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Sample records for idiopathic pulmonary fibrosis

  1. Idiopathic Pulmonary Fibrosis

    MedlinePlus

    ... the NHLBI on Twitter. What Is Idiopathic Pulmonary Fibrosis? Pulmonary fibrosis (PULL-mun-ary fi-BRO-sis) is a ... time. The formation of scar tissue is called fibrosis. As the lung tissue thickens, your lungs can' ...

  2. What Causes Idiopathic Pulmonary Fibrosis?

    MedlinePlus

    ... the NHLBI on Twitter. What Causes Idiopathic Pulmonary Fibrosis? Sometimes doctors can find out what is causing pulmonary fibrosis (lung scarring). For example, exposure to environmental pollutants ...

  3. Idiopathic pulmonary fibrosis.

    PubMed

    Xaubet, Antoni; Ancochea, Julio; Molina-Molina, María

    2017-02-23

    Idiopathic pulmonary fibrosis is a fibrosing interstitial pneumonia associated with the radiological and/or histological pattern of usual interstitial pneumonia. Its aetiology is unknown, but probably comprises the action of endogenous and exogenous micro-environmental factors in subjects with genetic predisposition. Its diagnosis is based on the presence of characteristic findings of high-resolution computed tomography scans and pulmonary biopsies in absence of interstitial lung diseases of other aetiologies. Its clinical evolution is variable, although the mean survival rate is 2-5 years as of its clinical presentation. Patients with idiopathic pulmonary fibrosis may present complications and comorbidities which modify the disease's clinical course and prognosis. In the mild-moderate disease, the treatment consists of the administration of anti-fibrotic drugs. In severe disease, the best therapeutic option is pulmonary transplantation. In this paper we review the diagnostic and therapeutic aspects of the disease.

  4. [Idiopathic pulmonary fibrosis].

    PubMed

    Cottin, Vincent; Cordier, Jean-François

    2008-11-01

    Idiopathic pulmonary fibrosis is a chronic disorder characterized histopathologically by a pattern of usual interstitial pneumonia, with heterogeneous and mutilating interstitial fibrosis with foci of proliferating fibroblasts, honeycomb lung, and little if any inflammation. The diagnosis is based on a pluridisciplinary analysis of the clinical symptoms, the chest high-resolution computerized tomography features, and pathology on video-thoracoscopic lung biopsy when indicated. In half of the cases, the typical tomodensitometric pattern allows to make a confident diagnosis without a lung biopsy. The median survival is only about 3 years and is presently not improved by any treatment. Treatment with N-acetylcysteine (antioxydant) in association with corticosteroids and azathioprine may slightly reduce the rate of functional worsening. Clinical trials are in progress to improve the treatment of this still incurable disease.

  5. 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.

  6. Epidemiology of idiopathic pulmonary fibrosis

    PubMed Central

    Ley, Brett; Collard, Harold R

    2013-01-01

    Idiopathic pulmonary fibrosis is a chronic fibrotic lung disease of unknown cause that occurs in adults and has a poor prognosis. Its epidemiology has been difficult to study because of its rarity and evolution in diagnostic and coding practices. Though uncommon, it is likely underappreciated both in terms of its occurrence (ie, incidence, prevalence) and public health impact (ie, health care costs and resource utilization). Incidence and mortality appear to be on the rise, and prevalence is expected to increase with the aging population. Potential risk factors include occupational and environmental exposures, tobacco smoking, gastroesophageal reflux, and genetic factors. An accurate understanding of its epidemiology is important, especially as novel therapies are emerging. PMID:24348069

  7. 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.

  8. Smoking and Idiopathic Pulmonary Fibrosis

    PubMed Central

    Oh, Chad K.; Murray, Lynne A.; Molfino, Nestor A.

