal human lung mesenchyme only at early fetal stage (week 9). Similar mesenchymal reexpression of GRHL2 was also observed in IPF. Immunofluorescence analysis in serial sections from three IPF patients revealed at least two subsets of alveolar epithelial cells (AEC), based on differential GRHL2 expression and the converse fluorescence intensities for epithelial vs. mesenchymal markers. Grhl2 was not detected in mesenchyme in intraperitoneal bleomycin-induced injury as well as in spontaneously occurring fibrosis in double-mutant HPS1 and HPS2 mice, whereas in contrast in a radiation-induced fibrosis model, with forced Forkhead box M1 (Foxm1) expression, an overlap of Grhl2 with a mesenchymal marker was observed in fibrotic regions. Grhl2's role in alveolar epithelial cell plasticity was confirmed by altered Grhl2 gene expression analysis in IPF and further validated by in vitro manipulation of its expression in alveolar epithelial cell lines. Our findings reveal important pathophysiological differences between human IPF and specific mouse models of fibrosis and support a crucial role of GRHL2 in epithelial activation in lung fibrosis and perhaps also in epithelial plasticity. PMID:24375798

The effects of collagen-rich extracellular matrix on the intracellular delivery of glycol chitosan nanoparticles in human lung fibroblasts.

PubMed

Yhee, Ji Young; Yoon, Hong Yeol; Kim, Hyunjoon; Jeon, Sangmin; Hergert, Polla; Im, Jintaek; Panyam, Jayanth; Kim, Kwangmeyung; Nho, Richard Seonghun

2017-01-01

Recent progress in nanomedicine has shown a strong possibility of targeted therapy for obstinate chronic lung diseases including idiopathic pulmonary fibrosis (IPF). IPF is a fatal lung disease characterized by persistent fibrotic fibroblasts in response to type I collagen-rich extracellular matrix. As a pathological microenvironment is important in understanding the biological behavior of nanoparticles, in vitro cellular uptake of glycol chitosan nanoparticles (CNPs) in human lung fibroblasts was comparatively studied in the presence or absence of type I collagen matrix. Primary human lung fibroblasts from non-IPF and IPF patients (n=6/group) showed significantly increased cellular uptake of CNPs (>33.6-78.1 times) when they were cultured on collagen matrix. To elucidate the underlying mechanism of enhanced cellular delivery of CNPs in lung fibroblasts on collagen, cells were pretreated with chlorpromazine, genistein, and amiloride to inhibit clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis, respectively. Amiloride pretreatment remarkably reduced the cellular uptake of CNPs, suggesting that lung fibroblasts mainly utilize the macropinocytosis-dependent mechanism when interacted with collagen. In addition, the internalization of CNPs was predominantly suppressed by a phosphoinositide 3-kinase (PI3K) inhibitor in IPF fibroblasts, indicating that enhanced PI3K activity associated with late-stage macropinocytosis can be particularly important for the enhanced cellular delivery of CNPs in IPF fibroblasts. Our study strongly supports the concept that a pathological microenvironment which surrounds lung fibroblasts has a significant impact on the intracellular delivery of nanoparticles. Based on the property of enhanced intracellular delivery of CNPs when fibroblasts are made to interact with a collagen-rich matrix, we suggest that CNPs may have great potential as a drug-carrier system for targeting fibrotic lung fibroblasts.

The Idiopathic Pulmonary Fibrosis Honeycomb Cyst Contains A Mucocilary Pseudostratified Epithelium

PubMed Central

Seibold, Max A.; Smith, Russell W.; Urbanek, Cydney; Groshong, Steve D.; Cosgrove, Gregory P.; Brown, Kevin K.; Schwarz, Marvin I.

2013-01-01

Background We previously identified a MUC5B gene promoter-variant that is a risk allele for sporadic and familial Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia (IPF/UIP). This allele was strongly associated with increased MUC5B gene expression in lung tissue from unaffected subjects. Despite the strong association of this airway epithelial marker with disease, little is known of mucin expressing structures or of airway involvement in IPF/UIP. Methods Immunofluorescence was used to subtype mucus cells according to MUC5B and MUC5AC expression and to identify ciliated, basal, and alveolar type II (ATII) cells in tissue sections from control and IPF/UIP subjects. Staining patterns were quantified for distal airways (Control and IPF/UIP) and in honeycomb cysts (HC). Results MUC5B-expressing cells (EC) were detected in the majority of control distal airways. MUC5AC-EC were identified in half of these airways and only in airways that contained MUC5B-EC. The frequency of MUC5B+ and MUC5AC+ distal airways was increased in IPF/UIP subjects. MUC5B-EC were the dominant mucus cell type in the HC epithelium. The distal airway epithelium from control and IPF/UIP subjects and HC was populated by basal and ciliated cells. Most honeycombing regions were distinct from ATII hyperplasic regions. ATII cells were undetectable in the overwhelming majority of HC. Conclusions The distal airway contains a pseudostratified mucocilary epithelium that is defined by basal epithelial cells and mucus cells that express MUC5B predominantly. These data suggest that the HC is derived from the distal airway. PMID:23527003

Daily Home Spirometry: An Effective Tool for Detecting Progression in Idiopathic Pulmonary Fibrosis

PubMed Central

Russell, Anne-Marie; Adamali, Huzaifa; Molyneaux, Philip L.; Lukey, Pauline T.; Marshall, Richard P.; Renzoni, Elisabetta A.; Wells, Athol U.

2016-01-01

Rationale: Recent clinical trial successes have created an urgent need for earlier and more sensitive endpoints of disease progression in idiopathic pulmonary fibrosis (IPF). Domiciliary spirometry permits more frequent measurement of FVC than does hospital-based assessment, which therefore affords the opportunity for a more granular insight into changes in IPF progression. Objectives: To determine the feasibility and reliability of measuring daily FVC in individuals with IPF. Methods: Subjects with IPF were given handheld spirometers and instruction on how to self-administer spirometry. Subjects recorded daily FEV1 and FVC for up to 490 days. Clinical assessment and hospital-based spirometry was undertaken at 6 and 12 months, and outcome data were collected for 3 years. Measurements and Main Results: Daily spirometry was recorded by 50 subjects for a median period of 279 days (range, 13–490 d). There were 18 deaths during the active study period. Home spirometry showed excellent correlation with hospital-obtained readings. The rate of decline in FVC was highly predictive of outcome and subsequent mortality when measured at 3 months (hazard ratio [HR], 1.040; 95% confidence interval [CI], 1.021–1.062; P ≤ 0.001), 6 months (HR, 1.024; 95% CI, 1.014–1.033; P < 0.001), and 12 months (HR, 1.012; 95% CI, 1.007–1.016; P = 0.001). Conclusions: Measurement of daily home spirometry in patients with IPF is highly clinically informative and is feasible to perform for most of these patients. The relationship between mortality and rate of change of FVC at 3 months suggests that daily FVC may be of value as a primary endpoint in short proof-of-concept IPF studies. PMID:27089018

Short-term Automated Quantification of Radiologic Changes in the Characterization of Idiopathic Pulmonary Fibrosis Versus Nonspecific Interstitial Pneumonia and Prediction of Long-term Survival.

PubMed

De Giacomi, Federica; Raghunath, Sushravya; Karwoski, Ronald; Bartholmai, Brian J; Moua, Teng

2018-03-01

Fibrotic interstitial lung diseases presenting with nonspecific and overlapping radiologic findings may be difficult to diagnose without surgical biopsy. We hypothesized that baseline quantifiable radiologic features and their short-term interval change may be predictive of underlying histologic diagnosis as well as long-term survival in idiopathic pulmonary fibrosis (IPF) presenting without honeycombing versus nonspecific interstitial pneumonia (NSIP). Forty biopsy-confirmed IPF and 20 biopsy-confirmed NSIP patients with available high-resolution chest computed tomography 4 to 24 months apart were studied. CALIPER software was used for the automated characterization and quantification of radiologic findings. IPF subjects were older (66 vs. 48; P<0.0001) with lower diffusion capacity for carbon monoxide and higher volumes of baseline reticulation (193 vs. 83 mL; P<0.0001). Over the interval period, compared with NSIP, IPF patients experienced greater functional decline (forced vital capacity, -6.3% vs. -1.7%; P=0.02) and radiologic progression, as noted by greater increase in reticulation volume (24 vs. 1.74 mL; P=0.048), and decrease in normal (-220 vs. -37.7 mL; P=0.045) and total lung volumes (-198 vs. 58.1 mL; P=0.03). Older age, male gender, higher reticulation volumes at baseline, and greater interval decrease in normal lung volumes were predictive of IPF. Both baseline and short-term changes in quantitative radiologic findings were predictive of mortality. Baseline quantitative radiologic findings and assessment of short-term disease progression may help characterize underlying IPF versus NSIP in those with difficult to differentiate clinicoradiologic presentations. Our study supports the possible utility of assessing serial quantifiable high-resolution chest computed tomographic findings for disease differentiation in these 2 entities.

Predicting survival of patients with idiopathic pulmonary fibrosis using GAP score: a nationwide cohort study.

PubMed

Lee, Sang Hoon; Kim, Song Yee; Kim, Dong Soon; Kim, Young Whan; Chung, Man Pyo; Uh, Soo Taek; Park, Choon Sik; Jeong, Sung Hwan; Park, Yong Bum; Lee, Hong Lyeol; Shin, Jong Wook; Lee, Eun Joo; Lee, Jin Hwa; Jegal, Yangin; Lee, Hyun Kyung; Kim, Yong Hyun; Song, Jin Woo; Park, Sung Woo; Park, Moo Suk

2016-10-18

The clinical course of idiopathic pulmonary fibrosis (IPF) varies widely. Although the GAP model is useful for predicting mortality, survivals have not yet been validated for each GAP score. We aimed to elucidate how prognosis is related to GAP score and GAP stage in IPF patients. The Korean Interstitial Lung Disease Study Group conducted a national survey to evaluate various characteristics in IPF patients from 2003 to 2007. Patients were diagnosed according to the 2002 criteria of the ATS/ERS. We enrolled 1,685 patients with IPF; 1,262 had undergone DL CO measurement. Patients were stratified based on GAP score (0-7): GAP score Group 0 (n = 26), Group 1 (n = 150), Group 2 (n = 208), Group 3 (n = 376), Group 4 (n = 317), Group 5 (n = 138), Group 6 (n = 39), and Group 7 (n = 8). Higher GAP score and GAP stage were associated with a poorer prognosis (p < 0.001, respectively). Survival time in Group 3 was lower than those in Groups 1 and 2 (p = 0.043 and p = 0.039, respectively), and higher than those in groups 4, 5, and 6 (p = 0.043, p = 0.032, and p = 0.003, respectively). Gender, age, and DL CO (%) differed significantly between Groups 2 and 3. All four variables in the GAP model differed significantly between Groups 3 and 4. The GAP system showed significant predictive ability for mortality in IPF patients. However, prognosis in IPF patients with a GAP score of 3 were significantly different from those in the other stage I groups and stage II groups of Asian patients.

Lipoxin A4 Attenuates Constitutive and TGF-β1–Dependent Profibrotic Activity in Human Lung Myofibroblasts

PubMed Central

Feghali-Bostwick, Carol A.; Amrani, Yassine; Bradding, Peter

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a common, progressive, and invariably lethal interstitial lung disease with no effective therapy. The key cell driving the development of fibrosis is the myofibroblast. Lipoxin A4 (LXA4) is an anti-inflammatory lipid, important in the resolution of inflammation, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts (HLMFs) have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 on TGF-β1–dependent responses in IPF- and nonfibrotic control (NFC)–derived HLMFs. HLMFs were isolated from IPF and NFC patients and grown in vitro. The effects of LXA4 on HLMF proliferation, collagen secretion, α-smooth muscle actin (αSMA) expression, and Smad2/3 activation were examined constitutively and following TGF-β1 stimulation. The LXA4 receptor (ALXR) was expressed in both NFC- and IPF-derived HLMFs. LXA4 (10−10 and 10−8 mol) reduced constitutive αSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and TGF-β1–dependent collagen secretion, αSMA expression, and Smad2/3 nuclear translocation in IPF-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of IPF. PMID:26276873

Antacid Therapy and Disease Progression in Patients with Idiopathic Pulmonary Fibrosis Who Received Pirfenidone.

PubMed

Kreuter, Michael; Spagnolo, Paolo; Wuyts, Wim; Renzoni, Elisabetta; Koschel, Dirk; Bonella, Francesco; Maher, Toby M; Kolb, Martin; Weycker, Derek; Kirchgässler, Klaus-Uwe; Costabel, Ulrich

2017-01-01

Gastroesophageal reflux disease is a potential risk factor for idiopathic pulmonary fibrosis (IPF) progression; however, the impact of antacid therapy (AAT) is under debate. To evaluate the effect of AAT on IPF progression in pirfenidone-treated patients. This post hoc analysis included patients with IPF who received pirfenidone in 3 trials (CAPACITY [PIPF-004/PIPF-006] and ASCEND [PIPF-016]). Pulmonary function, exercise tolerance, survival, hospitalizations, and adverse events (AEs) over 52 weeks were analyzed by baseline AAT use. Disease progression was defined as a decrease in forced vital capacity (FVC) of ≥10%, a decrease in 6-min walking distance of ≥50 m, or death over 1 year. Of 623 patients, 44% received AAT. No significant differences were found at 52 weeks (AAT versus non-AAT, respectively) in disease progression (24.9 vs. 30.6%; p = 0.12), all-cause mortality rate (2.9 vs. 4.0%; p = 0.47), IPF-related mortality rate (1.1 vs. 2.0%; p = 0.37), all-cause hospitalization rate (16.1 vs. 18.3%; p = 0.48), or mean change in percent FVC (-2.7 vs. -3.1%; p = 0.44). A relative, but not absolute, FVC decline of ≥10% favored AAT (15 vs. 22%; p = 0.03). Severe gastrointestinal AEs (3.7 vs. 0.9%; p = 0.015) and severe pulmonary infections (3.7 vs. 1.1%; p = 0.035) were more frequent with AAT. AAT and pirfenidone had outcomes comparable to those of pirfenidone alone in patients with IPF, underscoring the need for prospective trials to elucidate the role of AAT with or without antifibrotic drugs as a treatment for IPF. © 2017 The Author(s) Published by S. Karger AG, Basel.

Differential Expression of VEGF-Axxx Isoforms Is Critical for Development of Pulmonary Fibrosis.

PubMed

Barratt, Shaney L; Blythe, Thomas; Jarrett, Caroline; Ourradi, Khadija; Shelley-Fraser, Golda; Day, Michael J; Qiu, Yan; Harper, Steve; Maher, Toby M; Oltean, Sebastian; Hames, Thomas J; Scotton, Chris J; Welsh, Gavin I; Bates, David O; Millar, Ann B

2017-08-15

Fibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-A 165 a and VEGF-A 165 b, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF. To establish VEGF-A isoform expression and functional effects in IPF. We used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTA +/- TetoCre +/- LoxP-VEGF-A +/+ to conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice. IPF and normal lung fibroblasts differentially expressed and responded to VEGF-A 165 a and VEGF-A 165 b in terms of proliferation and matrix expression. Increased VEGF-A 165 b was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-A 165 b inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-A 165 b to wild-type mice. These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-A xxx a to VEGF-A xxx b, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair.

Sustained activation of toll-like receptor 9 induces an invasive phenotype in lung fibroblasts: possible implications in idiopathic pulmonary fibrosis.

PubMed

Kirillov, Varvara; Siler, Jonathan T; Ramadass, Mahalakshmi; Ge, Lingyin; Davis, James; Grant, Geraldine; Nathan, Steven D; Jarai, Gabor; Trujillo, Glenda

2015-04-01

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive scarring of the lung parenchyma, resulting in a steady decline of lung function and ultimately respiratory failure. The disease course of IPF is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and loss of lung function. Viral infections have been implicated in IPF and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, Toll-like receptor 9 (TLR9). Activation of TLR9 in vivo exacerbated IPF in mice and induced differentiation of myofibroblasts in vitro, but the mechanism of TLR9 up-regulation and progression of fibrosis are unknown. Herein, we investigate whether transforming growth factor (TGF)-β, a pleiotropic cytokine central to IPF pathogenesis, regulates TLR9 in lung myofibroblasts. Results showed induction of TLR9 expression by TGF-β in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the TLR9 agonist, CpG-DNA. Chronic TLR9 stimulation resulted in stably differentiated α-smooth muscle actin(+)/platelet-derived growth factor receptor α(+)/CD44(+)/matrix metalloproteinase-14(+)/matrix metalloproteinase-2(+) myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-β and TLR9 responses in myofibroblasts collaborate to drive rapid progression of IPF. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Morphologic and molecular study of lung cancers associated with idiopathic pulmonary fibrosis and other pulmonary fibroses.

PubMed

Guyard, Alice; Danel, Claire; Théou-Anton, Nathalie; Debray, Marie-Pierre; Gibault, Laure; Mordant, Pierre; Castier, Yves; Crestani, Bruno; Zalcman, Gérard; Blons, Hélène; Cazes, Aurélie

2017-06-15

Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry. Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%. This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.

Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis.

PubMed

Craig, Vanessa J; Zhang, Li; Hagood, James S; Owen, Caroline A

2015-11-01

Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis (PF) have demonstrated that most MMPs promote (rather than inhibit) the development of PF and have identified diverse mechanisms involved. These mechanisms include MMPs: (1) promoting epithelial-to-mesenchymal transition (MMP-3 and MMP-7); (2) increasing lung levels or activity of profibrotic mediators or reducing lung levels of antifibrotic mediators (MMP-3, MMP-7, and MMP-8); (3) promoting abnormal epithelial cell migration and other aberrant repair processes (MMP-3 and MMP-9); (4) inducing the switching of lung macrophage phenotypes from M1 to M2 types (MMP-10 and MMP-28); and (5) promoting fibrocyte migration (MMP-8). Two MMPs, MMP-13 and MMP-19, have antifibrotic activities in murine models of PF, and two MMPs, MMP-1 and MMP-10, have the potential to limit fibrotic responses to injury. Herein, we review what is known about the contributions of MMPs and TIMPs to the pathogenesis of IPF and discuss their potential as therapeutic targets for IPF.

Matrix Metalloproteinases as Therapeutic Targets for Idiopathic Pulmonary Fibrosis

PubMed Central

Craig, Vanessa J.; Zhang, Li; Hagood, James S.

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis (PF) have demonstrated that most MMPs promote (rather than inhibit) the development of PF and have identified diverse mechanisms involved. These mechanisms include MMPs: (1) promoting epithelial-to-mesenchymal transition (MMP-3 and MMP-7); (2) increasing lung levels or activity of profibrotic mediators or reducing lung levels of antifibrotic mediators (MMP-3, MMP-7, and MMP-8); (3) promoting abnormal epithelial cell migration and other aberrant repair processes (MMP-3 and MMP-9); (4) inducing the switching of lung macrophage phenotypes from M1 to M2 types (MMP-10 and MMP-28); and (5) promoting fibrocyte migration (MMP-8). Two MMPs, MMP-13 and MMP-19, have antifibrotic activities in murine models of PF, and two MMPs, MMP-1 and MMP-10, have the potential to limit fibrotic responses to injury. Herein, we review what is known about the contributions of MMPs and TIMPs to the pathogenesis of IPF and discuss their potential as therapeutic targets for IPF. PMID:26121236

Multi-dimensional scores to predict mortality in patients with idiopathic pulmonary fibrosis undergoing lung transplantation assessment.

PubMed

Fisher, Jolene H; Al-Hejaili, Faris; Kandel, Sonja; Hirji, Alim; Shapera, Shane; Mura, Marco

2017-04-01

The heterogeneous progression of idiopathic pulmonary fibrosis (IPF) makes prognostication difficult and contributes to high mortality on the waitlist for lung transplantation (LTx). Multi-dimensional scores (Composite Physiologic index [CPI], [Gender-Age-Physiology [GAP]; RIsk Stratification scorE [RISE]) demonstrated enhanced predictive power towards outcome in IPF. The lung allocation score (LAS) is a multi-dimensional tool commonly used to stratify patients assessed for LTx. We sought to investigate whether IPF-specific multi-dimensional scores predict mortality in patients with IPF assessed for LTx. The study included 302 patients with IPF who underwent a LTx assessment (2003-2014). Multi-dimensional scores were calculated. The primary outcome was 12-month mortality after assessment. LTx was considered as competing event in all analyses. At the end of the observation period, there were 134 transplants, 63 deaths, and 105 patients were alive without LTx. Multi-dimensional scores predicted mortality with accuracy similar to LAS, and superior to that of individual variables: area under the curve (AUC) for LAS was 0.78 (sensitivity 71%, specificity 86%); CPI 0.75 (sensitivity 67%, specificity 82%); GAP 0.67 (sensitivity 59%, specificity 74%); RISE 0.78 (sensitivity 71%, specificity 84%). A separate analysis conducted only in patients actively listed for LTx (n = 247; 50 deaths) yielded similar results. In patients with IPF assessed for LTx as well as in those actually listed, multi-dimensional scores predict mortality better than individual variables, and with accuracy similar to the LAS. If validated, multi-dimensional scores may serve as inexpensive tools to guide decisions on the timing of referral and listing for LTx. Copyright © 2017 Elsevier Ltd. All rights reserved.

Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis

PubMed Central

Naik, Payal K.; Bozyk, Paul D.; Bentley, J. Kelley; Popova, Antonia P.; Birch, Carolyn M.; Wilke, Carol A.; Fry, Christopher D.; White, Eric S.; Sisson, Thomas H.; Tayob, Nabihah; Carnemolla, Barbara; Orecchia, Paola; Flaherty, Kevin R.; Hershenson, Marc B.; Murray, Susan; Martinez, Fernando J.

2012-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective therapeutics. Periostin has been reported to be elevated in IPF patients relative to controls, but its sources and mechanisms of action remain unclear. We confirm excess periostin in lungs of IPF patients and show that IPF fibroblasts produce periostin. Blood was obtained from 54 IPF patients (all but 1 with 48 wk of follow-up). We show that periostin levels predict clinical progression at 48 wk (hazard ratio = 1.47, 95% confidence interval = 1.03–2.10, P < 0.05). Monocytes and fibrocytes are sources of periostin in circulation in IPF patients. Previous studies suggest that periostin may regulate the inflammatory phase of bleomycin-induced lung injury, but periostin effects during the fibroproliferative phase of the disease are unknown. Wild-type and periostin-deficient (periostin−/−) mice were anesthetized and challenged with bleomycin. Wild-type mice were injected with bleomycin and then treated with OC-20 Ab (which blocks periostin and integrin interactions) or control Ab during the fibroproliferative phase of disease, and fibrosis and survival were assessed. Periostin expression was upregulated quickly after treatment with bleomycin and remained elevated. Periostin−/− mice were protected from bleomycin-induced fibrosis. Instillation of OC-20 during the fibroproliferative phase improved survival and limited collagen deposition. Chimeric mouse studies suggest that hematopoietic and structural sources of periostin contribute to lung fibrogenesis. Periostin was upregulated by transforming growth factor-β in lung mesenchymal cells, and periostin promoted extracellular matrix deposition, mesenchymal cell proliferation, and wound closure. Thus periostin plays a vital role in late stages of pulmonary fibrosis and is a potential biomarker for disease progression and a target for therapeutic intervention. PMID:23043074

FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro.

PubMed

Joannes, Audrey; Brayer, Stéphanie; Besnard, Valérie; Marchal-Sommé, Joëlle; Jaillet, Madeleine; Mordant, Pierre; Mal, Hervé; Borie, Raphael; Crestani, Bruno; Mailleux, Arnaud A

2016-04-01

Idiopathic pulmonary fibrosis (IPF) is characterized by an accumulation of extracellular matrix proteins and fibroblasts in the distal airways. Key developmental lung signaling pathways are reactivated in IPF. For instance, fibroblast growth factor 9 (FGF9) and FGF18, involved in epithelial-mesenchymal interactions, are critical for lung development. We evaluated the expression of FGF9, FGF18, and FGF receptors (FGFRs) in lung tissue from controls and IPF patients and assessed their effect on proliferation, survival, migration, and differentiation of control and IPF human lung fibroblasts (HLFs). FGF9, FGF18, and all FGFRs were present in the remodeled alveolar epithelium close to the fibroblast foci in IPF lungs. FGFR3 was generally detected in fibroblast foci by immunohistochemistry. In vitro, HLFs mainly expressed mesenchyme-associated FGFR isoforms (FGFR1c and FGFR3c) and FGFR4. FGF9 did not affect fibroblast proliferation, whereas FGF18 inhibited cell growth in control fibroblasts. FGF9 and FGF18 decreased Fas-ligand-induced apoptosis in control but not in IPF fibroblasts. FGF9 prevented transforming growth factor β1-induced myofibroblast differentiation. FGF9 and FGF18 increased the migratory capacities of HLF, and FGF9 actively modulated matrix metalloproteinase activity. In addition, FGFR3 inhibition by small interfering RNA impacted p-ERK activation by FGF9 and FGF18 and their effects on differentiation and migration. These results identify FGF9 as an antiapoptotic and promigratory growth factor on HLF, maintaining fibroblasts in an undifferentiated state. The biological effects of FGF9 and FGF18 were partially driven by FGFR3. FGF18 was a less potent molecule. Both growth factors likely contribute to the fibrotic process in vivo. Copyright © 2016 the American Physiological Society.

The effects of collagen-rich extracellular matrix on the intracellular delivery of glycol chitosan nanoparticles in human lung fibroblasts

PubMed Central

Yhee, Ji Young; Yoon, Hong Yeol; Kim, Hyunjoon; Jeon, Sangmin; Hergert, Polla; Im, Jintaek; Panyam, Jayanth; Kim, Kwangmeyung; Nho, Richard Seonghun

2017-01-01

Recent progress in nanomedicine has shown a strong possibility of targeted therapy for obstinate chronic lung diseases including idiopathic pulmonary fibrosis (IPF). IPF is a fatal lung disease characterized by persistent fibrotic fibroblasts in response to type I collagen-rich extracellular matrix. As a pathological microenvironment is important in understanding the biological behavior of nanoparticles, in vitro cellular uptake of glycol chitosan nanoparticles (CNPs) in human lung fibroblasts was comparatively studied in the presence or absence of type I collagen matrix. Primary human lung fibroblasts from non-IPF and IPF patients (n=6/group) showed significantly increased cellular uptake of CNPs (>33.6–78.1 times) when they were cultured on collagen matrix. To elucidate the underlying mechanism of enhanced cellular delivery of CNPs in lung fibroblasts on collagen, cells were pretreated with chlorpromazine, genistein, and amiloride to inhibit clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis, respectively. Amiloride pretreatment remarkably reduced the cellular uptake of CNPs, suggesting that lung fibroblasts mainly utilize the macropinocytosis-dependent mechanism when interacted with collagen. In addition, the internalization of CNPs was predominantly suppressed by a phosphoinositide 3-kinase (PI3K) inhibitor in IPF fibroblasts, indicating that enhanced PI3K activity associated with late-stage macropinocytosis can be particularly important for the enhanced cellular delivery of CNPs in IPF fibroblasts. Our study strongly supports the concept that a pathological microenvironment which surrounds lung fibroblasts has a significant impact on the intracellular delivery of nanoparticles. Based on the property of enhanced intracellular delivery of CNPs when fibroblasts are made to interact with a collagen-rich matrix, we suggest that CNPs may have great potential as a drug-carrier system for targeting fibrotic lung fibroblasts. PMID:28860768

A systematic review of overlapping microRNA patterns in systemic sclerosis and idiopathic pulmonary fibrosis.

PubMed

Bagnato, Gianluca; Roberts, William Neal; Roman, Jesse; Gangemi, Sebastiano

2017-06-30

Lung fibrosis can be observed in systemic sclerosis and in idiopathic pulmonary fibrosis, two disorders where lung involvement carries a poor prognosis. Although much has been learned about the pathogenesis of these conditions, interventions capable of reversing or, at the very least, halting disease progression are not available. Recent studies point to the potential role of micro messenger RNAs (microRNAs) in cancer and tissue fibrogenesis. MicroRNAs are short non-coding RNA sequences (20-23 nucleotides) that are endogenous, evolutionarily conserved and encoded in the genome. By acting on several genes, microRNAs control protein expression. Considering the above, we engaged in a systematic review of the literature in search of overlapping observations implicating microRNAs in the pathogenesis of both idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). Our objective was to uncover top microRNA candidates for further investigation based on their mechanisms of action and their potential for serving as targets for intervention against lung fibrosis. Our review points to microRNAs of the -29 family, -21-5p and -92a-3p, -26a-5p and let-7d-5p as having distinct and counter-balancing actions related to lung fibrosis. Based on this, we speculate that readjusting the disrupted balance between these microRNAs in lung fibrosis related to SSc and IPF may have therapeutic potential. Copyright ©ERS 2017.

Patients' experiences of coping with Idiopathic Pulmonary Fibrosis and their recommendations for its clinical management.

PubMed

Senanayake, Sameera; Harrison, Kim; Lewis, Michael; McNarry, Melitta; Hudson, Joanne

2018-01-01

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive and life-limiting condition. From a healthcare perspective it is vital to establish effective methods of improving the quality of remaining life in these patients. This requires a detailed understanding of the multiple impacts of an IPF diagnosis on the individual. We sought to understand how patients coped with their initial diagnosis, how they live with the disease day-to-day, and their experiences and opinions of the professional support they receive. A patient-centred approach was used to explore the social, psychological and physical impacts of IPF. Semi-structured interviews were conducted by an experienced academic. Interview questions were written by the researchers but guided by informal conversations with patients and clinicians. An inductive thematic approach was used to analyse the data, allowing us to identify common themes in the patients' experiences. Of fifty invited participants, ten took part in the study (aged 53-81 years; 9 male). Inductive analysis of interviews identified seven second-order themes and eleven first-order themes, represented by two General Dimensions: 'Patient experience with the condition' and 'Patient-led recommendations for practice'. The key message on 'coping' in these patients was that acceptance of their condition led to a sense of optimism. Participants reported using appraisal-focused coping strategies to change their perspectives (thinking positively) and emotion-focused strategies to overcome depression (the main opportunity for emotional expression being an IPF support group). The support group also facilitated problem-focused coping: individuals exchanged knowledge and experience and gave one another tips on how to live with their condition. Health professionals should provide patients with information that focuses on living with IPF, encouraging them to make lifestyle changes and adaptations to improve quality of life. Family members should receive education about IPF so that they can support such changes. Patients should be encouraged to join a support group and to participate in physical activity (again preferably group-based). This study offers novel findings that will help inform much-needed changes in the practice of supporting IPF patients to cope with their diagnosis and disease progression.

Update in Diffuse Parenchymal Lung Disease 2013

PubMed Central

Kaminski, Naftali

2015-01-01

The period covered by this update can be considered as the most exciting period in idiopathic pulmonary fibrosis (IPF) research. It started with the identification of genetic variants that are associated with IPF in the majority of patients and continued with discovery of molecular and genetic biomarkers that predict distinct clinical presentations of patients with IPF and potential new biological mechanisms. More importantly, the period ends with the publication of two groundbreaking studies that confirmed that two drugs, pirfenidone and nintedanib, slowed disease progression, leading to a historic approval by the FDA. In this update, we describe these key advances, their scientific and significant clinical implications, and future directions. PMID:25635490

76 FR 26431 - Medicare Program; Inpatient Psychiatric Facilities Prospective Payment System-Update for Rate...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-06

...This final rule updates the prospective payment rates for Medicare inpatient hospital services provided by inpatient psychiatric facilities (IPFs) for discharges occurring during the rate year (RY) beginning July 1, 2011 through September 30, 2012. The final rule also changes the IPF prospective payment system (PPS) payment rate update period to a RY that coincides with a fiscal year (FY). In addition, the rule implements policy changes affecting the IPF PPS teaching adjustment. It also rebases and revises the Rehabilitation, Psychiatric, and Long-Term Care (RPL) market basket, and makes some clarifications and corrections to terminology and regulations text.

Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways

PubMed Central

Evans, Christopher M.; Fingerlin, Tasha E.; Schwarz, Marvin I.; Lynch, David; Kurche, Jonathan; Warg, Laura; Yang, Ivana V.; Schwartz, David A.

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts. Based on these considerations, we hypothesize that excessive production of MUC5B either enhances injury due to reduced mucociliary clearance or impedes repair consequent to disruption of normal regenerative mechanisms in the distal lung. In aggregate, these novel considerations should have broad impact, resulting in specific etiologic targets, early detection of disease, and novel biologic pathways for use in the design of future intervention, prevention, and mechanistic studies of IPF. PMID:27630174

Expression of mutant Sftpcin murine alveolar epithelia drives spontaneous lung fibrosis.

PubMed

Nureki, Shin-Ichi; Tomer, Yaniv; Venosa, Alessandro; Katzen, Jeremy; Russo, Scott J; Jamil, Sarita; Barrett, Matthew; Nguyen, Vivian; Kopp, Meghan; Mulugeta, Surafel; Beers, Michael F

2018-06-19

Epithelial cell dysfunction is postulated as an important component in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). Mutations in the Surfactant Protein C [SP-C] gene [SFTPC], an alveolar type 2 (AT2) cell restricted protein, have been found in sporadic and familial IPF. To causally link these events, we developed a knock-in mouse model capable of regulated expression of an IPF-associated Isoleucine to Threonine substitution at codon 73 [I73T] in Sftpc (SP-CI73T). Tamoxifen treated SP-CI73T cohorts developed rapid increases in SftpcI73T mRNA and misprocessed proSP-CI73T protein accompanied by increased early mortality (days 7-14). This acute phase was marked by diffuse parenchymal lung injury, tissue infiltration by monocytes, polycellular alveolitis, and elevations in bronchoalveolar lavage and AT2 mRNA contents of select inflammatory cytokines. Resolution of alveolitis (2-4 weeks), commensurate with a rise in TGFB1, was followed by aberrant remodeling marked by collagen deposition, AT2 cell hyperplasia, a-SMA positive cells, and restrictive lung physiology. The translational relevance of the model was supported by detection of multiple IPF biomarkers previously reported in human cohorts. These data provide proof of principle that mutant SP-C expression in vivo causes spontaneous lung fibrosis strengthening the role of AT2 dysfunction as a key upstream driver of IPF pathogenesis.

Pirfenidone: a review of its use in idiopathic pulmonary fibrosis.

PubMed

Kim, Esther S; Keating, Gillian M

2015-02-01

Pirfenidone (Esbriet®) is an orally administered, synthetic, pyridone compound that is approved for the treatment of adults with mild to moderate idiopathic pulmonary fibrosis (IPF) in the EU, and for the treatment of IPF in the USA. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of pirfenidone in these indications. In the randomized, double-blind, placebo-controlled, multinational CAPACITY trials in patients with mild to moderate IPF, a significant reduction in the rate of decline in forced vital capacity (FVC) was seen with pirfenidone versus placebo in study 004 but not in study 006. Pirfenidone also reduced the rate of decline in FVC to a significantly greater extent than placebo in the randomized, double-blind, multinational ASCEND trial in this patient population. In addition, pirfenidone showed a significant treatment effect on the 6-min walking test distance and progression-free survival in the ASCEND trial and in a pooled analysis of the CAPACITY trials. Pirfenidone had a manageable tolerability profile in all three studies. Gastrointestinal and skin-related events (e.g. nausea, rash, photosensitivity reaction), which were the most commonly occurring treatment-emergent adverse events, were generally mild to moderate in severity. In addition, a prespecified mortality analysis across all three studies demonstrated a significant reduction in IPF-related and all-cause mortality with pirfenidone. In conclusion, oral pirfenidone is a valuable agent for use in patients with IPF.

Loss of Twist1 in the Mesenchymal Compartment Promotes Increased Fibrosis in Experimental Lung Injury by Enhanced Expression of CXCL12

PubMed Central

Tan, Jiangning; Tedrow, John R.; Nouraie, Mehdi; Dutta, Justin A.; Miller, David T.; Li, Xiaoyun; Yu, Shibing; Chu, Yanxia; Juan-Guardela, Brenda; Kaminski, Naftali; Ramani, Kritika; Biswas, Partha S.; Zhang, Yingze

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a disease characterized by the accumulation of apoptosis-resistant fibroblasts in the lung. We have previously shown that high expression of the transcription factor Twist1 may explain this prosurvival phenotype in vitro. However, this observation has never been tested in vivo. We found that loss of Twist1 in COL1A2+ cells led to increased fibrosis characterized by very significant accumulation of T cells and bone marrow–derived matrix-producing cells. We found that Twist1-null cells expressed high levels of the T cell chemoattractant CXCL12. In vitro, we found that the loss of Twist1 in IPF lung fibroblasts increased expression of CXCL12 downstream of increased expression of the noncanonical NF-κB transcription factor RelB. Finally, blockade of CXCL12 with AMD3100 attenuated the exaggerated fibrosis observed in Twist1-null mice. Transcriptomic analysis of 134 IPF patients revealed that low expression of Twist1 was characterized by enrichment of T cell pathways. In conclusion, loss of Twist1 in collagen-producing cells led to increased bleomycin-induced pulmonary fibrosis, which is mediated by increased expression of CXCL12. Twist1 expression is associated with dysregulation of T cells in IPF patients. Twist1 may shape the IPF phenotype and regulate inflammation in fibrotic lung injury. PMID:28179498

Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study.

PubMed

Walsh, Simon L F; Wells, Athol U; Desai, Sujal R; Poletti, Venerino; Piciucchi, Sara; Dubini, Alessandra; Nunes, Hilario; Valeyre, Dominique; Brillet, Pierre Y; Kambouchner, Marianne; Morais, António; Pereira, José M; Moura, Conceição Souto; Grutters, Jan C; van den Heuvel, Daniel A; van Es, Hendrik W; van Oosterhout, Matthijs F; Seldenrijk, Cornelis A; Bendstrup, Elisabeth; Rasmussen, Finn; Madsen, Line B; Gooptu, Bibek; Pomplun, Sabine; Taniguchi, Hiroyuki; Fukuoka, Junya; Johkoh, Takeshi; Nicholson, Andrew G; Sayer, Charlie; Edmunds, Lilian; Jacob, Joseph; Kokosi, Maria A; Myers, Jeffrey L; Flaherty, Kevin R; Hansell, David M

2016-07-01

Diffuse parenchymal lung disease represents a diverse and challenging group of pulmonary disorders. A consistent diagnostic approach to diffuse parenchymal lung disease is crucial if clinical trial data are to be applied to individual patients. We aimed to evaluate inter-multidisciplinary team agreement for the diagnosis of diffuse parenchymal lung disease. We did a multicentre evaluation of clinical data of patients who presented to the interstitial lung disease unit of the Royal Brompton and Harefield NHS Foundation Trust (London, UK; host institution) and required multidisciplinary team meeting (MDTM) characterisation between March 1, 2010, and Aug 31, 2010. Only patients whose baseline clinical, radiological, and, if biopsy was taken, pathological data were undertaken at the host institution were included. Seven MDTMs, consisting of at least one clinician, radiologist, and pathologist, from seven countries (Denmark, France, Italy, Japan, Netherlands, Portugal, and the UK) evaluated cases of diffuse parenchymal lung disease in a two-stage process between Jan 1, and Oct 15, 2015. First, the clinician, radiologist, and pathologist (if lung biopsy was completed) independently evaluated each case, selected up to five differential diagnoses from a choice of diffuse lung diseases, and chose likelihoods (censored at 5% and summing to 100% in each case) for each of their differential diagnoses, without inter-disciplinary consultation. Second, these specialists convened at an MDTM and reviewed all data, selected up to five differential diagnoses, and chose diagnosis likelihoods. We compared inter-observer and inter-MDTM agreements on patient first-choice diagnoses using Cohen's kappa coefficient (κ). We then estimated inter-observer and inter-MDTM agreement on the probability of diagnosis using weighted kappa coefficient (κw). We compared inter-observer and inter-MDTM confidence of patient first-choice diagnosis. Finally, we evaluated the prognostic significance of a first-choice diagnosis of idiopathic pulmonary fibrosis (IPF) versus not IPF for MDTMs, clinicians, and radiologists, using univariate Cox regression analysis. 70 patients were included in the final study cohort. Clinicians, radiologists, pathologists, and the MDTMs assigned their patient diagnoses between Jan 1, and Oct 15, 2015. IPF made up 88 (18%) of all 490 MDTM first-choice diagnoses. Inter-MDTM agreement for first-choice diagnoses overall was moderate (κ=0·50). Inter-MDTM agreement on diagnostic likelihoods was good for IPF (κw=0·71 [IQR 0·64-0·77]) and connective tissue disease-related interstitial lung disease (κw=0·73 [0·68-0·78]); moderate for non-specific interstitial pneumonia (NSIP; κw=0·42 [0·37-0·49]); and fair for hypersensitivity pneumonitis (κw=0·29 [0·24-0·40]). High-confidence diagnoses (>65% likelihood) of IPF were given in 68 (77%) of 88 cases by MDTMs, 62 (65%) of 96 cases by clinicians, and in 57 (66%) of 86 cases by radiologists. Greater prognostic separation was shown for an MDTM diagnosis of IPF than compared with individual clinician's diagnosis of this disease in five of seven MDTMs, and radiologist's diagnosis of IPF in four of seven MDTMs. Agreement between MDTMs for diagnosis in diffuse lung disease is acceptable and good for a diagnosis of IPF, as validated by the non-significant greater prognostic separation of an IPF diagnosis made by MDTMs than the separation of a diagnosis made by individual clinicians or radiologists. Furthermore, MDTMs made the diagnosis of IPF with higher confidence and more frequently than did clinicians or radiologists. This difference is of particular importance, because accurate and consistent diagnoses of IPF are needed if clinical outcomes are to be optimised. Inter-multidisciplinary team agreement for a diagnosis of hypersensitivity pneumonitis is low, highlighting an urgent need for standardised diagnostic guidelines for this disease. National Institute of Health Research, Imperial College London. Copyright © 2016 Elsevier Ltd. All rights reserved.

Flame-Vortex Interactions Imaged in Microgravity - To Assess the Theory Flame Stretch

NASA Technical Reports Server (NTRS)

Driscoll, James F.

2001-01-01

The goals of this research are to: 1) Assess the Theory of Flame Stretch by operating a unique flame-vortex experiment under microgravity conditions in the NASA Glenn 2.2 Second Drop Tower (drops to identify operating conditions have been completed); 2) Obtain high speed shadowgraph images (500-1000 frames/s) using the drop rig (images were obtained at one-g, and the NASA Kodak RO camera is being mounted on the drop rig); 3) Obtain shadowgraph and PIV images at 1-g while varying the effects of buoyancy by controlling the Froude number (completed); 4) Numerically model the inwardly-propagating spherical flame that is observed in the experiment using full chemistry and the RUN 1DL code (completed); 5) Send images of the flame shape to Dr. G. Patniak at NRL who is numerically simulating the entire flame-vortex interaction of the present experiment (data transfer completed); and 6) Assess the feasibility of obtaining PIV velocity field images in the drop rig, which would be useful (but not required) for our assessment of the Theory of Flame Stretch (PIV images were obtained at one-g using same low laser power that is available from fiber optic cable in drop tower). The motivation for the work is to obtain novel measurement needed to develop a physically accurate model of turbulent combustion that can help in the control of engine pollutants. The unique experiment allows, for the first time, the detailed study of a negatively-curved (negatively stretched) flame, which is one of the five fundamental types of premixed flames. While there have been studies of flat flames, positively-curved (outwardly-propagating) cases and positively-strained (counterflow) cases, this is the first detailed study of a negatively-curved (inwardly-propagating) flame. The first set of drops in the 2.2 Second Drop Tower showed that microgravity provides more favorable conditions for achieving inwardly-propagating flames (IPFs) than 1-g. A vortex interacts with a flame and creates a spherical pocket, which burns inwardly. Shadowgraphs at 1000 frames/sec quantify the Markstein number and flame speed. A Low-Laser Power PIV System was developed and is being added to the drop package. Numerical computations were required to explain why the Markstein numbers measured for the inwardly-propagating flames differ from those of outward propagating flames; this is an important research issue in the assessment of the Theory of Flame Stretch. The RUN-1DL code (developed by Prof. B. Rogg) was run for IPF and OPFs with complex methane and propane chemistry. Results confirmed that Ma for the IPFs are larger than for OPFs as was observed experimentally. Physical reasons for these new findings about the Theory of Flame Stretch are being determined from the experiments and the computations. Several journal papers have been published; the drop package is described in the AIAA Journal, while the one-g results appear in three other journal papers.

Idiopathic pulmonary fibrosis misdiagnosed as sputum-negative pulmonary tuberculosis.

PubMed

Isah, Muhammad Danasabe; Abbas, Aminu; Abba, Abdullahi A; Umar, Mohammed

2016-01-01

Idiopathic pulmonary fibrosis (IPF), also known as cryptogenic fibrosing alveolitis, is one of a spectrum of idiopathic interstitial pneumonia. IPF is an increasingly common condition which poses many diagnostic and therapeutic challenges leading to misdiagnosis and mismanagement. We presented a 55-year-old male textile trader who was initially managed as sputum-negative pulmonary tuberculosis before histology report. He presented to our clinic with Breathlessness and cough of 3 years and 2.5 years, respectively. He had commenced anti-tuberculosis two months before presentation without significant relief. General Physical examination and vital signs were essentially normal. SPO2 was 96% on room air. Chest Examination revealed end-inspiratory bi-basal velcro-like crackles. Other systemic examinations were normal. Radiological examination by way of chest X- ray and chest CT showed features suggestive of IPF. The patient also had open Lung biopsy for histology and spirometry which demonstrated restrictive ventilatory function pattern. A diagnosis of Interstitial lung disease probably Idiopathic Pulmonary Fibrosis was entertained. He was commenced on Tab prednisolone, Tab Rabeprazole, with minimal improvement. IPF have often been misdiagnosed and treated as pulmonary tuberculosis with unfavorable outcome.

PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis

PubMed Central

Bueno, Marta; Lai, Yen-Chun; Romero, Yair; Brands, Judith; St. Croix, Claudette M.; Kamga, Christelle; Corey, Catherine; Herazo-Maya, Jose D.; Sembrat, John; Lee, Janet S.; Duncan, Steve R.; Rojas, Mauricio; Shiva, Sruti; Chu, Charleen T.; Mora, Ana L.

2014-01-01

Although aging is a known risk factor for idiopathic pulmonary fibrosis (IPF), the pathogenic mechanisms that underlie the effects of advancing age remain largely unexplained. Some age-related neurodegenerative diseases have an etiology that is related to mitochondrial dysfunction. Here, we found that alveolar type II cells (AECIIs) in the lungs of IPF patients exhibit marked accumulation of dysmorphic and dysfunctional mitochondria. These mitochondrial abnormalities in AECIIs of IPF lungs were associated with upregulation of ER stress markers and were recapitulated in normal mice with advancing age in response to stimulation of ER stress. We found that impaired mitochondria in IPF and aging lungs were associated with low expression of PTEN-induced putative kinase 1 (PINK1). Knockdown of PINK1 expression in lung epithelial cells resulted in mitochondria depolarization and expression of profibrotic factors. Moreover, young PINK1-deficient mice developed similarly dysmorphic, dysfunctional mitochondria in the AECIIs and were vulnerable to apoptosis and development of lung fibrosis. Our data indicate that PINK1 deficiency results in swollen, dysfunctional mitochondria and defective mitophagy, and promotes fibrosis in the aging lung. PMID:25562319

Monte Carlo simulation of edge placement error

NASA Astrophysics Data System (ADS)

Kobayashi, Shinji; Okada, Soichiro; Shimura, Satoru; Nafus, Kathleen; Fonseca, Carlos; Estrella, Joel; Enomoto, Masashi

2018-03-01

In the discussion of edge placement error (EPE), we proposed interactive pattern fidelity error (IPFE) as an indicator to judge pass/fail of integrated patterns. IPFE consists of lower and upper layer EPEs (CD and center of gravity: COG) and overlay, which is decided from the combination of each maximum variation. We succeeded in obtaining the IPFE density function by Monte Carlo simulation. In the results, we also found that the standard deviation (σ) of each indicator should be controlled by 4.0σ, at the semiconductor grade, such as 100 billion patterns per die. Moreover, CD, COG and overlay were analyzed by analysis of variance (ANOVA); we can discuss all variations from wafer to wafer (WTW), pattern to pattern (PTP), line edge roughness (LWR) and stochastic pattern noise (SPN) on an equal footing. From the analysis results, we can determine that these variations belong to which process and tools. Furthermore, measurement length of LWR is also discussed in ANOVA. We propose that the measurement length for IPFE analysis should not be decided to the micro meter order, such as >2 μm length, but for which device is actually desired.