    2012-01-01

    Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology with considerable morbidity and mortality. Cigarette smoking is one of the most recognized risk factors for development of IPF. Furthermore, recent work suggests that smoking may have a detrimental effect on survival of patients with IPF. The mechanism by which smoking may contribute to the pathogenesis of IPF is largely unknown. However, accumulating evidence suggests that increased oxidative stress might promote disease progression in IPF patients who are current and former smokers. In this review, potential mechanisms by which cigarette smoking affects IPF, the effects of cigarette smoking on accelerated loss of lung function in patients with IPF, key genetic studies evaluating the potential candidate genes and gene-environment (smoking) interaction, diagnosis, and treatment with emphasis on recently closed and ongoing clinical trials are presented. PMID:22448328

  9. Epigenetics of Idiopathic Pulmonary Fibrosis

    PubMed Central

    Yang, Ivana V.; Schwartz, David A.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is a complex lung disease of unknown etiology. Development of IPF is influenced by both genetic and environmental factors. Recent work by our and other groups has identified strong genetic predisposition factors for the development of pulmonary fibrosis while cigarette smoke remains the most strongly associated environmental exposure risk factor. Gene expression profiling studies of IPF lung have taught us quite a bit about the biology of this fatal disease and those in peripheral blood have provided important biomarkers. However, epigenetic marks may be the missing link that connects the environmental exposure in genetically predisposed individuals to transcriptional changes associated with disease development. Moreover, epigenetic marks represent a promising therapeutic target for IPF. In this review, we will introduce the disease, summarize genetic and gene expression studies in IPF, discuss exposures relevant to IPF and known epigenetic changes associated with cigarette smoke exposure, and summarize epigenetic studies conducted so far in IPF. We will end by discussing limitations, challenges and future opportunities in this field. PMID:24746870

  10. Is pirfenidone effective for idiopathic pulmonary fibrosis?

    PubMed

    Jeldres, Alejandro; Labarca, Gonzalo

    2017-01-17

    Idiopathic pulmonary fibrosis has an ominous prognosis and there are virtually no effective therapies. It has been suggested that pirfenidone, an antifibrotic agent, could change its course. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified 13 systematic reviews comprising nine trials addressing the question of this article, seven of which are randomized and whose results were analyzed in this summary. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded pirfenidone decreases disease progression and mortality in idiopathic pulmonary fibrosis. Although it is associated with frequent gastrointestinal and cutaneous adverse effects, these are generally not severe.

  11. 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

  12. Idiopathic Pulmonary Fibrosis: Treatment and Prognosis

    PubMed Central

    Fujimoto, Hajime; Kobayashi, Tetsu; Azuma, Arata

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a prognosis that can be worse than for many cancers. The initial stages of the condition were thought to mainly involve chronic inflammation; therefore, corticosteroids and other drugs that have anti-inflammatory and immunosuppressive actions were used. However, recently, agents targeting persistent fibrosis resulting from aberrant repair of alveolar epithelial injury have been in the spotlight. There has also been an increase in the number of available antifibrotic treatment options, starting with pirfenidone and nintedanib. These drugs prevent deterioration but do not improve IPF. Therefore, nonpharmacologic approaches such as long-term oxygen therapy, pulmonary rehabilitation, and lung transplantation must be considered as additional treatment modalities. PMID:27980445

  13. Bosentan for pulmonary hypertension secondary to idiopathic pulmonary fibrosis.

    PubMed

    Onda, Naomi; Tanaka, Yosuke; Hino, Mitsunori; Gemma, Akihiko

    2015-01-01

    Pulmonary hypertension is a poor prognostic factor in patients with interstitial lung disease. No established treatment exists for pulmonary hypertension secondary to interstitial pneumonia. We describe the case of an 81-year-old woman with idiopathic pulmonary fibrosis (IPF), who was admitted to our hospital due to aggravation of dyspnea and decreased oxygen saturation, as well as onset of orthopnea and rapidly progressing edema. The transthoracic echocardiography and right heart catheterization showed the mean pulmonary artery pressure was 39 mmHg and the mean pulmonary capillary wedge pressure was 9 mmHg. After various examinations, the diagnoses of pulmonary hypertension (PH) due to IPF and of congestive heart failure secondary to PH were established. Diuretic therapy was started, but the patient's condition showed poor improvement. Subsequent initiation of oral bosentan therapy led to improvement in symptoms and findings. At the follow-up assessment one year later her pulmonary function showed no significant changes and no apparent worsening of arterial blood gases, with evident improvement of PH, WHO functional class, maximum exercise tolerance on treadmill exercise testing, right heart catheterization, and transthoracic echocardiography. This report describes a case of successful treatment with bosentan for severe pulmonary hypertension in a patient with idiopathic pulmonary fibrosis. We also present a review of the literature on treatment of pulmonary hypertension in patients with chronic lung disease. Bosentan appears to be efficacious in some patients with pulmonary hypertension secondary to idiopathic interstitial pneumonitis.

  14. Idiopathic pulmonary fibrosis: Early detection and referral

    PubMed Central

    Oldham, Justin M.; Noth, Imre

    2016-01-01

    Summary Idiopathic pulmonary fibrosis (IPF), a devastating progressive interstitial lung disease (ILD) with no known cause or cure, is the most common and deadly of the idiopathic interstitial pneumonias. With a median survival of 3–5 years following diagnosis, IPF is characterized by a progressive decline in lung function and quality of life in most patients. Vigilance among clinicians in recognizing IPF early in the disease course remains critical to properly caring for these patients, as this provides the widest range of management options. When IPF is suspected, a multidisciplinary evaluation (MDE) by a clinician, radiologist and pathologist with ILD expertise should occur, as this improves diagnostic agreement in both community and academic settings. When community MDE is not possible, or diagnostic doubt exists, referral to an ILD center should be considered. ILD center referral may also provide access specialized care, including clinical trials and lung transplantation, and should be considered for any patient with an established diagnosis of IPF. PMID:24746629

  15. Acute Exacerbations of Idiopathic Pulmonary Fibrosis

    PubMed Central

    Collard, Harold R.; Moore, Bethany B.; Flaherty, Kevin R.; Brown, Kevin K.; Kaner, Robert J.; King, Talmadge E.; Lasky, Joseph A.; Loyd, James E.; Noth, Imre; Olman, Mitchell A.; Raghu, Ganesh; Roman, Jesse; Ryu, Jay H.; Zisman, David A.; Hunninghake, Gary W.; Colby, Thomas V.; Egan, Jim J.; Hansell, David M.; Johkoh, Takeshi; Kaminski, Naftali; Kim, Dong Soon; Kondoh, Yasuhiro; Lynch, David A.; Müller-Quernheim, Joachim; Myers, Jeffrey L.; Nicholson, Andrew G.; Selman, Moisés; Toews, Galen B.; Wells, Athol U.; Martinez, Fernando J.

    2007-01-01

    The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed. PMID:17585107

  16. Idiopathic pulmonary fibrosis: current and future directions.

    PubMed

    Soo, E; Adamali, H; Edey, A J

    2017-01-21

    Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and is increasingly recognised. Prior to the advent of effective therapies, achieving an early diagnosis was arguably of little prognostic consequence given IPF was considered an untreatable and uniformly fatal disease. The advent of new drug treatments has given hope for the future and raised the profile of IPF. International management guidelines highlight the critical role of radiology as part of an interstitial lung disease multidisciplinary team approach in reaching an accurate and early diagnosis of IPF. The diagnostic criteria and levels of diagnostic confidence for the radio-pathological pattern associated with the clinical syndrome of IPF, usual interstitial pneumonia (UIP), appear seemingly straightforward; however, with increasing research and recognition of radiopathological interobserver variability, limitations of this classification model are becoming increasingly apparent. This review describes ancillary radiological features, comorbidities, and emerging new entities that potentially co-exist with IPF. Beyond diagnosis radiology is developing as a key prognostic tool to inform longitudinal patient evaluation. These diagnostic and prognostic clinical challenges and the future role of radiology in IPF are discussed.

  17. Idiopathic pulmonary fibrosis: emerging concepts on pharmacotherapy.

    PubMed

    Thannickal, Victor J; Flaherty, Kevin R; Martinez, Fernando J; Lynch, Joseph P

    2004-08-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrosing disease of the distal air spaces of the lung of unknown aetiology. IPF is usually fatal with a median survival of < 3 years. There are currently no effective pharmacotherapeutic agents for the treatment of IPF. In this review, unifying concepts on the pathogenesis of IPF based on understanding of host responses to tissue injury are presented. These host responses involve tightly regulated and contextually orchestrated inflammatory and repair processes. Dysregulation of either of these processes can lead to pathological outcomes. Fibrosis results from an exaggerated or dysregulated repair process that proceeds 'uncontrolled' even after inflammatory responses have subsided. Disease heterogeneity may arise when inflammation and repair are in different (dys)regulatory phases, thus accounting for regional disparity. Usual interstitial pneumonia (UIP), the histopathological correlate of clinical IPF, represents a more fibrotic tissue reaction pattern and for which anti-inflammatory agents are ineffective. Emerging 'antifibrotic' drugs and strategies for UIP/IPF are discussed. The importance of accurately phenotyping a highly heterogeneous disease process that may require individualised and 'combined' therapies is emphasised.