020. Coexistence of lung adenocarcinoma and usual interstitial pneumonia: a case report

PubMed Central

Baliaka, Aggeliki; Papaemmanouil, Styliani; Spyratos, Dionysis; Zarogoulidis, Paul; Sakkas, Leonidas

2015-01-01

Background Usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause. The most common symptoms are progressively increased shortness of breath and dry cough. Some studies suggest an association between usual interstitial pneumonia and lung cancer through different pathogenetic mechanisms. Objective The case presentation of a patient with lung adenocarcinoma and UIP. Methods A 66-year-old male presented with persistent dry cough, hemoptysis and dyspnea. The chest radiographs revealed a mass in the lower lobe of the left lung, measuring 3 cm, as well as diffuse interstitial changes in the same lobe. Two partial lobectomies were performed. Results Histological examination of the mass showed moderately differentiated adenocarcinoma, focally with bronchoalveolar pattern (Immunohistochemical detection of EGFR: positive). The rest lung parenchyma presented histological appearance of UIP. Conclusions According to clinicopathological studies, the prevalence of lung cancer among patients with UIP/IPF varies between 4% and 9%. The overall median survival of IPF-Ca patients is seven months in comparison with IPF only patients (14 months).

Sleep disorders and health-related quality of life in patients with interstitial lung disease.

PubMed

Mavroudi, Maria; Papakosta, Despoina; Kontakiotis, Theodore; Domvri, Kaliopi; Kalamaras, George; Zarogoulidou, Vasiliki; Zarogoulidis, Paul; Latka, Paschalina; Huang, Haidong; Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Konstantinos

2018-05-01

Interstitial lung diseases (ILD) are chronic and restrictive lung diseases with poor survival and quality of life. The aim of this study was to investigate the frequency of sleep disorders in idiopathic pulmonary fibrosis (IPF) and sarcoidosis and to assess patients' quality of life in relation to these disorders. Forty patients, 19 with IPF, and 21 with sarcoidosis stage II/III were included. They were compared with 15 healthy subjects. All patients performed all-night polysomnography (PSG) and completed the Epworth, Berlin, and Stop-Bang questionnaires. In order to evaluate the quality of life, all patients completed the Short-Form 36 (SF-36) questionnaire. Of the IPF patients, 68% were diagnosed with mild obstructive sleep apnea (OSA), 5.2% with moderate to severe, 5.2% with severe OSA, and 21% with no OSA. Of patients with sarcoidosis, 52.4% were diagnosed with mild OSA and 4.8% with moderate severity OSA. The remaining 42.8% did not have OSA. The health-related quality of life in both patients with IPF and patients with sarcoidosis was impaired especially in the domains concerning physical health and the level of independence, compared to the control group. In this sample of patients with IPF and sarcoidosis, obstructive sleep apnea is common at least in a mild degree of severity. The SF-36 questionnaire may be a useful tool for the evaluation of the quality of life in these patients.

Patient confidence and quality of life in idiopathic pulmonary fibrosis and sarcoidosis.

PubMed

Kotecha, Jalpa; Atkins, Christopher; Wilson, Andrew

2016-12-23

Idiopathic pulmonary fibrosis (IPF) and sarcoidosis impact significantly on health-related quality of life (HRQOL). There are few studies on the impact of patient confidence on HRQOL in these conditions. 1. To investigate whether patient confidence is associated with HRQOL, anxiety, depression, dyspnoea or fatigue. 2. To assess if patient confidence is associated with inpatient admissions, access to community healthcare and, for IPF patients, mortality and disease severity. Study participants self-completed seven questionnaires: Hospital Anxiety and Depression Scale, EuroQol 5D (EQ5D), King's Brief Interstitial Lung Disease questionnaire, St George's Respiratory Questionnaire, MRC dyspnoea scale, Fatigue Assessment Scale and a non-validated questionnaire assessing patient confidence, symptom duration and access to community healthcare. Lung function and follow-up data were collected from hospital electronic databases. Spearman's rank correlation coefficients were calculated to assess for correlation between patient confidence, questionnaire variables and inpatient admissions. Chi-square tests were performed to assess for association between patient confidence, mortality and disease severity. 75 IPF patients and 69 sarcoidosis patients were recruited to the study. Patient confidence in IPF was significantly negatively correlated with depression and fatigue, and significantly positively correlated with EQ5D scores, but not healthcare outcomes. No associations were found between confidence and any of the variables assessed in sarcoidosis. Lower levels of confidence in IPF patients are associated with higher levels of depression and fatigue and worse HRQOL. Efforts should be made to improve patient confidence to assess the impact on HRQOL.

Romo1 expression contributes to oxidative stress-induced death of lung epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shin, Jung Ar; Chung, Jin Sil; Cho, Sang-Ho

Highlights: •Romo1 mediates oxidative stress-induced mitochondrial ROS production. •Romo1 induction by oxidative stress plays an important role in oxidative stress-induced apoptosis. •Romo1 overexpression correlates with epithelial cell death in patients with IPF. -- Abstract: Oxidant-mediated death of lung epithelial cells due to cigarette smoking plays an important role in pathogenesis in lung diseases such as idiopathic pulmonary fibrosis (IPF). However, the exact mechanism by which oxidants induce epithelial cell death is not fully understood. Reactive oxygen species (ROS) modulator 1 (Romo1) is localized in the mitochondria and mediates mitochondrial ROS production through complex III of the mitochondrial electron transport chain.more » Here, we show that Romo1 mediates mitochondrial ROS production and apoptosis induced by oxidative stress in lung epithelial cells. Hydrogen peroxide (H{sub 2}O{sub 2}) treatment increased Romo1 expression, and Romo1 knockdown suppressed the cellular ROS levels and cell death triggered by H{sub 2}O{sub 2} treatment. In immunohistochemical staining of lung tissues from patients with IPF, Romo1 was mainly localized in hyperplastic alveolar and bronchial epithelial cells. Romo1 overexpression was detected in 14 of 18 patients with IPF. TUNEL-positive alveolar epithelial cells were also detected in most patients with IPF but not in normal controls. These findings suggest that Romo1 mediates apoptosis induced by oxidative stress in lung epithelial cells.« less

Measurement of MMP-9 and -12 degraded elastin (ELM) provides unique information on lung tissue degradation

PubMed Central

2012-01-01

Background Elastin is an essential component of selected connective tissues that provides a unique physiological elasticity. Elastin may be considered a signature protein of lungs where matrix metalloprotease (MMP) -9-and -12, may be considered the signature proteases of the macrophages, which in part are responsible for tissue damage during disease progression. Thus, we hypothesized that a MMP-9/-12 generated fragment of elastin may be a relevant biochemical maker for lung diseases. Methods Elastin fragments were identified by mass-spectrometry and one sequence, generated by MMP-9 and -12 (ELN-441), was selected for monoclonal antibody generation and used in the development of an ELISA. Soluble and insoluble elastin from lung was cleaved in vitro and the time-dependent release of fragments was assessed in the ELN-441 assay. The release of ELN-441 in human serum from patients with chronic obstructive pulmonary disease (COPD) (n = 10) and idiopathic pulmonary fibrosis (IPF) (n = 29) were compared to healthy matched controls (n = 11). Results The sequence ELN-441 was exclusively generated by MMP-9 and -12 and was time-dependently released from soluble lung elastin. ELN-441 levels were 287% higher in patients diagnosed with COPD (p < 0.001) and 124% higher in IPF patients (p < 0.0001) compared with controls. ELN-441 had better diagnostic value in COPD patients (AUC 97%, p = 0.001) than in IPF patients (AUC 90%, p = 0.0001). The odds ratios for differentiating controls from COPD or IPF were 24 [2.06–280] for COPD and 50 [2.64–934] for IPF. Conclusions MMP-9 and -12 time-dependently released the ELN-441 epitope from elastin. This fragment was elevated in serum from patients with the lung diseases IPF and COPD, however these data needs to be validated in larger clinical settings. PMID:22818364

Pirfenidone Reduces Respiratory-related Hospitalizations in Idiopathic Pulmonary Fibrosis.

PubMed

Ley, Brett; Swigris, Jeffrey; Day, Bann-Mo; Stauffer, John L; Raimundo, Karina; Chou, Willis; Collard, Harold R

2017-09-15

Respiratory-related hospitalizations of patients with idiopathic pulmonary fibrosis (IPF) are more frequent than those for acute IPF exacerbations and are associated with poor outcomes. To compare the risk of nonelective hospitalization by type (all-cause, respiratory related, and non-respiratory related) and death after hospitalization with use of pirfenidone versus placebo over 52 weeks using data derived from three phase III IPF clinical trials. Individual patient data was pooled from three phase III randomized, placebo-controlled studies of pirfenidone for IPF (the two CAPACITY [Clinical Studies Assessing Pirfenidone in IPF: Research of Efficacy and Safety Outcomes] trials and the ASCEND [Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis] trial), including all patients randomized to pirfenidone 2,403 mg/d (n = 623) or placebo (n = 624). The risk of hospitalization over 52 weeks was compared using standard time-to-event methods. Among those hospitalized, the risk of death after hospitalization was compared with adjustment for treatment group propensity. A total of 1,247 patients (692 from the CAPACITY trials and 555 from the ASCEND trial) were included in the pooled analysis. Pirfenidone was associated with lower risk of respiratory-related hospitalization than placebo (7% vs. 12%; hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.36-0.77; P = 0.001), but all-cause (HR, 0.91; 95% CI, 0.70-1.19; P = 0.528) or non-respiratory-related hospitalization (HR, 1.32; 95% CI, 0.92-1.88; P = 0.145) was not. Among those hospitalized for any reason, treatment with pirfenidone was associated with lower risk of death after hospitalization up to 52 weeks after randomization, but this association was no longer significant with longer follow-up. In a pooled analysis of three phase III IPF clinical trials, patients receiving pirfenidone had a lower risk of nonelective respiratory-related hospitalization over the course of 1 year. The effect of pirfenidone on death after hospitalization is uncertain.

The JAK2 pathway is activated in idiopathic pulmonary fibrosis.

PubMed

Milara, Javier; Hernandez, Gracia; Ballester, Beatriz; Morell, Anselm; Roger, Inés; Montero, P; Escrivá, Juan; Lloris, José M; Molina-Molina, Maria; Morcillo, Esteban; Cortijo, Julio

2018-02-06

Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease. JAK2/p-JAK2 and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue (n = 10) both proteins were upregulated in the lung tissue of IPF patients (n = 12). Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin (IL)-6/IL-13 activated JAK2 and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-JAK2/p-STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using JAK2 or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-JAK2/p-STAT3, at a dose of 1 mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were JAK2 and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. JAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease.

Novel insights in cough and breathing patterns of patients with idiopathic pulmonary fibrosis performing repeated 24-hour-respiratory polygraphies.

PubMed

Schertel, Anke; Funke-Chambour, Manuela; Geiser, Thomas; Brill, Anne-Kathrin

2017-11-13

The main symptoms of patients with idiopathic pulmonary fibrosis (IPF) are cough and dyspnea. IPF leads to a restrictive lung disorder impacting daytime and nocturnal breathing patterns. In this pilot study we assessed the course of day- and nighttime respiration, oxygenation, and cough over a period of 8 months as well as differences between wakefulness and sleep in IPF patients. Repetitive 24-h respiratory polygraphies (RP) and pulmonary function tests were performed at baseline and after 3, 4, 7 and 8 months. Cough-index, oxygenation parameters (SpO2, time with SpO2 < 90%, desaturation index), respiratory rate and heart rate were assessed for differences between wakefulness and sleep. The first and the last RP were compared to identify changes of these parameters over time. Statistical analyses were performed with Wilcoxon signed rank tests. Nine IPF patients (8 male, median age 67 years (IQR 60, 77) with 37 valid 24-h RPs were included. Eight patients (88.9%) received antifibrotic treatment. Cough was more prevalent during wakefulness with a median cough-index of 14.8/h (IQR 10.9, 16.8) and 1.6/h (IQR 1.3-2.8) during sleep, p = 0.0039. Oxygenation parameters showed no difference, while respiratory- and heart rate were significantly higher during wakefulness. Despite stable pulmonary function tests over 8 months, the initially elevated respiratory rate increased further during wakefulness (baseline RR median 25.7/min (IQR 19.8, 26.6) vs. RR median 32.2/min (IQR 26.5, 40.9) at follow-up, p = 0.0273). The other respiratory parameters remained stable over time. Cough in IPF patients is more prevalent during wakefulness than during sleep. Further studies with a larger sample size and longer a follow-up period are needed to evaluate the role of the respiratory rate during wakefulness as a potential clinical follow up parameter in IPF.

Active CMV infection before lung transplantation: risk factors and clinical implications.

PubMed

Milstone, A P; Brumble, L M; Loyd, J E; Ely, E W; Roberts, J R; Pierson, R N; Dummer, J S

2000-08-01

Cytomegalovirus (CMV) infection is a major cause of morbidity following lung transplantation, but active CMV infection has not been described before transplantation. Since 1990, we have screened all lung-transplant recipients for CMV infection with viral urine cultures on the day of transplantation. We retrospectively reviewed the medical records of all 102 lung-allograft recipients transplanted between March 1990 and September 1998. Patients with positive urine cultures for CMV were compared to culture negative patients for age, gender, pretransplant diagnosis, time from diagnosis to transplantation, CMV serostatus, use of pretransplant immunosuppression, T-lymphocyte subsets, and presence of fever. Posttransplant outcomes assessed were duration of intubation and hospitalization, acute rejection, frequency of CMV disease, duration of Nashville rabbit antithymocyte serum or globulin (N-RATS/G) and ganciclovir, and survival. Five (5%) of 102 patients had positive urine cultures for CMV; none had symptoms of CMV infection. All 5 had idiopathic pulmonary fibrosis (IPF) (5/5 vs 27/97; p = 0.002). The age, gender, and CMV serostatus of these patients did not differ from the 97 patients in the culture negative group. Four (80%) of the 5 patients with positive cultures were receiving treatment with azathioprine or cyclophosphamide vs only 18 (19%) of the 97 patients with negative cultures (p = 0.007), and all 5 (100%) were receiving steroids compared to 50 (52%) of 97 patients with negative cultures (p = 0.06). Culture-positive IPF patients, when compared with the 27 culture-negative IPF patients, did not differ in any demographic variable or in the use of immunosuppression, but culture-positive patients were more likely to have a CD4/CD8 T-cell subset ratio <1.0 (p = 0.02). Following transplantation, 3 (60%) of 5 IPF patients with positive CMV cultures developed CMV disease compared to 3 (11%) of 27 IPF patients with negative cultures (p = 0.03). Patients with positive cultures also received more days of parenteral antiviral therapy (mean 44 +/- 11 days vs 16 +/- 10 days; p < 0.001). Utilizing pretransplant screening, we have discovered that 16% of patients with IPF had active CMV infection, which was associated with both alterations in their T-cell subsets and a greater risk for CMV disease after transplantation. This occurrence of occult CMV infection in patients with IPF has not been previously recognized, and has important implications.

Functional improvement in patients with idiopathic pulmonary fibrosis undergoing single lung transplantation *

PubMed Central

Rubin, Adalberto Sperb; Nascimento, Douglas Zaione; Sanchez, Letícia; Watte, Guilherme; Holand, Arthur Rodrigo Ronconi; Fassbind, Derrick Alexandre; Camargo, José Jesus

2015-01-01

Abstract Objective: To evaluate the changes in lung function in the first year after single lung transplantation in patients with idiopathic pulmonary fibrosis (IPF). Methods: We retrospectively evaluated patients with IPF who underwent single lung transplantation between January of 2006 and December of 2012, reviewing the changes in the lung function occurring during the first year after the procedure. Results: Of the 218 patients undergoing lung transplantation during the study period, 79 (36.2%) had IPF. Of those 79 patients, 24 (30%) died, and 11 (14%) did not undergo spirometry at the end of the first year. Of the 44 patients included in the study, 29 (66%) were men. The mean age of the patients was 57 years. Before transplantation, mean FVC, FEV1, and FEV1/FVC ratio were 1.78 L (50% of predicted), 1.48 L (52% of predicted), and 83%, respectively. In the first month after transplantation, there was a mean increase of 12% in FVC (400 mL) and FEV1 (350 mL). In the third month after transplantation, there were additional increases, of 5% (170 mL) in FVC and 1% (50 mL) in FEV1. At the end of the first year, the functional improvement persisted, with a mean gain of 19% (620 mL) in FVC and 16% (430 mL) in FEV1. Conclusions: Single lung transplantation in IPF patients who survive for at least one year provides significant and progressive benefits in lung function during the first year. This procedure is an important therapeutic alternative in the management of IPF. PMID:26398749

All-case post-marketing surveillance of 1371 patients treated with pirfenidone for idiopathic pulmonary fibrosis.

PubMed

Ogura, Takashi; Azuma, Arata; Inoue, Yoshikazu; Taniguchi, Hiroyuki; Chida, Kingo; Bando, Masashi; Niimi, Yuka; Kakutani, Shinichi; Suga, Moritaka; Sugiyama, Yukihiko; Kudoh, Shoji; Nukiwa, Toshihiro

2015-09-01

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease with a median survival of 2-5 years and limited treatment options. In 2008, pirfenidone became the first drug to be approved for IPF treatment in Japan. The aim of this study was to assess the safety of pirfenidone for IPF treatment in a clinical setting. We conducted a safety-oriented post-marketing surveillance of all patients with IPF who were administered pirfenidone in the first year after its launch in Japan. This was a prospective, non-interventional, observational study. Case report forms were used to collect survey data, comprising adverse events, acute exacerbations, patient demographics, concomitant drug use, and concurrent treatment data. Of the 1371 patients available for safety evaluation, two-thirds had stage III-IV disease. The incidence of total adverse drug reactions (ADRs) was 64.6%. ADRs with an incidence of ≥3% were decreased appetite, photosensitivity reaction, nausea, abdominal discomfort, malaise, somnolence, and hepatic function abnormal. This safety profile was consistent with the findings in phase II and III trials in Japan. The discontinuation rates due to adverse events at 12 months for each disease stage were similar; however, discontinuation caused by disease progression increased with disease severity. Treatment with pirfenidone stabilized both vital capacity and subjective symptoms in most patients (70-80%) treated for at least 6 months. This post-marketing surveillance in Japan showed that pirfenidone was generally well tolerated in patients with IPF, including those with severe lung function impairment. Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Characteristics of the Residential Neighborhood Environment Differentiate Intimate Partner Femicide in Urban Versus Rural Settings

PubMed Central

Beyer, Kirsten M. M.; Layde, Peter M.; Hamberger, L. Kevin; Laud, Purushottam W.

2012-01-01

Purpose A growing body of work examines the association between neighborhood environment and intimate partner violence (IPV). As in the larger literature examining the influence of place context on health, rural settings are understudied and urban and rural residential environments are rarely compared. In addition, despite increased attention to the linkages between neighborhood environment and IPV, few studies have examined the influence of neighborhood context on intimate partner femicide (IPF). In this paper, we examine the role for neighborhood-level factors in differentiating urban and rural IPFs in Wisconsin, USA. Methods We use a combination of Wisconsin Violent Death Reporting System (WVDRS) data and Wisconsin Coalition Against Domestic Violence (WCADV) reports from 2004–2008, in concert with neighborhood-level information from the US Census Bureau and US Department of Agriculture, to compare urban and rural IPFs. Findings Rates of IPF vary based on degree of rurality, and bivariate analyses show differences between urban and rural victims in race/ethnicity, marital status, country of birth, and neighborhood characteristics. After controlling for individual characteristics, the nature of the residential neighborhood environment significantly differentiates urban and rural IPFs. Conclusions Our findings suggest a different role for neighborhood context in affecting intimate violence risk in rural settings, and that different measures may be needed to capture the qualities of rural environments that affect intimate violence risk. Our findings reinforce the argument that multilevel strategies are required to understand and reduce the burden of intimate violence, and that interventions may need to be crafted for specific geographical contexts. PMID:23802930

Role of CD248 as a potential severity marker in idiopathic pulmonary fibrosis.

PubMed

Bartis, Domokos; Crowley, Louise E; D'Souza, Vijay K; Borthwick, Lee; Fisher, Andrew J; Croft, Adam P; Pongrácz, Judit E; Thompson, Richard; Langman, Gerald; Buckley, Christopher D; Thickett, David R

2016-04-14

CD248 or Endosialin is a transmembrane molecule expressed in stromal cells binding to extracellular matrix (ECM) components. It has been previously implicated in kidney fibrosis, rheumatoid arthritis as well as in tumour-stromal interactions. This study investigates the role of CD248 in the pathogenesis of fibrotic diseases in Idiopathic Pulmonary Fibrosis (IPF). CD248 quantitative immunohistochemistry (IHC) was performed on lung samples from 22 IPF patients and its expression was assayed in cultured pulmonary fibroblasts and epithelial cells. Effects of CD248 silencing was evaluated on fibroblast proliferation and myofibroblast differentiation. IHC revealed strong CD248 expression in mesenchymal cells of normal lung structures such as pleura and adventitia but not in epithelium. Fibrotic areas showed markedly stronger staining than unaffected lung tissue. The extent of CD248 staining showed a significant negative correlation to lung function parameters FEV1, FVC, TLC, and TLCO (r2 > 0 · 35, p < 0 · 01). CD248 protein levels were significantly greater in IPF-derived lung fibroblasts vs normal lung fibroblasts (p < 0 · 01) and CD248 silencing significantly reduced the proliferation of lung fibroblasts, but did not affected myofibroblast differentiation. We conclude that CD248 overexpression is possibly involved in the pathogenesis of IPF and it has potential as a disease severity marker. Given that CD248 ligands are collagen type I, IV and fibronectin, we hypothesise that CD248 signalling represents a novel matrix-fibroblast interaction that may be a potential therapeutic target in IPF.

Lung diffusing capacity for nitric oxide as a marker of fibrotic changes in idiopathic interstitial pneumonias.

PubMed

Barisione, Giovanni; Brusasco, Claudia; Garlaschi, Alessandro; Baroffio, Michele; Brusasco, Vito

2016-05-01

Lung diffusing capacity for carbon monoxide (DLCO) is decreased in both usual interstitial pneumonia-idiopathic pulmonary fibrosis (UIP-IPF) and nonspecific interstitial pneumonia (NSIP), but is moderately related to computed tomography (CT)-determined fibrotic changes. This may be due to the relative insensitivity of DLCO to changes in alveolar membrane diffusive conductance (DMCO). The purpose of this study was to determine whether measurement of lung diffusing capacity for nitric oxide (DLNO) better reflects fibrotic changes than DLCO DLNO-DLCO were measured simultaneously in 30 patients with UIP-IPF and 30 with NSIP. Eighty-one matched healthy subjects served as a control group. The amount of pulmonary fibrosis was estimated by CT volumetric analysis of visually bounded areas showing reticular opacities and honeycombing. DMCO and pulmonary capillary volume (VC) were calculated. DLNO was below the lower limit of normal in all patients irrespective of extent and nature of disease, whereas DLCO was within the normal range in a nonnegligible number of patients. Both DLNO and DLCO were significantly correlated with visual assessment of fibrosis but DLNO more closely than DLCO DMCO was also below the lower limit of normal in all UIP-IPF and NSIP patients and significantly correlated with fibrosis extent in both diseases, whereas VC was weakly correlated with fibrosis in UIP-IPF and uncorrelated in NSIP, with normal values in half of patients. In conclusion, measurement of DLNO may provide a more sensitive evaluation of fibrotic changes than DLCO in either UIP-IPF or NSIP, because it better reflects DMCO. Copyright © 2016 the American Physiological Society.

Obstructive sleep apnoea and related comorbidities in incident idiopathic pulmonary fibrosis.

PubMed

Gille, Thomas; Didier, Morgane; Boubaya, Marouane; Moya, Loris; Sutton, Angela; Carton, Zohra; Baran-Marszak, Fanny; Sadoun-Danino, Danielle; Israël-Biet, Dominique; Cottin, Vincent; Gagnadoux, Frederic; Crestani, Bruno; d'Ortho, Marie-Pia; Brillet, Pierre-Yves; Valeyre, Dominique; Nunes, Hilario; Planès, Carole

2017-06-01

The objectives of this prospective study were: 1) to determine the prevalence and determinants of obstructive sleep apnoea (OSA) in patients with newly diagnosed idiopathic pulmonary fibrosis (IPF); 2) to determine whether OSA was associated with cardiovascular disease (CVD) as well as increased oxidative stress and levels of IPF biomarkers in the blood.A group of 45 patients with newly diagnosed IPF attended polysomnography. The prevalence of CVD and the severity of coronary artery calcification were investigated by high-resolution computed tomography. The levels of 8-hydroxydeoxyguanosine (8-OH-DG) and various IPF biomarkers in the blood were compared between patients with no or mild OSA (apnoea-hypopnoea index (AHI) <15 events·h -1 ), with moderate OSA (15 ≤AHI <30 events·h -1 ) and with severe OSA (AHI ≥30 events·h -1 ).The prevalence of moderate-to-severe OSA and severe OSA was 62% and 40%, respectively. AHI did not correlate with demographic or physiological data. All patients with severe OSA had a medical history of CVD, versus 41.2% and 40% of those with no or mild OSA, or with moderate OSA, respectively (p<0.0001). Ischaemic heart disease (IHD) and moderate-to-severe coronary artery calcifications were strongly associated with severe OSA. The 8-OH-DG and matrix metalloproteinase-7 serum levels were significantly increased in the severe OSA group.Moderate-to-severe OSA is highly prevalent in incident IPF and severe OSA is strongly associated with the presence of CVD, particularly IHD. Copyright ©ERS 2017.

Statin Therapy and Outcomes in Trials of Nintedanib in Idiopathic Pulmonary Fibrosis.

PubMed

Kreuter, Michael; Costabel, Ulrich; Richeldi, Luca; Cottin, Vincent; Wijsenbeek, Marlies; Bonella, Francesco; Bendstrup, Elisabeth; Maher, Toby M; Wachtlin, Daniel; Stowasser, Susanne; Kolb, Martin

Cardiovascular comorbidities are frequent in patients with idiopathic pulmonary fibrosis (IPF), and many patients with IPF receive treatment with statins to reduce cardiovascular risk. We investigated whether statin use at baseline was associated with differences in disease progression in placebo-treated patients or influenced the treatment effect of nintedanib in the INPULSIS® trials. Post-hoc subgroup analyses of patients receiving versus not receiving statins at baseline using pooled data from the INPULSIS® trials. At baseline, 312 patients received statins and 749 did not. The annual rates of decline in forced vital capacity (FVC) in patients treated with nintedanib and placebo, respectively, were -78.9 and -187.6 mL/year in patients who received statins at baseline, and -127.9 and -237.9 mL/year in patients who did not. The effect of nintedanib was consistent across subgroups (p = 0.9590). In the INPULSIS® trials, there was a numerically lower FVC decline in placebo-treated patients with IPF who received statins at baseline versus those who did not. Use of statins at baseline did not influence the treatment effect of nintedanib. Prospective data are needed to assess the impact of statins on the course of IPF. © 2018 S. Karger AG, Basel.

Efficacy and adverse events of pirfenidone in treating idiopathic pulmonary fibrosis

PubMed Central

Ren, Hui; Wang, Kai; Yang, Hao; Gao, Lingyun

2017-01-01

Objectives: To analyze the efficacy and adverse events (AEs) of pirfenidone in idiopathic pulmonary fibrosis (IPF) trials. Methods: MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for studies published before June 2016. All studies of clinical trials with the key words IPF or idiopathic pulmonary fibrosis or lung fibrosis and pirfenidone or Esbriet were identified. Quality assessment and data extraction were conducted by 2 independent researchers. A meta-analysis of randomized controlled trials (RCTs) was performed, and relative risk (RR) and 95% confidence intervals (95% CIs) were calculated. Results: Five studies were included in this review, involving 1568 participants. The meta-analysis revealed that pirfenidone reduced the risk of decline in forced vital capacity (FVC)% ≥10% from baseline (relative risk: 0.62; 95% CI: 0.51-0.76, p<0.001). The pirfenidone group had a significantly higher rate of AEs compared with the placebo group. Pirfenidone did not reduce mortality from any cause significantly (odds ratio: 0.63; 95% CI: 0.36-1.09). Conclusions: This study showed that pirfenidone could reduce disease progression as assessed by the decline in FVC in IPF. Pirfenidone represents a suitable treatment option for patients with IPF. PMID:28889145

Characteristic patterns in the fibrotic lung. Comparing idiopathic pulmonary fibrosis with chronic lung allograft dysfunction.

PubMed

Fernandez, Isis E; Heinzelmann, Katharina; Verleden, Stijn; Eickelberg, Oliver

2015-03-01

Tissue fibrosis, a major cause of death worldwide, leads to significant organ dysfunction in any organ of the human body. In the lung, fibrosis critically impairs gas exchange, tissue oxygenation, and immune function. Idiopathic pulmonary fibrosis (IPF) is the most detrimental and lethal fibrotic disease of the lung, with an estimated median survival of 50% after 3-5 years. Lung transplantation currently remains the only therapeutic alternative for IPF and other end-stage pulmonary disorders. Posttransplant lung function, however, is compromised by short- and long-term complications, most importantly chronic lung allograft dysfunction (CLAD). CLAD affects up to 50% of all transplanted lungs after 5 years, and is characterized by small airway obstruction with pronounced epithelial injury, aberrant wound healing, and subepithelial and interstitial fibrosis. Intriguingly, the mechanisms leading to the fibrotic processes in the engrafted lung exhibit striking similarities to those in IPF; therefore, antifibrotic therapies may contribute to increased graft function and survival in CLAD. In this review, we focus on these common fibrosis-related mechanisms in IPF and CLAD, comparing and contrasting clinical phenotypes, the mechanisms of fibrogenesis, and biomarkers to monitor, predict, or prognosticate disease status.

Towards a global initiative for fibrosis treatment (GIFT)

PubMed Central

Agusti, Alvar; Crestani, Bruno; Schwartz, David A.; Chambers, Rachel C.; Maher, Toby M.; Faner, Rosa; Mora, Ana Lucia; Rojas, Mauricio; Antoniou, Katerina M.; Sellares, Jacobo

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterised by increased scarring of lung tissue. Despite the recent introduction of novel drugs that slow disease progression, IPF remains a deadly disease, and the benefits of these new drugs differ markedly between patients. Human diseases arise due to alterations in an almost limitless network of interconnected genes, proteins, metabolites, cells and tissues, in direct relationship with a continuously changing macro- or microenvironment. Systems biology is a novel research strategy that seeks to understand the structure and behaviour of the so-called “emergent properties” of complex systems, such as those involved in disease pathogenesis, which are most often overlooked when just one element of disease pathogenesis is observed in isolation. This article summarises the debate that took place during a European Respiratory Society research seminar in Barcelona, Spain on December 15–16, 2016, which focused on how systems biology could generate new data by integrating the different IPF pathogenic levels of complexity. The main conclusion of the seminar was to create a global initiative to improve IPF outcomes by integrating cutting-edge international research that leverages systems biology to develop a precision medicine approach to tackle this devastating disease. PMID:29214157

Successful management of acute respiratory failure in an Idiopathic Pulmonary Fibrosis patient using an extracorporeal carbon dioxide removal system.

PubMed

Vianello, Andrea; Arcaro, Giovanna; Paladini, Luciana; Iovino, Silvia

2016-08-01

Patients with Idiopathic Pulmonary Fibrosis (IPF) requiring Invasive Mechanical Ventilation (IMV) following unsuccessful treatment with Non-Invasive Ventilation (NIV) have a high mortality rate. IMV is, moreover, an independent predictor of poor outcome during the post-transplantation period in patients on waiting lists for Lung Transplantation (LT). Here we describe the successful management of an IPF patient with acute respiratory failure (ARF) using a pump-assisted veno-venous system for extracorporeal CO2 removal (ECCO2R) (ProLUNG® system) as an alternative to endotracheal intubation (ETI) following NIV failure. Given this positive experience, further studies are warranted focusing on the ECCO2R system's tolerability, safety, and efficacy in patients with IPF and severe ARF in whom NIV alone is ineffective.

Fatty Pancreas: Should We Be Concerned?

PubMed

Majumder, Shounak; Philip, Nissy A; Takahashi, Naoki; Levy, Michael J; Singh, Vijay P; Chari, Suresh T

The metabolic consequences of visceral fat deposition are well known, and the presence of intrapancreatic fat (IPF) has been recognized for decades. However, our knowledge about the distribution of fat in the pancreas and its clinical implications is in a nascent stage. Various terms have been proposed to describe IPF; for the purpose of this narrative review, we chose the general term fatty pancreas. Herein, we describe the radiologic, endoscopic, and histopathologic aspects of diagnosing fatty pancreas and provide an overview of the diseases associated with this condition. Our purpose is to highlight diagnostic challenges and identify specific clinical questions that would benefit from further study. As evident in this review, IPF is associated with various metabolic diseases, pancreatitis, pancreatic cancer, and precancer-yet establishing causality needs careful, further study.

Idiopathic Pulmonary Fibrosis and Myasthenia Gravis: An Unusual Association

PubMed Central

Chogtu, Bharti; Malik, Daliparty Vasudev

2016-01-01

Idiopathic Pulmonary Fibrosis (IPF) is a chronic fibrosing lung condition with high morbidity and mortality, accounting for about 25% of the cases of interstitial lung diseases. It usually has a progressive course resulting in death due to respiratory failure. Myasthenia Gravis (MG) is an autoimmune neuromuscular disease, caused by antibody mediated activity against acetylcholine receptor at the neuromuscular junction. It is characterized by fluctuating muscle weakness and fatigue. Extensive literature search did not reveal any case report of an association between these two conditions. Here we present a case of a patient with IPF who also developed MG. The diagnosis of IPF was based on High Resolution Computed Tomography (HRCT) of the lung and that of MG was based on clinical criteria and electrophysiological testing. The case was successfully managed. PMID:27190866

Do all patients with idiopathic pulmonary fibrosis warrant a trial of therapeutic intervention? A pro-con perspective.

PubMed

Moodley, Yuben; Corte, Tamera; Richeldi, Luca; King, Talmadge E

2015-04-01

Idiopathic pulmonary fibrosis (IPF) is an incurable condition that is characterized by progressive pulmonary fibrosis, architectural distortion of the lung and loss of gas exchange units. Until recently, there was no effective treatment for this condition. However, there were two landmark trials published earlier this year, which have changed the management of this condition. Pirfenidone (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis trial) and nintedanib (Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis-1 and -2 trials) have both demonstrated positive outcomes in patients with IPF. In this perspective, we critically discuss the role of these agents in IPF and in the broader pulmonary fibrosis population. © 2015 Asian Pacific Society of Respirology.

Delay and inequalities in the treatment of idiopathic pulmonary fibrosis: the case of two Nordic countries.

PubMed

Pesonen, Ida; Carlson, Lisa; Murgia, Nicola; Kaarteenaho, Riitta; Sköld, Carl Magnus; Myllärniemi, Marjukka; Ferrara, Giovanni

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive loss of lung function with high mortality within the first 5 years from diagnosis. In 2011-2014, two drugs, pirfenidone and nintedanib, have been approved worldwide for prevention of IPF progression. National IPF-registries have been established in both Finland and Sweden. Our study explored potential differences in the care of IPF in these two countries. Patients included consecutively in the Finnish and Swedish IPF-registries from January 1, 2014 through December 31, 2016 were included in the study. Data on demographics and lung function at the time of inclusion were collected. Access to antifibrotic drugs and data on disease outcomes, mortality and the proportion of patients who underwent lung transplantation, was collected during a 3-year follow up. One-hundred and fifty-two patients from the Finnish and 160 patients from the Swedish IPF-cohorts were included in the study. At inclusion, Finnish patients were significantly older than the Swedish patients (74.6 years vs 72.5 years, p  = 0.017). The proportion of non-smokers was significantly higher in the Finnish cohort (41.7% vs 26.9%, p  = 0.007). Forced vital capacity (FVC), % of predicted (78.2 vs 71.7 for Finnish and Swedish patients, respectively, p  = 0.01) and diffusion capacity for carbon monoxide (DL CO ), % of predicted (53.3 vs 48.2 for Finnish and Swedish patients, respectively, p  = 0.002) were significantly higher in the Finnish cohort compared to the Swedish cohort at the time of inclusion. During the 3-year follow up period, 45 (29.6%) Finnish and 111 (69.4%) Swedish patients, respectively, were initiated on treatment with an antifibrotic drug (pirfenidone or nintedanib) ( p  <  0.001). When comparing possible determinants of treatment, patients with higher FVC % were less likely to start antifibrotic drugs (OR 0.96, 95%CI 0.93-1.00, p  <  0.024). To be resident in Sweden was the main determinant for receiving antifibrotic drugs (OR 5.48, 95%CI 2.65-11.33, p  < 0.0001). No significant difference in number of deaths and lung transplantation during the follow up period was found. This study highlights differences concerning how IPF patients are treated in Finland and Sweden. How these differences will influence the long-term outcome of these patients is unknown.

Double-Blind Randomized Trial of Pirfenidone in Chinese Idiopathic Pulmonary Fibrosis Patients.

PubMed

Huang, Hui; Dai, Hua Ping; Kang, Jian; Chen, Bao Yuan; Sun, Tie Ying; Xu, Zuo Jun

2015-10-01

Idiopathic pulmonary fibrosis (IPF) lacks effective treatment. Pirfenidone has been used to treat IPF patients. N-acetylcysteine (NAC) exerts antioxidant and antifibrotic effects on IPF cases.This study is a double-blind, modified placebo-controlled, randomized phase II trial of pirfenidone in Chinese IPF patients. We randomly assigned the enrolled Chinese IPF patients with mild to moderate impairment of pulmonary function to receive either oral pirfenidone (1800 mg per day) and NAC (1800 mg per day) or placebo and NAC (1800 mg per day) for 48 weeks. The primary endpoints were the changes in forced vital capacity (FVC) and walking distance and the lowest SPO2 during the 6-minute walk test (6MWT) at week 48. The key secondary endpoint was the progression-free survival time. This study is registered in ClinicalTrials.gov as number NCT01504334.Eighty-six patients were screened, and 76 cases were enrolled (pirfenidone + NAC: 38; placebo + NAC: 38). The effect of pirfenidone treatment was significant at the 24th week, but this effect did not persist to the 48th week. At the 24th week, the mean decline in both FVC and ΔSPO2 (%) during the 6MWT in the pirfenidone group was lower than that in the control group (-0.08 ± 0.20 L vs -0.22 ± 0.29 L, P = 0.02 and -3.44% ± 4.51% vs -6.29% ± 6.06%, P = 0.03, respectively). However, there was no significant difference between these 2 groups at the 48th week (-0.15 ± 0.25 L vs -0.25 ± 0.28 L, P = 0.11 and -4.25% ± 7.27% vs -5.31% ± 5.49%, P = 0.51, respectively). The pirfenidone treatment group did not achieve the maximal distance difference on the 6MWT at either the 24th or the 48th week. But pirfenidone treatment prolonged the progression-free survival time in the IPF patients (hazard ratio = 1.88, 95% confidence interval: 1.092-3.242, P = 0.02). In the pirfenidone group, the adverse event (AE) rate (52.63%) was higher than that in the control group (26.3%, P = 0.03). Rash was more common in the pirfenidone group (39.5% vs 13.2%, P = 0.02).Compared with placebo combined with high-dose NAC, pirfenidone combined with high-dose NAC prolonged the progression-free survival of Chinese IPF patients with mild to moderate impairment of pulmonary function. (ClinicalTrials.gov number, NCT01504334).

Safety and efficacy of pirfenidone in severe Idiopathic Pulmonary Fibrosis: A real-world observational study.

PubMed

Tzouvelekis, Argyrios; Ntolios, Paschalis; Karampitsakos, Theodoros; Tzilas, Vasilios; Anevlavis, Stavros; Bouros, Evangelos; Steiropoulos, Paschalis; Koulouris, Nikolaos; Stratakos, Grigoris; Froudarakis, Marios; Bouros, Demosthenes

2017-10-01

Pirfenidone is a novel anti-fibrotic drug that has shown efficacy in five randomized multicenter clinical trials enrolling patients with Idiopathic Pulmonary Fibrosis of mild-to-moderate disease severity. Scarce data supports the use of pirfenidone in IPF patients with more advanced disease. To investigate the safety and efficacy profile of pirfenidone in IPF patients with severe lung function impairment. This was a retrospective study enrolling patients with advanced IPF (FVC%predicted < 50% and/or (DLco%predicted <35%) receiving pirfenidone for at least 6 months. Between September 2011 and March 2013, we identified 43 patients with severe IPF (baseline meanFVC%predicted±SD: 63.8 ± 20.3, meanDL CO %predicted: 27.3 ± 8.2), of mean age±SD: 66.3 + 9.7, 34 males (81%) that received pirfenidone (2.403 mg/daily) for one year. Pirfenidone treatment was associated with a trend towards decrease in functional decline compared to 6-months before treatment initiation but failed to show any benefit after one year of treatment (ΔFVC: -3.3 ± 4.6 vs 0.49 ± 11.4 and vs. -5.8 ± 11.8, p = 0.06 and p = 0.04, respectively and ΔDL CO : -13.3 ± 15.2 vs. -10.1 ± 16.6 and vs. 28.3 ± 19.2, p = 0.39 and p = 0.002, respectively). Gastrointestinal disorders (34.9%), fatigue (23.2%) and photosensitivity (18.6%) were the most common adverse events. Adverse events led to treatment discontinuation in 9 patients (20.9%) and dose reduction in 14 (32.5%). Pirfenidone appears to be safe when administered in patients with advanced IPF. Pirfenidone efficacy in IPF patients with severe lung function impairment may diminish after 6 months of treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Biomarkers to identify ILD and predict lung function decline in scleroderma lung disease or idiopathic pulmonary fibrosis.

PubMed

Kennedy, Barry; Branagan, Peter; Moloney, Fiachra; Haroon, Muhammad; O'Connell, Oisin J; O'Connor, Terence M; O'Regan, Kevin; Harney, Sinead; Henry, Michael T

2015-09-14

SSc-ILD and IPF demonstrate significant morbidity and mortality. Predicting disease progression is challenging in both diseases. We sought a serum biomarker that could identify patients with SSc-ILD or IPF and prospectively predict short-term decline in lung function in these patients. 10 healthy controls, 5 SSc w/o ILD, 6 SSc-ILD and 13 IPF patients underwent venesection. An array of cytokines including KL-6, SP-D and MMP7 were measured. PFTs were obtained at baseline and six months. Cytokine measurements were correlated with PFTs. KL-6 in IPF patients (633 ng/ml, IQR 492-1675) was significantly elevated compared to controls (198 ng/ml, IQR 52-360, p<0.01) and SSc w/o ILD patients (192 ng/ml, IQR 0-524, p<0.05); KL-6 in SSc-ILD patients (836 ng/ml, IQR 431-1303) was significantly higher than in controls (p<0.05). SP-D was significantly higher in IPF patients (542 ng/ml, IQR 305-577) compared to controls (137 ng/ml, IQR 97-284, p<0.01) or to SSc w/o ILD patients (169 ng/ml, IQR 137-219, p<0.05). In comparison with controls (0.0 ng/ml, IQR 0.0-0.6), MMP7 was significantly higher in both IPF patients (2.85 ng/ml, IQR 1.5-3.6, p<0.05) and SSc-ILD patients (5.41 ng/ml, IQR 2.6-7.2, p<0.001). Using a cut-off level of 459ng/ml for KL-6 and of 1.28 ng/ml for MMP7, 18 out of 19 patients with ILD had a serum value of either KL-6 or MMP7 above these thresholds. For all ILD patients, baseline serum SP-D correlated with ΔFVC %pred over six months (r=-0.63, p=0.005, 95% CI -0.85 to -0.24). Combining KL-6 with MMP7 may be a useful screening tool for patients at risk of ILD. SP-D may predict short-term decline in lung function.

CCN5 overexpression inhibits profibrotic phenotypes via the PI3K/Akt signaling pathway in lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis and in an in vivo model of lung fibrosis.

PubMed

Zhang, Lin; Li, Yingna; Liang, Chunlian; Yang, Weilin

2014-02-01

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with unknown etiology and undefined treatment modality. Fibroblasts are regarded as the major cell type that mediates the onset and progression of lung fibrosis by secreting large amounts of extracellular matrix (ECM) proteins, such as connective tissue growth factor (CTGF/CCN2). Current knowledge confers a crucial role of CCN2 in lung fibrosis. CCN5, another member of the CCN family, has been suggested to play an inhibitory role in some fibrotic diseases, such as cardiac fibrosis. However, the role of CCN5 in the process of IPF remains unknown. In the present study, using western blot analysis, we demonstrate that CCN2 is highly expressed in fibroblasts derived from IPF tissue, but is only slightly expressed in normal human lung fibroblasts. However, CCN5 was weakly expressed in all the above cells. qRT-PCR revealed that transforming growth factor (TGF)-β1 stimulation increased CCN2 expression in the IPF-derived cultures of primary human lung fibroblasts (PIFs) in a time- and concentration-dependent manner, but only slightly affected the expression of CCN5. The overexpression of CCN5 induced by the transfection of PIFs with recombinant plasmid did not affect cell viability, proliferation and apoptosis; however, it significantly suppressed the expression of CCN2, α-smooth muscle actin (α-SMA) and collagen type I. The TGF-β1-induced upregulation of the phosphorylation of Akt was reversed by CCN5 overexpression. Our results also demonstrated that adenovirus-mediated CCN5 overexpression in a mouse model of bleomycin-induced IPF significantly decreased the hydroxyproline content in the lungs, as well as TGF-β1 expression in bronchoalveolar lavage fluid. Taken together, our data demonstrate that CCN5 exerts an inhibitory effect on the fibrotic phenotypes of pulmonary fibroblasts in vitro and in vivo, and as such may be a promising target for the treatment of IPF.

Idiopathic Interstitial Pneumonia Associated With Autoantibodies: A Large Case Series Followed Over 1 Year.