  18. Lymphatics in lymphangioleiomyomatosis and idiopathic pulmonary fibrosis

    PubMed Central

    Glasgow, Connie G.; El-Chemaly, Souheil; Moss, Joel

    2013-01-01

    The primary function of the lymphatic system is absorbing and transporting macromolecules and immune cells to the general circulation, thereby regulating fluid, nutrient absorption and immune cell trafficking. Lymphangiogenesis plays an important role in tissue inflammation and tumour cell dissemination. Lymphatic involvement is seen in lymphangioleiomyomatosis (LAM) and idiopathic pulmonary fibrosis (IPF). LAM, a disease primarily affecting females, involves the lung (cystic destruction), kidney (angiomyolipoma) and axial lymphatics (adenopathy and lymphangioleiomyoma). LAM occurs sporadically or in association with tuberous sclerosis complex (TSC). Cystic lung destruction results from proliferation of LAM cells, which are abnormal smooth muscle-like cells with mutations in the TSC1 or TSC2 gene. Lymphatic abnormalities arise from infiltration of LAM cells into the lymphatic wall, leading to damage or obstruction of lymphatic vessels. Benign appearing LAM cells possess metastatic properties and are found in the blood and other body fluids. IPF is a progressive lung disease resulting from fibroblast proliferation and collagen deposition. Lymphangiogenesis is associated with pulmonary destruction and disease severity. A macrophage subset isolated from IPF bronchoalveolar lavage fluid (BALF) express lymphatic endothelial cell markers in vitro, in contrast to the same macrophage subset from normal BALF. Herein, we review lymphatic involvement in LAM and IPF. PMID:22941884

  19. 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

  20. Update on diagnosis and treatment of idiopathic pulmonary fibrosis

    PubMed Central

    Baddini-Martinez, José; Baldi, Bruno Guedes; da Costa, Cláudia Henrique; Jezler, Sérgio; Lima, Mariana Silva; Rufino, Rogério

    2015-01-01

    Idiopathic pulmonary fibrosis is a type of chronic fibrosing interstitial pneumonia, of unknown etiology, which is associated with a progressive decrease in pulmonary function and with high mortality rates. Interest in and knowledge of this disorder have grown substantially in recent years. In this review article, we broadly discuss distinct aspects related to the diagnosis and treatment of idiopathic pulmonary fibrosis. We list the current diagnostic criteria and describe the therapeutic approaches currently available, symptomatic treatments, the action of new drugs that are effective in slowing the decline in pulmonary function, and indications for lung transplantation. PMID:26578138

  1. Pirfenidone treatment of idiopathic pulmonary fibrosis

    PubMed Central

    Gan, Ye; Herzog, Erica L; Gomer, Richard H

    2011-01-01

    Idiopathic pulmonary fibrosis (IPF) is a discrete clinicopathologic entity defined by the presence of usual interstitial pneumonia on high-resolution CT scan and/or open lung biopsy and the absence of an alternate diagnosis or exposure explaining these findings. There are currently no FDA-approved therapies available to treat this disease, and the 5-year mortality is ∼80%. The pyridone derivative pirfenidone has been studied extensively as a possible therapeutic agent for use in this deadly disease. This review will present the unique clinical features and management issues encountered by physicians caring for IPF patients, including the poor response to conventional therapy. The biochemistry and preclinical efficacy of pirfenidone will be discussed along with a comprehensive review of the clinical efficacy, safety, and side effects and patient-centered foci such as quality of life and tolerability. It is hoped that this information will lend insight into the complex issues surrounding the use of pirfenidone in IPF and lead to further investigation of this agent as a possible therapy in this devastating disease. PMID:21339942

  2. Genetics Home Reference: idiopathic pulmonary fibrosis

    MedlinePlus

    ... Ma SF, Vij R, Collard HR, Wolters PJ, Garcia CK. Effect of telomere length on survival in ... Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK. Adult-onset pulmonary fibrosis caused by mutations ...