PubMed

Collins, Bridget F; Spiekerman, Charles F; Shaw, Megan A; Ho, Lawrence A; Hayes, Jennifer; Spada, Carolyn A; Stamato, Caroline M; Raghu, Ganesh

2017-07-01

Some patients with autoimmune characteristics and idiopathic interstitial pneumonia, particularly usual interstitial pneumonia (UIP), do not fit neatly into the category of connective tissue disease-associated interstitial lung disease (CTD-ILD), idiopathic pulmonary fibrosis (IPF), or recently proposed yet to be validated criteria for interstitial pneumonia with autoimmune features (IPAF). Outcomes of these patients are unknown. This was a retrospective single-center study. Analyses of variance compared differences in mean change in FVC and diffusion capacity (Dlco) over 1 year among 124 well-defined patients (20 patients with positive autoantibodies with or without symptoms of connective tissue disease [AI-ILD], 15 patients with IPAF, 36 patients with CTD-ILD, and 53 patients with IPF with negative CTD serologies [Lone-IPF]). Of the patients, 75% with AI-ILD, 33% with IPAF, and 33% with CTD-ILD had UIP. Initial FVC and Dlco were similarly moderately reduced across groups. Mean change in FVC over 12 months was as follows: -60 mL (IPAF), -110 mL (AI-ILD), -10 mL (CTD-ILD), and -90 mL (Lone-IPF) (P = .52). Mean change in Dlco was as follows: 2.39 mL/mm Hg/min (IPAF), -1.15 mL/mm Hg/min (AI-ILD), -0.27 mL/mm Hg/min (CTD-ILD), and -1.05 mL/mm Hg/min (Lone-IPF) (P < .001). By pattern of disease, the mean change in FVC was as follows: -140 mL (UIP), 10 mL (nonspecific interstitial pneumonia), and 12 mL (unclassifiable/other) (P = .001). No clinically significant differences in pulmonary function to distinguish between patients with AI-ILD, IPAF, CTD-ILD, and Lone-IPF were observed after 1 year. Longer periods of follow-up are needed to understand the outcomes of these patients. It is not yet clear whether AI-ILD is a distinct phenotype or a variant of the newly proposed entity IPAF. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

A bundled care approach to patients with idiopathic pulmonary fibrosis improves transplant-free survival.

PubMed

Kulkarni, Tejaswini; Willoughby, John; Acosta Lara, Maria Del Pilar; Kim, Young-Il; Ramachandran, Rekha; Alexander, C Bruce; Luckhardt, Tracy; Thannickal, Victor J; de Andrade, Joao A

2016-06-01

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with poor prognosis and limited therapeutic options. The 2011 ATS/ERS/JRS/ALAT consensus statement provided a number of recommendations for the management of IPF patients. The primary objective of this study was to determine if "bundling" these recommendations in the management of patients with IPF impacts clinical outcomes. We conducted a single center, retrospective cohort study of 284 patients diagnosed with IPF. The proposed bundle of care (BOC) components were: (1) visits to a specialized interstitial lung diseases clinic with evaluation of pulmonary function tests at least twice yearly; (2) referral to pulmonary rehabilitation yearly; (3) timed walk test yearly; (4) echocardiogram yearly; and (5) gastroesophageal reflux therapy. Each component of the BOC was given a score of "1" per year of follow up, and the average sum of the scores (ranging from 0 to 5) was determined for the entire period of follow-up (BOCS), as well as during the first year of follow-up (BOCY1). The primary outcome measure was transplant-free survival. Age, gender, smoking status, BMI, %FVC, %DLCO did not differ between levels of BOCS and BOCY1. Lowest BOCS (≤1) was associated with a lower transplant-free survival independent of age and %FVC compared to patients with the highest BOCS (>4) (HR 2.274, CI 1.12-4.64, p = 0.024). Lower BOCY1 was associated with a higher risk for transplant or death independent of age and %FVC in comparison to patients with highest BOCY1 (≤1 vs. >4, HR 2.23, p = 0.014; >1 to 2 vs. >4, HR 1.87, p = 0.011; >2 to 3 vs. >4, HR 1.72, p = 0.019). IPF patients with higher BOC scores had improved transplant-free survival. Prospective studies are needed to confirm these findings and determine the best strategies for the management of patients with IPF. Published by Elsevier Ltd.

Effect of smoking and comorbidities on survival in idiopathic pulmonary fibrosis.

PubMed

Kärkkäinen, Miia; Kettunen, Hannu-Pekka; Nurmi, Hanna; Selander, Tuomas; Purokivi, Minna; Kaarteenaho, Riitta

2017-08-22

Cigarette smoking has been associated with the risk of idiopathic pulmonary fibrosis (IPF). Certain comorbidities have been associated with reduced survival although some studies have indicated that current smokers have a longer survival than ex-smokers. Comorbidities in relation to smoking history have not been previously analyzed. Retrospective data was collected and patients were categorized according to gender and smoking habits. Comorbidities and medications were collected. Predictive values for mortality were identified by COX proportional hazard analyses. We examined 45 non-smokers (53.3% female), 66 ex-smokers (9.1% female) and 17 current smokers (17.6% female) with IPF. Current smokers were younger at baseline (58.1 ± 8.74 years) compared to non-smokers (71.4 ± 8.74, p < 0.001) and ex-smokers (72.5 ±7.95, p <0.001). Median survival of non-smokers and current smokers was longer (55.0 and 52.0 months, respectively) than that of ex-smokers (36.0 months) (p=0.028 and 0.034, respectively). In age and severity adjusted analyses, smoking was not related to survival. Cardiovascular diseases (CVD) (72.7 %) were the most common comorbidities, current smokers had more chronic obstructive pulmonary disease (COPD) and lung cancer compared to ex-smokers (p<0.001). CVD, COPD and use of insulin were related to poorer survival in adjusted analyses. Smoking seems to influence the course of disease in IPF since current smokers developed the disease at a younger age in comparison to non-smokers and ex-smokers. No significant differences in the major comorbidities were detected between IPF patients with different smoking histories. The mechanism through which smoking influences IPF progression requires further investigation.

Genome sequencing of idiopathic pulmonary fibrosis in conjunction with a medical school human anatomy course.

PubMed

Kumar, Akash; Dougherty, Max; Findlay, Gregory M; Geisheker, Madeleine; Klein, Jason; Lazar, John; Machkovech, Heather; Resnick, Jesse; Resnick, Rebecca; Salter, Alexander I; Talebi-Liasi, Faezeh; Arakawa, Christopher; Baudin, Jacob; Bogaard, Andrew; Salesky, Rebecca; Zhou, Qian; Smith, Kelly; Clark, John I; Shendure, Jay; Horwitz, Marshall S

2014-01-01

Even in cases where there is no obvious family history of disease, genome sequencing may contribute to clinical diagnosis and management. Clinical application of the genome has not yet become routine, however, in part because physicians are still learning how best to utilize such information. As an educational research exercise performed in conjunction with our medical school human anatomy course, we explored the potential utility of determining the whole genome sequence of a patient who had died following a clinical diagnosis of idiopathic pulmonary fibrosis (IPF). Medical students performed dissection and whole genome sequencing of the cadaver. Gross and microscopic findings were more consistent with the fibrosing variant of nonspecific interstitial pneumonia (NSIP), as opposed to IPF per se. Variants in genes causing Mendelian disorders predisposing to IPF were not detected. However, whole genome sequencing identified several common variants associated with IPF, including a single nucleotide polymorphism (SNP), rs35705950, located in the promoter region of the gene encoding mucin glycoprotein MUC5B. The MUC5B promoter polymorphism was recently found to markedly elevate risk for IPF, though a particular association with NSIP has not been previously reported, nor has its contribution to disease risk previously been evaluated in the genome-wide context of all genetic variants. We did not identify additional predicted functional variants in a region of linkage disequilibrium (LD) adjacent to MUC5B, nor did we discover other likely risk-contributing variants elsewhere in the genome. Whole genome sequencing thus corroborates the association of rs35705950 with MUC5B dysregulation and interstitial lung disease. This novel exercise additionally served a unique mission in bridging clinical and basic science education.

Validation of the Japanese disease severity classification and the GAP model in Japanese patients with idiopathic pulmonary fibrosis.

PubMed

Kondoh, Shun; Chiba, Hirofumi; Nishikiori, Hirotaka; Umeda, Yasuaki; Kuronuma, Koji; Otsuka, Mitsuo; Yamada, Gen; Ohnishi, Hirofumi; Mori, Mitsuru; Kondoh, Yasuhiro; Taniguchi, Hiroyuki; Homma, Sakae; Takahashi, Hiroki

2016-09-01

The clinical course of idiopathic pulmonary fibrosis (IPF) shows great inter-individual differences. It is important to standardize the severity classification to accurately evaluate each patient׳s prognosis. In Japan, an original severity classification (the Japanese disease severity classification, JSC) is used. In the United States, the new multidimensional index and staging system (the GAP model) has been proposed. The objective of this study was to evaluate the model performance for the prediction of mortality risk of the JSC and GAP models using a large cohort of Japanese patients with IPF. This is a retrospective cohort study including 326 patients with IPF in the Hokkaido prefecture from 2003 to 2007. We obtained the survival curves of each stage of the GAP and JSC models to perform a comparison. In the GAP model, the prognostic value for mortality risk of Japanese patients was also evaluated. In the JSC, patient prognoses were roughly divided into two groups, mild cases (Stages I and II) and severe cases (Stages III and IV). In the GAP model, there was no significant difference in survival between Stages II and III, and the mortality rates in the patients classified into the GAP Stages I and II were underestimated. It is difficult to predict accurate prognosis of IPF using the JSC and the GAP models. A re-examination of the variables from the two models is required, as well as an evaluation of the prognostic value to revise the severity classification for Japanese patients with IPF. Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

MAP3K19 Is a Novel Regulator of TGF-β Signaling That Impacts Bleomycin-Induced Lung Injury and Pulmonary Fibrosis

PubMed Central

Franz-Bacon, Karin; DiTirro, Danielle N.; Ly, Tai Wei; Bacon, Kevin B.

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine TGF-β has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, MAP3K19, upregulated in IPF tissue, in TGF-β-induced signal transduction and in bleomycin-induced pulmonary fibrosis. MAP3K19 has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. MAP3K19 was also found to be overexpressed in bronchoalveolar lavage macrophages from IPF patients compared to normal patients. Treatment of A549 or THP-1 cells with either MAP3K19 siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 & 3 nuclear translocation following TGF-β stimulation. TGF-β-induced gene transcription was also strongly inhibited by both the MAP3K19 inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the MAP3K19 inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of IPF, inhibition of MAP3K19 strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of MAP3K19 may have a beneficial therapeutic effect in the treatment of IPF and represents a novel strategy to target this disease. PMID:27144281

Lactic Acid Is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation via pH-Dependent Activation of Transforming Growth Factor-β

PubMed Central

Kottmann, Robert Matthew; Kulkarni, Ajit A.; Smolnycki, Katie A.; Lyda, Elizabeth; Dahanayake, Thinesh; Salibi, Rami; Honnons, Sylvie; Jones, Carolyn; Isern, Nancy G.; Hu, Jian Z.; Nathan, Steven D.; Grant, Geraldine; Phipps, Richard P.

2012-01-01

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF. Objectives: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. Methods: We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with IPF and determined the effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-β activation in vitro. Measurements and Main Results: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; α-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-β. TGF-β induced expression of LDH5 via hypoxia-inducible factor 1α (HIF1α). Importantly, overexpression of both HIF1α and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-β to induce differentiation. Furthermore, inhibition of both HIF1α and LDH5 inhibited TGF-β–induced myofibroblast differentiation. Conclusions: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of TGF-β. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders. PMID:22923663

Quantitative proteomic characterization of the lung extracellular matrix in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

PubMed

Åhrman, Emma; Hallgren, Oskar; Malmström, Lars; Hedström, Ulf; Malmström, Anders; Bjermer, Leif; Zhou, Xiao-Hong; Westergren-Thorsson, Gunilla; Malmström, Johan

2018-03-01

Remodeling of the extracellular matrix (ECM) is a common feature in lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Here, we applied a sequential tissue extraction strategy to describe disease-specific remodeling of human lung tissue in disease, using end-stages of COPD and IPF. Our strategy was based on quantitative comparison of the disease proteomes, with specific focus on the matrisome, using data-independent acquisition and targeted data analysis (SWATH-MS). Our work provides an in-depth proteomic characterization of human lung tissue during impaired tissue remodeling. In addition, we show important quantitative and qualitative effects of the solubility of matrisome proteins. COPD was characterized by a disease-specific increase in ECM regulators, metalloproteinase inhibitor 3 (TIMP3) and matrix metalloproteinase 28 (MMP-28), whereas for IPF, impairment in cell adhesion proteins, such as collagen VI and laminins, was most prominent. For both diseases, we identified increased levels of proteins involved in the regulation of endopeptidase activity, with several proteins belonging to the serpin family. The established human lung quantitative proteome inventory and the construction of a tissue-specific protein assay library provides a resource for future quantitative proteomic analyses of human lung tissues. We present a sequential tissue extraction strategy to determine changes in extractability of matrisome proteins in end-stage COPD and IPF compared to healthy control tissue. Extensive quantitative analysis of the proteome changes of the disease states revealed altered solubility of matrisome proteins involved in ECM regulators and cell-ECM communication. The results highlight disease-specific remodeling mechanisms associated with COPD and IPF. Copyright © 2018 Elsevier B.V. All rights reserved.

Lung disease severity in idiopathic pulmonary fibrosis is more strongly associated with impedance measures of bolus reflux than pH parameters of acid reflux alone.

PubMed

Gavini, S; Borges, L F; Finn, R T; Lo, W-K; Goldberg, H J; Burakoff, R; Feldman, N; Chan, W W

2017-05-01

Gastroesophageal reflux (GER) has been associated with idiopathic pulmonary fibrosis (IPF). Pathogenesis may be related to chronic micro-aspiration. We aimed to assess objective measures of GER on multichannel intraluminal impedance and pH study (MII-pH) and their relationship with pulmonary function testing (PFT) results, and to compare the performance of pH/acid reflux parameters vs corresponding MII/bolus parameters in predicting pulmonary dysfunction in IPF. This was a retrospective cohort study of IPF patients undergoing prelung transplant evaluation with MII-pH off acid suppression, and having received PFT within 3 months. Patients with prior fundoplication were excluded. Severe pulmonary dysfunction was defined using diffusion capacity of the lung for carbon monoxide (DLCO) ≤40%. Six pH/acid reflux parameters with corresponding MII/bolus reflux measures were specified a priori. Multivariate analyses were applied using forward stepwise logistic regression. Predictive value of each parameter for severe pulmonary dysfunction was calculated by area-under-the-receiver-operating-characteristic-curve or c-statistic. Forty-five subjects (67% M, age 59, 15 mild-moderate vs 30 severe) met criteria for inclusion. Patient demographics and clinical characteristics were similar between pulmonary dysfunction groups. Abnormal total reflux episodes and prolonged bolus clearance time were significantly associated with pulmonary dysfunction severity on univariate and multivariate analyses. No pH parameters were significant. The c-statistic of each pH parameter was lower than its MII counterpart in predicting pulmonary dysfunction. MII/bolus reflux, but not pH/acid reflux, was associated with pulmonary dysfunction in prelung transplant patients with IPF. MII-pH may be more valuable than pH testing alone in characterizing GER in IPF. © 2016 John Wiley & Sons Ltd.

A Novel Antifibrotic Mechanism of Nintedanib and Pirfenidone. Inhibition of Collagen Fibril Assembly.

PubMed

Knüppel, Larissa; Ishikawa, Yoshihiro; Aichler, Michaela; Heinzelmann, Katharina; Hatz, Rudolf; Behr, Jürgen; Walch, Axel; Bächinger, Hans Peter; Eickelberg, Oliver; Staab-Weijnitz, Claudia A

2017-07-01

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix, in particular, collagens. Two IPF therapeutics, nintedanib and pirfenidone, decelerate lung function decline, but their underlying mechanisms of action are poorly understood. In this study, we sought to analyze their effects on collagen synthesis and maturation at important regulatory levels. Primary human fibroblasts from patients with IPF and healthy donors were treated with nintedanib (0.01-1.0 μM) or pirfenidone (100-1,000 μM) in the absence or presence of transforming growth factor-β1. Effects on collagen, fibronectin, FKBP10, and HSP47 expression, and collagen I and III secretion, were analyzed by quantitative polymerase chain reaction and Western blot. The appearance of collagen fibrils was monitored by scanning electron microscopy, and the kinetics of collagen fibril assembly was assessed using a light-scattering approach. In IPF fibroblasts, nintedanib reduced the expression of collagen I and V, fibronectin, and FKBP10 and attenuated the secretion of collagen I and III. Pirfenidone also down-regulated collagen V but otherwise showed fewer and less pronounced effects. By and large, the effects were similar in donor fibroblasts. For both drugs, electron microscopy of IPF fibroblast cultures revealed fewer and thinner collagen fibrils compared with untreated controls. Finally, both drugs dose-dependently delayed fibril formation of purified collagen I. In summary, both drugs act on important regulatory levels in collagen synthesis and processing. Nintedanib was more effective in down-regulating profibrotic gene expression and collagen secretion. Importantly, both drugs inhibited collagen I fibril formation and caused a reduction in and an altered appearance of collagen fibril bundles, representing a completely novel mechanism of action for both drugs.

Genetic polymorphism in matrix metalloproteinase-9 and transforming growth factor-β1 and susceptibility to combined pulmonary fibrosis and emphysema in a Chinese population.

PubMed

Xu, Ling; Bian, Wei; Gu, Xiao-Hua; Shen, Ce

2017-03-01

In this study, we aimed to explore the association of genetic polymorphism in matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β1 (TGF-β1) and the susceptibility to combined pulmonary fibrosis and emphysema (CPFE). We examined the polymorphisms of the MMP-9 C-1562T and TGF-β1 T869C in 38 CPFE patients, 50 pulmonary emphysema patients, and 34 idiopathic pulmonary fibrosis (IPF) patients. The frequencies of polymorphic genotypes in MMP-9 were 78.95% CC and 21.05% CT in CPFE group, 76.0% CC and 24.0% CT in emphysema group, and 100.0% CC in IPF group. There were highly statistically significant increased frequencies of the CT genotype and T allele in CPFE and emphysema groups compared with IPF group (p < 0.05). The frequencies of polymorphic genotypes in TGF-β1 were 2.63% CC, 28.95% CT, 68.42% TT in CPFE group, 4.00% CC, 16.00% CT, 80.00% TT in emphysema group, and 5.88% CC, 41.18% CT, 52.94% TT in IPF group. Significant increases in the TT genotype and T allele frequencies were observed in emphysema group compared with IPF group (p < 0.05). Our study has showed that T allele in MMP-9 (C-1562T) and T allele in TGF-β1 (T869C) are risk factors of pulmonary emphysema. The T allele in MMP-9 (C-1562T) possibly predisposes patients with pulmonary fibrosis to develop emphysema. Copyright © 2017. Published by Elsevier Taiwan.

Post-transplant survival in idiopathic pulmonary fibrosis patients concurrently listed for single and double lung transplantation.

PubMed

Chauhan, Dhaval; Karanam, Ashwin B; Merlo, Aurelie; Tom Bozzay, P A; Zucker, Mark J; Seethamraju, Harish; Shariati, Nazly; Russo, Mark J

2016-05-01

Lung transplantation is a widely accepted treatment for patients with end-stage lung disease related to idiopathic pulmonary fibrosis (IPF). However, there are conflicting data on whether double lung transplant (DLT) or single lung transplant (SLT) is the superior therapy in these patients. The purpose of this study was to determine whether actuarial post-transplant graft survival among IPF patients concurrently listed for DLT and SLT is greater for recipients undergoing the former or the latter. The United Network for Organ Sharing provided de-identified patient-level data. Analysis included lung transplant candidates with IPF listed between January 1, 2001 and December 31, 2009 (n = 3,411). The study population included 1,001 (29.3%) lung transplant recipients concurrently listed for DLT and SLT, all ≥18 years of age. The primary outcome measure was actuarial post-transplant graft survival, expressed in years. Among the study population, 433 (43.26%) recipients underwent SLT and 568 (56.74%) recipients underwent DLT. The analysis included 2,722.5 years at risk, with median graft survival of 5.31 years. On univariate (p = 0.317) and multivariate (p = 0.415) regression analyses, there was no difference in graft survival between DLT and SLT. Among IPF recipients concurrently listed for DLT and SLT, there is no statistical difference in actuarial graft survival between recipients undergoing DLT vs SLT. This analysis suggests that increased use of SLT for IPF patients may increase the availability of organs to other candidates, and thus increase the net benefit of these organs, without measurably compromising outcomes. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

The Role of ADAR1 and ADAR2 in the Regulation of miRNA-21 in Idiopathic Pulmonary Fibrosis.

PubMed

Díaz-Piña, Gabriela; Ordoñez-Razo, Rosa Ma; Montes, Eduardo; Páramo, Ignacio; Becerril, Carina; Salgado, Alfonso; Santibañez-Salgado, J Alfredo; Maldonado, Mariel; Ruiz, Victor

2018-04-10

microRNAs (miRNAs) are small non-coding 1RNAs that post-transcriptionally regulate gene expression. Recent evidence shows that adenosine deaminases that act on RNA (ADAR) can edit miRNAs. miRNAs are involved in the development of different diseases, such as idiopathic pulmonary fibrosis (IPF). In IPF, about 40% of the miRNAs are differentially expressed with respect to controls. Among these miRNAs, miRNA-21 has been found over-expressed in IPF and its targets are anti-fibrosing molecules such as PELI1 and SPRY2. The objective of this study is to determine the role of ADAR1 and 2 on the expression of miRNA-21 in human lung fibroblasts trough quantification of gene expression, protein levels, and overexpression of ADAR1 and 2. Six control and six fibrotic primary fibroblast cell cultures were used for RNA extraction, ADAR1, ADAR2, PELI1, SPRY2, miRNA-21, and pri-miRNA-21 expression was measured. Subsequently, two fibrotic fibroblast cultures were used for overexpression of ADAR1 and ADAR2, and they were stimulated with TGFβ1. Real-time PCR and Western blot were performed. ADAR1 is significantly downregulated in IPF fibroblasts; the overexpression of ADAR1 and ADAR2 reestablishes the expression levels of miRNA-21, PELI1, and SPRY2 in fibroblasts of patients with IPF. These changes in the processing of miRNAs have great value in pathology diagnosis, including lung diseases, and play an important role in the understanding of molecular mechanisms involved in the development of different pathologies, as well as representing new therapeutic targets.

MAP3K19 Is a Novel Regulator of TGF-β Signaling That Impacts Bleomycin-Induced Lung Injury and Pulmonary Fibrosis.

PubMed

Boehme, Stefen A; Franz-Bacon, Karin; DiTirro, Danielle N; Ly, Tai Wei; Bacon, Kevin B

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine TGF-β has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, MAP3K19, upregulated in IPF tissue, in TGF-β-induced signal transduction and in bleomycin-induced pulmonary fibrosis. MAP3K19 has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. MAP3K19 was also found to be overexpressed in bronchoalveolar lavage macrophages from IPF patients compared to normal patients. Treatment of A549 or THP-1 cells with either MAP3K19 siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 & 3 nuclear translocation following TGF-β stimulation. TGF-β-induced gene transcription was also strongly inhibited by both the MAP3K19 inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the MAP3K19 inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of IPF, inhibition of MAP3K19 strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of MAP3K19 may have a beneficial therapeutic effect in the treatment of IPF and represents a novel strategy to target this disease.

Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers.

PubMed

Selman, Moisés; Pardo, Annie

2006-06-01

Idiopathic pulmonary fibrosis (IPF), a progressive and relentless lung scarring of unknown etiology, has been recognized as the most lethal interstitial lung disease. Despite the growing interest in IPF, the precise molecular mechanisms underlying the development of fibrosis and leading to the irreversible destruction of the lung are still unknown. Recently, it has been proposed that IPF, instead of being a chronic inflammatory disorder, results from multiple cycles of epithelial cell injury and activation. In turn, active alveolar epithelial cells provoke the migration, proliferation, and activation of mesenchymal cells with the formation of fibroblastic/myofibroblastic foci and the exaggerated accumulation of extracellular matrix, mirroring abnormal wound repair. In this article, some characteristics of the alveolar epithelium are briefly outlined, and the fibrogenic mechanisms specifically operated by active abnormal epithelial cells are examined.

INTEGRATED PROTECTIVE FABRIC SYSTEM (IPFS) PHASE III PROGRAM: AEROSOL PROTECTION REPORT

DTIC Science & Technology

2017-08-16

one layer control. It was observed that aerosol swatch measurements showed no correlation to aerosol system test performance for the materials and...the BRHA model employed. It was observed that aerosol swatch measurements showed no correlation to aerosol system test performance for the...Testing” (McVeety et al., 2015). This report includes a description of the materials and material controls, a description of the IPFS configurations

Personalized medicine in idiopathic pulmonary fibrosis: facts and promises.

PubMed

Spagnolo, Paolo; Tzouvelekis, Argyris; Maher, Toby M

2015-09-01

In this article, we summarize and discuss the most recent literature on personalized medicine in idiopathic pulmonary fibrosis (IPF), a chronic progressive and almost invariably lethal disease of unknown cause. This review is timely as major advances in our understanding of disease pathobiology and improvements in molecular techniques have recently led to the identification of potential surrogates of diagnosis, prognosis and response to treatment. The most promising and advanced candidate biomarkers are presented based on their proposed mechanistic pathways (e.g. alveolar epithelial cell dysfunction, immune dysregulation, microbiome, extracellular matrix remodeling and fibroproliferation, epigenetic markers and metabolomics). Recent data suggest that components of the immune system may contribute to the development of IPF. A potential role for infections as a cofactor in disease development and progression or as a trigger in disease exacerbation has also recently been proposed. Clinical management of IPF is unsatisfactory because of limited availability of truly effective therapies, lack of accurate predictors of disease behavior and absence of simple short-term measures of therapeutic response. A number of putative biomarkers have been identified in patients with IPF, although none has been validated to the standard necessary for their use in either therapeutic trials or clinical practice. Currently, ongoing prospective longitudinal studies will hopefully permit such validation.

Efficacy and adverse events of pirfenidone in treating idiopathic pulmonary fibrosis.

PubMed

Ren, Hui; Wang, Kai; Yang, Hao; Gao, Lingyun

2017-09-01

To analyze the efficacy and adverse events  (AEs) of pirfenidone in idiopathic pulmonary fibrosis (IPF) trials. Methods: MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for studies published before June 2016. All studies of clinical trials with the key words IPF or idiopathic pulmonary fibrosis or lung fibrosis and pirfenidone or Esbriet were identified. Quality assessment and data extraction nwere conducted by 2 independent researchers. A meta-analysis of randomized controlled trials (RCTs) was performed, and relative risk (RR) and 95% confidence intervals (95% CIs) were calculated.   Results: Five studies were included in this review, involving 1568 participants. The meta-analysis revealed that pirfenidone reduced the risk of decline in forced vital capacity (FVC)% ≥10% from baseline (relative risk: 0.62; 95% CI: 0.51-0.76, p less than 0.001). The pirfenidone group had a significantly higher rate of AEs compared with the placebo group. Pirfenidone did not reduce mortality from any cause significantly (odds ratio: 0.63; 95% CI: 0.36-1.09). Conclusions: This study showed that pirfenidone could reduce disease progression as assessed by the decline in FVC in IPF. Pirfenidone represents a suitable treatment option for patients with IPF.

The role of pirfenidone in the treatment of idiopathic pulmonary fibrosis

PubMed Central

2013-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease, with a median survival time of 2–5 years. The search for effective treatment has involved numerous clinical trials of investigational agents without significant success. However, in 2011, pirfenidone was the first drug to be approved for the treatment of IPF in Europe. Four key clinical trials supported the efficacy and tolerability of pirfenidone. In the two recently published Phase III CAPACITY trials evaluating pirfenidone (studies 004 and 006), patients with mild-to-moderate IPF were treated with pirfenidone or placebo. Study 004 and pooled analysis of primary endpoint data from both studies showed that pirfenidone significantly reduced decline in percent-predicted forced vital capacity (FVC) compared with placebo (p<0.005). Evidence of beneficial effects of pirfenidone treatment was also observed with regard to several secondary endpoints. Pirfenidone was generally well tolerated, with the most common side effects being gastrointestinal and photosensitivity. Data from the RECAP extension phase of the CAPACITY studies, where patients were treated with pirfenidone for up to three years, further support the manageable tolerability profile of pirfenidone. The efficacy data, coupled with long-term safety data, provide further evidence of a clinically-meaningful treatment effect with pirfenidone in patients with IPF. PMID:23734908

Dynamics of intrapericardial and extrapericardial fat tissues during long-term, dietary-induced, moderate weight loss.

PubMed

Tsaban, Gal; Wolak, Arik; Avni-Hassid, Hila; Gepner, Yftach; Shelef, Ilan; Henkin, Yaakov; Schwarzfuchs, Dan; Cohen, Noa; Bril, Nitzan; Rein, Michal; Serfaty, Dana; Kenigsbuch, Shira; Tene, Lilac; Zelicha, Hila; Yaskolka-Meir, Anat; Komy, Oded; Bilitzky, Avital; Chassidim, Yoash; Ceglarek, Uta; Stumvoll, Michael; Blüher, Matthias; Thiery, Joachim; Dicker, Dror; Rudich, Assaf; Stampfer, Meir J; Shai, Iris

2017-10-01

Background: In view of evidence linking pericardial fat accumulation with increased cardiovascular disease risk, strategies to reduce its burden are needed. Data comparing the effects of specific long-term dietary interventions on pericardial fat tissue mobilization are sparse. Objective: We sought to evaluate intrapericardial-fat (IPF) and extrapericardial-fat (EPF) changes during weight-loss interventions by different dietary regimens. Design: During 18 mo of a randomized controlled trial, we compared a Mediterranean/low-carbohydrate (MED/LC) diet plus 28 g walnuts/d with a calorically equal low-fat (LF) diet among randomly assigned participants with moderate abdominal obesity. We performed whole-body MRI and volumetrically quantified IPF and EPF among 80 participants to follow the 18-mo changes. Results: The participants [mean age: 48.6 y; mean body mass index (BMI; in kg/m 2 ); 31.7; 90% men] had baseline IPF and EPF (mean ± SD) volumes of 172.4 ± 53.3 mL and 194.9 ± 71.5 mL, respectively. The 18-mo moderate weight loss of 3.7 kg was similar in both groups, but the reduction in waist circumference was higher in the MED/LC group (-6.9 ± 6.6 cm) than in the LF diet group (-2.3 ± 6.5 cm; P = 0.01). After 18 mo, the IPF volume had reduced twice as much in the MED/LC group compared with the LF group [-37 ± 26.2 mL (-22% ± 15%) compared with -15.5 ± 26.2 mL (-8% ± 15%), respectively; P < 0.05, after adjustment for changes in weight or visceral adipose tissue]. The EPF volume had reduced similarly in both groups [-41.6 ± 30.2 mL (-23% ± 16%) in the MED/LC group compared with -37.9 ± 28.3 mL (-19% ± 14%) in the LF group; P > 0.1]. After controlling for weight loss, IPF and EPF volume reduction paralleled changes in lipid profile but not with improved glycemic profile variables: the IPF relative reduction was associated with a decrease in triglycerides (TGs) (β = 0.090; 95% CI: 0.026, 0.154; P = 0.007) and the ratio of TGs to high-density lipoprotein (HDL) cholesterol (β = 2.689; 95% CI: 0.373, 5.003; P = 0.024), and the EPF relative reduction was associated with an increase in HDL cholesterol (β = -0.452; 95% CI: -0.880, -0.023; P = 0.039) and a decrease in total cholesterol and HDL cholesterol (β = 3.766; 95% CI: 1.092, 6.440; P = 0.007). Conclusions: Moderate but persistent dietary-induced weight loss substantially decreased both IPF and EPF volumes. Reduction of pericardial adipose tissues is independently associated with an improved lipid profile. The Mediterranean diet, rich in unsaturated fats and restricted carbohydrates, is superior to an LF diet in terms of the IPF burden reduction. This trial was registered at clinicaltrials.gov as NCT01530724. © 2017 American Society for Nutrition.

Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic?

PubMed Central

Wolters, Paul J; Blackwell, Timothy S; Eickelberg, Oliver; Loyd, James E; Kaminski, Naftali; Jenkins, Gisli; Maher, Toby M; Molina-Molina, Maria; Noble, Paul W; Raghu, Ganesh; Richeldi, Luca; Schwarz, Marvin I; Selman, Moises; Wuyts, Wim A; Schwartz, David A

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and typically fatal lung disease characterised by subpleural fibrosis, subepithelial fibroblast foci, and microscopic honeycombing. Although understanding of the pathogenic mechanisms continues to evolve, evidence indicates that distal airway and alveolar epithelial cells are central drivers of the disease. In this Viewpoint, we review the history of naming and classifications used to define the disease now referred to as IPF, in the context of understanding the clinical presentation, causes, and pathogenesis of the disease. We aim to generate discussion on whether, given the substantial progress made in understanding the clinical, genetic, cellular, and molecular mechanisms involved in the development of IPF, a change of name should be considered. To initiate this discussion, we offer new suggestions to update the name of this disease and new approaches to classify all forms of pulmonary fibrosis. PMID:29413083

Computer-based quantitative computed tomography image analysis in idiopathic pulmonary fibrosis: A mini review.

PubMed

Ohkubo, Hirotsugu; Nakagawa, Hiroaki; Niimi, Akio

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is the most common type of progressive idiopathic interstitial pneumonia in adults. Many computer-based image analysis methods of chest computed tomography (CT) used in patients with IPF include the mean CT value of the whole lungs, density histogram analysis, density mask technique, and texture classification methods. Most of these methods offer good assessment of pulmonary functions, disease progression, and mortality. Each method has merits that can be used in clinical practice. One of the texture classification methods is reported to be superior to visual CT scoring by radiologist for correlation with pulmonary function and prediction of mortality. In this mini review, we summarize the current literature on computer-based CT image analysis of IPF and discuss its limitations and several future directions. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Organisation of diagnosis and treatment of idiopathic pulmonary fibrosis and other interstitial lung diseases in the Nordic countries

PubMed Central

Bendstrup, Elisabeth; Hyldgaard, Charlotte; Altraja, Alan; Sjåheim, Tone; Myllärniemi, Marjukka; Gudmundsson, Gunnar; Sköld, Magnus; Hilberg, Ole

2015-01-01

Introduction Differences in the organisation of idiopathic pulmonary fibrosis (IPF) and interstitial lung diseases (ILDs) in the Nordic countries are not well described. Diagnostic setups, treatment modalities and follow-up plans may vary due to national, cultural and epidemiological features. The aim of the present study was to describe the different organisation of diagnostics and treatment of IPF and ILD in the Nordic countries. Methods All university and regional hospitals with respiratory physicians were invited to respond to a questionnaire collecting data on the number of physicians, nurses, patients with ILD/IPF, the presence of and adherence to disease-specific national and international guidelines, diagnosis and treatment including ILD-specific palliation and rehabilitation programmes. Results Twenty-four university and 22 regional hospitals returned the questionnaire. ILD and IPF incidence varied between 1.4 and 20/100,000 and 0.4 and 10/100,000, respectively. Denmark and Estonia have official national plans for the organisation of ILD. The majority of patients are managed at the university hospitals. The regional hospitals each manage 46 (5–200) patients with ILD and 10 (0–20) patients with IPF. There are from one to four ILD centres in each country with a median of two ILD specialists employed. Specialised ILD nurses are present in nine hospitals. None of the Nordic countries have national guidelines made by health authorities. The respiratory societies in Sweden, Norway and Denmark have developed national guidelines. All hospitals except two use the ATS/ERS/JRS/ALAT IPF guidelines from 2011. The limited number of ILD specialists, ILD-specialised radiologists and pathologists and the low volume of ILD centres were perceived as bottlenecks for implementation of guidelines. Twenty of the 24 university hospitals have multidisciplinary conferences (MDCs). Pulmonologists and radiologists take part in all MDCs while pathologists only participate at 17 hospitals. Prescription of pirfenidone is performed by all university hospitals except in Estonia. Triple therapy with steroid, azathioprine and N-acetylcysteine is not used. No hospitals have specific palliation programmes for patients with ILD/IPF, but 36 hospitals have the possibility of referring patients for palliative care, mostly based on existing oncology palliative care teams; seven hospitals have rehabilitation programmes for ILD. Conclusion There are obvious differences between the organisations of ILD patients in the Nordic countries. We call for national plans that consider the challenge of cultural and geographical differences and suggest the establishment of national reference centres and satellite collaborative hospitals to enable development of common guidelines for diagnostics, therapy and palliation in this patient group. PMID:26557259

Effects and mechanisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models.

PubMed

Yu, Wencheng; Guo, Fang; Song, Xiaoxia

2017-12-01

Previous studies have reported that caveolin-1 (Cav-1) is associated with lung fibrosis. However, the role of Cav-1 expression in pirfenidone-treated idiopathic pulmonary fibrosis (IPF) is unknown. This study investigated Cav-1 expression in pirfenidone-treated IPF, and compared the effects of pirfenidone with acetylcysteine and prednisone on IPF. Rat IPF model was established by endotracheal injection of 5 mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone (P, 100 mg/kg once daily), prednisone (H, 5 mg/kg once daily) and acetylcysteine (N, 4 mg/kg 3 times per day) were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without IPF were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of tumour necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) was determined by enzyme-linked immunosorbent assay. After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower (p < 0.05) significance of airsacculitis and fibrosis scores of lung tissues, as well as expression of TGF-β1, TNF-α and PDGF, but the expression of Cav-1 was higher (p < 0.05). Compared with the N group, the fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group (p < 0.05). Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and fibrosis scores (r = -0.506, p < 0.01; r = -0.676, p < 0.01) as well as expression of TGF-β1, TNF-α and PDGF (r = -0.590, p < 0.01; r = -0.530, p < 0.01; r = -0.553, p < 0.01). Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and pulmonary fibrosis in rat IPF models, which may be related with enhanced caveolin-1, reduced TNF-α, TGF-β1, PDGF.

HFE gene variants and iron-induced oxygen radical generation in idiopathic pulmonary fibrosis.

PubMed

Sangiuolo, Federica; Puxeddu, Ermanno; Pezzuto, Gabriella; Cavalli, Francesco; Longo, Giuliana; Comandini, Alessia; Di Pierro, Donato; Pallante, Marco; Sergiacomi, Gianluigi; Simonetti, Giovanni; Zompatori, Maurizio; Orlandi, Augusto; Magrini, Andrea; Amicosante, Massimo; Mariani, Francesca; Losi, Monica; Fraboni, Daniela; Bisetti, Alberto; Saltini, Cesare

2015-02-01

In idiopathic pulmonary fibrosis (IPF), lung accumulation of excessive extracellular iron and macrophage haemosiderin may suggest disordered iron homeostasis leading to recurring microscopic injury and fibrosing damage. The current study population comprised 89 consistent IPF patients and 107 controls. 54 patients and 11 controls underwent bronchoalveolar lavage (BAL). Haemosiderin was assessed by Perls' stain, BAL fluid malondialdehyde (MDA) by high-performance liquid chromatography, BAL cell iron-dependent oxygen radical generation by fluorimetry and the frequency of hereditary haemochromatosis HFE gene variants by reverse dot blot hybridisation. Macrophage haemosiderin, BAL fluid MDA and BAL cell unstimulated iron-dependent oxygen radical generation were all significantly increased above controls (p<0.05). The frequency of C282Y, S65C and H63D HFE allelic variants was markedly higher in IPF compared with controls (40.4% versus 22.4%, OR 2.35, p=0.008) and was associated with higher iron-dependent oxygen radical generation (HFE variant 107.4±56.0, HFE wild type (wt) 59.4±36.4 and controls 16.7±11.8 fluorescence units per 10(5) BAL cells; p=0.028 HFE variant versus HFE wt, p=0.006 HFE wt versus controls). The data suggest iron dysregulation associated with HFE allelic variants may play an important role in increasing susceptibility to environmental exposures, leading to recurring injury and fibrosis in IPF. Copyright ©ERS 2015.

Safety of Nintedanib Added to Pirfenidone Treatment for Idiopathic Pulmonary Fibrosis.

PubMed

Flaherty, Kevin R; Fell, Charlene D; Huggins, J Terrill; Nunes, Hilario; Sussman, Robert; Valenzuela, Claudia; Petzinger, Ute; Stauffer, John L; Gilberg, Frank; Bengus, Monica; Wijsenbeek, Marlies

2018-06-25

We assessed safety and tolerability of treatment with pirfenidone (1602-2403 mg/day) and nintedanib (200-300 mg/day) in patients with idiopathic pulmonary fibrosis (IPF).This 24-week, single-arm, open-label Phase IV study (NCT02598193) enrolled patients with IPF with forced vital capacity (FVC) ≥50% and carbon monoxide diffusing capacity (DLco) ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg/day for ≥28 days. The primary endpoint was proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602-2403 mg/day) and nintedanib (200-300 mg/day). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither.Eighty-nine patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary endpoint) and 16 discontinued treatment prematurely (13 due to TEAEs). Seventy-four patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs.Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF. Copyright ©ERS 2018.

Validation of a Method To Screen for Pulmonary Hypertension in Advanced Idiopathic Pulmonary Fibrosis*

PubMed Central

Zisman, David A.; Karlamangla, Arun S.; Kawut, Steven M.; Shlobin, Oksana A.; Saggar, Rajeev; Ross, David J.; Schwarz, Marvin I.; Belperio, John A.; Ardehali, Abbas; Lynch, Joseph P.; Nathan, Steven D.

2008-01-01

Background We have developed a method to screen for pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) patients, based on a formula to predict mean pulmonary artery pressure (MPAP) from standard lung function measurements. The objective of this study was to validate this method in a separate group of IPF patients. Methods Cross-sectional study of 60 IPF patients from two institutions. The accuracy of the MPAP estimation was assessed by examining the correlation between the predicted and measured MPAPs and the magnitude of the estimation error. The discriminatory ability of the method for PH was assessed using the area under the receiver operating characteristic curve (AUC). Results There was strong correlation in the expected direction between the predicted and measured MPAPs (r = 0.72; p < 0.0001). The estimated MPAP was within 5 mm Hg of the measured MPAP 72% of the time. The AUC for predicting PH was 0.85, and did not differ by institution. A formula-predicted MPAP > 21 mm Hg was associated with a sensitivity, specificity, positive predictive value, and negative predictive value of 95%, 58%, 51%, and 96%, respectively, for PH defined as MPAP from right-heart catheterization > 25 mm Hg. Conclusions A prediction formula for MPAP using standard lung function measurements can be used to screen for PH in IPF patients. PMID:18198245

Lung transplantation for high-risk patients with idiopathic pulmonary fibrosis.

PubMed

De Oliveira, Nilto C; Julliard, Walker; Osaki, Satoru; Maloney, James D; Cornwell, Richard D; Sonetti, David A; Meyer, Keith C

2016-10-07

Survival for patients with idiopathic pulmonary fibrosis (IPF) and high lung allocation score (LAS) values may be significantly reduced in comparison to those with lower LAS values. To evaluate outcomes for high-risk IPF patients as defined by LAS values ≥46 (N=42) versus recipients with LAS values <46 (N=89). We retrospectively reviewed records of 131 consecutive patients with IPF who received lung transplants at our institution between 1999 and 2013. The mean LAS was significantly higher (59.5, interquartile range 43.9-75.9 vs. 39.3, interquartile range 37.7-44.3; p<0.01) for the high-risk cohort. The higher LAS cohort had significantly lower percent predicted forced vital capacity (FVC) versus recipients with LAS <46 (41.3±14.1% vs. 53.2±16.2%; p<0.01) and required more supplemental oxygen (7±5 vs. 4±2 L/min, p<0.01) prior to transplant versus recipients with LAS <46. Although the incidence of early post-LTX pulmonary complications was increased for the higher LAS group versus recipients with LAS <46, 30-day mortality and actuarial survival did not differ between the two cohorts. Although lung transplantation in patients with IPF and high LAS values is associated with increased risk of early post-transplant complications, long-term post-transplant survival for our high-LAS cohort was equivalent to that for the lower LAS recipients.

Fibrosis of Two: Epithelial Cell-Fibroblast Interactions in Pulmonary Fibrosis

PubMed Central

Sakai, Norihiko; Tager, Andrew M.

2013-01-01

Idiopathic pulmonary fibrosis (IPF) is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. IPF is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological fibrosis due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger IPF remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell death provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and death, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the “pas de deux” (steps of two), or perhaps more appropriate to IPF pathogenesis, the “folie à deux” (madness of two) of epithelial cells and fibroblasts that drives the progression of pulmonary fibrosis. We describe the signaling molecules that mediate the interactions of these cell types in their “fibrosis of two”, including transforming growth factor-β, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. PMID:23499992

Serum inter-alpha-trypsin inhibitor and matrix hyaluronan promote angiogenesis in fibrotic lung injury.

PubMed

Garantziotis, Stavros; Zudaire, Enrique; Trempus, Carol S; Hollingsworth, John W; Jiang, Dianhua; Lancaster, Lisa H; Richardson, Elizabeth; Zhuo, Lisheng; Cuttitta, Frank; Brown, Kevin K; Noble, Paul W; Kimata, Koji; Schwartz, David A

2008-11-01

The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-alpha-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury. To determine whether IaI promotes HA-mediated angiogenesis in tissue injury. An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined. IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC. Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627).

Microarray identifies ADAM family members as key responders to TGF-beta1 in alveolar epithelial cells.

PubMed

Keating, Dominic T; Sadlier, Denise M; Patricelli, Andrea; Smith, Sinead M; Walls, Dermot; Egan, Jim J; Doran, Peter P

2006-09-01

The molecular mechanisms of Idiopathic Pulmonary Fibrosis (IPF) remain elusive. Transforming Growth Factor beta 1(TGF-beta1) is a key effector cytokine in the development of lung fibrosis. We used microarray and computational biology strategies to identify genes whose expression is significantly altered in alveolar epithelial cells (A549) in response to TGF-beta1, IL-4 and IL-13 and Epstein Barr virus. A549 cells were exposed to 10 ng/ml TGF-beta1, IL-4 and IL-13 at serial time points. Total RNA was used for hybridisation to Affymetrix Human Genome U133A microarrays. Each in vitro time-point was studied in duplicate and an average RMA value computed. Expression data for each time point was compared to control and a signal log ratio of 0.6 or greater taken to identify significant differential regulation. Using normalised RMA values and unsupervised Average Linkage Hierarchical Cluster Analysis, a list of 312 extracellular matrix (ECM) proteins or modulators of matrix turnover was curated via Onto-Compare and Gene-Ontology (GO) databases for baited cluster analysis of ECM associated genes. Interrogation of the dataset using ontological classification focused cluster analysis revealed coordinate differential expression of a large cohort of extracellular matrix associated genes. Of this grouping members of the ADAM (A disintegrin and Metalloproteinase domain containing) family of genes were differentially expressed. ADAM gene expression was also identified in EBV infected A549 cells as well as IL-13 and IL-4 stimulated cells. We probed pathologenomic activities (activation and functional activity) of ADAM19 and ADAMTS9 using siRNA and collagen assays. Knockdown of these genes resulted in diminished production of collagen in A549 cells exposed to TGF-beta1, suggesting a potential role for these molecules in ECM accumulation in IPF.

miR-130b-3p Modulates Epithelial-Mesenchymal Crosstalk in Lung Fibrosis by Targeting IGF-1.

PubMed

Li, Shuhong; Geng, Jing; Xu, Xuefeng; Huang, Xiaoxi; Leng, Dong; Jiang, Dingyuan; Liang, Jiurong; Wang, Chen; Jiang, Dianhua; Dai, Huaping

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal fibrotic lung disease with largely unknown etiology and pathogenesis. Evidence suggests microRNAs (miRNA) contribute to pathogenesis of IPF. In this study, we sought to identify miRNA expression signatures and determine the role of miR-130b-3p in lung fibrosis. The miRNA expression profile of the lungs from patients with IPF and normal donors was determined by Affymetrix microarray, and transcriptome with Affymetrix array. The functions and signal pathways as well as miRNA-mRNA networks were established by bioinformatics analysis. Luciferase assays and ELISA were used to confirm the miRNA target gene. The effect of miRNA-transfected epithelium on fibroblast activities was assessed using a co-culture system. The fibroblast activities were determined by qRT-PCR, western blotting, Transwell and BrdU assays. Seven miRNAs were significantly decreased in IPF lungs, with miR-130b-3p being the highest in the miRNA-mRNA network. Insulin-like growth factor (IGF-1) was a target gene of miR-130b-3p in the epithelium. miR-130b-3p inhibition in the epithelium induced collagen I expression and enhanced the proliferation and migration ability of fibroblast in co-culture systems, which mimicked the functions of exogenous IGF-1 on fibroblasts. Neutralizing IGF-1 with an antibody significantly reduced the modulatory effects of miR-130b-3p inhibitor-transfected epithelium on the activation of fibroblasts. Our results show that miR-130b-3p was downregulated in IPF lungs. miR-130b-3p downregulation contributed to the activation of fibroblasts and the dysregulated epithelial-mesenchymal crosstalk by promoting IGF-1 secretion from lung epithelium, suggesting a key regulatory role for this miRNA in preventing lung fibrosis.

An Open-Label Study of the Long-Term Safety of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (RECAP).

PubMed

Costabel, Ulrich; Albera, Carlo; Lancaster, Lisa H; Lin, Chin-Yu; Hormel, Philip; Hulter, Henry N; Noble, Paul W

2017-01-01

RECAP (NCT00662038) was an open-label extension study in patients with idiopathic pulmonary fibrosis (IPF) who completed either the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) 016 phase 3 trial or the Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) 004/006 phase 3 trials. To obtain long-term safety data for pirfenidone in patients with IPF in RECAP. Of the 1,334 patients who participated in the phase 3 trials, 1,058 entered RECAP. The final analysis from enrollment (September 2008) to June 2015 is presented. Mean (SD) and median (range) pirfenidone exposures in RECAP were 122 (98) weeks and 88 (>0 to 349) weeks, respectively, with a mean daily dose of 2,091.1 mg. Cumulative total exposure was 2,482 patient exposure years (PEY). The treatment-emergent adverse event (TEAE) rate was 701.9 per 100 PEY. The serious TEAE rate was 53.5 per 100 PEY, with the most common serious TEAE being IPF (11.1 per 100 PEY). Of the 231 deaths (9.3 per 100 PEY), the most common cause was IPF (5.4 per 100 PEY). The treatment discontinuation rate due to a TEAE was 17.9 per 100 PEY; discontinuations were due to IPF (7.2 per 100 PEY), pneumonia, respiratory failure, acute respiratory failure, rash (0.5 per 100 PEY each), and nausea (0.4 per 100 PEY). For patients from CAPACITY 004/006 who entered RECAP, the mean change in percent predicted forced vital capacity from RECAP baseline at 180 weeks was -9.6%. Median on-treatment survival from the first pirfenidone dose in RECAP was 77.2 months. RECAP provides long-term follow-up and safety data for pirfenidone that were consistent with the known profile, with no new safety signals observed. © 2017 The Author(s) Published by S. Karger AG, Basel.

Longitudinal "Real-World" Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece.

PubMed

Tzouvelekis, Argyrios; Karampitsakos, Theodoros; Ntolios, Paschalis; Tzilas, Vasilios; Bouros, Evangelos; Markozannes, Evangelos; Malliou, Ioanna; Anagnostopoulos, Aris; Granitsas, Andreas; Steiropoulos, Paschalis; Dimakou, Katerina; Chrysikos, Serafeim; Koulouris, Nikolaos; Bouros, Demosthenes

2017-01-01

Pirfenidone is an antifibrotic compound able to slow down disease progression in patients with idiopathic pulmonary fibrosis (IPF). To investigate the safety and efficacy of pirfenidone in patients with IPF in a real-life setting. This was a multicenter, retrospective, real-life, observational study for patients with IPF receiving pirfenidone. We identified 92 patients with IPF receiving pirfenidone. Eighty patients (70 males and 10 females, mean age ± SD: 68.1 + 7.5, mean %FVC ± SD = 74.9 ± 17.2, mean %DL CO  ± SD = 48.1 ± 16.9) were included in the analysis. Skin-related (25%) and gastrointestinal (17.5%) adverse events were the most common and led to drug discontinuation in 22.5% of cases. The majority (87%) of patients experienced side effects during the first 6 months of treatment. At 36 months, changes in %FVC and %DL CO were -9.25 ± 16.34 and -9.26 ± 15.26, respectively. At 6, 12, and 24 months after treatment initiation ( n  = 80, 60, and 26), 18, 15, and 5 patients (22.5, 25, and 19.2%) experienced significant (>10%) and 11, 3, and 3 patients (13.8, 5, and 11.5%) experienced marginal (5-10%) %FVC improvement; and 13, 6, and 1 patient (16.2, 10, and 3.9%) experienced marginal (-5 to -10%) and 20, 21, and 8 patients (25, 35, and 30.8%) experienced significant decline (<-10%) in %FVCpred. Median survival was 851 days, and 41 patients died during the study period. Pirfenidone demonstrated an acceptable safety and therapeutic profile in patients with IPF on a longitudinal basis. Prospective observational registries are urgently needed to provide a real-world view of outcomes of pirfenidone in clinical practice.

Effect of inhaled N-acetylcysteine monotherapy on lung function and redox balance in idiopathic pulmonary fibrosis.

PubMed

Muramatsu, Yoko; Sugino, Keishi; Ishida, Fumiaki; Tatebe, Junko; Morita, Toshisuke; Homma, Sakae

2016-05-01

An oxidant-antioxidant imbalance is considered to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Therefore, administration of antioxidants, such as N-acetylcysteine (NAC), may represent a potential treatment option for IPF patients. The aim of this study was to evaluate the effect of inhaled NAC monotherapy on lung function and redox balance in patients with IPF. A retrospective observational study was done, involving 22 patients with untreated early IPF (19 men; mean [±S.D.] age, 71.8 [±6.3]y). At baseline and at 6 and 12 months after initiating inhaled NAC monotherapy, we assessed forced vital capacity (FVC) and measured the levels of total glutathione, oxidized glutathione (GSSG), and the ratio of reduced to oxidized glutathione in whole blood (hereafter referred to as the ratio), and of 8-hydroxy-2'-deoxyguanosine in urine. To evaluate response to treatment, we defined disease progression as a decrease in FVC of ≥5% from baseline and stable disease as a decrease in FVC of <5%, over a period of 6 months. Change in FVC in the stable group at 6 and 12 months were 95±170mL and -70±120mL, while those in the progressive group at 6 and 12 months were -210±80mL, -320±350mL, respectively. The serial mean change in GSSG from baseline decreased as the ratio of reduced to oxidized glutathione increased in patients with stable disease, while it increased as this ratio decreased in patients with progressive disease. Receiver operating characteristic curve analysis revealed that a baseline GSSG level of ≥1.579μM was optimal for identifying treatment responders. Inhaled NAC monotherapy was associated with improved redox imbalance in patients with early IPF. Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Idiopathic Pulmonary Fibrosis: Clinically Meaningful Primary Endpoints in Phase 3 Clinical Trials

PubMed Central

Collard, Harold R.; Anstrom, Kevin J.; Flaherty, Kevin R.; Fleming, Thomas R.; King, Talmadge E.; Martinez, Fernando J.; Brown, Kevin K.

2012-01-01

Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint—that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or funtional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints. PMID:22505745

Blood Biomarkers in Idiopathic Pulmonary Fibrosis.

PubMed

Guiot, Julien; Moermans, Catherine; Henket, Monique; Corhay, Jean-Louis; Louis, Renaud

2017-06-01

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease of unknown origin whose incidence has been increasing over the latest decade partly as a consequence of population ageing. New anti-fibrotic therapy including pirfenidone and nintedanib have now proven efficacy in slowing down the disease. Nevertheless, diagnosis and follow-up of IPF remain challenging. This review examines the recent literature on potentially useful blood molecular and cellular biomarkers in IPF. Most of the proposed biomarkers belong to chemokines (IL-8, CCL18), proteases (MMP-1 and MMP-7), and growth factors (IGBPs) families. Circulating T cells and fibrocytes have also gained recent interest in that respect. Up to now, though several interesting candidates are profiling there has not been a single biomarker, which proved to be specific of the disease and predictive of the evolution (decline of pulmonary function test values, risk of acute exacerbation or mortality). Large scale multicentric studies are eagerly needed to confirm the utility of these biomarkers.

Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model

PubMed Central

Zhang, Huilan; Oak, Sameer R.; Coelho, Ana Lucia; Herath, Athula; Flaherty, Kevin R.; Lee, Joyce; Bell, Matt; Knight, Darryl A.; Martinez, Fernando J.; Sleeman, Matthew A.; Herzog, Erica L.; Hogaboam, Cory M.

2014-01-01

The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung. PMID:24325475

Current approaches to the management of idiopathic pulmonary fibrosis.

PubMed

Raghu, Ganesh; Richeldi, Luca

2017-08-01

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease associated with dyspnoea, cough and impaired quality of life. Currently, the aims of patient care are to improve outcomes for patients by slowing the progression of the disease, extending life, and improving quality of life. A prompt, accurate diagnosis is important to enable patients to receive treatment early in the course of the disease and to be considered for lung transplantation. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been shown to reduce decline in lung function in patients with IPF. In addition to pharmacological therapy, optimal management of IPF includes treatment of comorbidities, symptom relief, pulmonary rehabilitation, and palliative care. Patient education is important to enable patients to make decisions about their care and to help them manage their disease and the side-effects of anti-fibrotic drugs. Research continues into new treatments and combinations of treatments that may improve outcomes for patients with this devastating disease. Copyright © 2017. Published by Elsevier Ltd.

Recent advances in managing idiopathic pulmonary fibrosis

PubMed Central

Scelfo, Chiara; Caminati, Antonella; Harari, Sergio

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a rare pulmonary disease with a poor prognosis and severe impact on quality of life. Early diagnosis is still challenging and important delays are registered before final diagnosis can be reached. Available tools fail to predict the variable course of the disease and to evaluate response to antifibrotic drugs. Despite the recent approval of pirfenidone and nintedanib, significant challenges remain to improve prognosis and quality of life. It is hoped that the new insights gained in pathobiology in the last few years will lead to further advances in the diagnosis and management of IPF. Currently, early diagnosis and prompt initiation of treatments reducing lung function loss offer the best hope for improved outcomes. This article aims at providing an overview of recent advances in managing patients with IPF and has a particular focus on how to reach a diagnosis, manage comorbidities and lung transplantation, care for the non-pharmacological needs of patients, and address palliative care. PMID:29225786

Prevalence and incidence of interstitial lung diseases in a multi-ethnic county of Greater Paris.

PubMed

Duchemann, Boris; Annesi-Maesano, Isabella; Jacobe de Naurois, Camille; Sanyal, Shreosi; Brillet, Pierre-Yves; Brauner, Michel; Kambouchner, Marianne; Huynh, Sophie; Naccache, Jean Marc; Borie, Raphael; Piquet, Jacques; Mekinian, Arsène; Virally, Jerôme; Uzunhan, Yurdagul; Cadranel, Jacques; Crestani, Bruno; Fain, Olivier; Lhote, Francois; Dhote, Robin; Saidenberg-Kermanac'h, Nathalie; Rosental, Paul-André; Valeyre, Dominique; Nunes, Hilario

2017-08-01

The objective of the study was to estimate the prevalence and incidence of interstitial lung diseases (ILDs) in Seine-Saint-Denis, a multi-ethnic county of Greater Paris, France.Patients with ILDs were identified between January and December 2012 by using several sources; all potentially involved medical specialists from public and private hospitals, community-based pulmonologists and general practitioners, and the Social Security system. Diagnoses were validated centrally by an expert multidisciplinary discussion.1170 ILD cases were reported (crude overall prevalence: 97.9/10 5 and incidence: 19.4/10 5 /year). In the 848 reviewed cases, the most prevalent diagnoses were sarcoidosis (42.6%), connective tissue diseases associated ILDs (CTDs-ILDs) (16%), idiopathic pulmonary fibrosis (IPF) (11.6%), and occupational ILDs (5.0%), which corresponded to a crude prevalence of 30.2/10 5 for sarcoidosis, 12.1/10 5 for CTDs-ILDs and 8.2/10 5 for IPF. The prevalence of fibrotic idiopathic interstitial pneumonias, merging IPF, nonspecific interstitial pneumonia and cases registered with code J84.1 was 16.34/10 5 An adjusted multinomial model demonstrated an increased risk of sarcoidosis in North Africans and Afro-Caribbeans and of CTDs-ILDs in Afro-Caribbeans, compared to that in Europeans.This study, with a comprehensive recruitment and stringent diagnostic criteria, emphasises the importance of secondary ILDs, particularly CTDs-ILDs and the relatively low prevalence of IPF, and confirms that sarcoidosis is a rare disease in France. Copyright ©ERS 2017.

Cooperation between human fibrocytes and endothelial colony forming cells increases angiogenesis via CXCR4 pathway

PubMed Central

Smadja, David M.; Dorfmüller, Peter; Bieche, Ivan; Guerin, Coralie; Badoual, Cécile; Boscolo, Elisa; Kambouchner, Marianne; Cazes, Aurélie; Mercier, Olaf; Humbert, Marc; Gaussem, Pascale; Bischoff, Joyce; Israël-Biet, Dominique

2016-01-01

Background Fibrotic diseases of the lung are associated with a vascular remodeling process. Fibrocytes (Fy) are a distinct population of blood-borne cells that coexpress hematopoietic cell antigens and fibroblast markers, which have been shown to contribute to organ fibrosis. The purpose of this study was to test the hypothesis that Fy might cooperate with endothelial colony forming cells to induce angiogenesis. Methods/Results We successfully isolated Fy from blood of idiopathic pulmonary fibrosis (IPF) patients, which were further characterized by flow cytometry, Reverse Transcriptase quantitative-PCR (RTQ-PCR), and confocal analysis. We investigated the interaction between Fy and cord blood derived endothelial colony forming cells (ECFC) angiogenic potential in vitro and in vivo in a Matrigel implant model. Compared to fibroblast culture media, secreted media from Fy increase ECFC proliferation and their differentiation ability via SDF-1/CXCR4 pathway. IPF-Fy co-implanted with human ECFC in a matrigel plug in immunodeficient mice formed functional microvascular beds, whereas fibroblasts did not. Evaluation of implants after 2 weeks revealed an extensive network of blood vessels containing erythrocytes. CXCR4 blockade significantly inhibited blood vessel formation in the implants. The clinical relevance of these data was confirmed by the high expression level of CXCR4 in vessels close to fibrotic areas in biopsy specimens from patients with IPF, in contrast to control lungs. Conclusions Circulating Fy might be contribute to the intense remodeling of the pulmonary vasculature in patients with IPF. PMID:25103869

Comprehensive assessment of the long-term safety of pirfenidone in patients with idiopathic pulmonary fibrosis

PubMed Central

Valeyre, Dominique; Albera, Carlo; Bradford, Williamson Z; Costabel, Ulrich; King, Talmadge E; Leff, Jonathan A; Noble, Paul W; Sahn, Steven A; du Bois, Roland M

2014-01-01

Background and objective Pirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis (IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF. Methods All patients receiving pirfenidone 2403 mg/day in the Phase 3 CAPACITY studies (Studies 004 and 006) and all patients receiving at least one dose of pirfenidone in one of two ongoing open-label studies in patients with IPF (Studies 002 and 012) were selected for inclusion. Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug. Results A total of 789 patients were included in the analysis. The median duration of exposure to pirfenidone was 2.6 years (range, 1 week–7.7 years), and the cumulative total exposure was 2059 person exposure years (PEY). Gastrointestinal and skin-related events were the most commonly reported adverse events; these were almost always mild to moderate in severity, and rarely led to treatment discontinuation. Elevations (>3× upper limit of normal) in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY. Conclusions This comprehensive analysis of safety in a large cohort of IPF patients receiving pirfenidone for a total of 2059 PEY demonstrates that long-term treatment with pirfenidone is safe and generally well tolerated. PMID:24836849

Predictors of the clinical effects of pirfenidone on idiopathic pulmonary fibrosis.

PubMed

Arai, Toru; Inoue, Yoshikazu; Sasaki, Yumiko; Tachibana, Kazunobu; Nakao, Keiko; Sugimoto, Chikatoshi; Okuma, Tomohisa; Akira, Masanori; Kitaichi, Masanori; Hayashi, Seiji

2014-03-01

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a poor prognosis. Recently, pirfenidone was reported to slow the rate of decline in vital capacity and improve progression-free survival in IPF. The purpose of this study was to clarify the factors that predicted a good response to pirfenidone, as well as its adverse effects. Forty-one IPF cases, treated with pirfenidone from January 2009 to January 2011, were enrolled in this investigation. Disease severity was classified into grades I-IV, as defined by the Japanese Respiratory Society (JRS). Short-term responsiveness to pirfenidone was evaluated by the modified criteria of the JRS. Predictors of nausea, anorexia, or both that represented important adverse effects were examined by multivariate Cox proportional hazard analyses. Predictors of short-time responsiveness were examined by multivariate logistic regression analyses. Diagnosed by a surgical lung biopsy (SLB), the mild cases of grade I/II were predictors of good, short-term responsiveness. Patients taking acid-secretion inhibitors, including proton pump inhibitors and histamine H2-receptor antagonists, showed less anorexia, nausea, or both. Only 1 case was administered drugs to activate gastrointestinal motility. We concluded that IPF patients with a mild disease, diagnosis by SLB, or both showed indications of a good response to pirfenidone. In addition, acid-secretion inhibitors may reduce the frequency of anorexia, nausea, or both from pirfenidone. © 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Lung Cancer in Patients With Combined Pulmonary Fibrosis and Emphysema and Idiopathic Pulmonary Fibrosis. A Descriptive Study in a Spanish Series.

PubMed

Portillo, Karina; Perez-Rodas, Nancy; García-Olivé, Ignasi; Guasch-Arriaga, Ignasi; Centeno, Carmen; Serra, Pere; Becker-Lejuez, Caroline; Sanz-Santos, José; Andreo García, Felip; Ruiz-Manzano, Juan

2017-06-01

Information on the association of lung cancer (LC) and combined pulmonary fibrosis and emphysema (CPFE) is limited and derived almost exclusively from series in Asian populations. The main objective of the study was to assess the impact of LC on survival in CPFE patients and in patients with idiopathic pulmonary fibrosis (IPF). A retrospective study was performed with data from patients with CFPE and IPF diagnosed in our hospital over a period of 5 years. Sixty-six patients were included, 29 with CPFE and 37 with IPF. Nine had a diagnosis of LC (6 with CPFE and 3 with IPF). Six patients (67%) received palliative treatment even though 3 of them were diagnosed atstage i-ii. Overall mortality did not differ significantly between groups; however, in patients with LC, survival was significantly lower compared to those without LC (P=.044). The most frequent cause of death was respiratory failure secondary to pulmonary fibrosis exacerbation (44%). In a multivariate analysis, the odds ratio of death among patients with LC compared to patients without LC was 6.20 (P=.037, 95% confidence interval: 1.11 to 34.48). Lung cancer reduces survival in both entities. The diagnostic and therapeutic management of LC is hampered by the increased risk of complications after any treatment modality, even after palliative treatment. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

miR-9-5p suppresses pro-fibrogenic transformation of fibroblasts and prevents organ fibrosis by targeting NOX4 and TGFBR2.

PubMed

Fierro-Fernández, Marta; Busnadiego, Óscar; Sandoval, Pilar; Espinosa-Díez, Cristina; Blanco-Ruiz, Eva; Rodríguez, Macarena; Pian, Héctor; Ramos, Ricardo; López-Cabrera, Manuel; García-Bermejo, Maria Laura; Lamas, Santiago

2015-10-01

Uncontrolled extracellular matrix (ECM) production by fibroblasts in response to injury contributes to fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Reactive oxygen species (ROS) generation is involved in the pathogenesis of IPF. Transforming growth factor-β1 (TGF-β1) stimulates the production of NADPH oxidase 4 (NOX4)-dependent ROS, promoting lung fibrosis (LF). Dysregulation of microRNAs (miRNAs) has been shown to contribute to LF. To identify miRNAs involved in redox regulation relevant for IPF, we performed arrays in human lung fibroblasts exposed to ROS. miR-9-5p was selected as the best candidate and we demonstrate its inhibitory effect on TGF-β receptor type II (TGFBR2) and NOX4 expression. Increased expression of miR-9-5p abrogates TGF-β1-dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin-induced LF, miR-9-5p dramatically reduces fibrogenesis and inhibition of miR-9-5p and prevents its anti-fibrotic effect both in vitro and in vivo. In lung specimens from patients with IPF, high levels of miR-9-5p are found. In omentum-derived mesothelial cells (MCs) from patients subjected to peritoneal dialysis (PD), miR-9-5p also inhibits mesothelial to myofibroblast transformation. We propose that TGF-β1 induces miR-9-5p expression as a self-limiting homeostatic response. © 2015 The Authors.

Treatment Rationale and Design for J-SONIC: A Randomized Study of Carboplatin Plus Nab-paclitaxel With or Without Nintedanib for Advanced Non-Small-cell Lung Cancer With Idiopathic Pulmonary Fibrosis.

PubMed

Otsubo, Kohei; Kishimoto, Junji; Kenmotsu, Hirotsugu; Minegishi, Yuji; Ichihara, Eiki; Shiraki, Akira; Kato, Terufumi; Atagi, Shinji; Horinouchi, Hidehito; Ando, Masahiko; Kondoh, Yasuhiro; Kusumoto, Masahiko; Ichikado, Kazuya; Yamamoto, Nobuyuki; Nakanishi, Yoichi; Okamoto, Isamu

2018-01-01

We describe the treatment rationale and procedure for a randomized study (J-SONIC; University Hospital Medical Information Network Clinical Trials Registry identification no., UMIN000026799) of carboplatin plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without nintedanib for patients with advanced non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF). The study was designed to examine the efficacy and safety of nintedanib administered with carboplatin plus nab-paclitaxel versus carboplatin plus nab-paclitaxel alone in chemotherapy-naive patients with advanced NSCLC associated with IPF. Eligible patients (enrollment target, n = 170) will be randomized at a 1:1 ratio to receive 4 cycles of carboplatin (area under the curve, 6 on day 1) plus nab-paclitaxel (100 mg/m 2 on days 1, 8, and 15) administered every 3 weeks either without (arm A) or with (arm B) nintedanib (150 mg twice daily), to be followed in arm B by single-agent administration of nintedanib (150 mg twice daily). The present trial is the first randomized controlled study for the treatment of NSCLC associated with IPF. The goal of the study is to demonstrate that nintedanib combined with carboplatin plus nab-paclitaxel prolongs the interval to acute exacerbation of IPF compared with carboplatin plus nab-paclitaxel alone. Copyright © 2017 Elsevier Inc. All rights reserved.

Serum Inter–α-Trypsin Inhibitor and Matrix Hyaluronan Promote Angiogenesis in Fibrotic Lung Injury

PubMed Central

Garantziotis, Stavros; Zudaire, Enrique; Trempus, Carol S.; Hollingsworth, John W.; Jiang, Dianhua; Lancaster, Lisa H.; Richardson, Elizabeth; Zhuo, Lisheng; Cuttitta, Frank; Brown, Kevin K.; Noble, Paul W.; Kimata, Koji; Schwartz, David A.

2008-01-01

Rationale: The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-α-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury. Objectives: To determine whether IaI promotes HA-mediated angiogenesis in tissue injury. Methods: An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined. Measurements and Main Results: IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC. Conclusions: Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627). PMID:18703791

Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials.

PubMed

Noble, Paul W; Albera, Carlo; Bradford, Williamson Z; Costabel, Ulrich; du Bois, Roland M; Fagan, Elizabeth A; Fishman, Robert S; Glaspole, Ian; Glassberg, Marilyn K; Lancaster, Lisa; Lederer, David J; Leff, Jonathan A; Nathan, Steven D; Pereira, Carlos A; Swigris, Jeffrey J; Valeyre, Dominique; King, Talmadge E

2016-01-01

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol.A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3-55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0-96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation.Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF. Copyright ©ERS 2016.

Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials

PubMed Central

Albera, Carlo; Bradford, Williamson Z.; Costabel, Ulrich; du Bois, Roland M.; Fagan, Elizabeth A.; Fishman, Robert S.; Glaspole, Ian; Glassberg, Marilyn K.; Lancaster, Lisa; Lederer, David J.; Leff, Jonathan A.; Nathan, Steven D.; Pereira, Carlos A.; Swigris, Jeffrey J.; Valeyre, Dominique; King, Talmadge E.

2016-01-01

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression. All patients randomised to pirfenidone 2403 mg·day−1 or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol. A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3–55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0–96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation. Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF. PMID:26647432

Determination of spallation neutron flux through spectral adjustment techniques

DOE PAGES

Mosby, Michelle A.; Engle, Jonathan Ward; Jackman, Kevin Richard; ...

2016-05-30

The Los Alamos Isotope Production Facility (IPF) creates medical isotopes using a proton beam impinged on a target stack. Spallation neutrons are created in the interaction of the beam with target. The use of these spallation neutrons to produce additional radionuclides has been proposed in this paper. However, the energy distribution and magnitude of the flux is not well understood. Finally, a modified SAND-II spectral adjustment routine has been used with radioactivation foils to determine the differential neutron fluence for these spallation neutrons during a standard IPF production run.

Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment.

PubMed

Khalil, Nasreen; O'Connor, Robert

2004-07-20

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary fibrotic lung disease. The diagnostic histological changes are called usual interstitial pneumonia and are characterized by histological temporal heterogeneity, whereby normal lung tissue is interspersed with interstitial fibrosis, honeycomb cysts and fibroblast foci. Pulmonary functions show restricted volumes and capacities, preserved flows and evidence of decreased gas exchange. High-resolution computed axial tomography demonstrates evidence of fibrosis and lung remodelling such as honeycomb cysts and traction bronchiectasis. There is no known effective treatment for IPF, but lung transplantation improves survival.

The UCSD Shortness of Breath Questionnaire has Longitudinal Construct Validity in Idiopathic Pulmonary Fibrosis

PubMed Central

Swigris, Jeffrey J.; Han, Meilan; Vij, Rekha; Noth, Imre; Eisenstein, Eric L.; Anstrom, Kevin J.; Brown, Kevin K.; Fairclough, Diane

2012-01-01

Background Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that often causes disabling dyspnea. In IPF and other lung diseases, patient-reported outcomes (PROs)—questionnaires designed to gather information from the patient's perspective—can determine whether therapies affect dyspnea or other outcomes meaningful to patients. Before a PRO can be used confidently as an outcome measure in a longitudinal trial, studies must demonstrate the PRO's ability to capture change over time in the target population. Our goal in this study was to examine whether the UCSD Shortness of Breath Questionnaire does so in patients with IPF. Methods We used data from the Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (STEP-IPF) to perform analyses that examined associations between UCSD scores and five external measures (anchors) at baseline and over time. Anchors included the Activity domain from St. George's Respiratory Questionnaire (SGRQ-A), the Physical Functioning domain from the SF-36 (SF36-PF), forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO), and distance walked during a timed walk test (6MWD). Linear regression models were used to examine relationships between UCSD scores and anchors over time. Results At baseline, UCSD scores were weakly correlated with percent predicted FVC (−0.21, p=0.005) and percent predicted DLCO (−0.20, p=0.008), moderately correlated with 6MWD (−0.39, p<0.0001) and strongly correlated with SGRQ-A (0.79, p<0.0001) and SF36-PF (−0.72, p<0.0001). Change over time in UCSD scores was associated with change in FVC (estimate=2.54, standard error [SE]=1.23, p=0.04), SGRQ-A (estimate=7.94, SE=1.11, p<0.0001), SF36-PF (estimate=6.00, SE=1.13, p<0.0001), and 6MWD (estimate=4.23, SE=1.18, p=0.0004) but not DLCO (estimate=0.33, SE=1.33, p=0.80). Conclusions These results support the validity of the UCSD to assess change in dyspnea over time in patients with IPF. PMID:22801586

An experimental and numerical study of the inwardly-propagating premixed flame

NASA Astrophysics Data System (ADS)

Ibarreta, Alfonso F.

Flame stretch, described as the time rate of change of the flame surface area, can cause large changes in burning velocity of laminar premixed flames. Many experimental studies have been conducted to quantify the effects of flame stretch, but most only deal with the hydrodynamic strain component of stretch rate. In this thesis, a new experimental technique was used to study the inwardly-propagating premixed flame. This flame configuration is significant because it is subjected to the curvature component of stretch rate without the competing effects of hydrodynamic strain. Inwardly-propagating premixed flames were formed using a vortex to wrinkle a flame and create a pocket of reactants. Experiments using lean propane/air mixtures were run at both one-g and microgravity conditions to optimize the formation of large pockets of reactants. Numerical simulations of the inwardly-propagating flame (IPF) and outwardly-propagating flame (OPF) were performed for lean propane/air, methane/air and hydrogen/air mixtures. Complex chemistry as well as three different one-step reaction models were employed. Markstein numbers obtained from the experiments and computations were compared to OPF experimental data available in the literature. Researchers have used different definitions of flame location and burning velocity; the effects of these differences on the Markstein number were assessed. Experimental and numerical results indicate that the Markstein numbers obtained for the IPF are typically two to three times larger than those for the OPF. It was concluded that the observed difference in Markstein number was not caused by the IPF flame-flame interaction or the presence of intermediate species. Analysis of results obtained from the one-step reaction models identified the reasons for the difference between IPFs and OPFs: (A) the thermo-diffusive mechanism, (B) the pure curvature mechanism and (C) gas expansion. The consumption speed (Sc) was found to depend only on the thermo-diffusive mechanism and to be less sensitive to the flame geometry than the displacement velocity (Su). Observed differences between IPF and OPF results lead to the conclusion that the effects of curvature and strain cannot be grouped into a single term, but two separate Markstein numbers should be defined, one for curvature and one for strain.

Quantitative CT analysis of honeycombing area in idiopathic pulmonary fibrosis: Correlations with pulmonary function tests.

PubMed

Nakagawa, Hiroaki; Nagatani, Yukihiro; Takahashi, Masashi; Ogawa, Emiko; Tho, Nguyen Van; Ryujin, Yasushi; Nagao, Taishi; Nakano, Yasutaka

2016-01-01

The 2011 official statement of idiopathic pulmonary fibrosis (IPF) mentions that the extent of honeycombing and the worsening of fibrosis on high-resolution computed tomography (HRCT) in IPF are associated with the increased risk of mortality. However, there are few reports about the quantitative computed tomography (CT) analysis of honeycombing area. In this study, we first proposed a computer-aided method for quantitative CT analysis of honeycombing area in patients with IPF. We then evaluated the correlations between honeycombing area measured by the proposed method with that estimated by radiologists or with parameters of PFTs. Chest HRCTs and pulmonary function tests (PFTs) of 36 IPF patients, who were diagnosed using HRCT alone, were retrospectively evaluated. Two thoracic radiologists independently estimated the honeycombing area as Identified Area (IA) and the percentage of honeycombing area to total lung area as Percent Area (PA) on 3 axial CT slices for each patient. We also developed a computer-aided method to measure the honeycombing area on CT images of those patients. The total honeycombing area as CT honeycombing area (HA) and the percentage of honeycombing area to total lung area as CT %honeycombing area (%HA) were derived from the computer-aided method for each patient. HA derived from three CT slices was significantly correlated with IA (ρ=0.65 for Radiologist 1 and ρ=0.68 for Radiologist 2). %HA derived from three CT slices was also significantly correlated with PA (ρ=0.68 for Radiologist 1 and ρ=0.70 for Radiologist 2). HA and %HA derived from all CT slices were significantly correlated with FVC (%pred.), DLCO (%pred.), and the composite physiologic index (CPI) (HA: ρ=-0.43, ρ=-0.56, ρ=0.63 and %HA: ρ=-0.60, ρ=-0.49, ρ=0.69, respectively). The honeycombing area measured by the proposed computer-aided method was correlated with that estimated by expert radiologists and with parameters of PFTs. This quantitative CT analysis of honeycombing area may be useful and reliable in patients with IPF. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Increased blood carboxyhaemoglobin concentrations in inflammatory pulmonary diseases

PubMed Central

Yasuda, H; Yamaya, M; Yanai, M; Ohrui, T; Sasaki, H

2002-01-01

Background: Exhaled carbon monoxide has been reported to increase in inflammatory pulmonary diseases and to be correlated with blood carboxyhaemoglobin (Hb-CO) concentration. A study was undertaken to determine whether arterial blood Hb-CO increases in patients with inflammatory pulmonary diseases. Methods: The Hb-CO concentration in arterial blood was measured with a spectrophotometer in 34 normal control subjects, 24 patients with bronchial asthma, 52 patients with pneumonia, and 21 patients with idiopathic pulmonary fibrosis (IPF). Results: The mean (SE) Hb-CO concentrations in patients with bronchial asthma during exacerbations (n=24, 1.05 (0.05)%), with pneumonia at the onset of illness (n=52, 1.08 (0.06)%), and with IPF (n=21, 1.03 (0.09)%) were significantly higher than those in control subjects (n=34, 0.60 (0.07)%) (mean difference 0.45% (95% confidence interval (CI) 0.23 to 0.67), p<0.01 in patients with bronchial asthma, mean difference 0.48% (95% CI 0.35 to 0.60), p<0.0001 in patients with pneumonia, and mean difference 0.43% (95% CI 0.26 to 0.61) p<0.001 in patients with IPF). In 20 patients with bronchial asthma the Hb-CO concentration decreased after 3 weeks of treatment with oral glucocorticoids (p<0.001). In 20 patients with pneumonia the Hb-CO concentration had decreased after 3 weeks when patients showed evidence of clinical improvement (p<0.001). The values of C-reactive protein (CRP), an acute phase protein, correlated with Hb-CO concentrations in patients with pneumonia (r=0.74, p<0.0001) and in those with IPF (r=0.46, p<0.01). In patients with bronchial asthma changes in Hb-CO concentrations were significantly correlated with those in forced expiratory volume in 1 second (FEV1) after 3 weeks (r=0.67, p<0.01). Exhaled carbon monoxide (CO) concentrations were correlated with Hb-CO concentrations (n=33, r=0.80, p<0.0001). Conclusions: Hb-CO concentrations are increased in inflammatory pulmonary diseases including bronchial asthma, pneumonia, and IPF. Measurement of arterial Hb-CO may be a useful means of monitoring pulmonary inflammation. PMID:12200522

Effect of statins on disease-related outcomes in patients with idiopathic pulmonary fibrosis.

PubMed

Kreuter, Michael; Bonella, Francesco; Maher, Toby M; Costabel, Ulrich; Spagnolo, Paolo; Weycker, Derek; Kirchgaessler, Klaus-Uwe; Kolb, Martin

2017-02-01

Data are conflicting regarding the possible effects of statins in patients with idiopathic pulmonary fibrosis (IPF). This post hoc analysis assessed the effects of statin therapy on disease-related outcomes in IPF. Patients randomised to placebo (n=624) in three controlled trials of pirfenidone in IPF (CAPACITY 004 and 006, ASCEND) were categorised by baseline statin use. Outcomes assessed during the 1-year follow-up included disease progression, mortality, hospitalisation and composite outcomes of death or ≥10% absolute decline in FVC and death or ≥50 m decline in 6-minute walk distance (6MWD). At baseline, 276 (44%) patients were statin users versus 348 (56%) non-users. Baseline characteristics were similar between groups, except statin users were older and had higher prevalence of cardiovascular disease and risk factors. In multivariate analyses adjusting for differences in baseline characteristics, statin users had lower risks of death or 6MWD decline (HR 0.69; 95% CI 0.48 to 0.99, p=0.0465), all-cause hospitalisation (HR 0.58; 95% CI 0.35 to 0.94, p=0.0289), respiratory-related hospitalisation (HR 0.44; 95% CI 0.25 to 0.80, p=0.0063) and IPF-related mortality (HR 0.36; 95% CI 0.14 to 0.95, p=0.0393) versus non-users. Non-significant treatment effects favouring statin use were observed for disease progression (HR 0.75; 95% CI 0.52 to 1.07, p=0.1135), all-cause mortality (HR 0.54; 95% CI 0.24 to 1.21, p=0.1369) and death or FVC decline (HR 0.71; 95% CI 0.48 to 1.07, p=0.1032). This post hoc analysis supports the hypothesis that statins may have a beneficial effect on clinical outcomes in IPF. Prospective clinical trials are required to validate these observations. NCT01366209, NCT00287729 and NCT00287716. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Dynamic patient counseling: a novel concept in idiopathic pulmonary fibrosis.

PubMed

Brown, A Whitney; Shlobin, Oksana A; Weir, Nargues; Albano, Maria C; Ahmad, Shahzad; Smith, Mary; Leslie, Kevin; Nathan, Steven D

2012-10-01

The characteristics of long-term survivors with idiopathic pulmonary fibrosis (IPF) have never been fully elucidated. We sought to illustrate the attenuated mortality and describe the characteristics of patients with IPF who survived at least 5 years beyond their initial presentation. Patients with IPF evaluated between 1997 and 2006 were identified through the clinic database. Patients who survived beyond 5 years from the time of their evaluation were compared with those who died or underwent lung transplantation within 5 years. Survival analyses were performed from the time of initial evaluation and contingent on annualized survival thereafter. Eighty-seven patients who survived at least 5 years formed the comparator group to whom other patients were contrasted. These patients had a higher BMI, FVC % predicted, FEV1 % predicted, total lung capacity % predicted, and diffusing capacity of lung for carbon monoxide % predicted, but a lower FEV1/FVC ratio and lower mean pulmonary artery pressures. More than one-half of these patients had moderate or severe disease at the time of presentation. Our annualized contingent survival analyses revealed a progressively increasing median survival dependent on the duration of the disease. Although we were able to demonstrate differences in our 5-year survivors, rather than being a distinct group, these patients appear to exist within a continuum of improving survival dependent on prior disease duration. This progressively improving time-dependent prognosis mandates the serial reevaluation of an individual patient’s projected outcomes. The implementation of dynamic counseling is an important concept in more accurately predicting life expectancy for patients with IPF who are frequently haunted by the prospects of a dismal survival.

Current Australasian practice for diagnosis and management of idiopathic pulmonary fibrosis: Where are we now?

PubMed

Troy, Lauren K; Chapman, Sally A; Lake, Fiona; Wilsher, Margaret L; Honeysett, Liarna B; Macansh, Sacha; Corte, Tamera J

2015-05-01

Recent international consensus statements have refined evidence-based guidelines for the diagnosis and management of idiopathic pulmonary fibrosis (IPF). This study sought to investigate how closely these guidelines are adhered to and to compare current practices with those of a similar cohort 15 years ago. A questionnaire on IPF diagnosis and management was distributed to respiratory physicians practising in Australia and New Zealand, in 2012-2013, and results were compared with a similar survey conducted in 1999. A total of 172 and 144 questionnaires were completed in 1999 and 2012-2013, respectively. The most important investigations in both survey populations were high-resolution computed tomography scans, spirometry, diffusing capacity for carbon monoxide, chest X-ray, static lung volumes and autoimmune serology. In 1999, physicians were more likely to perform arterial blood gases, bronchoalveolar lavage and transbronchial lung biopsy. In the 2012-2013 cohort, 6-min walk tests and pulse oximetry were more widely utilized. Treatment choices differed considerably between the two survey populations. In 1999, the majority would offer a steroid-based regimen, whereas most would not use any specific treatment or would refer for trial participation in 2012-2013. Approach to IPF diagnosis and management is not uniform and has changed over 15 years. Surveyed respiratory physicians were generally practising in accordance with clinical guidelines, although significant variation in practice was identified in both cohorts. This study identifies the need to standardize care of IPF patients across Australia and New Zealand. © 2015 Asian Pacific Society of Respirology.

Comprehensive assessment of the long-term safety of pirfenidone in patients with idiopathic pulmonary fibrosis.

PubMed

Valeyre, Dominique; Albera, Carlo; Bradford, Williamson Z; Costabel, Ulrich; King, Talmadge E; Leff, Jonathan A; Noble, Paul W; Sahn, Steven A; du Bois, Roland M

2014-07-01

Pirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis (IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF. All patients receiving pirfenidone 2403 mg/day in the Phase 3 CAPACITY studies (Studies 004 and 006) and all patients receiving at least one dose of pirfenidone in one of two ongoing open-label studies in patients with IPF (Studies 002 and 012) were selected for inclusion. Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug. A total of 789 patients were included in the analysis. The median duration of exposure to pirfenidone was 2.6 years (range, 1 week-7.7 years), and the cumulative total exposure was 2059 person exposure years (PEY). Gastrointestinal and skin-related events were the most commonly reported adverse events; these were almost always mild to moderate in severity, and rarely led to treatment discontinuation. Elevations (>3× upper limit of normal) in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY. This comprehensive analysis of safety in a large cohort of IPF patients receiving pirfenidone for a total of 2059 PEY demonstrates that long-term treatment with pirfenidone is safe and generally well tolerated. © 2014 The Authors. Respirology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Respirology.

The purinergic receptor subtype P2Y2 mediates chemotaxis of neutrophils and fibroblasts in fibrotic lung disease

PubMed Central

Karmouty-Quintana, Harry; Cicko, Sanja; Ayata, Korcan; Zissel, Gernot; Goldmann, Torsten; Lungarella, Giuseppe; Ferrari, Davide; Di Virgilio, Francesco; Robaye, Bernard; Boeynaems, Jean-Marie; Blackburn, Michael R.; Idzko, Marco

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with few available treatment options. Recently, the involvement of purinergic receptor subtypes in the pathogenesis of different lung diseases has been demonstrated. Here we investigated the role of the purinergic receptor subtype P2Y2 in the context of fibrotic lung diseases. The concentration of different nucleotides was measured in the broncho-alveolar lavage (BAL) fluid derived from IPF patients and animals with bleomycin-induced pulmonary fibrosis. In addition expression of P2Y2 receptors by different cell types was determined. To investigate the functional relevance of P2Y2 receptors for the pathogenesis of the disease the bleomycin model of pulmonary fibrosis was used. Finally, experiments were performed in pursuit of the involved mechanisms. Compared to healthy individuals or vehicle treated animals, extracellular nucleotide levels in the BAL fluid were increased in patients with IPF and in mice after bleomycin administration, paralleled by a functional up-regulation of P2Y2R expression. Both bleomycin-induced inflammation and fibrosis were reduced in P2Y2R-deficient compared to wild type animals. Mechanistic studies demonstrated that recruitment of neutrophils into the lungs, proliferation and migration of lung fibroblasts as well as IL6 production are key P2Y2R mediated processes. Our results clearly demonstrate the involvement of P2Y2R subtypes in the pathogenesis of fibrotic lung diseases in humans and mice and hence support the development of selective P2Y2R antagonists for the treatment of IPF. PMID:28415591

Utility of the immature platelet fraction in pediatric immune thrombocytopenia: Differentiating from bone marrow failure and predicting bleeding risk.

PubMed

McDonnell, Alicia; Bride, Karen L; Lim, Derick; Paessler, Michele; Witmer, Char M; Lambert, Michele P

2018-02-01

Differentiating childhood immune thrombocytopenia (ITP) from other cause of thrombocytopenia remains a diagnosis of exclusion. Additionally factors that predict bleeding risk for those patients with ITP are currently not well understood. Previous small studies have suggested that immature platelet fraction (IPF) may differentiate ITP from other causes of thrombocytopenia and in combination with other factors may predict bleeding risk. We performed a retrospective chart review of thrombocytopenic patients with an IPF measured between November 1, 2013 and July 1, 2015. Patients were between 2 months and 21 years of age with a platelet count <50 × 10 9 /l. Each patient chart was reviewed for final diagnosis and bleeding symptoms. A bleeding severity score was retrospectively assigned. Two hundred seventy two patients met inclusion criteria, 97 with ITP, 11 with bone marrow failure (BMF), 126 with malignancy, and 38 with other causes of thrombocytopenia. An IPF > 5.2% differentiated ITP from BMF with 93% sensitivity and 91% specificity. Absolute immature platelet number (AIPN) was significantly lower in ITP patients with severe to life-threatening hemorrhage than those without, despite similar platelet counts. On multivariate analysis, an IPF < 10.4% was confirmed as an independent predictor of bleeding risk at platelet counts <10 × 10 9 /l in patients with ITP. IPF measurement alone has utility in both the diagnosis of ITP and identifying patients at increased risk of hemorrhage. Further study is required to understand the pathophysiological differences of ITP patients with lower IPF/AIPN. © 2017 Wiley Periodicals, Inc.

Commissioning and initial operation of the Isotope Production Facility at the Los Alamos Neutron Science Center (LANSCE).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, K. F.; Alvestad, H. W.; Barkley, W. C.

The recently completed 100-MeV H{sup +} Isotope Production Facility (IPF) at the LANSCE will provide radioisotopes for medical research and diagnosis, for basic research and for commercial use. A change to the LANSCE accelerator facility allowed for the installation of the IPF. Three components make up the LANSCE accelerator: an injector that accelerates the H{sup +} beam to 750-KeV, a drift-tube linac (DTL) that increases the beam energy to 100-MeV, and a side-coupled cavity linac (SCCL) that accelerates the beam to 800-MeV. The transition region, a space between the DTL and the SCCL, was modified to permit the insertion ofmore » a kicker magnet (23{sup o} kick angle) for the purpose of extracting a portion of the 100-MeV H{sup +} beam. A new beam line was installed to transport the extracted H{sup +} beam to the radioisotope production target chamber. This paper will describe the commissioning and initial operating experiences of IPF.« less

Molecular classification of idiopathic pulmonary fibrosis: personalized medicine, genetics and biomarkers.

PubMed

Hambly, Nathan; Shimbori, Chiko; Kolb, Martin

2015-10-01

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease associated with high morbidity and poor survival. Characterized by substantial disease heterogeneity, the diagnostic considerations, clinical course and treatment response in individual patients can be variable. In the past decade, with the advent of high-throughput proteomic and genomic technologies, our understanding of the pathogenesis of IPF has greatly improved and has led to the recognition of novel treatment targets and numerous putative biomarkers. Molecular biomarkers with mechanistic plausibility are highly desired in IPF, where they have the potential to accelerate drug development, facilitate early detection in susceptible individuals, improve prognostic accuracy and inform treatment recommendations. Although the search for candidate biomarkers remains in its infancy, attractive targets such as MUC5B and MPP7 have already been validated in large cohorts and have demonstrated their potential to improve clinical predictors beyond that of routine clinical practices. The discovery and implementation of future biomarkers will face many challenges, but with strong collaborative efforts among scientists, clinicians and the industry the ultimate goal of personalized medicine may be realized. © 2015 Asian Pacific Society of Respirology.

The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis

PubMed Central

Desai, Omkar; Winkler, Julia; Minasyan, Maksym; Herzog, Erica L.

2018-01-01

The contribution of the immune system to idiopathic pulmonary fibrosis (IPF) remains poorly understood. While most sources agree that IPF does not result from a primary immunopathogenic mechanism, evidence gleaned from animal modeling and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. This review will synthesize the available data regarding the complex role of professional immune cells in IPF. The role of innate immune populations such as monocytes, macrophages, myeloid suppressor cells, and innate lymphoid cells will be discussed, as will the activation of these cells via pathogen-associated molecular patterns derived from invading or commensural microbes, and danger-associated molecular patterns derived from injured cells and tissues. The contribution of adaptive immune responses driven by T-helper cells and B cells will be reviewed as well. Each form of immune activation will be discussed in the context of its relationship to environmental and genetic factors, disease outcomes, and potential therapies. We conclude with discussion of unanswered questions and opportunities for future study in this area. PMID:29616220

Temporally consistent segmentation of point clouds

NASA Astrophysics Data System (ADS)

Owens, Jason L.; Osteen, Philip R.; Daniilidis, Kostas

2014-06-01

We consider the problem of generating temporally consistent point cloud segmentations from streaming RGB-D data, where every incoming frame extends existing labels to new points or contributes new labels while maintaining the labels for pre-existing segments. Our approach generates an over-segmentation based on voxel cloud connectivity, where a modified k-means algorithm selects supervoxel seeds and associates similar neighboring voxels to form segments. Given the data stream from a potentially mobile sensor, we solve for the camera transformation between consecutive frames using a joint optimization over point correspondences and image appearance. The aligned point cloud may then be integrated into a consistent model coordinate frame. Previously labeled points are used to mask incoming points from the new frame, while new and previous boundary points extend the existing segmentation. We evaluate the algorithm on newly-generated RGB-D datasets.