  3. Collagen polymorphism in idiopathic chronic pulmonary fibrosis.

    PubMed Central

    Seyer, J M; Hutcheson, E T; Kang, A H

    1976-01-01

    Collagens in normal human lung and in idiopathic chronic fibrosis were investigated in terms of their covalent structure and compared for possible alterations in the diseased state. Collagens were solubilized by limited digestion with pepsin under nondenaturing conditions, and after purification they, were fractionated into types I and III. Carboxymethylcellulose and agarose chromatography of both types I and III collagens, and amino acid and carbohydrate analyses of the resulting alpha-chains indicated that the alpha 1 (I), alpha 2, and alpha 1 (III) chains of normal human lung were identical with the human skin alpha-chains in all respects examined except that the normal lung chains contained higher levels of hydroxylysine. Examination of collagens obtained from the diseased lung revealed that the content of hydroxylysine of the alpha 1 (I) and the alpha 1 (III) chains appeared to be diminished as compared to the normal lung chains. The values, expressed as residues per 1,000 residues, are 7.1 and 8.3 for the alpha 1 (I) and the alpha 1 (III) chains, respectively, as compared to 10.0 and 11.1 for the alpha-chains from the normal tissue. The chromatographic properties and amino acid and carbohydrate composition of the alpha-chains from the diseased tissue were otherwise indistinguishable from those of normal lung. In addition, isolation and characterization of the CNBr peptides of alpha 1 (I), alpha 2 and alpha 1 (III) from the diseased lung revealed no significant differences from the CNBr peptides from other human tissues reported previously. Normal and diseased lungs were also digested with CNBr, and the resultant alpha 1 (I) and alpha 1 (III) peptides were separated chromatographically. The relative quantities of these peptides indicate that type III collagen constitutes 33% of the total collagen in normal human lung, with the remainder being type I, whereas in idiopathic chronic pulmonary fibrosis, the relative content of type III collagen is markedly

  4. Practical management of Idiopathic Pulmonary Fibrosis.

    PubMed

    Kishaba, Tomoo

    2015-07-22

    Idiopathic Pulmonary Fibrosis (IPF) is relentless progressive interstitial lung disease (ILD) of unknown etiology. Main pathogenesis is aberrant recovery of epithelial injury and collagen deposition. Majority of IPF patients have been elderly men with smokers. However, there are important differential diagnosis such as fibrotic non-specific interstitial pneumonia (NSIP), Connective Tissue Disease (CTD) associated ILD, chronic hypersensitivity pneumonia (CHP). Clinical point of view, non-productive cough and progressive exertional dyspnea are main symptoms. In addition, scalene muscle hypertrophy, fine crackles and finger clubbing are key findings. Serum marker such as lactate deydrogenase (LDH), Krebs von den Lungeng-6 (KL-6) are sensitive for ILD detection and activity. Pulmonary function test and 6 minute walk test (6MWT) are quite meaningful physiological examination. Serial change of forced vital capacity 6MWT distance predict mortality of IPF. International IPF guideline published recently and highlighted on the importance of high resolution computed tomography (HRCT) findings. Key findings of IPF are honeycombing, traction bronchiectasis and subpleural reticular opacity. IPF is chronic progressive disease. Therefore, tracing disease behavior is crucial and unifying clinical, physiological, imaging information over time provide useful information for physicians.In management, many candidate agent failed to have positive result. Pirfenidone which is anti-fibrotic agent showed to slow the decline of vital capacity and prevent of acute exacerbation. Molecular agent such as nintedanib is promising agent for prevention of progression of IPF. In this review, we review the clinical information of IPF and IPF guideline. Lastly, we show the clinical algorithm of this devastated disease.

  5. Perceptions, experiences and needs of patients with idiopathic pulmonary fibrosis

    PubMed Central

    Duck, Annette; Spencer, Lisa G; Bailey, Simon; Leonard, Colm; Ormes, Jennifer; Caress, Ann-Louise

    2015-01-01

    Aims To understand the perceptions, needs and experiences of patients with Idiopathic Pulmonary Fibrosis. Background Idiopathic pulmonary fibrosis is a progressive interstitial lung disease, with a mean life expectancy similar to some forms of cancer of 2–4 years from diagnosis. Unlike the cancer literature, which is rich with studies exploring the needs of their disease group, few publications exist on patient needs with this severe fibrotic lung disease. Design A Qualitative study which took place between 2007–2012. Methods Seventeen patients with a multidisciplinary team confirmed diagnosis of Idiopathic Pulmonary Fibrosis, with moderate to advanced disease severity and six of their informal carers were interviewed. An interview topic guide was developed by the researchers and service user group. The interviews were audio-recorded, semi-structured and took place at a regional respiratory and lung transplant centre in North West England. Interviews were transcribed verbatim and data analysed using Framework Analysis. Findings Three main themes were identified: ‘Struggling to get a diagnosis’; ‘Loss of the life I previously had’; and ‘Living with Idiopathic Pulmonary Fibrosis’. Patients reported struggling to get a diagnosis and coping with a life-limiting, rapidly progressive illness with no good treatment and few support structures. Conclusions There is an urgent need for a better understanding of the difficulties faced by people with Idiopathic Pulmonary Fibrosis and their carers. This can be used to develop better supportive care in the United Kingdom and ultimately improve the quality of life of these patients. PMID:25533573

  6. Precision Medicine: The New Frontier in Idiopathic Pulmonary Fibrosis.

    PubMed

    Brownell, Robert; Kaminski, Naftali; Woodruff, Prescott G; Bradford, Williamson Z; Richeldi, Luca; Martinez, Fernando J; Collard, Harold R

    2016-06-01

    Precision medicine is defined by the National Institute of Health's Precision Medicine Initiative Working Group as an approach to disease treatment that takes into account individual variability in genes, environment, and lifestyle. There has been increased interest in applying the concept of precision medicine to idiopathic pulmonary fibrosis, in particular to search for genetic and molecular biomarker-based profiles (so called endotypes) that identify mechanistically distinct disease subgroups. The relevance of precision medicine to idiopathic pulmonary fibrosis is yet to be established, but we believe that it holds great promise to provide targeted and highly effective therapies to patients. In this manuscript, we describe the field's nascent efforts in genetic/molecular endotype identification and how environmental and behavioral subgroups may also be relevant to disease management.

  7. Familial Pulmonary Fibrosis

    MedlinePlus

    ... Training Home Conditions Familial Pulmonary Fibrosis Familial Pulmonary Fibrosis Make an Appointment Find a Doctor Ask a ... members within the same family have Idiopathic Pulmonary Fibrosis (IPF) or any other form of Idiopathic Interstitial ...

  8. 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.

  9. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report.

    PubMed

    Collard, Harold R; Ryerson, Christopher J; Corte, Tamera J; Jenkins, Gisli; Kondoh, Yasuhiro; Lederer, David J; Lee, Joyce S; Maher, Toby M; Wells, Athol U; Antoniou, Katerina M; Behr, Juergen; Brown, Kevin K; Cottin, Vincent; Flaherty, Kevin R; Fukuoka, Junya; Hansell, David M; Johkoh, Takeshi; Kaminski, Naftali; Kim, Dong Soon; Kolb, Martin; Lynch, David A; Myers, Jeffrey L; Raghu, Ganesh; Richeldi, Luca; Taniguchi, Hiroyuki; Martinez, Fernando J

    2016-08-01

    Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. Finally, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis.

  10. 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.

  11. Multidisciplinary interobserver agreement in the diagnosis of idiopathic pulmonary fibrosis.

    PubMed

    Thomeer, M; Demedts, M; Behr, J; Buhl, R; Costabel, U; Flower, C D R; Verschakelen, J; Laurent, F; Nicholson, A G; Verbeken, E K; Capron, F; Sardina, M; Corvasce, G; Lankhorst, I

    2008-03-01

    The purpose of the present study was to evaluate the accuracy of the diagnosis of idiopathic pulmonary fibrosis (IPF) by respiratory physicians in six European countries, and to calculate the interobserver agreement between high-resolution computed tomography reviewers and histology reviewers in IPF diagnosis. The diagnosis of usual interstitial pneumonia (UIP) was assessed by a local investigator, following the American Thoracic Society/European Respiratory Society consensus statement, and confirmed when a minimum of two out of three expert reviewers from each expert panel agreed with the diagnosis. The level of agreement between readers within each expert panel was calculated by weighted kappa. The diagnosis of UIP was confirmed by the expert panels in 87.2% of cases. A total of 179 thoracic high-resolution computed tomography scans were independently reviewed, and an interobserver agreement of 0.40 was found. Open or thoracoscopic lung biopsy was performed in 97 patients, 82 of whom could be reviewed by the expert committee. The weighted kappa between histology readers was 0.30. It is concluded that, although the level of agreement between the readers within each panel was only fair to moderate, the overall accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis in expert centres is good (87.2%).