Estimated spectrum adaptive postfilter and the iterative prepost filtering algirighms

NASA Technical Reports Server (NTRS)

Linares, Irving (Inventor)

2004-01-01

The invention presents The Estimated Spectrum Adaptive Postfilter (ESAP) and the Iterative Prepost Filter (IPF) algorithms. These algorithms model a number of image-adaptive post-filtering and pre-post filtering methods. They are designed to minimize Discrete Cosine Transform (DCT) blocking distortion caused when images are highly compressed with the Joint Photographic Expert Group (JPEG) standard. The ESAP and the IPF techniques of the present invention minimize the mean square error (MSE) to improve the objective and subjective quality of low-bit-rate JPEG gray-scale images while simultaneously enhancing perceptual visual quality with respect to baseline JPEG images.

High-frequency video capture and a computer program with frame-by-frame angle determination functionality as tools that support judging in artistic gymnastics.

PubMed

Omorczyk, Jarosław; Nosiadek, Leszek; Ambroży, Tadeusz; Nosiadek, Andrzej

2015-01-01

The main aim of this study was to verify the usefulness of selected simple methods of recording and fast biomechanical analysis performed by judges of artistic gymnastics in assessing a gymnast's movement technique. The study participants comprised six artistic gymnastics judges, who assessed back handsprings using two methods: a real-time observation method and a frame-by-frame video analysis method. They also determined flexion angles of knee and hip joints using the computer program. In the case of the real-time observation method, the judges gave a total of 5.8 error points with an arithmetic mean of 0.16 points for the flexion of the knee joints. In the high-speed video analysis method, the total amounted to 8.6 error points and the mean value amounted to 0.24 error points. For the excessive flexion of hip joints, the sum of the error values was 2.2 error points and the arithmetic mean was 0.06 error points during real-time observation. The sum obtained using frame-by-frame analysis method equaled 10.8 and the mean equaled 0.30 error points. Error values obtained through the frame-by-frame video analysis of movement technique were higher than those obtained through the real-time observation method. The judges were able to indicate the number of the frame in which the maximal joint flexion occurred with good accuracy. Using the real-time observation method as well as the high-speed video analysis performed without determining the exact angle for assessing movement technique were found to be insufficient tools for improving the quality of judging.

A comparison of health-related quality of life in idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis.

PubMed

Lubin, Molly; Chen, Hubert; Elicker, Brett; Jones, Kirk D; Collard, Harold R; Lee, Joyce S

2014-06-01

Patients with interstitial lung disease (ILD) have poor health-related quality of life (HRQL). However, whether HRQL differs among different subtypes of ILD is unclear. The aim of this study was to determine whether HRQL was different among patients with idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (CHP). We identified patients from an ongoing longitudinal cohort of patients with ILD. HRQL was assessed using the Short Form (SF)-36 medical outcomes form (version 2.0). Regression analysis was used to determine the association between clinical covariates and HRQL, primarily the physical component summary (PCS) and mental component summary (MCS) score. A multivariate regression model was created to identify potential covariates that could help explain the association between the ILD subtype and HRQL. Patients with IPF (n = 102) were older, more likely to be men, and more likely to have smoked. Pulmonary function was similar between the groups. The patients with CHP (n = 69) had worse HRQL across all eight domains of the SF-36, as well as the PCS and MCS, compared with patients with IPF (P < .01-.09). This pattern remained after controlling for age and pulmonary function (P < .01-.02). Covariates explaining part of the relationship between disease subtype and PCS score included severity of dyspnea (P < .01) and fatigue (P < .01). Covariates explaining part of the relationship between disease subtype and MCS score included severity of dyspnea (P < .01), female sex (P = .02), and fatigue (P = .02). HRQL is worse in CHP compared with IPF. HRQL differences between ILD subtypes are explained in part by differences in sex, dyspnea, and fatigue.

Modelling the isometric force response to multiple pulse stimuli in locust skeletal muscle.

PubMed

Wilson, Emma; Rustighi, Emiliano; Mace, Brian R; Newland, Philip L

2011-02-01

An improved model of locust skeletal muscle will inform on the general behaviour of invertebrate and mammalian muscle with the eventual aim of improving biomedical models of human muscles, embracing prosthetic construction and muscle therapy. In this article, the isometric response of the locust hind leg extensor muscle to input pulse trains is investigated. Experimental data was collected by stimulating the muscle directly and measuring the force at the tibia. The responses to constant frequency stimulus trains of various frequencies and number of pulses were decomposed into the response to each individual stimulus. Each individual pulse response was then fitted to a model, it being assumed that the response to each pulse could be approximated as an impulse response and was linear, no assumption were made about the model order. When the interpulse frequency (IPF) was low and the number of pulses in the train small, a second-order model provided a good fit to each pulse. For moderate IPF or for long pulse trains a linear third-order model provided a better fit to the response to each pulse. The fit using a second-order model deteriorated with increasing IPF. When the input comprised higher IPFs with a large number of pulses the assumptions that the response was linear could not be confirmed. A generalised model is also presented. This model is second-order, and contains two nonlinear terms. The model is able to capture the force response to a range of inputs. This includes cases where the input comprised of higher frequency pulse trains and the assumption of quasi-linear behaviour could not be confirmed.

Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study.

PubMed

Okuda, Ryo; Matsushima, Hidekazu; Oba, Tomohiro; Kawabe, Rie; Matsubayashi, Minako; Amano, Masako; Nishizawa, Tomotaka; Honda, Koujiro

2016-05-01

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. The efficacy of N-acetylcysteine in patients with IPF remains controversial. The aim of this research was to investigate the efficacy of inhaled N-acetylcysteine. This study was designed as a single-center, single-arm, prospective clinical trial. Each patient who had IPF received 352.4mg of inhaled N-acetylcysteine twice daily. In total, 28 patients were enrolled. The mean values of the respiratory function parameters at the initiation of therapy were as follows: forced vital capacity (FVC), 2.27L and %FVC, 76.2%. The mean change in FVC during 26 weeks prior to the inhaled N-acetylcysteine therapy was -170mL, a significant decrease (p=0.019). The mean change in FVC during 26 weeks after the initiation of inhaled N-acetylcysteine therapy was -70mL (p=0.06). When the patients were classified into two groups according to the degree of decline in FVC (≥100mL vs. <100mL) during the 26-week period prior to the initiation of therapy, inhaled N-acetylcysteine showed a greater efficacy in attenuating FVC decline in the ≥100-mL group than in the <100-mL group. Inhaled N-acetylcysteine therapy was effective in patients with mild-to-moderate IPF and was more beneficial in patients who had greater declines in FVC before the initiation of therapy. (UMIN title: Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis, UMIN000016706, 2015/03/04.). Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Heart rate recovery after six-minute walk test predicts pulmonary hypertension in patients with idiopathic pulmonary fibrosis.

PubMed

Swigris, Jeffrey J; Olson, Amy L; Shlobin, Oksana A; Ahmad, Shahzad; Brown, Kevin K; Nathan, Steven D

2011-04-01

In patients with IPF, we sought to validate that abnormal heart rate recovery at 1 min (HRR1) after six-minute walk test (6MWT) predicts mortality and to explore the relationship between abnormal HRR1 and pulmonary hypertension (PH). We identified IPF patients who performed a 6MWT as part of their clinical evaluation between 2006 and 2009 and were followed to lung transplantation or death. Right heart catheterization (RHC) data were collated and analysed for the subgroup who had this procedure. There were 160 subjects who qualified for the survival analysis, and those with an abnormal HRR1 had worse survival than subjects with normal HRR1 (log-rank P = 0.01). Eighty-two subjects had a right heart catheter (RHC); among them, abnormal HRR1 was associated with RHC-confirmed PH (χ(2) = 4.83, P = 0.03) and had a sensitivity, specificity, positive predictive value and negative predictive value of 52%, 74%, 41% and 82%, respectively, for PH. In bivariate and multivariable analyses, abnormal HRR1 appeared to be the strongest predictor of RHC-confirmed PH (odds ratio (OR) = 4.0, 95% CI: 1.17-13.69, P = 0.02 in the multivariable analysis). This study adds to data that support the validity of abnormal HRR1 as a predictor of mortality and of RHC-confirmed PH in IPF. Research is needed to further investigate the link between abnormal HRR1 and PH and to elucidate heart-lung interactions at work during exercise and recovery in patients with IPF. © 2011 The Authors. Respirology © 2011 Asian Pacific Society of Respirology.

Lactic Acid is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation Via pH-Dependent Activation of Transforming Growth Factor-β

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kottman, R. M.; Kulkarni, Ajit A.; Smolnycki, Katie A.

2012-10-15

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF. Objectives: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. Methods:We used metabolomic analysis to examine cellular metabolism in lung tissuefrom patients with IPFanddeterminedthe effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-b activation in vitro. Measurements and Main Results: Lactic acid concentrations from healthy and IPF lung tissue weremore » determined by nuclear magnetic resonance spectroscopy; a-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-b. TGF-b induced expression of LDH5 via hypoxia-inducible factor 1a (HIF1a). Importantly, overexpression of both HIF1a and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low dose TGF-b to induce differentiation. Furthermore, inhibition of both HIF1a and LDH5 inhibited TGF-b–induced myofibroblast differentiation. Conclusions: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pHdependent activation of TGF-b. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.« less

Open lung biopsy performed in idiopathic pulmonary fibrosis is a safe procedure

PubMed Central

Halman, Joanna; Taniewska, Sonia; Burzyńska, Natalia; Piekarska, Anna; Sawicka, Wioletta

2017-01-01

Introduction Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a fatal prognosis. The diagnosis is made on the basis of high-resolution computed tomography and histological examination in selected cases. Aim To determine the risk of complications of open lung biopsy performed in patients with IPF. Material and methods We performed a retrospective analysis of 51 patients who underwent diagnostic excision of pulmonary parenchyma due to IPF in the period 1995–2014. We assessed the complication rate, length of drainage, postoperative period and 30-day mortality. We compared the results of treatment in the groups of patients operated on with thoracotomy and videothoracoscopy. Results The mean age of patients was 58 (47% female, 53% male) forced vital capacity (FVC) was 81%, forced expiratory volume in 1 s (FEV1) was 80% and body mass index (BMI) was 27 kg/m2. Thoracotomies (lateral, muscle sparing or anterior) were performed in 20 patients between 1995 and 2012 and videothoracoscopy in 31 patients operated on in the years 2009–2014. Patients in study groups did not differ considering age (p = 0.40), gender (p = 0.81), FVC (p = 0.08), FEV1 (p = 0.13) or BMI (p = 0.75). Postoperative complications occurred in 3.9% of patients (atrial arrhythmia 1.9% and recurrent pneumothorax 1.9%) with equal incidence in both study groups (p = 0.75). Median stay after thoracotomy was 4 days while after videothoracoscopy it was 3 days (p = 0.04). Conclusions Open lung biopsy performed on patients with IPF is a safe procedure. Open lung biopsy performed through thoracotomy could be as safe as through VATS, however is characterized by longer postoperative stay. PMID:29354175

Translation to Spanish and Validation of the Specific Saint George's Questionnaire for Idiopathic Pulmonary Fibrosis.

PubMed

Capparelli, Ignacio; Fernandez, Martín; Saadia Otero, Marcela; Steimberg, Jimena; Brassesco, María; Campobasso, Ana; Palacios, Sandra; Caro, Fabian; Alberti, María Laura; Rabinovich, Roberto A; Paulin, Francisco

2018-02-01

Interstitial lung disease (ILD) is associated with low exercise tolerance, dyspnea, and decreased health-related quality of life (HRQL). Idiopathic pulmonary fibrosis (IPF) is one of the most prevalent in the group. A specific version of the Saint George's questionnaire (SGRQ-I) has been developed to quantify the HRQL of IPF patients. However, this tool is not currently validated in the Spanish language. The objective was to translate into Spanish and validate the specific Saint George's Respiratory Questionnaire for idiopathic pulmonary fibrosis (SGRQ-I). The repeatability, internal consistency and construct validity of the SGRQ-I in Spanish were analyzed after a backtranslation process. In total, 23 outpatients with IPF completed the translated SGRQ-I twice, 7 days apart. Repeatability was studied, revealing good concordance in test-retest with an ICC (interclass correlation coefficient) of 0.96 (P<.001). Internal consistency was good for different questionnaire items (Cronbach's alpha of 0.9 including and 0.81 excluding the total value) (P<.001). The total score of the questionnaire showed good correlation with forced vital capacity FVC% (r=-0.44; P=.033), diffusing capacity of the lungs for carbon monoxide (DL CO %) (r=-0.55; P=.011), partial pressure of oxygen in arterial blood PaO 2 (r=-0.44; P=.036), Medical Research Council Dyspnea scale (r=-0.65; P<.001), and number of steps taken in 24hours (r=-0.47; P=.024). The Spanish version of SGRQ-Ideveloped by our group shows good internal consistency, reproducibility and validity, so it can be used for the evaluation of quality of life (QOL) in IPF patients. Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

The effect of bronchodilators on forced vital capacity measurement in patients with idiopathic pulmonary fibrosis

PubMed Central

Assayag, Deborah; Vittinghoff, Eric; Ryerson, Christopher J.; Cocconcelli, Elisabetta; Tonelli, Roberto; Hu, Xiaowen; Elicker, Brett M.; Golden, Jeffrey A.; Jones, Kirk D.; King, Talmadge E.; Koth, Laura L.; Lee, Joyce S.; Ley, Brett; Shum, Anthony K.; Wolters, Paul J.; Ryu, Jay H.; Collard, Harold R.

2015-01-01

Background Forced vital capacity (FVC) is a key measure of disease severity in patients with idiopathic pulmonary fibrosis (IPF) and is an important clinical trial endpoint. We hypothesize that reversible airflow limitation co-exists in a subgroup of patients with IPF, and that bronchodilator use will improve the performance characteristics of FVC. Methods IPF patients with pre and post-bronchodilator spirometry testing performed were identified from two tertiary referral cohorts. The difference between pre and post-bronchodilator FVC (intra-test difference) was calculated. The test characteristics of pre and post-bronchodilator FVC change over time (inter-test difference) were assessed in patients with sequential spirometry, and were used to generate sample size estimates for hypothetical clinical trials using change in FVC as the primary endpoint. Results There were 551 patients, contributing 967 unique spirometry tests. The mean intra-test increase in FVC with bronchodilator use was 0.04 liters (2.71 vs. 2.75 liters, p <0.001). Reversible airflow limitation (increase in FEV1 or FVC of ≥12% and ≥200 milliliters) occurred in 9.1% of patients. The inter-test difference in change in FVC over time were equivalent for pre and post-bronchodilator (p = 0.65), leading to similar sample size estimates in a hypothetical clinical trial using change in FVC as the primary endpoint. Conclusion Approximately one in ten patients with IPF has physiological evidence of reversible airflow limitation, and bronchodilator use in these patients may improve the assessment of disease progression based on FVC change over time. Bronchodilator use does not appear to meaningfully impact the precision of FVC as an endpoint in clinical trials. PMID:26140806

Safety and efficacy of pirfenidone in idiopathic pulmonary fibrosis in clinical practice.

PubMed

Okuda, Ryo; Hagiwara, Eri; Baba, Tomohisa; Kitamura, Hideya; Kato, Terufumi; Ogura, Takashi

2013-09-01

Previous pirfenidone trials have only involved patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the safety and efficacy of pirfenidone in patients with mild-to-severe IPF in clinical practice. The clinical records of 76 patients who were diagnosed with IPF and received pirfenidone were reviewed. The most frequent adverse event was anorexia, although the grade of anorexia in most patients was mild. Dose reduction of pirfenidone improved anorexia in 84% affected patients, which resulted in a high medication compliance rate. The mean forced vital capacity (FVC) at the initiation of pirfenidone therapy in this study was approximately 10% lower than that in previous clinical trials. The mean change in FVC during the 6-month period prior to the therapy initiation was -188 mL, which improved to -19 mL during the 6-month period after therapy. Significant attenuation in percentage predicted diffusion capacity of the lung for carbon monoxide decline was also achieved after pirfenidone therapy initiation. The efficacy of pirfenidone in attenuating the degree of FVC decline was higher in the group with FVC decline of ≥150 mL during the 6-month period prior to therapy initiation. The levels of serum markers, such as KL-6 and SP-D, were also lowered by the therapy. These results showed that pirfenidone was well-tolerated and had beneficial effects in patients with mild-to-severe and/or progressive IPF. The degree of disease progression prior to the initiation of pirfenidone therapy had an impact on the response to the therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Nintedanib with Add-on Pirfenidone in Idiopathic Pulmonary Fibrosis. Results of the INJOURNEY Trial.

PubMed

Vancheri, Carlo; Kreuter, Michael; Richeldi, Luca; Ryerson, Christopher J; Valeyre, Dominique; Grutters, Jan C; Wiebe, Sabrina; Stansen, Wibke; Quaresma, Manuel; Stowasser, Susanne; Wuyts, Wim A

2018-02-01

Nintedanib and pirfenidone slow the progression of idiopathic pulmonary fibrosis (IPF), but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with nintedanib and add-on pirfenidone. To investigate safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in patients treated with nintedanib and add-on pirfenidone versus nintedanib alone. Patients with IPF and FVC greater than or equal to 50% predicted at screening who completed a 4- to 5-week run-in with nintedanib 150 mg twice daily without dose reduction or treatment interruption were randomized to receive nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times daily) or nintedanib 150 mg twice daily alone in an open-label manner for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to Week 12. Analyses were descriptive and exploratory. On-treatment gastrointestinal adverse events were reported in 37 of 53 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 of 51 patients (52.9%) treated with nintedanib alone. Predose plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone. Mean (SE) changes from baseline in FVC at Week 12 were -13.3 (17.4) ml and -40.9 (31.4) ml in patients treated with nintedanib with add-on pirfenidone (n = 48) and nintedanib alone (n = 44), respectively. Nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF, in line with the adverse event profiles of each drug. These data support further research into combination regimens in the treatment of IPF. Clinical trial registered with www.clinicaltrials.gov (NCT02579603).

Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis.

PubMed

Tominaga, Masaki; Okamoto, Masaki; Kawayama, Tomotaka; Matsuoka, Masanobu; Kaieda, Shinjiro; Sakazaki, Yuki; Kinoshita, Takashi; Mori, Daisuke; Inoue, Akira; Hoshino, Tomoaki

2017-09-01

Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

P2Y6 Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis

PubMed Central

Müller, Tobias; Fay, Susanne; Vieira, Rodolfo Paula; Karmouty-Quintana, Harry; Cicko, Sanja; Ayata, Cemil Korcan; Zissel, Gernot; Goldmann, Torsten; Lungarella, Giuseppe; Ferrari, Davide; Di Virgilio, Francesco; Robaye, Bernard; Boeynaems, Jean-Marie; Lazarowski, Eduardo R.; Blackburn, Michael R.; Idzko, Marco

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL) cells derived from IPF patients as well as in animals following bleomycin administration. Furthermore, BAL fluid levels of the P2Y6R agonist uridine-5′-diphosphate were elevated in animals with bleomycin-induced pulmonary fibrosis. Inflammation and fibrosis following bleomycin administration were reduced in P2Y6R-deficient compared to wild-type animals confirming the pathophysiological relevance of P2Y6R subtypes for fibrotic lung diseases. Experiments with bone marrow chimeras revealed the importance of P2Y6R expression on lung structural cells for pulmonary inflammation and fibrosis. Similar effects were obtained when animals were treated with the P2Y6R antagonist MRS2578. In vitro studies demonstrated that proliferation and secretion of the pro-inflammatory/pro-fibrotic cytokine IL-6 by lung fibroblasts are P2Y6R-mediated processes. In summary, our results clearly demonstrate the involvement of P2Y6R subtypes in the pathogenesis of pulmonary fibrosis. Thus, blocking pulmonary P2Y6 receptors might be a new target for the treatment of IPF. PMID:28878780

Arterial Carboxyhemoglobin Measurement Is Useful for Evaluating Pulmonary Inflammation in Subjects with Interstitial Lung Disease.

PubMed

Hara, Yu; Shinkai, Masaharu; Kanoh, Soichiro; Fujikura, Yuji; K Rubin, Bruce; Kawana, Akihiko; Kaneko, Takeshi

2017-01-01

Objective The arterial concentration of carboxyhemoglobin (CO-Hb) in subjects with inflammatory pulmonary disease is higher than that in healthy individuals. We retrospectively analyzed the relationship between the CO-Hb concentration and established markers of disease severity in subjects with interstitial lung disease (ILD). Methods The CO-Hb concentration was measured in subjects with newly diagnosed or untreated ILD and the relationships between the CO-Hb concentration and the serum biomarker levels, lung function, high-resolution CT (HRCT) findings, and the uptake in gallium-67 ( 67 Ga) scintigraphy were evaluated. Results Eighty-one non-smoking subjects were studied (mean age, 67 years). Among these subjects, (A) 17 had stable idiopathic pulmonary fibrosis (IPF), (B) 9 had an acute exacerbation of IPF, (C) 44 had stable non-IPF, and (D) 11 had an exacerbation of non-IPF. The CO-Hb concentrations of these subjects were (A) 1.5±0.5%, (B) 2.1±0.5%, (C) 1.2±0.4%, and (D) 1.7±0.5%. The CO-Hb concentration was positively correlated with the serum levels of surfactant protein (SP)-A (r=0.38), SP-D (r=0.39), and the inflammation index (calculated from HRCT; r=0.57) and was negatively correlated with the partial pressure of oxygen in the arterial blood (r=-0.56) and the predicted diffusion capacity of carbon monoxide (r=-0.61). The CO-Hb concentrations in subjects with a negative heart sign on 67 Ga scintigraphy were higher than those in subjects without a negative heart sign (1.4±0.5% vs. 1.1±0.3%, p=0.018). Conclusion The CO-Hb levels of subjects with ILD were increased, particularly during an exacerbation, and were correlated with the parameters that reflect pulmonary inflammation.

Pathogenetic pathways and novel pharmacotherapeutic targets in idiopathic pulmonary fibrosis.

PubMed

Antoniou, Katerina M; Pataka, Athanasia; Bouros, Demosthenes; Siafakas, Nikolaos M

2007-01-01

Idiopathic pulmonary fibrosis (IPF) is a poorly understood disease that usually leads to death within 5 years of diagnosis. Despite our better understanding of IPF pathogenesis, the etiology and the precise cellular and molecular mechanisms involved are not well known. Current therapies are of unproven benefit. The aim of this review is to identify possible candidate pathways that might offer novel therapeutic targets changing the natural course of this disease. Current therapeutic approaches target at apoptosis, epithelial replacement, fibroblasts/myofibroblasts, procoagulant activity, growth factors production, angiogenesis, Th1 and Th2 cytokines and oxidative stress. Increased epithelial cells apoptosis can contribute to fibrosis, while on the other hand, decreased fibroblast or myofibroblast apoptosis promotes fibrosis. Recent findings support the notion that therapy directed at either inhibition of angiogenic or augmentation of angiostatic CXC chemokines may be a novel approach in the treatment of IPF. Additionally, there is little doubt that the development of novel therapeutic strategies for pulmonary fibrosis should target some profibrotic growth factors and key type II cytokines, such as inteleukin-13. Importantly, persistent activation of intra-alveolar procoagulant activity and subsequent abnormal fibrin turnover enhances a fibrotic response. Furthermore, increased procoagulant activity may interfere with fibrin accumulation and lack of activation of some matrix metalloproteinases responsible for an imbalance in matrix turnover. Finally, oxidative stress with increased production of oxidants in IPF is an additional mechanism proposed to explain epithelial cell apoptosis in this disease. The challenge of future targets for therapeutic intervention is to reconcile different pathogenetic pathways, and we strongly suspect that no single approach will be sufficient for a lethal disease with few therapeutic options.

Activation and overexpression of Sirt1 attenuates lung fibrosis via P300.

PubMed

Zeng, Zhilin; Cheng, Sheng; Chen, Huilong; Li, Qinghai; Hu, Yinan; Wang, Qi; Zhu, Xianying; Wang, Jun

2017-05-13

Persistent fibroblast activation is a predominant feature of idiopathic pulmonary fibrosis (IPF), but the transcriptional and epigenetic mechanisms controlling this process are not well understood. Silent information regulator type-1 (Sirt1) is a member of class Ⅲ histone deacetylase with important regulatory roles in a variety of pathophysiologic processes, but its role in fibrotic lung diseases is not clearly elucidated. Sirt1 expression in lung tissues of IPF patients and in a mouse model of bleomycin (BLM)-induced lung fibrosis were evaluated by immunofluorescence. The function of Sirt1 in BLM-induced lung fibrosis in the mouse model or transforming growth factor β1 (TGF-β1)-mediated lung fibroblast cellular model was investigated by Sirt1 activation, overexpression and knockdown of Sirt1. Finally, the involvement of p300 signaling pathways was assessed. In this study, we found up-regulation of Sirt1 in BLM-induced lung fibrosis, as well as in the lungs of IPF patients, including in the aggregated pulmonary fibroblasts of fibrotic foci. Activation or overexpression of Sirt1 attenuated TGF-β1-mediated lung fibroblast differentiation and activation and diminished the severity of experimental lung fibrosis in mice. Whereas knockdown of Sirt1 promoted the pro-fibrogenic activity of TGF-β1 in lung fibroblasts. A potential mechanism for the role of Sirt1 in lung fibrosis was through regulating the expression of p300. Thus, we characterized Sirt1 as an important regulator of lung fibrosis and provides a proof of principle for activation or overexpression of Sirt1 as a potential novel therapeutic strategy for IPF. Copyright © 2017 Elsevier Inc. All rights reserved.

Design of the INPULSIS™ trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis.

PubMed

Richeldi, Luca; Cottin, Vincent; Flaherty, Kevin R; Kolb, Martin; Inoue, Yoshikazu; Raghu, Ganesh; Taniguchi, Hiroyuki; Hansell, David M; Nicholson, Andrew G; Le Maulf, Florence; Stowasser, Susanne; Collard, Harold R

2014-07-01

Nintedanib is in clinical development as a treatment for idiopathic pulmonary fibrosis (IPF). Data from the Phase II TOMORROW study suggested that nintedanib 150 mg twice daily had clinical benefits with an acceptable safety profile. The INPULSIS™ trials are replicate Phase III, randomized, double-blind, studies comparing the efficacy and safety of nintedanib 150 mg twice daily with placebo in patients with IPF. Eligible patients were aged ≥40 years with a diagnosis of IPF within 5 years before randomization who had undergone a chest high-resolution computed tomography (HRCT) scan within 1-year before screening, and who had a forced vital capacity (FVC) of ≥50% predicted and a diffusing capacity for carbon monoxide of 30-79% predicted. Participants were randomized 3:2 to receive nintedanib or placebo for 52 weeks. The primary endpoint is the annual rate of decline in FVC. The key secondary endpoints are change from baseline in the total score on the St. George's Respiratory Questionnaire (a measure of health-related quality of life) over 52 weeks and time to first acute exacerbation. Enrolment of 1066 patients in 24 countries was completed in September 2012. Results will be reported in the first half of 2014. The INPULSIS™ trials will determine the efficacy of nintedanib in patients with IPF, including its impact on disease progression as defined by decline in FVC, acute exacerbations and health-related quality of life. In addition, they will characterise the adverse event profile of nintedanib in this patient population. Registered at ClinicalTrials.gov (identifiers: NCT01335464 and NCT01335477). Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Mars Science Laboratory Frame Manager for Centralized Frame Tree Database and Target Pointing

NASA Technical Reports Server (NTRS)

Kim, Won S.; Leger, Chris; Peters, Stephen; Carsten, Joseph; Diaz-Calderon, Antonio

2013-01-01

The FM (Frame Manager) flight software module is responsible for maintaining the frame tree database containing coordinate transforms between frames. The frame tree is a proper tree structure of directed links, consisting of surface and rover subtrees. Actual frame transforms are updated by their owner. FM updates site and saved frames for the surface tree. As the rover drives to a new area, a new site frame with an incremented site index can be created. Several clients including ARM and RSM (Remote Sensing Mast) update their related rover frames that they own. Through the onboard centralized FM frame tree database, client modules can query transforms between any two frames. Important applications include target image pointing for RSM-mounted cameras and frame-referenced arm moves. The use of frame tree eliminates cumbersome, error-prone calculations of coordinate entries for commands and thus simplifies flight operations significantly.

What a speaker's choice of frame reveals: reference points, frame selection, and framing effects.

PubMed

McKenzie, Craig R M; Nelson, Jonathan D

2003-09-01

Framing effects are well established: Listeners' preferences depend on how outcomes are described to them, or framed. Less well understood is what determines how speakers choose frames. Two experiments revealed that reference points systematically influenced speakers' choices between logically equivalent frames. For example, speakers tended to describe a 4-ounce cup filled to the 2-ounce line as half full if it was previously empty but described it as half empty if it was previously full. Similar results were found when speakers could describe the outcome of a medical treatment in terms of either mortality or survival (e.g., 25% die vs. 75% survive). Two additional experiments showed that listeners made accurate inferences about speakers' reference points on the basis of the selected frame (e.g., if a speaker described a cup as half empty, listeners inferred that the cup used to be full). Taken together, the data suggest that frames reliably convey implicit information in addition to their explicit content, which helps explain why framing effects are so robust.

[Nonspecific interstitial pneumonitis: a clinicopathologic entity, histologic pattern or unclassified group of heterogeneous interstitial pneumonitis?].

PubMed

Morais, António; Moura, M Conceição Souto; Cruz, M Rosa; Gomes, Isabel

2004-01-01

Nonspecific interstitial pneumonitis (NSIP) initially described by Katzenstein and Fiorelli in 1994, seems to be a distinct clinicopathologic entity among idiopathic interstitial pneumonitis (IIP). Besides different histologic features from other IIP, NSIP is characterized by a better long-term outcome, associated with a better steroids responsiveness than idiopathic pulmonar fibrosis (IPF), where usually were included. Thus, differentiating NSIP from other IIP, namely IPF is very significant, since it has important therapeutic and prognostic implications. NSIP encloses different pathologies, namely those with inflammatory predominance (cellular subtype) or fibrous predominance (fibrosing subtype). NSIP is reviewed and discussed by the authors, after two clinical cases description.

Acute interstitial pneumonia (Hamman-Rich syndrome) in idiopathic pulmonary fibrosis and bronchoalveolar carcinoma: a case report.

PubMed

Plasek, Jiri; Dvorackova, Jana; Jahoda, Jan; Trulikova, Kristina; Mokosova, Radka; Danek, Tomas; Hrabovsky, Vladimir; Martinek, Arnost

2011-12-01

Acute interstitial pneumonia is characterized by rapid progressive dyspnoea degenerating into respiratory failure requiring mechanical ventilation. Acute interstitial pneumonia (AIP) and idiopathic pulmonary fibrosis (IPF) are separate clinic/pathological entities although overlap may be present. It is well-known that patients with IPF have increased risk of lung carcinoma; Adenocarcinoma in connection with IPF is less common. Moreover the subtype of adenocarcinoma, diffuse bronchoalveolar carcinoma has not yet been described. We report the case of 45 yr old former hockey player with increased bilateral reticular shadowing on chest radiograph, dyspnoea, velcro-like crackles, restrictive respiratory disease and mixed high-resolution computed tomography finding. During brief in-patient treatment the patient developed acute respiratory failure accompanied by multiorgan failure and disseminated coagulopathy. Deterioration of the microcirculation was followed by loss of peripheral vascular resistance, which was irreversible even with normalization of the blood gases achieved by extracorporeal membrane oxygenation. At autopsy, bronchoalveolar carcinoma in usual interstitial pneumonia (UIP) combined with areas of alveolar damage with hyaline membranes was found. This case alerts clinicians to unusual idiopathic pulmonary fibrosis manifestations and its complications. Close collaboration between clinicians, pathologists and laboratory physicians is highly recommended for early diagnosis and appropriate treatment.

VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats

PubMed Central

Farkas, Laszlo; Farkas, Daniela; Ask, Kjetil; Möller, Antje; Gauldie, Jack; Margetts, Peter; Inman, Mark; Kolb, Martin

2009-01-01

Idiopathic pulmonary fibrosis (IPF) can lead to the development of secondary pulmonary hypertension (PH) and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of IPF, we explored the role of the proangiogenic and antiapoptotic growth factor VEGF in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active TGF-β1 induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and increased pulmonary arterial pressure (PAP). Immunohistochemistry and mRNA analysis revealed decreased levels of VEGF and its receptor, which were inversely correlated with PAP and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of IPF rats with adenoviral delivery of VEGF resulted in reduced endothelial apoptosis, increased vascularization, and improved PAP due to reduced remodeling but worsened PF. These data show that experimental pulmonary fibrosis (PF) leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of VEGF ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, VEGF-based therapies should be used with caution. PMID:19381013

Future Directions in Idiopathic Pulmonary Fibrosis Research. An NHLBI Workshop Report

PubMed Central

Blackwell, Timothy S.; Tager, Andrew M.; Borok, Zea; Moore, Bethany B.; Schwartz, David A.; Anstrom, Kevin J.; Bar-Joseph, Ziv; Bitterman, Peter; Blackburn, Michael R.; Bradford, William; Brown, Kevin K.; Chapman, Harold A.; Collard, Harold R.; Cosgrove, Gregory P.; Deterding, Robin; Doyle, Ramona; Flaherty, Kevin R.; Garcia, Christine Kim; Hagood, James S.; Henke, Craig A.; Herzog, Erica; Hogaboam, Cory M.; Horowitz, Jeffrey C.; King, Talmadge E.; Loyd, James E.; Lawson, William E.; Marsh, Clay B.; Noble, Paul W.; Noth, Imre; Sheppard, Dean; Olsson, Julie; Ortiz, Luis A.; O’Riordan, Thomas G.; Oury, Tim D.; Raghu, Ganesh; Roman, Jesse; Sime, Patricia J.; Sisson, Thomas H.; Tschumperlin, Daniel; Violette, Shelia M.; Weaver, Timothy E.; Wells, Rebecca G.; White, Eric S.; Kaminski, Naftali; Martinez, Fernando J.; Wynn, Thomas A.; Thannickal, Victor J.

2014-01-01

The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI. PMID:24160862

Occupational risks for idiopathic pulmonary fibrosis mortality in the United States.

PubMed

Pinheiro, Germania A; Antao, Vinicius C; Wood, John M; Wassell, James T

2008-01-01

Metal and wood dust exposures have been identified as possible occupational risk factors for idiopathic pulmonary fibrosis (IPF). We analyzed mortality data using ICD-10 code J84.1--"Other interstitial pulmonary diseases with fibrosis," derived age-adjusted mortality rates for 1999-2003, and assessed occupational risks for 1999, by calculating proportionate mortality ratios (PMRs) and mortality odds ratios (MORs) using a matched case-control approach. We identified 84,010 IPF deaths, with an age-adjusted mortality rate of 75.7 deaths/million. Mortality rates were highest among males, whites, and those aged 85 and older. Three industry categories with potential occupational exposures recognized as risk factors for IPF were identified: "Wood buildings and mobile homes" (PMR = 4.5, 95% confidence interval (CI) 1.2-11.6 and MOR = 5.3, 95% CI 1.2-23.8), "Metal mining" (PMR = 2.4, 95% CI 1.3-4.0 and MOR = 2.2, 95% CI 1.1-4.4), and "Fabricated structural metal products" (PMR = 1.9, 95% CI 1.1-3.1 and MOR = 1.7, 95% CI 1.0-3.1). Workers in these industry categories may benefit from toxicological studies and improved surveillance for this disease.

[Evaluation of angiogenic activity in sera from patients with interstitial lung diseases].

PubMed

Zielonka, T M; Demkow, U; Kowalski, J; Kuś, J; Krychniak-Soszka, A; Radzikowska, E; Skopińska-Rózewska, E; Rowińska-Zakrzewska, E

1997-01-01

Angiogenesis is a process of new blood vessels' formation occurring in many physiological and pathological conditions. Neovascularisation is the principal vascular response in chronic inflammation and concomitant fibrotic process. Microvascular changes in various organ sites in sarcoidosis (BBS) and some of the symptoms of the disease may be related to microangiopathy. Moreover, vascular alterations were also observed in lung specimens from idiopathic pulmonary fibrosis (IPF) and avian fanciers lung (AFL) patients. The present study was aimed at testing the effects of serum from 43 patients with ILD (24 BBS, 8 AFL, 8 IPF, 3 DIPF--drug induced pulmonary fibrosis) and 11 healthy controls on angiogenic capability of normal blood peripheral mononuclear cells (PBMC) in the murine intradermal angiogenesis assay (according to Sidky and Auerbach). The data demonstrated that sera from ILD patients significantly enhanced angiogenic capacity of normal PBMC as compared to control sera (p < 0.001). The effect was more pronounced for AFL patients than for BBS and IPF ones (p < 0.05). Sera from DIPF did not stimulate angiogenesis compared to control sera. The data showed that sera from ILD patients constitute sources of mediators participating in angiogenesis. This phenomenon may play role in pathogenesis of chronic immunological processes in lung.

Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report.

PubMed

Blackwell, Timothy S; Tager, Andrew M; Borok, Zea; Moore, Bethany B; Schwartz, David A; Anstrom, Kevin J; Bar-Joseph, Ziv; Bitterman, Peter; Blackburn, Michael R; Bradford, William; Brown, Kevin K; Chapman, Harold A; Collard, Harold R; Cosgrove, Gregory P; Deterding, Robin; Doyle, Ramona; Flaherty, Kevin R; Garcia, Christine Kim; Hagood, James S; Henke, Craig A; Herzog, Erica; Hogaboam, Cory M; Horowitz, Jeffrey C; King, Talmadge E; Loyd, James E; Lawson, William E; Marsh, Clay B; Noble, Paul W; Noth, Imre; Sheppard, Dean; Olsson, Julie; Ortiz, Luis A; O'Riordan, Thomas G; Oury, Tim D; Raghu, Ganesh; Roman, Jesse; Sime, Patricia J; Sisson, Thomas H; Tschumperlin, Daniel; Violette, Shelia M; Weaver, Timothy E; Wells, Rebecca G; White, Eric S; Kaminski, Naftali; Martinez, Fernando J; Wynn, Thomas A; Thannickal, Victor J; Eu, Jerry P

2014-01-15

The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI.

An autopsy study of combined pulmonary fibrosis and emphysema: correlations among clinical, radiological, and pathological features

PubMed Central

2014-01-01

Background Clinical evaluation to differentiate the characteristic features of pulmonary fibrosis and emphysema is often difficult in patients with combined pulmonary fibrosis and emphysema (CPFE), but diagnosis of pulmonary fibrosis is important for evaluating treatment options and the risk of acute exacerbation of interstitial pneumonia of such patients. As far as we know, it is the first report describing a correlation among clinical, radiological, and whole-lung pathological features in an autopsy cases of CPFE patients. Methods Experts retrospectively reviewed the clinical charts and examined chest computed tomography (CT) images and pathological findings of an autopsy series of 22 CPFE patients, and compared these with findings from 8 idiopathic pulmonary fibrosis (IPF) patients and 17 emphysema-alone patients. Results All patients had a history of heavy smoking. Forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC%) was significantly lower in the emphysema-alone group than the CPFE and IPF-alone groups. The percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) was significantly lower in the CPFE group than the IPF- and emphysema-alone groups. Usual interstitial pneumonia (UIP) pattern was observed radiologically in 15 (68.2%) CPFE and 8 (100%) IPF-alone patients and was pathologically observed in all patients from both groups. Pathologically thick-cystic lesions involving one or more acini with dense wall fibrosis and occasional fibroblastic foci surrounded by honeycombing and normal alveoli were confirmed by post-mortem observation as thick-walled cystic lesions (TWCLs). Emphysematous destruction and enlargement of membranous and respiratory bronchioles with fibrosis were observed in the TWCLs. The cystic lesions were always larger than the cysts of honeycombing. The prevalence of both radiological and pathological TWCLs was 72.7% among CPFE patients, but no such lesions were observed in patients with IPF or emphysema alone (p = 0.001). The extent of emphysema in CPFE patients with TWCLs was greater than that in patients without such lesions. Honeycombing with emphysema was also observed in 11 CPFE patients. Conclusions TWCLs were only observed in the CPFE patients. They were classified as lesions with coexistent fibrosing interstitial pneumonia and emphysema, and should be considered an important pathological and radiological feature of CPFE. PMID:24972672

miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin-1

PubMed Central

Courcot, Elisabeth; Roderburg, Christoph; Cauffiez, Christelle; Aubert, Sébastien; Copin, Marie-Christine; Wallaert, Benoit; Glowacki, François; Dewaeles, Edmone; Milosevic, Jadranka; Maurizio, Julien; Tedrow, John; Marcet, Brice; Lo-Guidice, Jean-Marc; Kaminski, Naftali; Barbry, Pascal; Luedde, Tom; Perrais, Michael

2013-01-01

As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. PMID:23459460

Bounce universe from string-inspired Gauss-Bonnet gravity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bamba, Kazuharu; Makarenko, Andrey N.; Myagky, Alexandr N.

2015-04-01

We explore cosmology with a bounce in Gauss-Bonnet gravity where the Gauss-Bonnet invariant couples to a dynamical scalar field. In particular, the potential and and Gauss-Bonnet coupling function of the scalar field are reconstructed so that the cosmological bounce can be realized in the case that the scale factor has hyperbolic and exponential forms. Furthermore, we examine the relation between the bounce in the string (Jordan) and Einstein frames by using the conformal transformation between these conformal frames. It is shown that in general, the property of the bounce point in the string frame changes after the frame is movedmore » to the Einstein frame. Moreover, it is found that at the point in the Einstein frame corresponding to the point of the cosmological bounce in the string frame, the second derivative of the scale factor has an extreme value. In addition, it is demonstrated that at the time of the cosmological bounce in the Einstein frame, there is the Gauss-Bonnet coupling function of the scalar field, although it does not exist in the string frame.« less

[Ultrastructure and cytochemistry of the pellicle and apical complexes of the kinete of Babesia bigemina and Babesia ovis in the hemolymph and oavry of the tick].

PubMed

Weber, G

1980-02-01

The term kinete is used in this paper for the cigar-shaped, motile development stages (VERMICULE") OF Babesia occurring intra- and extracellularly in hemolymph and overy (including oocytes) of vectors, hard ticks (Ixodoidea). The structure of, and cytochemical activities of hydrolases (acid phosphatase, nonspecific esterase) in the pellicle and the apical complex was studied at the fine-structural level in kinetes of Babesia bigemina Smith & Kilborne, in hemolympho of female Boophilus microplus Canestrini. The cytochemistry of acid hydrolases was studied also in kinetes of Babesia ovis (Babès) Starcovici, in hemolymph and ovary of Rhipicephalus bursa Canestrini & Fanzago. The pellicle of the B. bigemina kinetes is composted of 3 membranes (pellicular complex): an outer membrane, approximately 8 nm thick (the plasmalemma) and 2 innder ones, each approximately nm thick, lying closely together. The outer membrane appears to be covered by a structureless coat, 3 nm thick. The space between the inner double membrane and the plasmalemma is 7.5 nm. The whole pellicular complex is 30 nm in diameter. The 2 inner pellicular membranes appear to be derived from the endoplasmic reticulum (ER) for the following reasons: (a) a layer of hydrolase-active material is enclosed by these membranes; (b) in the spheroid parasite stages which transform from kinetes inside hemocytes, the inner double membrane is apparently replaced by an ER cisterna; (c) the thickness of each of the inner pellicular membranes is approximately the same as that of the ER membrane. There are circular openings in the pellicular double membrane with average diameters of 100 nm; despite some similarity to micropores, they have a specific structure. The term Intrapellikularfenster (IPF) (intrapellicular windows) or pseudomicropores is proposed for these pellicular differentiations. The margin of an IPF is formed by the 2 inner membranes folding into each other; cytoplasmic, electron-dense material is accumulated alongside this edge. Unlike that of micropores, the plasmalemma of the IPF is not invaginated. The IPF appears as a single, dark ring in tangential sections. At times, rhoptry-like bodies are associated with the openings. The function of the IPF is not known. An intrapellicular opening similar to the IPF, although wider, is present at the apex of the parasite. Its margin coincides with the inners edge of the apical ring. Typical subpellicular microtubuli were not observed in the Babesia kinetes. The apical complex of the B. bigemina kinetes consists of an Apikalschirm (apical umbrella), a crown of microtubuli beneath it, and rhoptries: micronemes are also present in large numbers. The Apikalschirm is located beneath the pellicle of the apical pole of the parasite. It is a wheel-like structure composed of spokes radiating from a wide, hub=like central ring (apical ring). It should be stressed that the apical ring is not identical with the polar ring described as an integral part of the pellicular complex in other Apicomplexa...

Expandable space frames

NASA Technical Reports Server (NTRS)

Schoen, A. H. (Inventor)

1973-01-01

Expandable space frames having essentially infinite periodicity limited only by practical considerations, are described. Each expandable space frame comprises a plurality of hinge joint assemblies having arms that extend outwardly in predetermined symmetrically related directions from a central or vertex point. The outer ends of the arms form one part of a hinge point. The outer expandable space frame also comprises a plurality of struts. The outer ends of the struts from the other part of the hinged joint. The struts interconnect the plurality of hinge point in sychronism, the spaceframes can be expanded or collapsed. Three-dimensional as well as two-dimensional spaceframes of this general nature are described.

White donor, younger donor and double lung transplant are associated with better survival in sarcoidosis patients.

PubMed

Salamo, Oriana; Roghaee, Shiva; Schweitzer, Michael D; Mantero, Alejandro; Shafazand, Shirin; Campos, Michael; Mirsaeidi, Mehdi

2018-05-03

Sarcoidosis commonly affects the lung. Lung transplantation (LT) is required when there is a severe and refractory involvement. We compared post-transplant survival rates of sarcoidosis patients with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). We also explored whether the race and age of the donor, and double lung transplant have any effect on the survival in the post transplant setting. We analyzed 9,727 adult patients with sarcoidosis, COPD, and IPF who underwent LT worldwide between 2005-2015 based on United Network for Organ Sharing (UNOS) database. Survival rates were compared with Kaplan-Meier, and risk factors were investigated by Cox-regression analysis. 469 (5%) were transplanted because of sarcoidosis, 3,688 (38%) for COPD and 5,570 (57%) for IPF. Unadjusted survival analysis showed a better post-transplant survival rate for patients with sarcoidosis (p < 0.001, Log-rank test). In Cox-regression analysis, double lung transplant and white race of the lung donor showed to have a significant survival advantage. Since double lung transplant, those who are younger and have lower Lung Allocation Score (LAS) at the time of transplant have a survival advantage, we suggest double lung transplant as the procedure of choice, especially in younger sarcoidosis subjects and with lower LAS scores.

Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis

PubMed Central

O'Donoghue, Robert J J; Knight, Darryl A; Richards, Carl D; Prêle, Cecilia M; Lau, Hui Ling; Jarnicki, Andrew G; Jones, Jessica; Bozinovski, Steven; Vlahos, Ross; Thiem, Stefan; McKenzie, Brent S; Wang, Bo; Stumbles, Philip; Laurent, Geoffrey J; McAnulty, Robin J; Rose-John, Stefan; Zhu, Hong Jian; Anderson, Gary P; Ernst, Matthias R; Mutsaers, Steven E

2012-01-01

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin (IL)-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor (TGF)-β signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;µMT−/− compound mutant mice, but fibrosis still occurred in their Smad3−/− counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1α1 gene transcription independently of canonical TGF-β/Smad3 signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of Stat3 protected mice from bleomycin-induced lung fibrosis. PMID:22684844

Transient Overexpression of Gremlin Results in Epithelial Activation and Reversible Fibrosis in Rat Lungs

PubMed Central

Farkas, Laszlo; Farkas, Daniela; Gauldie, Jack; Warburton, David; Shi, Wei; Kolb, Martin

2011-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of the lung parenchyma, without curative treatment. Gremlin is a bone morphogenic protein (BMP) antagonist, its expression being increased in IPF lungs. It has been implicated in promoting myofibroblast accumulation, likely through inhibited fibroblast apoptosis and epithelial-to-mesenchymal transition. In the current study, we examined the effects of selective adenovirus-mediated overexpression of Gremlin in rat lungs. We show that transient Gremlin overexpression results in activation of alveolar epithelial cells with proliferation and apoptosis, as well as partly reversible lung fibrosis. We found myofibroblasts arranged in fibroblastic foci. Fibroblast proliferation occurred delayed as compared with epithelial changes. Fibrotic pathology significantly declined after Day 14, the reversal being associated with an increase of the epithelium-protective element, fibroblast growth factor (FGF)–10. Our data indicate that Gremlin-mediated BMP inhibition results in activation of epithelial cells and transient fibrosis, but also induction of epithelium-protective FGF10. A Gremlin–BMP–FGF10 loop may explain these results, and demonstrate that the interactions between different factors are quite complex in fibrotic lung disease. Increased Gremlin expression in human IPF tissue may be an expression of continuing epithelial injury, and Gremlin may be part of activated repair mechanisms. PMID:20705941

Inhibitory effects of amines from Citrus reticulata on bleomycin-induced pulmonary fibrosis in rats

PubMed Central

ZHOU, XIAN-MEI; CAO, ZHEN-DONG; XIAO, NA; SHEN, QI; LI, JIAN-XIN

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease for which, thus far, there are no effective treatments. The pericarp of Citrus reticulata, as a traditional herbal drug, has been used for the clinical treatment of lung-related diseases in China for many years. In the present study, the amines from the pericarp of Citrus reticulata were isolated, and their hydrochlorides were prepared. The results of screening using cultured human embryonic lung fibroblasts (hELFs) revealed that, of the amines, 4-methoxyphenethylamine hydrochloride (designated as amine hydrochloride 1) possessed the most potent inhibitory effect. Further in vivo experiments using a rat model of bleomycin-induced pulmonary fibrosis demonstrated that the oral administration of amine hydrochloride 1 significantly lowered the hydroxyproline content in both serum and lung tissue, and alleviated pulmonary alveolitis and fibrosis. Immunohistochemical analysis revealed that amine hydrochloride 1 exerted its inhibitory effect against IPF through the downregulation of lung transforming growth factor (TGF)-β1 protein expression. Our results demonstrated that amine hydrochloride 1 prevented the development of bleomycin-induced lung fibrosis in rats. Thus, our data suggest that the amines from the pericarp of Citrus reticulata have therapeutic potential for use in the treatment of IPF. PMID:26675886

Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis.

PubMed

Aumiller, Verena; Strobel, Benjamin; Romeike, Merrit; Schuler, Michael; Stierstorfer, Birgit E; Kreuz, Sebastian

2017-03-10

Extracellular matrix (ECM) composition and stiffness are major driving forces for the development and persistence of fibrotic diseases. Lysyl oxidase (LOX) and LOX-like (LOXL) proteins play crucial roles in ECM remodeling due to their collagen crosslinking and intracellular functions. Here, we systematically investigated LOX/L expression in primary fibroblasts and epithelial cells under fibrotic conditions, Bleomycin (BLM) induced lung fibrosis and in human IPF tissue. Basal expression of all LOX/L family members was detected in epithelial cells and at higher levels in fibroblasts. Various pro-fibrotic stimuli broadly induced LOX/L expression in fibroblasts, whereas specific induction of LOXL2 and partially LOX was observed in epithelial cells. Immunohistochemical analysis of lung tissue from 14 IPF patients and healthy donors revealed strong induction of LOX and LOXL2 in bronchial and alveolar epithelium as well as fibroblastic foci. Using siRNA experiments we observed that LOXL2 and LOXL3 were crucial for fibroblast-to-myofibroblast transition (FMT). As FMT could only be reconstituted with an enzymatically active LOXL2 variant, we conclude that LOXL2 enzymatic function is crucial for fibroblast transdifferentiation. In summary, our study provides a comprehensive analysis of the LOX/L family in fibrotic lung disease and indicates prominent roles for LOXL2/3 in fibroblast activation and LOX/LOXL2 in IPF.

Kinetics and formation mechanisms of intragranular ferrite in V-N microalloyed 600 MPa high strength rebar steel

NASA Astrophysics Data System (ADS)

Zhang, Jing; Wang, Fu-ming; Li, Chang-rong

2016-04-01

To systematically investigate the kinetics and formation mechanisms of intragranular ferrite (IGF), isothermal heat treatment in the temperature range of 450°C to 600°C with holding for 30 s to 300 s, analysis of the corresponding microstructures, and observation of the precipitated particles were conducted in V-N microalloyed 600 MPa high strength rebar steel. The potency of V(C,N) for IGF nucleation was also analyzed statistically. The results show that the dominant microstructure transforms from bainite (B) and acicular ferrite (AF) to grain boundary ferrite (GBF), intragranular polygonal ferrite (IPF), and pearlite (P) as the isothermal temperature increases from 450°C to 600°C. When the holding time at 600°C is extended from 30 s to 60 s, 120 s, and 300 s, the GBF content ranges from 6.0vol% to 6.5vol% and the IPF content increases from 0.5vol% to 2.8vol%, 13.1vol%, and 13.5vol%, respectively, because the ferrite transformation preferentially occurs at the grain boundaries and then occurs at the austenite grains. Notably, V(C,N) particles are the most effective nucleation site for the formation of IPF, accounting for 51% of the said formation.

IPF-LASSO: Integrative L 1-Penalized Regression with Penalty Factors for Prediction Based on Multi-Omics Data

PubMed Central

Jiang, Xiaoyu; Fuchs, Mathias

2017-01-01

As modern biotechnologies advance, it has become increasingly frequent that different modalities of high-dimensional molecular data (termed “omics” data in this paper), such as gene expression, methylation, and copy number, are collected from the same patient cohort to predict the clinical outcome. While prediction based on omics data has been widely studied in the last fifteen years, little has been done in the statistical literature on the integration of multiple omics modalities to select a subset of variables for prediction, which is a critical task in personalized medicine. In this paper, we propose a simple penalized regression method to address this problem by assigning different penalty factors to different data modalities for feature selection and prediction. The penalty factors can be chosen in a fully data-driven fashion by cross-validation or by taking practical considerations into account. In simulation studies, we compare the prediction performance of our approach, called IPF-LASSO (Integrative LASSO with Penalty Factors) and implemented in the R package ipflasso, with the standard LASSO and sparse group LASSO. The use of IPF-LASSO is also illustrated through applications to two real-life cancer datasets. All data and codes are available on the companion website to ensure reproducibility. PMID:28546826

Motion-Compensated Compression of Dynamic Voxelized Point Clouds.

PubMed

De Queiroz, Ricardo L; Chou, Philip A

2017-05-24

Dynamic point clouds are a potential new frontier in visual communication systems. A few articles have addressed the compression of point clouds, but very few references exist on exploring temporal redundancies. This paper presents a novel motion-compensated approach to encoding dynamic voxelized point clouds at low bit rates. A simple coder breaks the voxelized point cloud at each frame into blocks of voxels. Each block is either encoded in intra-frame mode or is replaced by a motion-compensated version of a block in the previous frame. The decision is optimized in a rate-distortion sense. In this way, both the geometry and the color are encoded with distortion, allowing for reduced bit-rates. In-loop filtering is employed to minimize compression artifacts caused by distortion in the geometry information. Simulations reveal that this simple motion compensated coder can efficiently extend the compression range of dynamic voxelized point clouds to rates below what intra-frame coding alone can accommodate, trading rate for geometry accuracy.

A Possible Approach to Inclusion of Space and Time in Frame Fields of Quantum Representations of Real and Complex Numbers

DOE PAGES

Benioff, Paul

2009-01-01

Tmore » his work is based on the field of reference frames based on quantum representations of real and complex numbers described in other work. Here frame domains are expanded to include space and time lattices. Strings of qukits are described as hybrid systems as they are both mathematical and physical systems. As mathematical systems they represent numbers. As physical systems in each frame the strings have a discrete Schrodinger dynamics on the lattices. he frame field has an iterative structure such that the contents of a stage j frame have images in a stage j - 1 (parent) frame. A discussion of parent frame images includes the proposal that points of stage j frame lattices have images as hybrid systems in parent frames. he resulting association of energy with images of lattice point locations, as hybrid systems states, is discussed. Representations and images of other physical systems in the different frames are also described.« less

Comparative analysis of effects of dietary arachidonic acid and EPA on growth, tissue fatty acid composition, antioxidant response and lipid metabolism in juvenile grass carp, Ctenopharyngodon idellus.

PubMed

Tian, Jing-Jing; Lei, Cai-Xia; Ji, Hong; Kaneko, Gen; Zhou, Ji-Shu; Yu, Hai-Bo; Li, Yang; Yu, Er-Meng; Xie, Jun

2017-09-01

Four isonitrogenous and isoenergetic purified diets containing free arachidonic acid (ARA) or EPA (control group), 0·30 % ARA, 0·30 % EPA and 0·30 % ARA+EPA (equivalent) were designed to feed juvenile grass carp (10·21 (sd 0·10) g) for 10 weeks. Only the EPA group presented better growth performance compared with the control group (P<0·05). Dietary ARA and EPA were incorporated into polar lipids more than non-polar lipids in hepatopancreas but not intraperitoneal fat (IPF) tissue. Fish fed ARA and EPA showed an increase of serum superoxide dismutase and catalase activities, and decrease of glutathione peroxidase activity and malondialdehyde contents (P<0·05). The hepatopancreatic TAG levels decreased both in ARA and EPA groups (P<0·05), accompanied by the decrease of lipoprotein lipase (LPL) activity in the ARA group (P<0·05). Fatty acid synthase (FAS), diacylglycerol O-acyltransferase and apoE gene expression in the hepatopancreas decreased in fish fed ARA and EPA, but only the ARA group exhibited increased mRNA level of adipose TAG lipase (ATGL) (P<0·05). Decreased IPF index and adipocyte sizes were found in the ARA group (P<0·05). Meanwhile, the ARA group showed decreased expression levels of adipogenic genes CCAAT enhancer-binding protein α, LPL and FAS, and increased levels of the lipid catabolic genes PPAR α, ATGL, hormone-sensitive lipase and carnitine palmitoyltransferase 1 (CPT-1) in IPF, whereas the EPA group only increased PPAR α and CPT-1 mRNA expression and showed less levels than the ARA group. Overall, dietary EPA is beneficial to the growth performance, whereas ARA is more potent in inducing lipolysis and inhibiting adipogenesis, especially in IPF. Meanwhile, dietary ARA and EPA showed the similar preference in esterification and the improvement in antioxidant response.

Role of atmospheric pollution on the natural history of idiopathic pulmonary fibrosis.

PubMed

Sesé, Lucile; Nunes, Hilario; Cottin, Vincent; Sanyal, Shreosi; Didier, Morgane; Carton, Zohra; Israel-Biet, Dominique; Crestani, Bruno; Cadranel, Jacques; Wallaert, Benoit; Tazi, Abdellatif; Maître, Bernard; Prévot, Grégoire; Marchand-Adam, Sylvain; Guillot-Dudoret, Stéphanie; Nardi, Annelyse; Dury, Sandra; Giraud, Violaine; Gondouin, Anne; Juvin, Karine; Borie, Raphael; Wislez, Marie; Valeyre, Dominique; Annesi-Maesano, Isabella

2018-02-01

Idiopathic pulmonary fibrosis (IPF) has an unpredictable course corresponding to various profiles: stability, physiological disease progression and rapid decline. A minority of patients experience acute exacerbations (AEs). A recent study suggested that ozone and nitrogen dioxide might contribute to the occurrence of AE. We hypothesised that outdoor air pollution might influence the natural history of IPF. Patients were selected from the French cohort COhorte FIbrose (COFI), a national multicentre longitudinal prospective cohort of IPF (n=192). Air pollutant levels were assigned to each patient from the air quality monitoring station closest to the patient's geocoded residence. Cox proportional hazards model was used to evaluate the impact of air pollution on AE, disease progression and death. Onset of AEs was significantly associated with an increased mean level of ozone in the six preceding weeks, with an HR of 1.47 (95% CI 1.13 to 1.92) per 10 µg/m 3 (p=0.005). Cumulative levels of exposure to particulate matter PM 10 and PM 2.5 were above WHO recommendations in 34% and 100% of patients, respectively. Mortality was significantly associated with increased levels of exposure to PM 10 (HR=2.01, 95% CI 1.07 to 3.77) per 10 µg/m 3 (p=0.03), and PM 2.5 (HR=7.93, 95% CI 2.93 to 21.33) per 10 µg/m 3 (p<0.001). This study suggests that air pollution has a negative impact on IPF outcomes, corroborating the role of ozone on AEs and establishing, for the first time, the potential role of long-term exposure to PM 10 and PM 2.5 on overall mortality. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Impact of irrigation flow rate and intrapericardial fluid on cooled-tip epicardial radiofrequency ablation.

PubMed

Aryana, Arash; O'Neill, Padraig Gearoid; Pujara, Deep K; Singh, Steve K; Bowers, Mark R; Allen, Shelley L; d'Avila, André

2016-08-01

The optimal irrigation flow rate (IFR) during epicardial radiofrequency (RF) ablation has not been established. This study specifically examined the impact of IFR and intrapericardial fluid (IPF) accumulation during epicardial RF ablation. Altogether, 452 ex vivo RF applications (10 g for 60 seconds) delivered to the epicardial surface of bovine myocardium using 3 open-irrigated ablation catheters (ThermoCool SmartTouch, ThermoCool SmartTouch-SF, and FlexAbility) and 50 in vivo RF applications delivered (ThermoCool SmartTouch-SF) in 4 healthy adult swine in the presence or absence of IPF were examined. Ex vivo, RF was delivered at low (≤3 mL/min), reduced (5-7 mL/min), and high (≥10 mL/min) IFRs using intermediate (25-35 W) and high (35-45 W) power. In vivo, applications were delivered (at 9.3 ± 2.2 g for 60 seconds at 39 W) using reduced (5 mL/min) and high (15 mL/min) IFRs. Ex vivo, surface lesion diameter inversely correlated with IFR, whereas maximum lesion diameter and depth did not differ. While steam pops occurred more frequently at low IFR using high power (ThermoCool SmartTouch and ThermoCool SmartTouch-SF), tissue disruption was rare and did not vary with IFR. In vivo, charring/steam pop was not detected. Although there were no discernible differences in lesion size with IFR, surface lesion diameter, maximum diameter, depth, and volume were all smaller in the presence of IPF at both IFRs. Cooled-tip epicardial RF ablation created using reduced IFRs (5-7 mL/min) yields lesion sizes similar to those created using high IFRs (≥10 mL/min) without an increase in steam pop/tissue disruption, whereas the presence of IPF significantly reduces the lesion size. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

A retrospective chart review of pirfenidone-treated patients in Sweden: the REPRIS study.

PubMed

Sköld, Carl Magnus; Janson, Christer; Elf, Åsa Klackenberg; Fiaschi, Marie; Wiklund, Kerstin; Persson, Hans Lennart

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that usually results in respiratory failure and death. Pirfenidone was approved as the first licensed therapy for IPF in Europe based on phase III trials where patients with a forced vital capacity (FVC) >50% of predicted were included. The aim of this study was to characterise patients treated with pirfenidone in Swedish clinical practice and to describe the adherence to the reimbursement restriction since reimbursement was only applied for patients with FVC below 80% of predicted. This was a retrospective, observational chart review of IPF patients treated with pirfenidone from three Swedish university clinics. Patients initiated on treatment during the period 28 June 2012 to 20 November 2014 were included. Data on patient characteristics, basis of diagnosis, treatment duration, quality of life, and adverse drug reactions (ADRs) were collected from medical charts. Forty-four patients were screened and 33 were included in the study. The mean treatment duration from start of pirfenidone until discontinuation or end of study was 38 weeks. At the initiation of pirfenidone treatment, FVC was 62.7% (12.1) [mean (SD)], diffusion capacity (DLco) was 45.1% (13.8) of predicted, and the ratio of forced expiratory volume on 1 sec (FEV1) to FVC was 0.78 (0.1). The percentage of patients with an FVC between 50 and 80% was 87%. Ten of the patients had ADRs including gastrointestinal and skin-related events, cough and signs of impaired hepatic function, but this led to treatment discontinuation in only two patients. Data from this chart review showed that adherence to the Swedish reimbursement restriction was followed in the majority of patients during the study period. At the start of pirfenidone treatment, lung function, measured as FVC, was lower in the present cohort of Swedish IPF patients compared with other registry and real-life data. About a third of the patients had ADRs, but discontinuation of the treatment because of ADRs was relatively uncommon.

Pirfenidone and nintedanib modulate properties of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis.

PubMed

Lehtonen, Siri T; Veijola, Anniina; Karvonen, Henna; Lappi-Blanco, Elisa; Sormunen, Raija; Korpela, Saara; Zagai, Ulrika; Sköld, Magnus C; Kaarteenaho, Riitta

2016-02-04

Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease with a poor prognosis. Fibroblasts and myofibroblasts are the key cells in the fibrotic process. Recently two drugs, pirfenidone and nintedanib, were approved for clinical use as they are able to slow down the disease progression. The mechanisms by which these two drugs act in in vitro cell systems are not known. The aim of this study was therefore to examine the effects of pirfenidone and nintedanib on fibroblasts and myofibroblasts structure and function established from patients with or without IPF. Stromal cells were collected and cultured from control lung (n = 4) or IPF (n = 7). The cells were treated with pirfenidone and/or nintedanib and the effect of treatment was evaluated by measuring cell proliferation, alpha smooth muscle actin (α-SMA) and fibronectin expression by Western analysis and/or immunoelectron microscopy, ultrastructural properties by transmission electron microscopy and functional properties by collagen gel contraction and invasion assays. Both pirfenidone and nintedanib reduced in vitro proliferation of fibroblastic cells in a dose dependent manner. The number of cells from control lung was reduced to 47 % (p = 0.04) and of IPF cells to 42 % (p = 0.04) by 1 mM pirfenidone and correspondingly to 67 % (p = 0.04) and 68 % (p = 0.04), by 1 μM nintedanib. If both drugs were used together, a further reduced proliferation was observed. Both pirfenidone and nintedanib were able to reduce the amount of α-SMA and the myofibroblastic appearance although the level of reduction was cell line dependent. In functional assays, the effect of both drugs was also variable. We conclude that the ultrastructure and function of fibroblasts and myofibroblasts are affected by pirfenidone and nintedanib. Combination of the drugs reduced cell proliferation more than either of them individually. Human lung derived cell culture systems represent a potential platform for screening and testing drugs for fibrotic diseases.

The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial.

PubMed

Dowman, Leona M; McDonald, Christine F; Hill, Catherine J; Lee, Annemarie L; Barker, Kathryn; Boote, Claire; Glaspole, Ian; Goh, Nicole S L; Southcott, Anne M; Burge, Angela T; Gillies, Rebecca; Martin, Alicia; Holland, Anne E

2017-07-01

Uncertainty exists regarding the clinical relevance of exercise training across the range of interstitial lung diseases (ILDs). To establish the impact of exercise training in patients with ILDs of differing aetiology and severity. 142 participants with ILD (61 idiopathic pulmonary fibrosis (IPF), 22 asbestosis, 23 connective tissue disease-related ILD (CTD-ILD) and 36 with other aetiologies) were randomised to either 8 weeks of supervised exercise training or usual care. Six-minute walk distance (6MWD), Chronic Respiratory Disease Questionnaire (CRDQ), St George Respiratory Questionnaire IPF-specific version (SGRQ-I) and modified Medical Research Council dyspnoea score were measured at baseline, 9 weeks and 6 months. Exercise training significantly increased 6MWD (25 m, 95% CI 2 to 47 m) and health-related quality of life (CRDQ and SGRQ-I) in people with ILD. Larger improvements in 6MWD, CRDQ, SGRQ-I and dyspnoea occurred in asbestosis and IPF compared with CTD-ILD, but with few significant differences between subgroups. Benefits declined at 6 months except in CTD-ILD. Lower baseline 6MWD and worse baseline symptoms were associated with greater benefit in 6MWD and symptoms following training. Greater gains were seen in those whose exercise prescription was successfully progressed according to the protocol. At 6 months, sustained improvements in 6MWD and symptoms were associated with better baseline lung function and less pulmonary hypertension. Exercise training is effective in patients across the range of ILDs, with clinically meaningful benefits in asbestosis and IPF. Successful exercise progression maximises improvements and sustained treatment effects favour those with milder disease. Results, ACTRN12611000416998. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Arterial Carboxyhemoglobin Measurement Is Useful for Evaluating Pulmonary Inflammation in Subjects with Interstitial Lung Disease

PubMed Central

Hara, Yu; Shinkai, Masaharu; Kanoh, Soichiro; Fujikura, Yuji; K. Rubin, Bruce; Kawana, Akihiko; Kaneko, Takeshi

2017-01-01

Objective The arterial concentration of carboxyhemoglobin (CO-Hb) in subjects with inflammatory pulmonary disease is higher than that in healthy individuals. We retrospectively analyzed the relationship between the CO-Hb concentration and established markers of disease severity in subjects with interstitial lung disease (ILD). Methods The CO-Hb concentration was measured in subjects with newly diagnosed or untreated ILD and the relationships between the CO-Hb concentration and the serum biomarker levels, lung function, high-resolution CT (HRCT) findings, and the uptake in gallium-67 (67Ga) scintigraphy were evaluated. Results Eighty-one non-smoking subjects were studied (mean age, 67 years). Among these subjects, (A) 17 had stable idiopathic pulmonary fibrosis (IPF), (B) 9 had an acute exacerbation of IPF, (C) 44 had stable non-IPF, and (D) 11 had an exacerbation of non-IPF. The CO-Hb concentrations of these subjects were (A) 1.5±0.5%, (B) 2.1±0.5%, (C) 1.2±0.4%, and (D) 1.7±0.5%. The CO-Hb concentration was positively correlated with the serum levels of surfactant protein (SP)-A (r=0.38), SP-D (r=0.39), and the inflammation index (calculated from HRCT; r=0.57) and was negatively correlated with the partial pressure of oxygen in the arterial blood (r=-0.56) and the predicted diffusion capacity of carbon monoxide (r=-0.61). The CO-Hb concentrations in subjects with a negative heart sign on 67Ga scintigraphy were higher than those in subjects without a negative heart sign (1.4±0.5% vs. 1.1±0.3%, p=0.018). Conclusion The CO-Hb levels of subjects with ILD were increased, particularly during an exacerbation, and were correlated with the parameters that reflect pulmonary inflammation. PMID:28321059

Xenon-Enhanced Dual-Energy CT Imaging in Combined Pulmonary Fibrosis and Emphysema

PubMed Central

Kobayashi, Masahiro; Nakamura, Yasuhiko; Gocho, Kyoko; Ishida, Fumiaki; Isobe, Kazutoshi; Shiraga, Nobuyuki; Homma, Sakae

2017-01-01

Background Little has been reported on the feasibility of xenon-enhanced dual-energy computed tomography (Xe-DECT) in the visual and quantitative analysis of combined pulmonary fibrosis and emphysema (CPFE). Objectives We compared CPFE with idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), as well as correlation with parameters of pulmonary function tests (PFTs). Methods Studied in 3 groups were 25 patients with CPFE, 25 with IPF without emphysema (IPF alone), 30 with COPD. Xe-DECT of the patients’ entire thorax was taken from apex to base after a patient’s single deep inspiration of 35% stable nonradioactive xenon. The differences in several parameters of PFTs and percentage of areas enhanced by xenon between 3 groups were compared and analyzed retrospectively. Results The percentage of areas enhanced by xenon in both lungs were calculated as CPFE/IPF alone/COPD = 72.2 ± 15.1% / 82.2 ± 14.7% /45.2 ± 23.2%, respectively. In the entire patients, the percentage of areas enhanced by xenon showed significantly a positive correlation with FEV1/FVC (R = 0.558, P < 0.0001) and %FEV1, (R = 0.528, P < 0.0001) and a negative correlation with %RV (R = -0.594, P < 0.0001) and RV/TLC (R = -0.579, P < 0.0001). The percentage of areas enhanced by xenon in patients with CPFE showed significantly a negative correlation with RV/TLC (R = -0.529, P = 0.007). Xenon enhancement of CPFE indicated 3 different patterns such as upper predominant, diffuse, and multifocal defect. The percentage of areas enhanced by xenon in upper predominant defect pattern was significantly higher than that in diffuse defect and multifocal defect pattern among these 3 different patterns in CPFE. Conclusion The percentage of areas enhanced by xenon demonstrated strong correlations with obstructive ventilation impairment. Therefore, we conclude that Xe-DECT may be useful for distinguishing emphysema lesion from fibrotic lesion in CPFE. PMID:28107411

Xenon-Enhanced Dual-Energy CT Imaging in Combined Pulmonary Fibrosis and Emphysema.

PubMed

Sugino, Keishi; Kobayashi, Masahiro; Nakamura, Yasuhiko; Gocho, Kyoko; Ishida, Fumiaki; Isobe, Kazutoshi; Shiraga, Nobuyuki; Homma, Sakae

2017-01-01

Little has been reported on the feasibility of xenon-enhanced dual-energy computed tomography (Xe-DECT) in the visual and quantitative analysis of combined pulmonary fibrosis and emphysema (CPFE). We compared CPFE with idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), as well as correlation with parameters of pulmonary function tests (PFTs). Studied in 3 groups were 25 patients with CPFE, 25 with IPF without emphysema (IPF alone), 30 with COPD. Xe-DECT of the patients' entire thorax was taken from apex to base after a patient's single deep inspiration of 35% stable nonradioactive xenon. The differences in several parameters of PFTs and percentage of areas enhanced by xenon between 3 groups were compared and analyzed retrospectively. The percentage of areas enhanced by xenon in both lungs were calculated as CPFE/IPF alone/COPD = 72.2 ± 15.1% / 82.2 ± 14.7% /45.2 ± 23.2%, respectively. In the entire patients, the percentage of areas enhanced by xenon showed significantly a positive correlation with FEV1/FVC (R = 0.558, P < 0.0001) and %FEV1, (R = 0.528, P < 0.0001) and a negative correlation with %RV (R = -0.594, P < 0.0001) and RV/TLC (R = -0.579, P < 0.0001). The percentage of areas enhanced by xenon in patients with CPFE showed significantly a negative correlation with RV/TLC (R = -0.529, P = 0.007). Xenon enhancement of CPFE indicated 3 different patterns such as upper predominant, diffuse, and multifocal defect. The percentage of areas enhanced by xenon in upper predominant defect pattern was significantly higher than that in diffuse defect and multifocal defect pattern among these 3 different patterns in CPFE. The percentage of areas enhanced by xenon demonstrated strong correlations with obstructive ventilation impairment. Therefore, we conclude that Xe-DECT may be useful for distinguishing emphysema lesion from fibrotic lesion in CPFE.

[Efficacy and safety of Danhong injection for idiopathic pulmonary fibrosis：Meta-analysis].

PubMed

Xin, Li-Li; Jiang, Miao; Zhang, Geng; Gong, Jie-Ning

2016-10-01

To systematically review the efficacy and safety of Danhong injection for patients with idiopathic pulmonary fibrosis(IPF), two researchers electronically searched PubMed, EMbase, Web of Science, Cochrane Library, CNKI, CBM, WanFang Data and VIP databases from the date of establishment to May 2016 for all randomized controlled trials(RCTs) and quasi-RCTs on the use of Danhong injection in patients with IPF. Manual search in relevant journals and search of relevant literature on other websites were also performed. The data extraction and quality assessment of included RCTs and quasi-RCT were conducted by two reviewers independently. Then, Meta-analysis was conducted by using RevMan 5.3 software. A total of 12 RCTs involving 844 patients were included, 423 cases in experiment group and 421 cases in control group. The results of meta-analysis indicated that the Danhong injection group was superior than the control group in clinical effectiveness(RR=1.36, 95%CI 1.25 to 1.49, P<0.000 01), increased DLCO value(MD=4.25, 95%CI 3.32 to 5.18, P<0.000 01), and increased PaO2 value(MD=14.51, 95%CI 12.35 to 16.68, P<0.000 01). The analysis results showed that Danhong injection could significantly reduce the level of TGF-β1 in serum. There were no serious or frequently happened adverse effects in the Danhong injection group, indicating high safety and good tolerance of Danhong injection in treatment of IPF. The current evidences suggested that Danhong injection in short term use(<12 weeks) could increase clinical effectiveness, improve DLCO and PaO2, and decrease the level of TGF-β1 in serum of IPF patients, with less adverse effects. However, these results should be carefully interpreted due to the low methodology quality and small sample size of trials, and this conclusion had to be further verified by high quality, large scale and double blinded RCTs. Copyright© by the Chinese Pharmaceutical Association.

Analysis and Comparison of Various Requirements Management Tools for Use in the Shipbuilding Industry

DTIC Science & Technology

2006-09-01

such products as MS Word, MS Excel, MS PowerPoint, Adobe Acrobat, Adobe FrameMaker , Claris FileMaker, Adobe PhotoShop and Adobe Illustrator, it is easy...Adobe FrameMaker , etc. Information can be exported out in the same formats as above plus HTML, MS PowerPoint, and MS Outlook. DOORS is very user...including Postscript, RTF (for PowerPoint), HTML, Interleaf, SVG, FrameMaker , HP LaserJet, HPGL, and EPS. Examples of such charts produced by DOORS

Efficacy of concurrent treatments in idiopathic pulmonary fibrosis patients with a rapid progression of respiratory failure: an analysis of a national administrative database in Japan.

PubMed

Oda, Keishi; Yatera, Kazuhiro; Fujino, Yoshihisa; Ishimoto, Hiroshi; Nakao, Hiroyuki; Hanaka, Tetsuya; Ogoshi, Takaaki; Kido, Takashi; Fushimi, Kiyohide; Matsuda, Shinya; Mukae, Hiroshi

2016-06-08

Some IPF patients show a rapid progression of respiratory failure. Most patients are treated with high-dose corticosteroids. However, no large clinical studies have investigated the prognosis or efficacy of combined treatments including high-dose corticosteroids in IPF patients with a rapid progression of respiratory failure. We enrolled IPF patients who received mechanical ventilation and high-dose corticosteroids between April 2010 and March 2013. Records were extracted from a Japanese nationwide inpatient database. We conducted a retrospective epidemiologic and prognostic analysis. Two hundred nine patients receiving an average of 12.8 days of ventilatory support were enrolled. There were 138 (66 %) fatal cases; the median survival was 21 days. The short-term (within 30 days) and long-term (within 90 days) survival rates were 44.6 and 24.6 %, respectively. The average monthly admission rate among the IPF patients with the rapid progression of respiratory failure in the winter was significantly higher than that in spring (p = 0.018). Survival did not differ to a statistically significant extent in the different geographic areas of Japan. Survivors were significantly younger (p = 0.002) with higher rates of mild dyspnea on admission (p = 0.012), they more frequently underwent bronchoscopy (p < 0.001), and received anticoagulants (p = 0.027), co-trimoxazole (p < 0.001) and macrolide (p = 0.02) more frequently than non-survivors. A multivariate logistic analysis demonstrated that two factors were significantly associated with a poor prognosis: >80 years of age (OR = 2.94, 95 % Cl 1.044-8.303; p = 0.041) and the intravenous administration of high-dose cyclophosphamide (OR = 3.17, 95 % Cl 1.101-9.148; p = 0.033). Undergoing bronchoscopy during intubation (OR = 0.25, 95 % Cl 0.079-0.798; p = 0.019) and the administration of co-trimoxazole (OR = 0.28, 95 % Cl 0.132-0.607; p = 0.001) and macrolides (OR = 0.37, 95 % Cl 0.155-0.867; p = 0.033) were significantly associated with a good prognosis. The dosage of co-trimoxazole significantly correlated with survival. Co-trimoxazole and macrolides may be a good addition to high-dose corticosteroids in the treatment of IPF patients with a rapid progression of respiratory failure.

Noninvasive ventilation in the event of acute respiratory failure in patients with idiopathic pulmonary fibrosis.

PubMed

Vianello, Andrea; Arcaro, Giovanna; Battistella, Laura; Pipitone, Emanuela; Vio, Stefania; Concas, Alessandra; Paladini, Luciana; Gallan, Federico; Marchi, Maria Rita; Tona, Francesco; Iliceto, Sabino

2014-08-01

Some patients with idiopathic pulmonary fibrosis (IPF) develop severe acute respiratory failure (ARF) requiring admission to an intensive care unit (ICU) and ventilatory support. A limited number of observational studies have reported that noninvasive ventilation (NIV) can be an effective treatment to support breathing and to prevent use of invasive mechanical ventilation in these patients. This study aimed to retrospectively investigate the clinical status and outcomes in IPF patients receiving NIV for ARF and to identify those clinical and laboratory characteristics, which could be considered risk factors for its failure. This is a retrospective analysis of short-term outcomes in 18 IPF patients being administered NIV for ARF. This study was conducted in a 4-bed respiratory ICU (RICU) in a university hospital. Eighteen IPF patients who were administered NIV between January 1, 2005, and April 30, 2013, were included. The outcome measures are the need for endotracheal intubation despite NIV treatment and mortality rate during their RICU stay. The length of the patients' stay in the RICU and their survival rate following RICU admission were also evaluated. Noninvasive ventilation was successful in 8 patients and unsuccessful in 10 who required endotracheal intubation. All the patients in the NIV failure group died within 20.2±15.3 days of intubation. The patients in the NIV success group spent fewer days in the RICU (11.6±4.5 vs 24.6±13.7; P=.0146). The median survival time was significantly shorter for the patients in the NIV failure with respect to the success group (18.0 [95% confidence interval {CI}, 9.0-25.0] vs 90.0 [95% CI, 65.0-305.0] days; P<.0001); the survival rate at 90 days was, likewise, lower in the NIV failure group (0% vs 34%±19.5%). At admission, the patients in the failure group had significantly higher respiratory rate values (36.9±7.8 vs 30.5±3.3 breaths/min; P=.036), plasma N-terminal fragment of the prohormone of B-type natriuretic peptide (NT-proBNP) levels (4528.8±4012.8 vs 634.6±808.0 pg/mL; P=.023) and serum C-reactive protein values (72.0±50.0 vs 20.7±24.0 μg/mL; P=.0289) with respect to those in the success group. Noninvasive ventilation failure was correlated to the plasma NT-proBNP levels at RICU admission (P=.0326) with an odds ratio of 12.2 (95% CI, 1.2 to infinity) in the patients with abnormally high values (>900 pg/mL). The outcome of IPF patients who were administered NIV was quite poor. The use of NIV was, nevertheless, found to be associated with clinical benefits in selected IPF patients, preventing the need for intubation and reducing the rate of complications/death. Elevated plasma NT-proBNP levels at the time of ICU admission is a simple clinical marker for poor NIV outcome. Copyright © 2014 Elsevier Inc. All rights reserved.

Video shot boundary detection using region-growing-based watershed method

NASA Astrophysics Data System (ADS)

Wang, Jinsong; Patel, Nilesh; Grosky, William

2004-10-01

In this paper, a novel shot boundary detection approach is presented, based on the popular region growing segmentation method - Watershed segmentation. In image processing, gray-scale pictures could be considered as topographic reliefs, in which the numerical value of each pixel of a given image represents the elevation at that point. Watershed method segments images by filling up basins with water starting at local minima, and at points where water coming from different basins meet, dams are built. In our method, each frame in the video sequences is first transformed from the feature space into the topographic space based on a density function. Low-level features are extracted from frame to frame. Each frame is then treated as a point in the feature space. The density of each point is defined as the sum of the influence functions of all neighboring data points. The height function that is originally used in Watershed segmentation is then replaced by inverting the density at the point. Thus, all the highest density values are transformed into local minima. Subsequently, Watershed segmentation is performed in the topographic space. The intuitive idea under our method is that frames within a shot are highly agglomerative in the feature space and have higher possibilities to be merged together, while those frames between shots representing the shot changes are not, hence they have less density values and are less likely to be clustered by carefully extracting the markers and choosing the stopping criterion.

Manual on characteristics of Landsat computer-compatible tapes produced by the EROS Data Center digital image processing system

USGS Publications Warehouse

Holkenbrink, Patrick F.

1978-01-01

Landsat data are received by National Aeronautics and Space Administration (NASA) tracking stations and converted into digital form on high-density tapes (HDTs) by the Image Processing Facility (IPF) at the Goddard Space Flight Center (GSFC), Greenbelt, Maryland. The HDTs are shipped to the EROS Data Center (EDC) where they are converted into customer products by the EROS Data Center digital image processing system (EDIPS). This document describes in detail one of these products: the computer-compatible tape (CCT) produced from Landsat-1, -2, and -3 multispectral scanner (MSS) data and Landsat-3 only return-beam vidicon (RBV) data. Landsat-1 and -2 RBV data will not be processed by IPF/EDIPS to CCT format.

High resolution multidetector CT aided tissue analysis and quantification of lung fibrosis

NASA Astrophysics Data System (ADS)

Zavaletta, Vanessa A.; Karwoski, Ronald A.; Bartholmai, Brian; Robb, Richard A.

2006-03-01

Idiopathic pulmonary fibrosis (IPF, also known as Idiopathic Usual Interstitial Pneumontis, pathologically) is a progressive diffuse lung disease which has a median survival rate of less than four years with a prevalence of 15-20/100,000 in the United States. Global function changes are measured by pulmonary function tests and the diagnosis and extent of pulmonary structural changes are typically assessed by acquiring two-dimensional high resolution CT (HRCT) images. The acquisition and analysis of volumetric high resolution Multi-Detector CT (MDCT) images with nearly isotropic pixels offers the potential to measure both lung function and structure. This paper presents a new approach to three dimensional lung image analysis and classification of normal and abnormal structures in lungs with IPF.

Section BB Hatch Coating; Framing Plan on Line C Lodging ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Section B-B Hatch Coating; Framing Plan on Line C Lodging Knees at Hatch; Elevation A-A Hull Framing; Section at Hatch Frame 36, Starboard Looking Aft; Midship Section Frame 37, Port Looking Aft - Steam Schooner WAPAMA, Kaiser Shipyard No. 3 (Shoal Point), Richmond, Contra Costa County, CA

Levels of circulating MMP-7 degraded elastin are elevated in pulmonary disorders.

PubMed

Kristensen, J H; Larsen, L; Dasgupta, B; Brodmerkel, C; Curran, M; Karsdal, M A; Sand, J M B; Willumsen, N; Knox, A J; Bolton, C E; Johnson, S R; Hägglund, P; Svensson, B; Leeming, D J

2015-11-01

Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantification of MMP-7 generated elastin fragments (ELM7) was therefore developed to investigate MMP-7 derived elastin degradation in pulmonary disorders such as idiopathic pulmonary fibrosis (IPF) and lung cancer. Monoclonal antibodies (mABs) were raised against eight carefully selected MMP-7 cleavage sites on elastin. After characterisation and validation of the mABs, one mAB targeting the ELM7 fragment was chosen. ELM7 fragment levels were assessed in serum samples from patients diagnosed with IPF (n=123, baseline samples, CTgov reg. NCT00786201), and lung cancer (n=40) and compared with age- and sex-matched controls. The ELM7 assay was specific towards in vitro MMP-7 degraded elastin and the ELM7 neoepitope but not towards other MMP-7 derived elastin fragments. Serum ELM7 levels were significantly increased in IPF (113%, p<0.0001) and lung cancer (96%, p<0.0001) compared to matched controls. MMP-7-generated elastin fragments can be quantified in serum and may reflect pathological lung tissue turnover in several important lung diseases. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Anti-fibrotic effects of pirfenidone and rapamycin in primary IPF fibroblasts and human alveolar epithelial cells.

PubMed

Molina-Molina, M; Machahua-Huamani, C; Vicens-Zygmunt, V; Llatjós, R; Escobar, I; Sala-Llinas, E; Luburich-Hernaiz, P; Dorca, J; Montes-Worboys, A

2018-04-27

Pirfenidone, a pleiotropic anti-fibrotic treatment, has been shown to slow down disease progression of idiopathic pulmonary fibrosis (IPF), a fatal and devastating lung disease. Rapamycin, an inhibitor of fibroblast proliferation could be a potential anti-fibrotic drug to improve the effects of pirfenidone. Primary lung fibroblasts from IPF patients and human alveolar epithelial cells (A549) were treated in vitro with pirfenidone and rapamycin in the presence or absence of transforming growth factor β1 (TGF-β). Extracellular matrix protein and gene expression of markers involved in lung fibrosis (tenascin-c, fibronectin, collagen I [COL1A1], collagen III [COL3A1] and α-smooth muscle actin [α-SMA]) were analyzed. A cell migration assay in pirfenidone, rapamycin and TGF-β-containing media was performed. Gene and protein expression of tenascin-c and fibronectin of fibrotic fibroblasts were reduced by pirfenidone or rapamycin treatment. Pirfenidone-rapamycin treatment did not revert the epithelial to mesenchymal transition pathway activated by TGF-β. However, the drug combination significantly abrogated fibroblast to myofibroblast transition. The inhibitory effect of pirfenidone on fibroblast migration in the scratch-wound assay was potentiated by rapamycin combination. These findings indicate that the combination of pirfenidone and rapamycin widen the inhibition range of fibrogenic markers and prevents fibroblast migration. These results would open a new line of research for an anti-fibrotic combination therapeutic approach.

Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis.

PubMed

Jacob, Joseph; Bartholmai, Brian J; Rajagopalan, Srinivasan; Kokosi, Maria; Maher, Toby M; Nair, Arjun; Karwoski, Ronald; Renzoni, Elisabetta; Walsh, Simon L F; Hansell, David M; Wells, Athol U

2017-07-01

This study aimed to investigate whether the combination of fibrosis and emphysema has a greater effect than the sum of its parts on functional indices and outcome in idiopathic pulmonary fibrosis (IPF), using visual and computer-based (CALIPER) computed tomography (CT) analysis.Consecutive patients (n=272) with a multidisciplinary IPF diagnosis had the extent of interstitial lung disease (ILD) scored visually and by CALIPER. Visually scored emphysema was subcategorised as isolated or mixed with fibrotic lung. The CT scores were evaluated against functional indices forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide ( D LCO ), transfer coefficient of the lung for carbon monoxide ( K CO ), composite physiologic index (CPI)) and mortality.The presence and extent of emphysema had no impact on survival. Results were maintained following correction for age, gender, smoking status and baseline severity using D LCO , and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (p<0.0001), with no independent effect on FVC from isolated emphysema. Conversely, only isolated emphysema (p<0.0001) reduced gas transfer ( D LCO ).There is no prognostic impact of emphysema in IPF, beyond that explained by the additive extents of both fibrosis and emphysema. With respect to the location of pulmonary fibrosis, emphysema distribution determines the functional effects of emphysema. Copyright ©ERS 2017.

Inference and quantification of peptidoforms in large sample cohorts by SWATH-MS

PubMed Central

Röst, Hannes L; Ludwig, Christina; Buil, Alfonso; Bensimon, Ariel; Soste, Martin; Spector, Tim D; Dermitzakis, Emmanouil T; Collins, Ben C; Malmström, Lars; Aebersold, Ruedi

2017-01-01

The consistent detection and quantification of protein post-translational modifications (PTMs) across sample cohorts is an essential prerequisite for the functional analysis of biological processes. Data-independent acquisition (DIA), a bottom-up mass spectrometry based proteomic strategy, exemplified by SWATH-MS, provides complete precursor and fragment ion information of a sample and thus, in principle, the information to identify peptidoforms, the modified variants of a peptide. However, due to the convoluted structure of DIA data sets the confident and systematic identification and quantification of peptidoforms has remained challenging. Here we present IPF (Inference of PeptidoForms), a fully automated algorithm that uses spectral libraries to query, validate and quantify peptidoforms in DIA data sets. The method was developed on data acquired by SWATH-MS and benchmarked using a synthetic phosphopeptide reference data set and phosphopeptide-enriched samples. The data indicate that IPF reduced false site-localization by more than 7-fold in comparison to previous approaches, while recovering 85.4% of the true signals. IPF was applied to detect and quantify peptidoforms carrying ten different types of PTMs in DIA data acquired from more than 200 samples of undepleted blood plasma of a human twin cohort. The data approportioned, for the first time, the contribution of heritable, environmental and longitudinal effects on the observed quantitative variability of specific modifications in blood plasma of a human population. PMID:28604659

New parameters available on Sysmex XE-5000 hematology analyzers contribute to differentiating dengue from leptospirosis and enteric fever.

PubMed

Oehadian, A; Michels, M; de Mast, Q; Prihatni, D; Puspita, M; Hartantri, Y; Sinarta, S; van der Ven, A J A M; Alisjahbana, B

2015-12-01

Distinguishing dengue virus infection from other febrile thrombocytopenic illnesses such as leptospirosis or enteric fever is important but difficult, due to the unavailability of reliable diagnostic tests. Sysmex XE-5000 hematology analyzers use fluorescence flow cytometry to quantitate new parameters including cells in the atypical lymphocyte area (AL), high-fluorescent lymphocyte counts (HFLC), immature granulocytes (IG), and immature platelets (IPF). This study aimed to investigate whether these parameters can help to discriminate between the diseases. We compared hematocytometry performed by a Sysmex XE-5000 analyzer in Indonesian adults with dengue (n = 93), leptospirosis (n = 11), and enteric fever (n = 6) infection, and in healthy controls (n = 28). Receiver operating characteristic curves comparing dengue and leptospirosis showed that dengue was characterized by increased %AL (AUC 0.87; 95% CI 0.70-1.03), %HFLC (AUC 0.89; 95% CI 0.78-0.99), and %IPF (AUC 0.81; 95% CI 0.65-0.97), while patients with leptospirosis had increased %IG (AUC 0.86; 95% CI 0.71-1.02). Low %AL, %HFLC, and %IG supported a diagnosis of enteric fever. The detection of AL, HFLC, IG, and IPF by Sysmex XE-5000 hematology analyzers can help to differentiate between common causes of febrile illnesses with thrombocytopenia in dengue endemic areas. We recommend further investigating the discriminatory value of these parameters in clinical practice. © 2015 John Wiley & Sons Ltd.

Personalized medicine in interstitial lung diseases.