  12. [Pneumology. Treatment of idiopathic pulmonary fibrosis: hopes and disappointment].

    PubMed

    Rochat, T; Leuenberger, P

    2005-01-12

    Idiopathic pulmonary fibrosis (IPF) is now recognized as a separate nosological entity. Despite the progresses in understanding the basic mechanisms of the disease, its prognosis remains poor. The classical treatment combines prednisone with a cytotoxic agent. Interferon gamma has the in vitro capacity of inhibiting fibroblasts proliferation. A pilot study showed positive results, but a more recent randomized double blind trial was unable to demonstrate a clear benefit to the patients. On the other hand there are many evidences for an oxydant-antioxydant imbalance in the pathogenesis of IPF. In a human controlled study N-acetylcysteine (NAC) at high doses (1800 mg per day orally) improved the pulmonary function tests when given on top of a combined therapy with prednisone and azathioprine.

  13. Viruses in Idiopathic Pulmonary Fibrosis. Etiology and Exacerbation

    PubMed Central

    Moore, Thomas A.

    2015-01-01

    Viral infections are important contributors to exacerbation of asthma and chronic obstructive pulmonary disease; however, the role of viruses in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is less clear. This likely reflects that fact that IPF acute exacerbations are defined clinically as “noninfectious,” and little attention has been paid to the outcomes of patients with IPF with diagnosed infections. However, accumulating evidence suggests that infections (both bacterial and viral) may influence disease outcomes either as exacerbating agents or initiators of disease. Support for a viral role in disease initiation comes from studies demonstrating the presence of herpesviral DNA and epithelial cell stress in the lungs of asymptomatic relatives at risk for developing familial IPF. In addition, the number of studies that can associate viral (especially herpesviral) signatures in the lung with the development of IPF is steadily growing, and activated leukocyte signatures in patients with IPF provide further support for infectious processes driving IPF progression. Animal modeling has been used to better understand how a gamma herpesvirus infection can modulate the pathogenesis of lung fibrosis and has demonstrated that preceding infections appear to reprogram lung epithelial cells during latency to produce profibrotic factors, making the lung more susceptible to subsequent fibrotic insult, whereas exacerbations of existing fibrosis, or infections in susceptible hosts, involve active viral replication and are influenced by antiviral therapy. In addition, there is new evidence that bacterial burden in the lungs of patients with IPF may predict a poor prognosis. PMID:26595738

  14. Efficacy of N-Acetylcysteine in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Sun, Tong; Liu, Jing; Zhao, De Wei

    2016-01-01

    Abstract There are a number of conflicting reports describing the clinical outcomes of using N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis. We have, therefore, performed a meta-analysis to evaluate the efficacy of N-acetylcysteine, compared with control, for the treatment of idiopathic pulmonary fibrosis. Original controlled clinical trials evaluating the efficacy of N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis were included in the analysis. Searches for relevant articles were carried out in July 2014 by 2 independent researchers using PubMed, Embase, Cochrane Central, and Google Scholar. Change in forced vital capacity, change in percentage of predicted vital capacity, change in percentage of predicted carbon monoxide diffusing capacity, changes in 6 minutes walking test distance, rate of adverse events, and rate of death were expressed as outcomes using RevMan 5.0.1. Five trials, with a total of 564 patients, were included in this meta-analysis. The meta-analysis showed that the control group had significant decreases in percentage of predicted vital capacity (standardized mean difference [SMD] = 0.37; 95% confidence interval [CI]: 0.13 to −0.62; P = 0.003) and 6 minutes walking test distance (SMD = 0.25; 95% CI: 0.02–0.48; P = 0.04). There were no statistically significant differences in forced vital capacity (SMD = 0.07; 95% CI: −0.13–0.27; P = 0.52), percentage of predicted carbon monoxide diffusing capacity (SMD = 0.12; 95% CI: −0.06–0.30; P = 0.18), rates of adverse events (odd ratio = 4.50; 95% CI: 0.19–106.41; P = 0.35), or death rates (odd ratio = 1.79; 95% CI: 0.3–5.12; P = 0.28) between the N-acetylcysteine group and the control group. N-Acetylcysteine was found to have a significant effect only on decreases in percentage of predicted vital capacity and 6 minutes walking test distance. N-acetylcysteine showed no beneficial effect on changes