PubMed

Spagnolo, Paolo; Oldham, Justin M; Jones, Mark G; Lee, Joyce S

2017-05-01

A number of recent studies have explored the possibility to apply personalized medicine to interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF), the most common and deadly of the idiopathic interstitial pneumonias. In our review, we summarize and discuss the most recent literature on personalized medicine in IPF as well as hypersensitivity pneumonitis and sarcoidosis, with emphasis on patient subgroups for which a personalized approach to disease prognostication and management may become a reality in the near future. Most of the studies that have explored the applicability of personalized medicine to ILDs have been conducted in patients with IPF. Such studies have suggested the existence of several distinct disease subgroups defined by similar genetic profiles, molecular pathways, exposures and individual lifestyles. Personalized medicine in hypersensitivity pneumonitis is in its infancy. The development and applicability of personalized medicine to sarcoidosis, on the other hand, remains problematic for several reasons, including the lack of a diagnostic gold standard, the highly variable and unpredictable disease course, particularly across patients of different ethnicities, the poor correlation between disease activity and disease severity and the lack of a validated management algorithm. A number of distinct patient subgroups have been identified in ILDs. Although available data need to be validated longitudinally, the possibility to study homogeneous groups of patients may allow prediction of disease behavior and response to treatment with dramatic clinical implications.

Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis.

PubMed

Lancaster, Lisa H; de Andrade, Joao A; Zibrak, Joseph D; Padilla, Maria L; Albera, Carlo; Nathan, Steven D; Wijsenbeek, Marlies S; Stauffer, John L; Kirchgaessler, Klaus-Uwe; Costabel, Ulrich

2017-12-31

Pirfenidone is one of two approved therapies for the treatment of idiopathic pulmonary fibrosis (IPF). Randomised controlled clinical trials and subsequent post hoc analyses have demonstrated that pirfenidone reduces lung function decline, decreases mortality and improves progression-free survival. Long-term extension trials, registries and real-world studies have also shown similar treatment effects with pirfenidone. However, for patients with IPF to obtain the maximum benefits of pirfenidone treatment, the potential adverse events (AEs) associated with pirfenidone need to be managed. This review highlights the well-known and established safety profile of pirfenidone based on randomised controlled clinical trials and real-world data. Key strategies for preventing and managing the most common pirfenidone-related AEs are described, with the goal of maximising adherence to pirfenidone with minimal AEs. Copyright ©ERS 2017.

Mortality from idiopathic pulmonary fibrosis: a temporal trend analysis in Brazil, 1979-2014

PubMed Central

Algranti, Eduardo; Saito, Cézar Akiyoshi; Silva, Diego Rodrigues Mendonça e; Carneiro, Ana Paula Scalia; Bussacos, Marco Antonio

2017-01-01

ABSTRACT Objective: To analyze mortality from idiopathic pulmonary fibrosis (IPF) in Brazil over the period 1979-2014. Methods: Microdata were extracted from the Brazilian National Ministry of Health Mortality Database. Only deaths for which the underlying cause was coded as International Classification of Diseases version 9 (ICD-9) 515 or 516.3 (until 1995) or as ICD version 10 (ICD-10) J84.1 (from 1996 onward) were included in our analysis. Standardized mortality rates were calculated for the 2010 Brazilian population. The annual trend in mortality rates was analyzed by joinpoint regression. We calculated risk ratios (RRs) by age group, time period of death, and gender, using a person-years denominator. Results: A total of 32,092 deaths were recorded in the study period. Standardized mortality rates trended upward, rising from 0.24/100,000 population in 1979 to 1.10/100,000 population in 2014. The annual upward trend in mortality rates had two inflection points, in 1992 and 2008, separating three distinct time segments with an annual growth of 2.2%, 6.8%, and 2.4%, respectively. The comparison of RRs for the age groups, using the 50- to 54-year age group as a reference, and for the study period, using 1979-1984 as a reference, were 16.14 (14.44-16.36) and 6.71 (6.34-7.12), respectively. Men compared with women had higher standardized mortality rates (per 100,000 person-years) in all age groups. Conclusion: Brazilian IPF mortality rates are lower than those of other countries, suggesting underdiagnosis or underreporting. The temporal trend is similar to those reported in the literature and is not explained solely by population aging. PMID:29340493

Point cloud registration from local feature correspondences-Evaluation on challenging datasets.

PubMed

Petricek, Tomas; Svoboda, Tomas

2017-01-01

Registration of laser scans, or point clouds in general, is a crucial step of localization and mapping with mobile robots or in object modeling pipelines. A coarse alignment of the point clouds is generally needed before applying local methods such as the Iterative Closest Point (ICP) algorithm. We propose a feature-based approach to point cloud registration and evaluate the proposed method and its individual components on challenging real-world datasets. For a moderate overlap between the laser scans, the method provides a superior registration accuracy compared to state-of-the-art methods including Generalized ICP, 3D Normal-Distribution Transform, Fast Point-Feature Histograms, and 4-Points Congruent Sets. Compared to the surface normals, the points as the underlying features yield higher performance in both keypoint detection and establishing local reference frames. Moreover, sign disambiguation of the basis vectors proves to be an important aspect in creating repeatable local reference frames. A novel method for sign disambiguation is proposed which yields highly repeatable reference frames.

Idiopathic Pulmonary Fibrosis

MedlinePlus

... IPF. More research is needed to confirm this theory. Signs, Symptoms, and Complications The signs and symptoms ... conserving techniques Breathing strategies Psychological counseling and/or group support For more information, go to the Health ...

Familial Pulmonary Fibrosis

MedlinePlus

... called Familial Pulmonary Fibrosis (FPF) or Familial Interstitial Pneumonia (FIP). The most common definition of FPF is two or more primary biological family members (parent, child, or sibling) with the diagnosis of IPF or ...

Frame synchronization methods based on channel symbol measurements

NASA Technical Reports Server (NTRS)

Dolinar, S.; Cheung, K.-M.

1989-01-01

The current DSN frame synchronization procedure is based on monitoring the decoded bit stream for the appearance of a sync marker sequence that is transmitted once every data frame. The possibility of obtaining frame synchronization by processing the raw received channel symbols rather than the decoded bits is explored. Performance results are derived for three channel symbol sync methods, and these are compared with results for decoded bit sync methods reported elsewhere. It is shown that each class of methods has advantages or disadvantages under different assumptions on the frame length, the global acquisition strategy, and the desired measure of acquisition timeliness. It is shown that the sync statistics based on decoded bits are superior to the statistics based on channel symbols, if the desired operating region utilizes a probability of miss many orders of magnitude higher than the probability of false alarm. This operating point is applicable for very large frame lengths and minimal frame-to-frame verification strategy. On the other hand, the statistics based on channel symbols are superior if the desired operating point has a miss probability only a few orders of magnitude greater than the false alarm probability. This happens for small frames or when frame-to-frame verifications are required.

A Didactical Framework for Studying Students' and Teachers' Activities when Learning and Teaching Mathematics

ERIC Educational Resources Information Center

Robert, Aline

2012-01-01

This paper draws an Activity Theoretical frame specific to mathematics at school with reference to both Vygotskian and Piagetian approaches. At a local point of view, the frame is oriented toward analysis of students' mathematical activities in the classroom. This local point of view is extended to a global point of view, to gain access to what…

Heart Rate Recovery After 6-Min Walk Test Predicts Survival in Patients With Idiopathic Pulmonary Fibrosis

PubMed Central

Swigris, Jeffrey J.; Swick, Jeff; Wamboldt, Frederick S.; Sprunger, David; du Bois, Roland; Fischer, Aryeh; Cosgrove, Gregory P.; Frankel, Stephen K.; Fernandez-Perez, Evans R.; Kervitsky, Dolly; Brown, Kevin K.

2009-01-01

Background: In patients with idiopathic pulmonary fibrosis (IPF), our objectives were to identify predictors of abnormal heart rate recovery (HRR) at 1 min after completion of a 6-min walk test (6MWT) [HRR1] and 2 min after completion of a 6MWT (HRR2), and to determine whether abnormal HRR predicts mortality. Methods: From 2003 to 2008, we identified IPF patients who had been evaluated at our center (n = 76) with a pulmonary physiologic examination and the 6MWT. We used logistic regression to identify predictors of abnormal HRR, the product-limit method to compare survival in the sample stratified on HRR, and Cox proportional hazards analysis to estimate the prognostic capability of abnormal HRR. Results: Cutoff values were 13 beats for abnormal HRR1 and 22 beats for HRR2. In a multivariable model, predictors of abnormal HRR1 were diffusing capacity of the lung for carbon monoxide (odds ratio [OR], 0.4 per 10% predicted; 95% confidence interval [CI], 0.2 to 0.7; p = 0.003), change in heart rate from baseline to maximum (OR, 0.9; 95% CI, 0.8 to 0.97; p = 0.01), and having a right ventricular systolic pressure > 35 mm Hg as determined by transthoracic echocardiogram (OR, 12.7; 95% CI, 2.0 to 79.7; p = 0.01). Subjects with an abnormal HRR had significantly worse survival than subjects with a normal HRR (for HRR1, p = 0.0007 [log-rank test]; for HRR2, p = 0.03 [log-rank test]); these results held for the subgroup of 30 subjects without resting pulmonary hypertension (HRR1, p = 0.04 [log-rank test]). Among several candidate variables, abnormal HRR1 appeared to be the most potent predictor of mortality (hazard ratio, 5.2; 95% CI, 1.8 to 15.2; p = 0.004). Conclusion: Abnormal HRR after 6MWT predicts mortality in IPF patients. Research is needed to confirm these findings prospectively and to examine the mechanisms of HRR in IPF patients. PMID:19395579

The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury.

PubMed

Rathinasabapathy, Anandharajan; Horowitz, Alana; Horton, Kelsey; Kumar, Ashok; Gladson, Santhi; Unger, Thomas; Martinez, Diana; Bedse, Gaurav; West, James; Raizada, Mohan K; Steckelings, Ulrike M; Sumners, Colin; Katovich, Michael J; Shenoy, Vinayak

2018-01-01

Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH) is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies. Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT 2 ) receptor confers protection against a host of diseases. In this study, we investigated the therapeutic potential of Compound 21 (C21), a selective AT 2 receptor agonist in the bleomycin model of lung injury. A single intra-tracheal administration of bleomycin (2.5 mg/kg) to 8-week old male Sprague Dawley rats resulted in lung fibrosis and PH. Two experimental protocols were followed: C21 was administered (0.03 mg/kg/day, ip) either immediately (prevention protocol, BCP) or after 3 days (treatment protocol, BCT) of bleomycin-instillation. Echocardiography, hemodynamic, and Fulton's index assessments were performed after 2 weeks of bleomycin-instillation. Lung tissue was processed for gene expression, hydroxyproline content (a marker of collagen deposition), and histological analysis. C21 treatment prevented as well as attenuated the progression of lung fibrosis, and accompanying PH. The beneficial effects of C21 were associated with decreased infiltration of macrophages in the lungs, reduced lung inflammation and diminished pulmonary collagen accumulation. Further, C21 treatment also improved pulmonary pressure, reduced muscularization of the pulmonary vessels and normalized cardiac function in both the experimental protocols. However, there were no major differences in any of the outcomes measured from the two experimental protocols. Collectively, our findings indicate that stimulation of the AT 2 receptor by C21 attenuates bleomycin-induced lung injury and associated cardiopulmonary pathology, which needs to be further explored as a promising approach for the clinical treatment of IPF and Group III PH.

Alignment of olivine crystals during diffusion creep in oceanic peridotite mylonites

NASA Astrophysics Data System (ADS)

Deems, N. J.; Warren, J. M.; Wolfson-Schwehr, M.

2014-12-01

At small grain sizes (<10 µm), olivine is expected to deform by diffusion creep at lithospheric conditions. Microstructural analysis by electron backscatter diffraction of 13 peridotite mylonites from St. Paul's Rocks (SPR) indicates that olivine has a pronounced axial-[010] lattice preferred orientation (i.e. [010] clusters perpendicular to foliation, while [100] and [001] are dispersed in the foliation plane) and a mean grain size of ~7µm. Holtzman et al. (2003) has observed similar LPOs in partially molten samples experimentally deformed under simple shear at lithospheric conditions. The occurrence of a lattice preferred orientation (LPO) is typically interpreted as indicating deformation by dislocation creep. In addition, compositional maps of the samples show that amphibole (pargasite) is ubiquitous. As the presence of pargasite in peridotites is controlled in part by the activity of plagioclase and water at high temperatures (Lynkins and Jenkins, 1992), we infer this as evidence for the presence of pre- to syn-tectonic trapped melt. In order to explain the observed LPO in SPR mylonites, we evaluate the hypothesis that alignment occurred during diffusion creep, such as observed in experiments by Sundberg and Cooper (2008) and Miyazaki et al., (2013). To explore this hypothesis, we conducted analyses of low angle (2-10°) rotation axis inverse pole figures (IPFs), which can often provide insight into the operative slip system(s). Analyses of low angle IPFs from SPR, however, showed no definitive correlation to any one particular slip system. On the other hand, high angle IPFs showed intense clustering of rotational axes at 75-90° about [010], indicating that [100] and [001] align nearly perpendicular to [010]. Based on the IPF analysis and evidence of pre- to syn-tectonic melt, we conclude that the presence of melt lubricated grain boundaries, which resulted in rigid rotation of grains and alignment of the [010] axes controlled by the orthorhombic crystal habit of olivine. That is, as [010] is shortest in terms of habit, this allows [010] to align perpendicular to the shear plane, while the [100] and [001] axes are dispersed in the plane parallel to shear. Thus, SPR mylonites represent a natural example of olivine LPO formation during diffusion creep.

Evaluation of permeability alteration and epithelial-mesenchymal transition induced by transforming growth factor-β1 in A549, NCI-H441, and Calu-3 cells: Development of an in vitro model of respiratory epithelial cells in idiopathic pulmonary fibrosis.

PubMed

Togami, Kohei; Yamaguchi, Kotaro; Chono, Sumio; Tada, Hitoshi

2017-07-01

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease, which is accompanied by changes in lung structure. With regard to treatment, aerosolized drugs administered intrapulmonarily are rapidly distributed into the plasma and do not remain in the lungs due to damage to the alveolar epithelium that occurs from pulmonary fibrosis. In this study, we sought to develop an in vitro model of respiratory epithelial cells in IPF for the evaluation of the intrapulmonary distribution of aerosolized drugs. We investigated transforming growth factor (TGF)-β 1 -induced epithelial-mesenchymal transition (EMT) and permeability alteration in A549, NCI-H441, and Calu-3 cell monolayers. After TGF-β 1 treatment of A549, NCI-H441, and Calu-3 cells, EMT markers including E-cadherin and vimentin and tight junction proteins including claudins-1, -3, and -5 were stained using immunofluorescence methods and detected using immunoblotting methods. Transport experiments were performed using TGF-β 1 -treated cell monolayers and fluorescein isothiocyanate dextrans (FD; 4.4, 10, and 70kDa). In addition, TGF-β 1 -induced apoptosis and necrosis were evaluated by flow cytometry using Annexin V and ethidium homodimer III, respectively. In NCI-H441 cells, incomplete EMT, destruction of claudins-1 and -3, and enhancement of FD permeability were caused by TGF-β 1 treatment. In A549 cells, complete EMT occurred but was not adequate for transport experiments because of low transepithelial electrical resistance. Whereas in Calu-3 cells, no changes were observed. TGF-β 1 -induced apoptosis and necrosis were not observed in any of the cell lines. Incomplete EMT and permeability enhancement were observed in the alveolar epithelium of IPF. Therefore, our results indicate that TGF-β 1 -treated NCI-H441 cell monolayers may serve as a useful in vitro model of respiratory epithelial cells for IPF. Copyright © 2017 Elsevier Inc. All rights reserved.

Four-Year-Olds Use a Mixture of Spatial Reference Frames

PubMed Central

Negen, James; Nardini, Marko

2015-01-01

Keeping track of unseen objects is an important spatial skill. In order to do this, people must situate the object in terms of different frames of reference, including body position (egocentric frame of reference), landmarks in the surrounding environment (extrinsic frame reference), or other attached features (intrinsic frame of reference). Nardini et al. hid a toy in one of 12 cups in front of children, turned the array when they were not looking, and then asked them to point to the cup with the toy. This forced children to use the intrinsic frame (information about the array of cups) to locate the hidden toy. Three-year-olds made systematic errors by using the wrong frame of reference, 4-year-olds were at chance, and only 5- and 6-year-olds were successful. Can we better understand the developmental change that takes place at four years? This paper uses a modelling approach to re-examine the data and distinguish three possible strategies that could lead to the previous results at four years: (1) Children were choosing cups randomly, (2) Children were pointing between the egocentric/extrinsic-cued location and the correct target, and (3) Children were pointing near the egocentric/extrinsic-cued location on some trials and near the target on the rest. Results heavily favor the last possibility: 4-year-olds were not just guessing or trying to combine the available frames of reference. They were using the intrinsic frame on some trials, but not doing so consistently. These insights suggest that accounts of improving spatial performance at 4 years need to explain why there is a mixture of responses. Further application of the selected model also suggests that children become both more reliant on the correct frame and more accurate with any chosen frame as they mature. PMID:26133990

Spatial Updating Strategy Affects the Reference Frame in Path Integration.

PubMed

He, Qiliang; McNamara, Timothy P

2018-06-01

This study investigated how spatial updating strategies affected the selection of reference frames in path integration. Participants walked an outbound path consisting of three successive waypoints in a featureless environment and then pointed to the first waypoint. We manipulated the alignment of participants' final heading at the end of the outbound path with their initial heading to examine the adopted reference frame. We assumed that the initial heading defined the principal reference direction in an allocentric reference frame. In Experiment 1, participants were instructed to use a configural updating strategy and to monitor the shape of the outbound path while they walked it. Pointing performance was best when the final heading was aligned with the initial heading, indicating the use of an allocentric reference frame. In Experiment 2, participants were instructed to use a continuous updating strategy and to keep track of the location of the first waypoint while walking the outbound path. Pointing performance was equivalent regardless of the alignment between the final and the initial headings, indicating the use of an egocentric reference frame. These results confirmed that people could employ different spatial updating strategies in path integration (Wiener, Berthoz, & Wolbers Experimental Brain Research 208(1) 61-71, 2011), and suggested that these strategies could affect the selection of the reference frame for path integration.

What Causes Idiopathic Pulmonary Fibrosis?

MedlinePlus

... IPF. More research is needed to confirm this theory. Signs, Symptoms, and Complications The signs and symptoms ... conserving techniques Breathing strategies Psychological counseling and/or group support For more information, go to the Health ...

VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease.

PubMed

Barratt, Shaney L; Flower, Victoria A; Pauling, John D; Millar, Ann B

2018-04-24

Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease.

WISP1 mediates IL-6-dependent proliferation in primary human lung fibroblasts.

PubMed

Klee, S; Lehmann, M; Wagner, D E; Baarsma, H A; Königshoff, M

2016-02-12

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. IPF is characterized by epithelial cell injury and reprogramming, increases in (myo)fibroblasts, and altered deposition of extracellular matrix. The Wnt1-inducible signaling protein 1 (WISP1) is involved in impaired epithelial-mesenchymal crosstalk in pulmonary fibrosis. Here, we aimed to further investigate WISP1 regulation and function in primary human lung fibroblasts (phLFs). We demonstrate that WISP1 is directly upregulated by Transforming growth factor β1 (TGFβ1) and Tumor necrosis factor α (TNFα) in phLFs, using a luciferase-based reporter system. WISP1 mRNA and protein secretion increased in a time- and concentration-dependent manner by TGFβ1 and TNFα in phLFs, as analysed by qPCR and ELISA, respectively. Notably, WISP1 is required for TGFβ1- and TNFα-dependent induction of interleukin 6 (IL-6), a mechanism that is conserved in IPF phLFs. The siRNA-mediated WISP1 knockdown led to a significant IL-6 reduction after TGFβ1 or TNFα stimulation. Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of WISP1 reduced phLFs proliferation, a process that was in part rescued by IL-6. Taken together, these results strongly indicate that WISP1-induced IL-6 expression contributes to the pro-proliferative effect on fibroblasts, which is likely orchestrated by a variety of profibrotic mediators, including Wnts, TGFβ1 and TNFα.

Microbiological, Nutritional, and Sensory Quality of Bread Produced from Wheat and Potato Flour Blends

PubMed Central

Ijah, Udeme Joshua Josiah; Aduloju, Mercy Oluwayemisi; Aransiola, Sesan Abiodun

2014-01-01

Dehydrated uncooked potato (Irish and sweet) flour was blended by weight with commercial wheat flour at 0 to 10% levels of substitution to make bread. Comparative study of the microbial and nutritional qualities of the bread was undertaken. The total aerobic bacterial counts ranged from 3.0 × 105 cfu/g to 1.09 × 106 cfu/g while the fungal counts ranged from 8.0 × 101 cfu/g to 1.20 × 103 cfu/g of the sample. Coliforms were not detected in the bread. Bacteria isolated were species of Bacillus, Staphylococcus, and Micrococcus while fungi isolates were species of Aspergillus, Penicillium, Rhizopus, and Mucor. The mean sensory scores (color, aroma, taste, texture, and general acceptability) were evaluated. The color of the bread baked from WF/IPF2 (wheat/Irish potato flour, 95 : 5%) blend was preferred to WF (wheat flour, 100%) while WF/SPF1 (wheat/sweet potato flour, 100%) and WF/IPF1 (wheat/Irish potato flour, 90 : 10%) aroma were preferred to WF. However, the bread baked from WF, WF/IPF2 (wheat flour/Irish potato flour, 95 : 5%), and WF/SPF2 (wheat/sweet potato flour, 95 : 5%) was more acceptable than other blends. The use of hydrated potato flour in bread making is advantageous due to increased nutritional value, higher bread yield, and reduced rate of staling. PMID:26904642

Pirfenidone treatment in idiopathic pulmonary fibrosis: A Saudi experience.

PubMed

Alhamad, Esam H

2015-01-01

Recent trials involving pirfenidone suggest a beneficial effect in the treatment of idiopathic pulmonary fibrosis (IPF). To report on the efficacy and safety of pirfenidone in the treatment of patients with IPF, at a tertiary care hospital in Saudi Arabia. The study included 58 patients with IPF who were evaluated from March 2012 to March 2013. During the study period, 33 patients received pirfenidone, and the remaining patients (n = 25) served as a control group. Baseline clinical characteristics, physiological parameters and the results of a 36-Item Short Form Health Survey (SF-36) were compared between the groups. Furthermore, we compared changes in forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLco), six-minute walk distance (6MWD) and SF-36 for both groups during follow-up. The last follow-up period ended in January 2014. There were no significant differences in baseline clinical characteristics between the groups. Furthermore, we found no differences in FVC, DLco and SF-36 during follow-up (median, 12 months). However, patients receiving pirfenidone treatment were less likely to experience reductions in 6MWD compared with the control group (13% vs. 52%, respectively; P = 0.001). Although adverse events were more frequently reported by the pirfenidone group compared with the control group (85 vs. 56%, respectively; P = 0.015), these patients did not require discontinuation of treatment. Pirfenidone treatment preserves functional capacity, as reflected by the 6MWD. Adverse events associated with pirfenidone treatment were generally well tolerated by the patients.

Hypoxia induces pulmonary fibroblast proliferation through NFAT signaling.

PubMed

Senavirathna, Lakmini Kumari; Huang, Chaoqun; Yang, Xiaoyun; Munteanu, Maria Cristina; Sathiaseelan, Roshini; Xu, Dao; Henke, Craig A; Liu, Lin

2018-02-09

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and typically fatal lung disease with a very low survival rate. Excess accumulation of fibroblasts, myofibroblasts and extracellular matrix creates hypoxic conditions within the lungs, causing asphyxiation. Hypoxia is, therefore, one of the prominent features of IPF. However, there have been few studies concerning the effects of hypoxia on pulmonary fibroblasts. In this study, we investigated the molecular mechanisms of hypoxia-induced lung fibroblast proliferation. Hypoxia increased the proliferation of normal human pulmonary fibroblasts and IPF fibroblasts after exposure for 3-6 days. Cell cycle analysis demonstrated that hypoxia promoted the G1/S phase transition. Hypoxia downregulated cyclin D1 and A2 levels, while it upregulated cyclin E1 protein levels. However, hypoxia had no effect on the protein expression levels of cyclin-dependent kinase 2, 4, and 6. Chemical inhibition of hypoxia-inducible factor (HIF)-2 reduced hypoxia-induced fibroblast proliferation. Moreover, silencing of Nuclear Factor Activated T cell (NFAT) c2 attenuated the hypoxia-mediated fibroblasts proliferation. Hypoxia also induced the nuclear translocation of NFATc2, as determined by immunofluorescence staining. NFAT reporter assays showed that hypoxia-induced NFAT signaling activation is dependent on HIF-2, but not HIF-1. Furthermore, the inhibition or silencing of HIF-2, but not HIF-1, reduced the hypoxia-mediated NFATc2 nuclear translocation. Our studies suggest that hypoxia induces the proliferation of human pulmonary fibroblasts through NFAT signaling and HIF-2.

Protein Folding and the Challenges of Maintaining Endoplasmic Reticulum Proteostasis in Idiopathic Pulmonary Fibrosis.

PubMed

Romero, Freddy; Summer, Ross

2017-11-01

Alveolar epithelial type II (AEII) cells are "professional" secretory cells that synthesize and secrete massive quantities of proteins to produce pulmonary surfactant and maintain airway immune defenses. To facilitate this high level of protein synthesis, AEII cells are equipped with an elaborate endoplasmic reticulum (ER) structure and possess an abundance of the machinery needed to fold, assemble, and secrete proteins. However, conditions that suddenly increase the quantity of new proteins entering the ER or that impede the capacity of the ER to fold proteins can cause misfolded or unfolded proteins to accumulate in the ER lumen, also called ER stress. To minimize this stress, AEII cells adapt by (1) reducing the quantity of proteins entering the ER, (2) increasing the amount of protein-folding machinery, and (3) removing misfolded proteins when they accumulate. Although these adaptive responses, aptly named the unfolded protein response, are usually effective in reducing ER stress, chronic aggregation of misfolded proteins is recognized as a hallmark feature of AEII cells in patients with idiopathic pulmonary fibrosis (IPF). Although mutations in surfactant proteins are linked to the development of ER stress in some rare IPF cases, the mechanisms causing protein misfolding in most cases are unknown. In this article, we review the mechanisms regulating ER proteostasis and highlight specific aspects of protein folding and the unfolded protein response that are most vulnerable to failure. Then, we postulate mechanisms other than genetic mutations that might contribute to protein aggregation in the alveolar epithelium of IPF lung.

Gremlin-1 Overexpression in Mouse Lung Reduces Silica-Induced Lymphocyte Recruitment – A Link to Idiopathic Pulmonary Fibrosis through Negative Correlation with CXCL10 Chemokine

PubMed Central

Koli, Katri; Sutinen, Eva; Rönty, Mikko; Rantakari, Pia; Fortino, Vittorio; Pulkkinen, Ville; Greco, Dario; Sipilä, Petra; Myllärniemi, Marjukka

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is characterized by activation and injury of epithelial cells, the accumulation of connective tissue and changes in the inflammatory microenvironment. The bone morphogenetic protein (BMP) inhibitor protein gremlin-1 is associated with the progression of fibrosis both in human and mouse lung. We generated a transgenic mouse model expressing gremlin-1 in type II lung epithelial cells using the surfactant protein C (SPC) promoter and the Cre-LoxP system. Gremlin-1 protein expression was detected specifically in the lung after birth and did not result in any signs of respiratory insufficiency. Exposure to silicon dioxide resulted in reduced amounts of lymphocyte aggregates in transgenic lungs while no alteration in the fibrotic response was observed. Microarray gene expression profiling and analyses of bronchoalveolar lavage fluid cytokines indicated a reduced lymphocytic response and a downregulation of interferon-induced gene program. Consistent with reduced Th1 response, there was a downregulation of the mRNA and protein expression of the anti-fibrotic chemokine CXCL10, which has been linked to IPF. In human IPF patient samples we also established a strong negative correlation in the mRNA expression levels of gremlin-1 and CXCL10. Our results suggest that in addition to regulation of epithelial-mesenchymal crosstalk during tissue injury, gremlin-1 modulates inflammatory cell recruitment and anti-fibrotic chemokine production in the lung. PMID:27428020

Gremlin-1 Overexpression in Mouse Lung Reduces Silica-Induced Lymphocyte Recruitment - A Link to Idiopathic Pulmonary Fibrosis through Negative Correlation with CXCL10 Chemokine.

PubMed

Koli, Katri; Sutinen, Eva; Rönty, Mikko; Rantakari, Pia; Fortino, Vittorio; Pulkkinen, Ville; Greco, Dario; Sipilä, Petra; Myllärniemi, Marjukka

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is characterized by activation and injury of epithelial cells, the accumulation of connective tissue and changes in the inflammatory microenvironment. The bone morphogenetic protein (BMP) inhibitor protein gremlin-1 is associated with the progression of fibrosis both in human and mouse lung. We generated a transgenic mouse model expressing gremlin-1 in type II lung epithelial cells using the surfactant protein C (SPC) promoter and the Cre-LoxP system. Gremlin-1 protein expression was detected specifically in the lung after birth and did not result in any signs of respiratory insufficiency. Exposure to silicon dioxide resulted in reduced amounts of lymphocyte aggregates in transgenic lungs while no alteration in the fibrotic response was observed. Microarray gene expression profiling and analyses of bronchoalveolar lavage fluid cytokines indicated a reduced lymphocytic response and a downregulation of interferon-induced gene program. Consistent with reduced Th1 response, there was a downregulation of the mRNA and protein expression of the anti-fibrotic chemokine CXCL10, which has been linked to IPF. In human IPF patient samples we also established a strong negative correlation in the mRNA expression levels of gremlin-1 and CXCL10. Our results suggest that in addition to regulation of epithelial-mesenchymal crosstalk during tissue injury, gremlin-1 modulates inflammatory cell recruitment and anti-fibrotic chemokine production in the lung.

Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive

PubMed Central

Newton, Chad A.; Batra, Kiran; Torrealba, Jose; Kozlitina, Julia; Glazer, Craig S.; Aravena, Carlos; Meyer, Keith; Raghu, Ganesh; Collard, Harold R.; Garcia, Christine Kim

2017-01-01

Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals. 115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed. Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year−1 and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis. Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive. PMID:27540018

Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive.

PubMed

Newton, Chad A; Batra, Kiran; Torrealba, Jose; Kozlitina, Julia; Glazer, Craig S; Aravena, Carlos; Meyer, Keith; Raghu, Ganesh; Collard, Harold R; Garcia, Christine Kim

2016-12-01

Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals.115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed.Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year -1 and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis.Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive. Copyright ©ERS 2016.

CryoSat SAR/SARin Level1b products: assessment of BaselineC and improvements towards BaselineD

NASA Astrophysics Data System (ADS)

Scagliola, Michele; Fornari, Marco; Bouffard, Jerome; Parrinello, Tommaso

2017-04-01

CryoSat was launched on the 8th April 2010 and is the first European ice mission dedicated to the monitoring of precise changes in the thickness of polar ice sheets and floating sea ice. Cryosat carries an innovative radar altimeter called the Synthetic Aperture Interferometric Altimeter (SIRAL), that transmits pulses at a high pulse repetition frequency thus making the received echoes phase coherent and suitable for azimuth processing. This allows to reach a significantly improved along track resolution with respect to traditional pulse-width limited altimeters. CryoSat is the first altimetry mission operating in SAR mode and continuous improvements in the Level1 Instrument Processing Facility (IPF1) are being identified, tested and validated in order to improve the quality of the Level1b products. The current IPF, Baseline C, was released in operation in April 2015 and the second CryoSat reprocessing campaign was jointly initiated, taking benefit of the upgrade implemented in the IPF1 processing chain but also of some specific configurations for the calibration corrections. In particular, the CryoSat Level1b BaselineC products generated in the framework of the second reprocessing campaign include refined information for what concerns the mispointing angles and the calibration corrections. This poster will thus detail thus the evolutions that are currently planned for the CryoSat BaselineD SAR/SARin Level1b products and the corresponding quality improvements that are expected.

Unsupervised segmentation of MRI knees using image partition forests

NASA Astrophysics Data System (ADS)

Marčan, Marija; Voiculescu, Irina

2016-03-01

Nowadays many people are affected by arthritis, a condition of the joints with limited prevention measures, but with various options of treatment the most radical of which is surgical. In order for surgery to be successful, it can make use of careful analysis of patient-based models generated from medical images, usually by manual segmentation. In this work we show how to automate the segmentation of a crucial and complex joint -- the knee. To achieve this goal we rely on our novel way of representing a 3D voxel volume as a hierarchical structure of partitions which we have named Image Partition Forest (IPF). The IPF contains several partition layers of increasing coarseness, with partitions nested across layers in the form of adjacency graphs. On the basis of a set of properties (size, mean intensity, coordinates) of each node in the IPF we classify nodes into different features. Values indicating whether or not any particular node belongs to the femur or tibia are assigned through node filtering and node-based region growing. So far we have evaluated our method on 15 MRI knee images. Our unsupervised segmentation compared against a hand-segmented gold standard has achieved an average Dice similarity coefficient of 0.95 for femur and 0.93 for tibia, and an average symmetric surface distance of 0.98 mm for femur and 0.73 mm for tibia. The paper also discusses ways to introduce stricter morphological and spatial conditioning in the bone labelling process.

Implementing system simulation of C3 systems using autonomous objects

NASA Technical Reports Server (NTRS)

Rogers, Ralph V.

1987-01-01

The basis of all conflict recognition in simulation is a common frame of reference. Synchronous discrete-event simulation relies on the fixed points in time as the basic frame of reference. Asynchronous discrete-event simulation relies on fixed-points in the model space as the basic frame of reference. Neither approach provides sufficient support for autonomous objects. The use of a spatial template as a frame of reference is proposed to address these insufficiencies. The concept of a spatial template is defined and an implementation approach offered. Discussed are the uses of this approach to analyze the integration of sensor data associated with Command, Control, and Communication systems.

Assessing the mental frame syncing in the elderly: a virtual reality protocol.

PubMed

Serino, Silvia; Cipresso, Pietro; Gaggioli, Andrea; Riva, Giuseppe

2014-01-01

Decline in spatial memory in the elderly is often underestimated, and it is crucial to fully investigate the cognitive underpinnings of early spatial impairment. A virtual reality-based procedure was developed to assess deficit in the "mental frame syncing", namely the cognitive ability that allows an effective orientation by synchronizing the allocentric view-point independent representation with the allocentric view-point dependent representation. A pilot study was carried out to evaluate abilities in the mental frame syncing in a sample of 16 elderly participants. Preliminary results indicated that the general cognitive functioning was associated with the ability in the synchronization between these two allocentric references frames.

50 CFR Figures 18a, 18b and 18c to... - Large Frame TED Escape Opening; Minimum Dimensions Using All-Bar Cuts (Triangular Cuts); Large...

Code of Federal Regulations, 2013 CFR

2013-10-01

... Dimensions Using All-Bar Cuts (Triangular Cuts); Large Frame TED Escape Opening; Minimum Dimensions Using All-Bar Cuts and Leading Edge Cut; Large Frame TED Escape Opening; Minimum Dimensions Using All-Points...—Large Frame TED Escape Opening; Minimum Dimensions Using All-Bar Cuts (Triangular Cuts); Large Frame TED...

50 CFR Figures 18a, 18b and 18c to... - Large Frame TED Escape Opening; Minimum Dimensions Using All-Bar Cuts (Triangular Cuts); Large...

Code of Federal Regulations, 2012 CFR

2012-10-01

... Dimensions Using All-Bar Cuts (Triangular Cuts); Large Frame TED Escape Opening; Minimum Dimensions Using All-Bar Cuts and Leading Edge Cut; Large Frame TED Escape Opening; Minimum Dimensions Using All-Points...—Large Frame TED Escape Opening; Minimum Dimensions Using All-Bar Cuts (Triangular Cuts); Large Frame TED...

50 CFR Figures 18a, 18b and 18c to... - Large Frame TED Escape Opening; Minimum Dimensions Using All-Bar Cuts (Triangular Cuts); Large...

Code of Federal Regulations, 2014 CFR

2014-10-01

... Dimensions Using All-Bar Cuts (Triangular Cuts); Large Frame TED Escape Opening; Minimum Dimensions Using All-Bar Cuts and Leading Edge Cut; Large Frame TED Escape Opening; Minimum Dimensions Using All-Points...—Large Frame TED Escape Opening; Minimum Dimensions Using All-Bar Cuts (Triangular Cuts); Large Frame TED...

A novel infrared small moving target detection method based on tracking interest points under complicated background

NASA Astrophysics Data System (ADS)

Dong, Xiabin; Huang, Xinsheng; Zheng, Yongbin; Bai, Shengjian; Xu, Wanying

2014-07-01

Infrared moving target detection is an important part of infrared technology. We introduce a novel infrared small moving target detection method based on tracking interest points under complicated background. Firstly, Difference of Gaussians (DOG) filters are used to detect a group of interest points (including the moving targets). Secondly, a sort of small targets tracking method inspired by Human Visual System (HVS) is used to track these interest points for several frames, and then the correlations between interest points in the first frame and the last frame are obtained. Last, a new clustering method named as R-means is proposed to divide these interest points into two groups according to the correlations, one is target points and another is background points. In experimental results, the target-to-clutter ratio (TCR) and the receiver operating characteristics (ROC) curves are computed experimentally to compare the performances of the proposed method and other five sophisticated methods. From the results, the proposed method shows a better discrimination of targets and clutters and has a lower false alarm rate than the existing moving target detection methods.

Three questions you need to ask about your brand.

PubMed

Keller, Kevin Lane; Sternthal, Brian; Tybout, Alice

2002-09-01

Traditionally, the people responsible for positioning brands have concentrated on the differences that set each brand apart from the competition. But emphasizing differences isn't enough to sustain a brand against competitors. Managers should also consider the frame of reference within which the brand works and the features the brand shares with other products. Asking three questions about your brand can help: HAVE WE ESTABLISHED A FRAME?: A frame of reference--for Coke, it might be as narrow as other colas or as broad as all thirst-quenching drinks--signals to consumers the goal they can expect to achieve by using a brand. Brand managers need to pay close attention to this issue, in some cases expanding their focus in order to preempt the competition. ARE WE LEVERAGING OUR POINTS OF PARITY?: Certain points of parity must be met if consumers are to perceive your product as a legitimate player within its frame of reference. For instance, consumers might not consider a bank truly a bank unless it offers checking and savings plans. ARE THE POINTS OF DIFFERENCE COMPELLING?: A distinguishing characteristic that consumers find both relevant and believable can become a strong, favorable, unique brand association, capable of distinguishing the brand from others in the same frame of reference. Frames of reference, points of parity, and points of difference are moving targets. Maytag isn't the only dependable brand of appliance, Tide isn't the only detergent with whitening power, and BMWs aren't the only cars on the road with superior handling. The key questions you need to ask about your brand may not change, but their context certainly will. The saviest brand positioners are also the most vigilant.

46 CFR 69.109 - Under-deck tonnage.

Code of Federal Regulations, 2010 CFR

2010-10-01

... intersects the line of the inboard faces of the ordinary side frames to the point aft where the line of the tonnage deck intersects the inboard face of the transom frames or cant frames. (See § 69.123, figure 3.) (2) For a vessel having a headblock or square end with framing which extends from the tonnage deck to...

Predicting Life Expectancy for Pirfenidone in Idiopathic Pulmonary Fibrosis.

PubMed

Fisher, Mark; Nathan, Steven D; Hill, Christian; Marshall, Jade; Dejonckheere, Fred; Thuresson, Per-Olof; Maher, Toby M

2017-03-01

Conducting an adequately powered survival study in idiopathic pulmonary fibrosis (IPF) is challenging due to the rare nature of the disease and the need for extended follow-up. Consequently, registration trials of IPF treatments have not been designed to estimate long-term survival. To predict life expectancy for patients with IPF receiving pirfenidone versus best supportive care (BSC) in a population that met the inclusion criteria of patients enrolled in the ASCEND and CAPACITY trials. Kaplan-Meier survival data for pirfenidone and BSC were obtained from randomized controlled clinical studies (CAPACITY, ASCEND), an open-label extension study (RECAP), and the Inova Fairfax Hospital database. Data from the Inova registry were matched to the inclusion criteria of the CAPACITY and ASCEND trials. Life expectancy was estimated by the area under the curve of parametric survival distributions fit to the Kaplan-Meier data. Mean (95% confidence interval) life expectancy was calculated as 8.72 (7.65-10.15) years with pirfenidone and 6.24 (5.38-7.18) years with BSC. Therefore, pirfenidone improved life expectancy by 2.47 (1.26-4.17) years compared with BSC. In addition, treatment with pirfenidone recuperated 25% of the expected years of life lost due to IPF. Sensitivity analyses found that results were sensitive to the choice of parametric survival distribution, and alternative piecewise and parametric approaches. This analysis suggests that this population of patients with IPF has an improved life expectancy if treated with pirfenidone compared with BSC. This study was funded by InterMune International AG, a wholly owned Roche subsidiary since 2014. Fisher was previously employed by InterMune UK, a wholly owned Roche subsidiary, until July 2015. He is currently employed by FIECON, which has received funding from F. Hoffmann-La Roche for consulting services. Nathan has received consulting fees from Roche-Genentech and Boehringer Ingelheim. He is also on the speakers' bureau for Roche-Genentech and Boehringer Ingelheim and has received research funding from both companies. Hill was previously employed by InterMune UK until October 2014. Hill and Marshall are employees of MAP BioPharma, which has received funding from F. Hoffmann-La Roche for consulting services. Dejonckheere and Thuresson are employees of F. Hoffmann-La Roche. Maher has received grants, consulting fees, and speaker fees from GlaxoSmithKline and UCB, and grants from Novartis. He has also received consulting fees and speaker fees from AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, Lanthio, InterMune International AG, F. Hoffmann-La Roche, Sanofi-Aventis, and Takeda. Maher is supported by a National Institute for Health Research Clinician Scientist Fellowship (NIHR Ref: CS: -2013-13-017). Study concept and design were contributed by Fisher, Hill, Marshall, and Dejonckheere. Fisher, Nathan, and Thuresson collected the data, along with Hill and Marshall. Data interpretation was performed by Fisher, Maher, Nathan, and Dejonckheere. The manuscript was written primarily by Fisher, along with Maher and Dejonckheere, and revised by Fisher and Maher, along with the other authors.

Extracting grain-orientation-dependent data from in situ time-of-flight neutron diffraction. I. Inverse pole figures

DOE PAGES

Stoica, Grigoreta M.; Stoica, Alexandru Dan; An, Ke; ...

2014-11-28

The problem of calculating the inverse pole figure (IPF) is analyzed from the perspective of the application of time-of flight neutron diffraction toin situmonitoring of the thermomechanical behavior of engineering materials. On the basis of a quasi-Monte Carlo (QMC) method, a consistent set of grain orientations is generated and used to compute the weighting factors for IPF normalization. The weighting factors are instrument dependent and were calculated for the engineering materials diffractometer VULCAN (Spallation Neutron Source, Oak Ridge National Laboratory). The QMC method is applied to face-centered cubic structures and can be easily extended to other crystallographic symmetries. Examples includemore » 316LN stainless steelin situloaded in tension at room temperature and an Al–2%Mg alloy, substantially deformed by cold rolling and in situannealed up to 653 K.« less

Influences of innate immunity, autophagy, and fibroblast activation in the pathogenesis of lung fibrosis

PubMed Central

O'Dwyer, David N.; Ashley, Shanna L.

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by accumulation of extracellular matrix (ECM) and impaired gas exchange. The pathobiological mechanisms that account for disease progression are poorly understood but likely involve alterations in innate inflammatory cells, epithelial cells, and fibroblasts. Thus we seek to review the most recent literature highlighting the complex roles of neutrophils and macrophages as both promoters of fibrosis and defenders against infection. With respect to epithelial cells and fibroblasts, we review the data suggesting that defective autophagy promotes the fibrogenic potential of both cell types and discuss new evidence related to matrix metalloproteinases, growth factors, and cellular metabolism in the form of lactic acid generation that may have consequences for promoting fibrogenesis. We discuss potential cross talk between innate and structural cell types and also highlight literature that may help explain the limitations of current IPF therapies. PMID:27474089

Influences of innate immunity, autophagy, and fibroblast activation in the pathogenesis of lung fibrosis.

PubMed

O'Dwyer, David N; Ashley, Shanna L; Moore, Bethany B

2016-09-01

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by accumulation of extracellular matrix (ECM) and impaired gas exchange. The pathobiological mechanisms that account for disease progression are poorly understood but likely involve alterations in innate inflammatory cells, epithelial cells, and fibroblasts. Thus we seek to review the most recent literature highlighting the complex roles of neutrophils and macrophages as both promoters of fibrosis and defenders against infection. With respect to epithelial cells and fibroblasts, we review the data suggesting that defective autophagy promotes the fibrogenic potential of both cell types and discuss new evidence related to matrix metalloproteinases, growth factors, and cellular metabolism in the form of lactic acid generation that may have consequences for promoting fibrogenesis. We discuss potential cross talk between innate and structural cell types and also highlight literature that may help explain the limitations of current IPF therapies. Copyright © 2016 the American Physiological Society.

24 CFR 3280.306 - Windstorm protection.

Code of Federal Regulations, 2011 CFR

2011-04-01

... URBAN DEVELOPMENT MANUFACTURED HOME CONSTRUCTION AND SAFETY STANDARDS Body and Frame Construction... frame structure to be used as the points for connection of diagonal ties, no specific connecting devices need be provided on the main frame structure. (b) Contents of instructions. (1) The manufacturer must...

24 CFR 3280.306 - Windstorm protection.

Code of Federal Regulations, 2010 CFR

2010-04-01

... URBAN DEVELOPMENT MANUFACTURED HOME CONSTRUCTION AND SAFETY STANDARDS Body and Frame Construction... frame structure to be used as the points for connection of diagonal ties, no specific connecting devices need be provided on the main frame structure. (b) Contents of instructions. (1) The manufacturer must...

Networked Mediated Influence 2.0

DTIC Science & Technology

2014-12-12

but they communicate the information through different frames of reference. . . . Frames work by accessing a particular perspective on an issue...nature yet attention grabbers.214 Framing. A form of communications where information is presented in a unique slant, focal point, or frame of reference...mental frameworks differ in their implications for decision making, the results can be dramatic.215 Information Communication Technologies (ICTs). A term

Spatial vision within egocentric and exocentric frames of reference

NASA Technical Reports Server (NTRS)

Howard, Ian P.

1991-01-01

It is remarkable that we are able to perceive a stable visual world and judge the directions, orientations, and movements of visual objects given that images move on the retina, the eyes move in the head, the head moves on the body, and the body moves in space. An understanding of the mechanisms underlying perceptual stability and spatial judgements requires precise definitions of relevant coordinate systems. An egocentric frame of reference is defined with respect to some part of the observer. There are four principal egocentric frames of reference, a station-point frame associated with the nodal point of the eye, an retinocentric frame associated with the retina, a headcentric frame associated with the head, and a bodycentric frame (torsocentric) associated with the torso. Additional egocentric frames can be identified with respect to any segment of the body. An egocentric task is one in which the position, orientation, or motion of an object is judged with respect to an egocentric frame of reference. A proprioceptive is a special kind of egocentric task in which the object being judged is also part of the body. An example of a proprioceptive task is that of directing the gaze toward the seen or unseen toe. An exocentric frame of reference is external to the observer. Geographical coordinates and the direction of gravity are examples of exocentric frames of reference. These various frames are listed in tabular form, together with examples of judgements of each type.

Subclinical Lung Disease, Macrocytosis, and Premature Graying in Kindreds With Telomerase (TERT) Mutations

PubMed Central

Diaz de Leon, Alberto; Cronkhite, Jennifer T.; Yilmaz, Cuneyt; Brewington, Cecelia; Wang, Richard; Xing, Chao; Hsia, Connie C. W.

2011-01-01

Background: Mutations in the human gene encoding the protein component of telomerase (TERT) are the most common genetic defect in patients with familial idiopathic pulmonary fibrosis (IPF). The subclinical phenotypes of asymptomatic members of these families have not been evaluated with respect to TERT mutation status or telomere length. Methods: We measured a variety of pulmonary, blood, skin, and bone parameters for 20 subjects with heterozygous TERT mutations (carriers) and 20 family members who had not inherited a TERT mutation (noncarriers) to identify the spectrum of phenotypes associated with mutations in this gene. The two groups were matched for sex, age, and cigarette smoking. Three TERT mutation carriers had IPF (IPF carriers). The rest of the carriers were apparently healthy (asymptomatic carriers) and were compared with the noncarriers. Results: Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (Dlco), impaired recruitment of Dlco with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. RBC and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status is more accurately predicted by short telomere lengths than any of these measured phenotypes. Conclusions: TERT mutation carriers exhibit early preclinical signs of lung fibrosis, bone marrow dysfunction, and premature graying. These clinical features and short telomere lengths characterize patients with germline TERT mutations. PMID:21349926

Limited fibrosis accompanies triple-negative breast cancer metastasis in multiple model systems and is not a preventive target.

PubMed

Brooks, Danielle; Zimmer, Alexandra; Wakefield, Lalage; Lyle, L Tiffany; Difilippantonio, Simone; Tucci, Fabio C; Illiano, Stephane; Annunziata, Christina M; Steeg, Patricia S

2018-05-04

The lysophosphatidic acid receptor 1 (LPAR1) is mechanistically implicated in both tumor metastasis and tissue fibrosis. Previously, metastasis was increased when fulminant fibrosis was first induced in mice, suggesting a direct connection between these processes. The current report examined the extent of metastasis-induced fibrosis in breast cancer model systems, and tested the metastasis preventive efficacy and fibrosis attenuation of antagonists for LPAR1 and Idiopathic Pulmonary Fibrosis (IPF) in breast and ovarian cancer models. Staining analysis demonstrated only focal, low-moderate levels of fibrosis in lungs from eleven metastasis model systems. Two orally available LPAR1 antagonists, SAR100842 and EPGN9878, significantly inhibited breast cancer motility to LPA in vitro . Both compounds were negative for metastasis prevention and failed to reduce fibrosis in the experimental MDA-MB-231T and spontaneous murine 4T1 in vivo breast cancer metastasis models. SAR100842 demonstrated only occasional reductions in invasive metastases in the SKOV3 and OVCAR5 ovarian cancer experimental metastasis models. Two approved drugs for IPF, nintedanib and pirfenidone, were investigated. Both were ineffective at preventing MDA-MB-231T metastasis, with no attenuation of fibrosis. In summary, metastasis-induced fibrosis is only a minor component of metastasis in untreated progressive breast cancer. LPAR1 antagonists, despite in vitro evidence of specificity and efficacy, were ineffective in vivo as oral agents, as were approved IPF drugs. The data argue against LPAR1 and fibrosis as monotherapy targets for metastasis prevention in triple-negative breast cancer and ovarian cancer.

Simple determination of L-hydroxyproline in idiopathic pulmonary fibrosis lung tissues of rats using non-extractive high-performance liquid chromatography coupled with fluorescence detection after pre-column derivatization with novel synthetic 9-acetylimidazol-carbazole.

PubMed

Ren, Yan; Zhao, Juanjuan; Shi, Yanan; Chen, Caiyun; Chen, Xiangming; Lv, Changjun

2017-08-05

L-Hydroxyproline (L-Hyp) is an important biomarker for idiopathic pulmonary fibrosis (IPF). The quantitative methods based on high-performance liquid chromatography coupled with fluorescence detection after pre-column derivatization typically requires complicated derivatization conditions and obtains unstable derivatives. Here, a novel derivatization reagent, 9-acetylimidazol-carbazole, was synthesized for the first time to efficiently and rapidly label the amino groups of L-Hyp. The high-performance liquid chromatography method with pre-column derivatization was performed on an Agilent ZORBAX SB-C 18 column (4.6×250mm, 5μm). The product was measured using fluorescence detection at excitation and emission wavelengths of 232 and 370nm, respectively. The method was validated in specificity, linearity, limit of detection (66.7 fmol), limit of quantification (333.3fmol), intra-day precision (0.75%), inter-day precision (3.82%), stability (3.15%), and recovery (90.7-109.4%). The validated method was successfully applied to the determination of L-Hyp in the lung tissues of healthy and IPF rats. The results showed that the concentration of L-Hyp (3.64mg/g) in the IPF model was significantly higher than the concentration (2.33mg/g) in the healthy control group with P<0.01. This is a new method for the determination of L-Hyp and can be used for other amino acid-related studies in the future. Copyright © 2017. Published by Elsevier B.V.

Impairment of Immunoproteasome Function by Cigarette Smoke and in Chronic Obstructive Pulmonary Disease.

PubMed

Kammerl, Ilona E; Dann, Angela; Mossina, Alessandra; Brech, Dorothee; Lukas, Christina; Vosyka, Oliver; Nathan, Petra; Conlon, Thomas M; Wagner, Darcy E; Overkleeft, Hermen S; Prasse, Antje; Rosas, Ivan O; Straub, Tobias; Krauss-Etschmann, Susanne; Königshoff, Melanie; Preissler, Gerhard; Winter, Hauke; Lindner, Michael; Hatz, Rudolf; Behr, Jürgen; Heinzelmann, Katharina; Yildirim, Ali Ö; Noessner, Elfriede; Eickelberg, Oliver; Meiners, Silke

2016-06-01

Patients with chronic obstructive pulmonary disease (COPD) and in particular smokers are more susceptible to respiratory infections contributing to acute exacerbations of disease. The immunoproteasome is a specialized type of proteasome destined to improve major histocompatibility complex (MHC) class I-mediated antigen presentation for the resolution of intracellular infections. To characterize immunoproteasome function in COPD and its regulation by cigarette smoke. Immunoproteasome expression and activity were determined in bronchoalveolar lavage (BAL) and lungs of human donors and patients with COPD or idiopathic pulmonary fibrosis (IPF), as well as in cigarette smoke-exposed mice. Smoke-mediated alterations of immunoproteasome activity and MHC I surface expression were analyzed in human blood-derived macrophages. Immunoproteasome-specific MHC I antigen presentation was evaluated in spleen and lung immune cells that had been smoke-exposed in vitro or in vivo. Immunoproteasome and MHC I mRNA expression was reduced in BAL cells of patients with COPD and in isolated alveolar macrophages of patients with COPD or IPF. Exposure of immune cells to cigarette smoke extract in vitro reduced immunoproteasome activity and impaired immunoproteasome-specific MHC I antigen presentation. In vivo, acute cigarette smoke exposure dynamically regulated immunoproteasome function and MHC I antigen presentation in mouse BAL cells. End-stage COPD lungs showed markedly impaired immunoproteasome activities. We here show that the activity of the immunoproteasome is impaired by cigarette smoke resulting in reduced MHC I antigen presentation. Regulation of immunoproteasome function by cigarette smoke may thus alter adaptive immune responses and add to prolonged infections and exacerbations in COPD and IPF.

Automated Quantitative Computed Tomography Versus Visual Computed Tomography Scoring in Idiopathic Pulmonary Fibrosis: Validation Against Pulmonary Function.

PubMed

Jacob, Joseph; Bartholmai, Brian J; Rajagopalan, Srinivasan; Kokosi, Maria; Nair, Arjun; Karwoski, Ronald; Raghunath, Sushravya M; Walsh, Simon L F; Wells, Athol U; Hansell, David M

2016-09-01

The aim of the study was to determine whether a novel computed tomography (CT) postprocessing software technique (CALIPER) is superior to visual CT scoring as judged by functional correlations in idiopathic pulmonary fibrosis (IPF). A total of 283 consecutive patients with IPF had CT parenchymal patterns evaluated quantitatively with CALIPER and by visual scoring. These 2 techniques were evaluated against: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLco), carbon monoxide transfer coefficient (Kco), and a composite physiological index (CPI), with regard to extent of interstitial lung disease (ILD), extent of emphysema, and pulmonary vascular abnormalities. CALIPER-derived estimates of ILD extent demonstrated stronger univariate correlations than visual scores for most pulmonary function tests (PFTs): (FEV1: CALIPER R=0.29, visual R=0.18; FVC: CALIPER R=0.41, visual R=0.27; DLco: CALIPER R=0.31, visual R=0.35; CPI: CALIPER R=0.48, visual R=0.44). Correlations between CT measures of emphysema extent and PFTs were weak and did not differ significantly between CALIPER and visual scoring. Intriguingly, the pulmonary vessel volume provided similar correlations to total ILD extent scored by CALIPER for FVC, DLco, and CPI (FVC: R=0.45; DLco: R=0.34; CPI: R=0.53). CALIPER was superior to visual scoring as validated by functional correlations with PFTs. The pulmonary vessel volume, a novel CALIPER CT parameter with no visual scoring equivalent, has the potential to be a CT feature in the assessment of patients with IPF and requires further exploration.

The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

PubMed Central

Moeller, Antje; Ask, Kjetil; Warburton, David; Gauldie, Jack; Kolb, Martin

2008-01-01

Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 246 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. In 221 of the studies we found enough details about the timing of drug application to allow inter-study comparison. 211 of those used a preventive regimen (drug given ≤ day 7 after last bleomycin application), only 10 were therapeutic trials (> 7 days after last bleomycin application). It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted. PMID:17936056

Lysyl Oxidase-Like 1 Protein Deficiency Protects Mice from Adenoviral Transforming Growth Factor-β1-induced Pulmonary Fibrosis.

PubMed

Bellaye, Pierre-Simon; Shimbori, Chiko; Upagupta, Chandak; Sato, Seidai; Shi, Wei; Gauldie, Jack; Ask, Kjetil; Kolb, Martin

2018-04-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by excessive deposition of extracellular matrix (ECM) in the lung parenchyma. The abnormal ECM deposition slowly overtakes normal lung tissue, disturbing gas exchange and leading to respiratory failure and death. ECM cross-linking and subsequent stiffening is thought to be a major contributor of disease progression and also promotes the activation of transforming growth factor (TGF)-β1, one of the main profibrotic growth factors. Lysyl oxidase-like (LOXL) 1 belongs to the cross-linking enzyme family and has been shown to be up-regulated in active fibrotic regions of bleomycin-treated mice and patients with IPF. We demonstrate in this study that LOXL1-deficient mice are protected from experimental lung fibrosis induced by overexpression of TGF-β1 using adenoviral (Ad) gene transfer (AdTGF-β1). The lack of LOXL1 prevented accumulation of insoluble cross-linked collagen in the lungs, and therefore limited lung stiffness after AdTGF-β1. In addition, we applied mechanical stretch to lung slices from LOXL1 +/+ and LOXL1 -/- mice treated with AdTGF-β1. Lung stiffness (Young's modulus) of LOXL1 -/- lung slices was significantly lower compared with LOXL1 +/+ lung slices. Moreover, the release of activated TGF-β1 after mechanical stretch was significantly lower in LOXL1 -/- mice compared with LOXL1 +/+ mice after AdTGF-β1. These data support the concept that cross-linking enzyme inhibition represents an interesting therapeutic target for drug development in IPF.

Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion.

PubMed

Ahluwalia, Neil; Grasberger, Paula E; Mugo, Brian M; Feghali-Bostwick, Carol; Pardo, Annie; Selman, Moisés; Lagares, David; Tager, Andrew M

2016-06-01

Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-β, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.

Body size-adjusted dose analysis of pirfenidone in patients with interstitial pneumonia.

PubMed

Uehara, Masahiro; Enomoto, Noriyuki; Oyama, Yoshiyuki; Suzuki, Yuzo; Kono, Masato; Furuhashi, Kazuki; Fujisawa, Tomoyuki; Inui, Naoki; Nakamura, Yutaro; Suda, Takafumi

2018-03-01

Pirfenidone is an effective anti-fibrotic agent for idiopathic pulmonary fibrosis (IPF). Although adverse events (AE) sometimes prevent patients from continuing treatment, current dose adjustment guidance does not consider patient body size or weight (BW). The aim of this study was to evaluate the importance of pirfenidone dose adjustment by body surface area (BSA) or BW for preventing AE and permitting continuous treatment in patients with interstitial pneumonia (IP). Sixty-seven Japanese patients with IP including 46 patients with IPF treated with pirfenidone between 2009 and 2015 were retrospectively evaluated. Pirfenidone doses were adjusted by BSA or BW and were compared with clinical parameters. Forty-two of 67 patients (62.7%) with IP showed AE, most commonly gastrointestinal symptoms (77.5%). Patients having AE received significantly higher adjusted doses of pirfenidone by both BSA and BW (P = 0.024 and P = 0.010, respectively), while unadjusted doses did not differ. BSA-adjusted dose discriminated patients with AE from those without (area under the curve = 0.666 at 1085 mg/m 2 ). Six of seven patients (85.7%) who discontinued pirfenidone due to AE took ≥1085 mg/m 2 of pirfenidone. In a subgroup with IPF, patients taking a medium dose (median: 876 median-1085 mg/m 2 ) showed a lower annual decline in % forced vital capacity than patients taking a lower dose (P = 0.025). BSA-adjusted pirfenidone dosing may be useful to prevent AE whilst achieving a long-term treatment effect in patients with IP. © 2017 Asian Pacific Society of Respirology.

Analysis of lung function and survival in RECAP: An open-label extension study of pirfenidone in patients with idiopathic pulmonary fibrosis.

PubMed

Costabel, Ulrich; Albera, Carlo; Bradford, Williamson Z; Hormel, Phil; King, Talmadge E; Noble, Paul W; Sahn, Steven A; Valeyre, Dominique; du Bois, Roland M

2014-10-20

RECAP is an open-label extension study evaluating pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) who completed the Phase 3 CAPACITY program. We examined the effect of pirfenidone on lung function and survival in patients who were previously randomised to the placebo group in one of the two CAPACITY studies and received pirfenidone for the first time in RECAP. Eligible patients received oral pirfenidone 2403 mg/day. Forced vital capacity (FVC) was measured at baseline and at weeks 12, 36, and 60. To facilitate comparison with CAPACITY outcomes, analyses were based on patients newly treated with pirfenidone in RECAP who had baseline FVC and carbon monoxide diffusing capacity (DLCO) values that met CAPACITY entry criteria. A total of 178 patients were included in the analysis. Among these, 16.3% experienced an FVC decline ≥10% at week 60, compared with 16.8% and 24.8%, respectively, in the CAPACITY pirfenidone (n=345) and placebo (n=347) groups. The mean change from baseline to week 60 in %FVC was -5.9%, compared with -7.0% and -9.4% in the CAPACITY pirfenidone and placebo groups. Overall survival was similar to that of pirfenidone treated patients in CAPACITY. Treatment was safe and generally well tolerated; the type and frequency of adverse events were consistent with previous clinical experience. FVC and survival outcomes in IPF patients newly treated with pirfenidone in RECAP were similar to those in the CAPACITY pirfenidone group. These data provide further evidence to support the use of pirfenidone in patients with IPF.

Retrospective observational study of trends in hospital admissions for idiopathic pulmonary fibrosis in Spain (2004-2013) using administrative data.

PubMed

Pedraza-Serrano, Fernando; López de Andrés, Ana; Jiménez-García, Rodrigo; Jiménez-Trujillo, Isabel; Hernández-Barrera, Valentín; Sánchez-Muñoz, Gema; Puente-Maestu, Luis; de Miguel-Díez, Javier

2017-02-13

To assess changes in incidence, diagnostic procedures, comorbidity profiles, length of hospital stay (LOHS), economic costs and in-hospital mortality (IHM) associated with idiopathic pulmonary fibrosis (IPF). We identified patients hospitalised with IPF in Spain from 2004 to 2013. Data were collected from the National Hospital Discharge Database. The study population comprised 22 214 patients. Overall crude incidence increased from 3.82 to 6.98 admissions per 100 000 inhabitants from 2004 to 2013 (p<0.05). The percentage of lung biopsies decreased significantly from 10.68% in 2004 to 9.04% in 2013 (p<0.05). The percentage of patients with a Charlson comorbidity index ≥2 was 15.14% in 2004, increasing to 26.95% in 2013 (p<0.05). IHM decreased from 14.77% in 2004 to 13.72% in 2013 (adjusted OR 0.98; 95% CI 0.97 to 0.99). Mean LOHS was 11.87±11.18 days in 2004, decreasing to 10.20±11.12 days in 2013 (p<0.05). The mean cost per patient increased from €4838.51 in 2004 to €5410.90 in 2013 (p<0.05). The frequency of hospital admissions for IPF increased during the study period, as did healthcare costs. However, IHM and LOHS decreased. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Pulmonary phenotypes associated with genetic variation in telomere-related genes.

PubMed

Hoffman, Thijs W; van Moorsel, Coline H M; Borie, Raphael; Crestani, Bruno

2018-05-01

Genomic mutations in telomere-related genes have been recognized as a cause of familial forms of idiopathic pulmonary fibrosis (IPF). However, it has become increasingly clear that telomere syndromes and telomere shortening are associated with various types of pulmonary disease. Additionally, it was found that also single nucleotide polymorphisms (SNPs) in telomere-related genes are risk factors for the development of pulmonary disease. This review focuses on recent updates on pulmonary phenotypes associated with genetic variation in telomere-related genes. Genomic mutations in seven telomere-related genes cause pulmonary disease. Pulmonary phenotypes associated with these mutations range from many forms of pulmonary fibrosis to emphysema and pulmonary vascular disease. Telomere-related mutations account for up to 10% of sporadic IPF, 25% of familial IPF, 10% of connective-tissue disease-associated interstitial lung disease, and 1% of COPD. Mixed disease forms have also been found. Furthermore, SNPs in TERT, TERC, OBFC1, and RTEL1, as well as short telomere length, have been associated with several pulmonary diseases. Treatment of pulmonary disease caused by telomere-related gene variation is currently based on disease diagnosis and not on the underlying cause. Pulmonary phenotypes found in carriers of telomere-related gene mutations and SNPs are primarily pulmonary fibrosis, sometimes emphysema and rarely pulmonary vascular disease. Genotype-phenotype relations are weak, suggesting that environmental factors and genetic background of patients determine disease phenotypes to a large degree. A disease model is presented wherever genomic variation in telomere-related genes cause specific pulmonary disease phenotypes whenever triggered by environmental exposure, comorbidity, or unknown factors.

The Rho Kinases: Critical Mediators of Multiple Profibrotic Processes and Rational Targets for New Therapies for Pulmonary Fibrosis

PubMed Central

Knipe, Rachel S.; Tager, Andrew M.

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring, short median survival, and limited therapeutic options, creating great need for new pharmacologic therapies. IPF is thought to result from repetitive environmental injury to the lung epithelium, in the context of aberrant host wound healing responses. Tissue responses to injury fundamentally involve reorganization of the actin cytoskeleton of participating cells, including epithelial cells, fibroblasts, endothelial cells, and macrophages. Actin filament assembly and actomyosin contraction are directed by the Rho-associated coiled-coil forming protein kinase (ROCK) family of serine/threonine kinases (ROCK1 and ROCK2). As would therefore be expected, lung ROCK activation has been demonstrated in humans with IPF and in animal models of this disease. ROCK inhibitors can prevent fibrosis in these models, and more importantly, induce the regression of already established fibrosis. Here we review ROCK structure and function, upstream activators and downstream targets of ROCKs in pulmonary fibrosis, contributions of ROCKs to profibrotic cellular responses to lung injury, ROCK inhibitors and their efficacy in animal models of pulmonary fibrosis, and potential toxicities of ROCK inhibitors in humans, as well as involvement of ROCKs in fibrosis in other organs. As we discuss, ROCK activation is required for multiple profibrotic responses, in the lung and multiple other organs, suggesting ROCK participation in fundamental pathways that contribute to the pathogenesis of a broad array of fibrotic diseases. Multiple lines of evidence therefore indicate that ROCK inhibition has great potential to be a powerful therapeutic tool in the treatment of fibrosis, both in the lung and beyond. PMID:25395505

Apollo 12 photography 70 mm, 16 mm, and 35 mm frame index

NASA Technical Reports Server (NTRS)

1970-01-01

For each 70-mm frame, the index presents information on: (1) the focal length of the camera, (2) the photo scale at the principal point of the frame, (3) the selenographic coordinates at the principal point of the frame, (4) the percentage of forward overlap of the frame, (5) the sun angle (medium, low, high), (6) the quality of the photography, (7) the approximate tilt (minimum and maximum) of the camera, and (8) the direction of tilt. A brief description of each frame is also included. The index to the 16-mm sequence photography includes information concerning the approximate surface coverage of the photographic sequence and a brief description of the principal features shown. A column of remarks is included to indicate: (1) if the sequence is plotted on the photographic index map and (2) the quality of the photography. The pictures taken using the lunar surface closeup stereoscopic camera (35 mm) are also described in this same index format.

47 CFR 1.10014 - What happens after officially filing my application?

Code of Federal Regulations, 2010 CFR

2010-10-01

... ARC-xxxxx Foreign Carrier Affiliation Notification FCN-xxxxx International High Frequency IHF-xxxxx... PN released International High Frequency IHF-xxxxx International Public Fixed IPF-xxxxx Recognized... Foreign Carrier Affiliation Notification. International High Frequency: Construction Permits,Licenses...

47 CFR 1.10014 - What happens after officially filing my application?

Code of Federal Regulations, 2011 CFR

2011-10-01

... ARC-xxxxx Foreign Carrier Affiliation Notification FCN-xxxxx International High Frequency IHF-xxxxx... PN released International High Frequency IHF-xxxxx International Public Fixed IPF-xxxxx Recognized... Foreign Carrier Affiliation Notification. International High Frequency: Construction Permits,Licenses...

CryoSat Level1b SAR/SARin BaselineC: Product Format and Algorithm Improvements

NASA Astrophysics Data System (ADS)

Scagliola, Michele; Fornari, Marco; Di Giacinto, Andrea; Bouffard, Jerome; Féménias, Pierre; Parrinello, Tommaso

2015-04-01

CryoSat was launched on the 8th April 2010 and is the first European ice mission dedicated to the monitoring of precise changes in the thickness of polar ice sheets and floating sea ice. Cryosat carries an innovative radar altimeter called the Synthetic Aperture Interferometric Altimeter (SIRAL), that transmits pulses at a high pulse repetition frequency thus making the received echoes phase coherent and suitable for azimuth processing. This allows to reach a significantly improved along track resolution with respect to traditional pulse-width limited altimeters. CryoSat is the first altimetry mission operating in SAR mode and continuous improvements in the Level1 Instrument Processing Facility (IPF1) are being identified, tested and validated in order to improve the quality of the Level1b products. The current IPF, Baseline B, was released in operation in February 2012. A reprocessing campaign followed, in order to reprocess the data since July 2010. After more than 2 years of development, the release in operations of Baseline C is expected in the first half of 2015. BaselineC Level1b products will be distributed in an updated format, including for example the attitude information (roll, pitch and yaw) and, for SAR/SARIN, the waveform length doubled with respect to Baseline B. Moreveor, various algorithm improvements have been identified: • a datation bias of about -0.5195 ms will be corrected (SAR/SARIn) • a range bias of about 0.6730 m will be corrected (SAR/SARIn) • a roll bias of 0.1062 deg and a pitch bias of 0.0520 deg • Surface sample stack weighting to filter out the single look echoes acquired at highest look angle, that results in a sharpening of the 20Hz waveforms With the operational release of BaselineC, the second CryoSat reprocessing campaign will be initiated, taking benefit of the upgrade implemented in the IPF1 processing chain but also at IPF2 level. The reprocessing campaign will cover the full Cryosat mission starting on 16th July 2010. This poster details the new information that will be added in the CryoSat BaselineC Level1b SAR/SARin products and the main quality improvements will be described.

Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) promotes lung fibroblast proliferation, survival and differentiation to myofibroblasts.

PubMed

Hasaneen, Nadia A; Cao, Jian; Pulkoski-Gross, Ashleigh; Zucker, Stanley; Foda, Hussein D

2016-02-17

Idiopathic pulmonary fibrosis (IPF) is a chronic progressively fatal disease. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) is a glycosylated transmembrane protein that induces the expression of some matrix metalloproteinase (MMP) in neighboring stromal cells through direct epithelial-stromal interactions. EMMPRIN is highly expressed in type II alveolar epithelial cells at the edges of the fibrotic areas in IPF lung sections. However, the exact role of EMMPRIN in IPF is unknown. To determine if EMMPRIN contributes to lung fibroblast proliferation, resistance to apoptosis, and differentiation to myofibroblasts, normal Human lung fibroblasts (NHLF) transiently transfected with either EMMPRIN/GFP or GFP were treated with TGF- β1 from 0 to 10 ng/ml for 48 h and examined for cell proliferation (thymidine incorporation), apoptosis (FACS analysis and Cell Death Detection ELISA assay), cell migration (Modified Boyden chamber) and differentiation to myofibroblasts using Western blot for α-smooth actin of cell lysates. The effect of EMMPRIN inhibition on NHLF proliferation, apoptosis, migration and differentiation to myofibroblasts after TGF- β1 treatment was examined using EMMPRIN blocking antibody. We examined the mechanism by which EMMPRIN induces its effects on fibroblasts by studying the β-catenin/canonical Wnt signaling pathway using Wnt luciferase reporter assays and Western blot for total and phosphorylated β-catenin. Human lung fibroblasts overexpressing EMMPRIN had a significant increase in cell proliferation and migration compared to control fibroblasts. Furthermore, EMMPRIN promoted lung fibroblasts resistance to apoptosis. Lung fibroblasts overexpressing EMMPRIN showed a significantly increased expression of α- smooth muscle actin, a marker of differentiation to myofibroblasts compared to control cells. TGF-β1 increased the expression of EMMPRIN in lung fibroblasts in a dose-dependent manner. Attenuation of EMMPRIN expression with the use of an EMMPRIN blocking antibody markedly inhibited TGF-β1 induced proliferation, migration, and differentiation of fibroblasts to myofibroblasts. EMMPRIN overexpression in lung fibroblasts was found to induce an increase in TOPFLASH luciferase reporter activity when compared with control fibroblasts. These findings indicate that TGF-β1 induces the release of EMMPRIN that activates β-catenin/canonical Wnt signaling pathway. EMMPRIN overexpression induces an anti-apoptotic and pro-fibrotic phenotype in lung fibroblasts that may contribute to the persistent fibro-proliferative state seen in IPF.

Cardiorespiratory adaptation in a 6-minute walk test by fibrotic idiopathic interstitial pneumonia patients who did or did not respond to pulmonary rehabilitation.

PubMed

Chéhère, Baptiste; Bougault, Valérie; Chenivesse, Cécile; Grosbois, Jean-Marie; Wallaert, Benoit

2018-06-14

Pulmonary rehabilitation (PR) improves performance in the 6-min walk test (6MWT) in a subset of patients with fibrotic idiopathic interstitial pneumonia (f-IIP); however, a large proportion of patients do not respond to PR. To investigate the effects of a PR program on cardiorespiratory responses during a 6MWT and to identify the characteristics of patients who do not show improved performance after PR. An observational study. Patients were recruited from the Competence Centre for Rare Pulmonary Diseases at Lille University Hospital, France and completed an 8-week home-based PR program. A total of 19 patients with f-IIP; 12 with idiopathic pulmonary fibrosis (IPF) and 7 with fibrotic non-specific interstitial pneumonia. Patients underwent spirometry and completed a 6MWT before and after an 8- week PR program. Gas exchange, heart rate, and pulse O2 saturation were measured continuously during the 6MWT. Quality of life, dyspnoea, and anxiety/depression were assessed using the Short-Form 36 (SF-36), the baseline/transition dyspnoea index (BDI/TDI), and the Hospital Anxiety and Depression Scale (HADS) questionnaires. Patients who did and did not improve the distance walked in the 6MWT by at least 30 m after PR were classified as responders (n=9) and non-responders (n=10), respectively. O2 uptake, ventilation rate, and distance covered during the 6MWT were significantly improved only in the responder group (p<0.05). Changes in SF-36, BDI/TDI, and HADS scores did not differ significantly between responders and non-responders. The non-responder group contained significantly more patients with IPF (p<0.05) and experienced greater arterial oxygen desaturation during the 6MWT compared with the responder group. Failure to improve performance in the 6MWT after PR was associated with a diagnosis of IPF, non-improvement in gas exchange, and greater arterial oxygen desaturation. Most f-IIP patients who did not respond to PR were diagnosed with IPF and displayed greater hypoxemia during exercise. Clinical practitioners should seek to determine why patients fail to improve exercise performance after PR and propose an alternative exercise regimen to these patients.

Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial.

PubMed

Behr, Jürgen; Bendstrup, Elisabeth; Crestani, Bruno; Günther, Andreas; Olschewski, Horst; Sköld, C Magnus; Wells, Athol; Wuyts, Wim; Koschel, Dirk; Kreuter, Michael; Wallaert, Benoît; Lin, Chin-Yu; Beck, Jürgen; Albera, Carlo

2016-06-01

Oral acetylcysteine (also known as N-acetylcysteine) is used with pirfenidone to treat idiopathic pulmonary fibrosis (IPF) in Europe. However, no randomised studies have investigated the safety and tolerability of this combination. The PANORAMA study assessed the safety and tolerability of acetylcysteine combined with pirfenidone in patients with IPF. Exploratory efficacy endpoints were also assessed. We did a double-blind randomised trial at 48 sites in eight countries. Patients with IPF aged 40-80 years and established on pirfenidone (at least 1602 mg/day for 8 weeks or longer) were randomly assigned in a 1:1 ratio by interactive voice response system to receive concomitant oral acetylcysteine (600 mg, three times daily) or placebo for 24 weeks. A stratified blocked randomisation scheme was used with a block size of 4. Randomisation was stratified by dose of pirfenidone (2403 mg/day [the maximum dose] or <2403 mg/day). Patients, physicians, study staff and the sponsor were masked to treatment group allocation. The primary endpoint was assessment of adverse events, which were collected at each visit and for 28 days after the last dose of study drug. Exploratory efficacy measurements included forced vital capacity (FVC), carbon monoxide diffusing capacity, and 6 min walk distance. Analyses were done in the modified intention-to-treat population, which included all patients who were randomised and received at least one dose of study medication. This study is registered with the European Clinical Trials Database (EudraCT number 2012-000564-14) and has been completed. 123 patients participated in the study between June 28, 2013, and Feb 24, 2015. 61 were assigned to the acetylcysteine group (60 received study medication and included in analysis) and 62 were assigned to the placebo group (all included in analysis). The occurrence of at least one adverse event (46 [77%] patients receiving acetylcysteine vs 50 [81%] receiving placebo), adverse events related to study treatment (17 [28%] vs 16 [26%]), and the number of patients experiencing severe adverse events (three [5%] vs two [3%]), life-threatening adverse events (one [2%] vs one [2%]), or death (one [2%] vs three [5%]) was similar between treatment groups. One case of diarrhoea in the acetylcysteine group was considered severe and related to study treatment. Nine serious adverse events were reported by seven patients: dyspnoea, headache, hypertension, intervertebral disc protrusion, and malignant lung neoplasm in the acetylcysteine group, and aortic aneurysm, contusion, forearm fracture, and worsening IPF in the placebo group. The most common adverse events were cough, nasopharyngitis, and diarrhoea. Photosensitivity occurred more frequently with acetylcysteine (eight [13%] patients) than placebo (one [2%] patient; difference 11·7%; 95% CI 2·6-20·9; p=0·016]), and was not attributable to differences in location, season, or concomitant medication. Four (7%) patients receiving acetylcysteine and three (5%) receiving placebo discontinued study treatment due to adverse events. In the exploratory analysis, change in FVC indicated that clinical benefit from addition of acetylcysteine to pirfenidone is unlikely, with the possibility of a harmful effect in patients with IPF (adjusted rate of decline 125·6 mL/6 months for acetylcysteine vs 34·3 mL/6 months for placebo; difference -91·3 mL; 95% CI -174·4 to -8·3; p=0·031). Findings from the PANORAMA study suggest that addition of acetylcysteine to pirfenidone does not substantially alter the tolerability profile of pirfenidone, and is unlikely to be beneficial in IPF. InterMune International AG (Roche). Copyright © 2016 Elsevier Ltd. All rights reserved.

Apollo 17 Index: 70 mm, 35 mm, and 16 mm Photographs

NASA Technical Reports Server (NTRS)

Wells, Ronald A. (Compiler)

1974-01-01

This index lists and provides supplemental data for all Apollo 17 70 mm, 35 mm, and 16 mm photographs. The 70 mm and 35 mm photographs are indexed in three ways: (1) all photographs are listed in numerical sequence according to NASA photograph number, (2) photographs exposed in lunar orbit are listed according to longitude in 10deg increments, and (3) all photographs exposed on the lunar surface are listed in chronological order. In indexing the 70 mm and 35 mm orbital photographs, individual frames were matched to imagery on the 1:2,750,000 scale Lunar Planning Charts (LOC). Each frame was outlined on the LOC base map, and the principal point determined. The latitude and longitude of each principal point, to the nearest 0.1 degree, is recorded in this index, If the principal point of a photograph is in space or its location obscured by shadow, an approximate longitude was recorded so that the photograph would not be excluded from the computer-generated listing by longitude. Each frame is described in terms of a named lunar surface feature within the boundaries of the frame or, if no named features are within the frame boundaries, a major nearby feature.

Unitary cocycle representations of the Galilean line group: Quantum mechanical principle of equivalence

DOE Office of Scientific and Technical Information (OSTI.GOV)

MacGregor, B.R.; McCoy, A.E.; Wickramasekara, S., E-mail: wickrama@grinnell.edu

2012-09-15

We present a formalism of Galilean quantum mechanics in non-inertial reference frames and discuss its implications for the equivalence principle. This extension of quantum mechanics rests on the Galilean line group, the semidirect product of the real line and the group of analytic functions from the real line to the Euclidean group in three dimensions. This group provides transformations between all inertial and non-inertial reference frames and contains the Galilei group as a subgroup. We construct a certain class of unitary representations of the Galilean line group and show that these representations determine the structure of quantum mechanics in non-inertialmore » reference frames. Our representations of the Galilean line group contain the usual unitary projective representations of the Galilei group, but have a more intricate cocycle structure. The transformation formula for the Hamiltonian under the Galilean line group shows that in a non-inertial reference frame it acquires a fictitious potential energy term that is proportional to the inertial mass, suggesting the equivalence of inertial mass and gravitational mass in quantum mechanics. - Highlights: Black-Right-Pointing-Pointer A formulation of Galilean quantum mechanics in non-inertial reference frames is given. Black-Right-Pointing-Pointer The key concept is the Galilean line group, an infinite dimensional group. Black-Right-Pointing-Pointer Unitary, cocycle representations of the Galilean line group are constructed. Black-Right-Pointing-Pointer A non-central extension of the group underlies these representations. Black-Right-Pointing-Pointer Quantum equivalence principle and gravity emerge from these representations.« less

Ocular and Densimeter Estimates of Understory Foliar Cover in Forests of Alabama

Treesearch

Thomas W. Popham; Roger L. Baker

1987-01-01

Foliar cover estimates of woody and herbaceous understory vegetation were done on twenty l-m2 plots for a variety of forest types in Alabama. The methods of estimation were ocular, loop-densimeter assisted ocular, and point frame. The point frame was used as the standard and the other two methods were compared using chi-square. Some ocular...

An alternative resolution to the Mansuripur paradox

NASA Astrophysics Data System (ADS)

Redfern, Francis

2016-04-01

In 2013 an article published online by the journal Science declared that the paradox proposed by Masud Mansuripur was resolved. This paradox concerns a point charge-Amperian magnetic dipole system as seen in a frame of reference where they are at rest and one in which they are moving. In the latter frame an electric dipole appears on the magnetic dipole. A torque is then exerted upon the electric dipole by the point charge, a torque that is not observed in the at-rest frame. Mansuripur points out this violates the relativity principle and suggests the Lorentz force responsible for the torque be replaced by the Einstein-Laub force. The resolution of the paradox reported by Science, based on numerous papers in the physics literature, preserves the Lorentz force but depends on the concept of hidden momentum. Here I propose a different resolution based on the overlooked fact that the charge-magnetic dipole system contains linear and angular electromagnetic field momentum. The time rate of change of the field angular-momentum in the frame through which the system is moving cancels that due to the charge-electric dipole interaction. From this point of view hidden momentum is not needed in the resolution of the paradox.

The Swarm Archiving Payload Data Facility, an Instance Configuration of the ESA Multi-Mission Facility

NASA Astrophysics Data System (ADS)

Pruin, B.; Martini, A.; Shanmugam, P.; Lopes, C.

2015-04-01

The Swarm mission consists of 3 satellites, each carrying an identical set of instruments. The scientific algorithms for processing are organized in 11 separate processing steps including automated product quality control. In total, the mission data consists of data products of several hundred distinct types from raw to level 2 product types and auxiliary data. The systematic production for Swarm within the ESA Archiving and Payload Data Facility (APDF) is performed up to level 2. The production up to L2 (CAT2-mature algorithm) is performed completely within the APDF. A separate systematic production chain from L1B to L2 (CAT1-evolving algorithm) is performed by an external facility (L2PS) with output files archived within the APDF as well. The APDF also performs re-processing exercises. Re-processing may start directly from the acquired data or from any other intermediate level resulting in the need for a refined product version and baseline management. Storage, dissemination and circulation functionality is configurable in the ESA generic multi-mission elements and does not require any software coding. The control of the production is more involved. While the interface towards the algorithmic entities is standardized due to the introduction of a generic IPF interface by ESA, the orchestration of the individual IPFs into the overall workflows is distinctly mission-specific and not as amenable to standardization. The ESA MMFI production management system provides extension points to integrate additional logical elements for the build-up of complex orchestrated workflows. These extension points have been used to inject the Swarm-specific production logic into the system. A noteworthy fact about the APDF is that the dissemination elements are hosted in a high bandwidth infrastructure procured as a managed service, thus affording users a considerable access bandwidth. This paper gives an overview of the Swarm APDF data flows. It describes the elements of the solution with particular focus on how the available generic multi-mission functionality of the ESA MMFI was utilized and where there was a need to implement missionspecific extensions and plug-ins. The paper concludes with some statistics on the system output during commissioning and early operational phases as well as some general considerations on the utilization of a framework like the ESA MMFI, discussing benefits and pitfalls of the approach.

A Direct Georeferencing Method for Terrestrial Laser Scanning Using GNSS Data and the Vertical Deflection from Global Earth Gravity Models

PubMed Central

Borkowski, Andrzej; Owczarek-Wesołowska, Magdalena; Gromczak, Anna

2017-01-01

Terrestrial laser scanning is an efficient technique in providing highly accurate point clouds for various geoscience applications. The point clouds have to be transformed to a well-defined reference frame, such as the global Geodetic Reference System 1980. The transformation to the geocentric coordinate frame is based on estimating seven Helmert parameters using several GNSS (Global Navigation Satellite System) referencing points. This paper proposes a method for direct point cloud georeferencing that provides coordinates in the geocentric frame. The proposed method employs the vertical deflection from an external global Earth gravity model and thus demands a minimum number of GNSS measurements. The proposed method can be helpful when the number of georeferencing GNSS points is limited, for instance in city corridors. It needs only two georeferencing points. The validation of the method in a field test reveals that the differences between the classical georefencing and the proposed method amount at maximum to 7 mm with the standard deviation of 8 mm for all of three coordinate components. The proposed method may serve as an alternative for the laser scanning data georeferencing, especially when the number of GNSS points is insufficient for classical methods. PMID:28672795

A Direct Georeferencing Method for Terrestrial Laser Scanning Using GNSS Data and the Vertical Deflection from Global Earth Gravity Models.

PubMed

Osada, Edward; Sośnica, Krzysztof; Borkowski, Andrzej; Owczarek-Wesołowska, Magdalena; Gromczak, Anna

2017-06-24

Terrestrial laser scanning is an efficient technique in providing highly accurate point clouds for various geoscience applications. The point clouds have to be transformed to a well-defined reference frame, such as the global Geodetic Reference System 1980. The transformation to the geocentric coordinate frame is based on estimating seven Helmert parameters using several GNSS (Global Navigation Satellite System) referencing points. This paper proposes a method for direct point cloud georeferencing that provides coordinates in the geocentric frame. The proposed method employs the vertical deflection from an external global Earth gravity model and thus demands a minimum number of GNSS measurements. The proposed method can be helpful when the number of georeferencing GNSS points is limited, for instance in city corridors. It needs only two georeferencing points. The validation of the method in a field test reveals that the differences between the classical georefencing and the proposed method amount at maximum to 7 mm with the standard deviation of 8 mm for all of three coordinate components. The proposed method may serve as an alternative for the laser scanning data georeferencing, especially when the number of GNSS points is insufficient for classical methods.

Fast generation of complex modulation video holograms using temporal redundancy compression and hybrid point-source/wave-field approaches

NASA Astrophysics Data System (ADS)

Gilles, Antonin; Gioia, Patrick; Cozot, Rémi; Morin, Luce

2015-09-01

The hybrid point-source/wave-field method is a newly proposed approach for Computer-Generated Hologram (CGH) calculation, based on the slicing of the scene into several depth layers parallel to the hologram plane. The complex wave scattered by each depth layer is then computed using either a wave-field or a point-source approach according to a threshold criterion on the number of points within the layer. Finally, the complex waves scattered by all the depth layers are summed up in order to obtain the final CGH. Although outperforming both point-source and wave-field methods without producing any visible artifact, this approach has not yet been used for animated holograms, and the possible exploitation of temporal redundancies has not been studied. In this paper, we propose a fast computation of video holograms by taking into account those redundancies. Our algorithm consists of three steps. First, intensity and depth data of the current 3D video frame are extracted and compared with those of the previous frame in order to remove temporally redundant data. Then the CGH pattern for this compressed frame is generated using the hybrid point-source/wave-field approach. The resulting CGH pattern is finally transmitted to the video output and stored in the previous frame buffer. Experimental results reveal that our proposed method is able to produce video holograms at interactive rates without producing any visible artifact.

77 FR 68209 - Medicare and Medicaid Programs: Hospital Outpatient Prospective Payment and Ambulatory Surgical...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-15

...-through devices, brachytherapy sources, intraoperative radiation therapy (IORT), brachytherapy composite... Modulated Radiation Therapy I/OCE Integrated Outpatient Code Editor IOL Intraocular lens IOM Institute of Medicine IORT Intraoperative radiation treatment IPF Inpatient Psychiatric Facility IPPS [Hospital...

Creating Joint Attentional Frames and Pointing to Evidence in the Reading and Writing Process

ERIC Educational Resources Information Center

Unger, John A.; Liu, Rong; Scullion, Vicki A.

2015-01-01

This theory-into-practice paper integrates Tomasello's concept of Joint Attentional Frames and well-known ideas related to the work of Russian psychologist, Lev Vygotsky, with more recent ideas from social semiotics. Classroom procedures for incorporating student-created Joint Attentional Frames into literacy lessons are explained by links to…

Pleural mesothelial cells in pleural and lung diseases

PubMed Central

Antony, Veena B.

2015-01-01

During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells (PMCs) derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition (EMT). An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as idiopathic pulmonary fibrosis (IPF). The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor (TLR) recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of pleural effusions occurs due to an imbalance in the dynamic interaction between junctional proteins, n-cadherin and β-catenin, and phosphorylation of adherens junctions between PMCs, which is caused in part by vascular endothelial growth factor (VEGF) released by PMCs. PMCs play an important role in defense mechanisms against bacterial and mycobacterial pleural infections, and in pathogenesis of malignant pleural effusion, asbestos related pleural disease and malignant pleural mesothelioma. PMCs also play a key role in the resolution of inflammation, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-β, platelet-derived growth factor (PDGF), and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of IPF suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of IPF and other lung diseases need further exploration. PMID:26150910

FK506-binding protein 10 (FKBP10) regulates lung fibroblast migration via collagen VI synthesis.

PubMed

Knüppel, Larissa; Heinzelmann, Katharina; Lindner, Michael; Hatz, Rudolf; Behr, Jürgen; Eickelberg, Oliver; Staab-Weijnitz, Claudia A

2018-04-19

In idiopathic pulmonary fibrosis (IPF), fibroblasts gain a more migratory phenotype and excessively secrete extracellular matrix (ECM), ultimately leading to alveolar scarring and progressive dyspnea. Here, we analyzed the effects of deficiency of FK506-binding protein 10 (FKBP10), a potential IPF drug target, on primary human lung fibroblast (phLF) adhesion and migration. Using siRNA, FKBP10 expression was inhibited in phLF in absence or presence of 2ng/ml transforming growth factor-β1 (TGF-β1) and 0.1mM 2-phosphoascorbate. Effects on cell adhesion and migration were monitored by an immunofluorescence (IF)-based attachment assay, a conventional scratch assay, and single cell tracking by time-lapse microscopy. Effects on expression of key players in adhesion dynamics and migration were analyzed by qPCR and Western Blot. Colocalization was evaluated by IF microscopy and by proximity ligation assays. FKBP10 knockdown significantly attenuated adhesion and migration of phLF. Expression of collagen VI was decreased, while expression of key components of the focal adhesion complex was mostly upregulated. The effects on migration were 2-phosphoascorbate-dependent, suggesting collagen synthesis as the underlying mechanism. FKBP10 colocalized with collagen VI and coating culture dishes with collagen VI, and to a lesser extent with collagen I, abolished the effect of FKBP10 deficiency on migration. These findings show, to our knowledge for the first time, that FKBP10 interacts with collagen VI and that deficiency of FKBP10 reduces phLF migration mainly by downregulation of collagen VI synthesis. The results strengthen FKBP10 as an important intracellular regulator of ECM remodeling and support the concept of FKBP10 as drug target in IPF.

Serological assessment of neutrophil elastase activity on elastin during lung ECM remodeling.

PubMed

Kristensen, Jacob H; Karsdal, Morten A; Sand, Jannie Mb; Willumsen, Nicholas; Diefenbach, Claudia; Svensson, Birte; Hägglund, Per; Oersnes-Leeming, Diana J

2015-05-03

During the pathological destruction of lung tissue, neutrophil elastase (NE) degrades elastin, one of the major constituents of lung parenchyma. However there are no non-invasive methods to quantify NE degradation of elastin. We selected specific elastin fragments generated by NE for antibody generation and developed an ELISA assay (EL-NE) for the quantification of NE-degraded elastin. Monoclonal antibodies were developed against 10 NE-specific cleavage sites on elastin. One EL-NE assay was tested for analyte stability, linearity and intra- and inter-assay variation. The NE specificity was demonstrated using elastin cleaved in vitro with matrix metalloproteinases (MMPs), cathepsin G (CatG), NE and intact elastin. Clinical relevance was assessed by measuring levels of NE-generated elastin fragments in serum of patients diagnosed with idiopathic pulmonary fibrosis (IPF, n = 10) or lung cancer (n = 40). Analyte recovery of EL-NE for human serum was between 85% and 104%, the analyte was stable for four freeze/thaw cycles and after 24 h storage at 4°C. EL-NE was specific for NE-degraded elastin. Levels of NE-generated elastin fragments for elastin incubated in the presence of NE were 900% to 4700% higher than those seen with CatG or MMP incubation or in intact elastin. Serum levels of NE-generated elastin fragments were significantly increased in patients with IPF (137%, p = 0.002) and in patients with lung cancer (510%, p < 0.001) compared with age- and sex-matched controls. The EL-NE assay was specific for NE-degraded elastin. The EL-NE assay was able to specifically quantify NE-degraded elastin in serum. Serum levels of NE-degraded elastin might be used to detect excessive lung tissue degradation in lung cancer and IPF.