  15. Candidate genes of idiopathic pulmonary fibrosis: current evidence and research

    PubMed Central

    Zhou, Wei; Wang, Yaping

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a group of common and lethal forms of idiopathic interstitial pulmonary disease. IPF is characterized by a progressive decline in lung function with a median survival of 2–3 years after diagnosis. Although the pathogenesis of the disease remains unknown, genetic predisposition could play a causal role in IPF. A set of genes have been identified as candidate genes of IPF in the past 20 years. However, the recent technological advances that allow for the analysis of millions of polymorphisms in different subjects have deepened the understanding of the genetic complexity of IPF susceptibility. Genome-wide association studies and whole-genome sequencing continue to reveal the genetic loci associated with IPF risk. In this review, we describe candidate genes on the basis of their functions and aim to gain a better understanding of the genetic basis of IPF. The discovered candidate genes may help to clarify pivotal aspects in the diagnosis, prognosis, and therapies of IPF. PMID:26893575

  16. 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

  17. Eosinophil alveolitis in two patients with idiopathic pulmonary fibrosis.

    PubMed

    Brix, Ninna; Rasmussen, Finn; Poletti, Venerino; Bendstrup, Elisabeth

    2016-01-01

    Bronchoalveolar lavage fluid (BALF) in patients with idiopathic pulmonary fibrosis (IPF) is typically characterized by a neutrophil inflammatory pattern and to a lesser extent (<25%) a mild eosinophil alveolitis. We here present two patients with a definite usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography of the thorax (HRCT) which demonstrated unusually high eosinophil counts in the BALF (40% and 51%). Based on HRCT, lack of response to steroids and the disease course they were both diagnosed as IPF after a multidisciplinary team discussion. This report discusses the diagnostic and etiological considerations of a coexisting UIP pattern and an eosinophil alveolitis. We conclude that these cases illustrate that high level BALF eosinophilia (40-50%) may occur among patients with IPF.

  18. Idiopathic pulmonary fibrosis in a Christmas Island nuclear test veteran

    PubMed Central

    Parfrey, H; Babar, J; Fiddler, CA; Chilvers, ER

    2010-01-01

    We describe the case of a 71-year-old man with idiopathic pulmonary fibrosis (usual interstitial pneumonia (UIP) pattern) diagnosed on clinical, radiological and lung function criteria, in accordance with the American Thoracic Society/European Respiratory Society consensus criteria (2000), who had been in close proximity to three atmospheric nuclear bomb blasts during military service in 1957. He does not have clubbing and clinically and radiologically his lung disease is stable. He also has bladder carcinoma and carotid arteriosclerosis, both recognised consequences of radiation injury. This is the first reported case of UIP in a nuclear test veteran. Awareness of this potential association is important given the current attempts of the British Nuclear Test Veterans Association to gain compensation for claimed injuries. PMID:22797205

  19. Investigational approaches to therapies for idiopathic pulmonary fibrosis

    PubMed Central

    Gomer, Richard H.; Lupher, Mark L.

    2010-01-01

    Importance of the field In fibrosing diseases, scar tissue begins to replace normal tissue, causing tissue dysfunction. For instance, in lung fibrosis, foci of what resembles scar tissue form in the lungs, impeding the ability of patients to breath. These conditions represent a significant source of morbidity and mortality. More than 150,000 people in the US have some form of fibrotic lung disease, and the five-year mortality rate for these diseases can be as high as 80%. Despite this large unmet medical need, there are no FDA-approved therapies. Although our understanding of the causes and the biology of fibrosing diseases remains relatively poor, we have made impressive advances in identifying the major cell populations and many biochemical mediators that can drive this process. As a result, novel therapeutics are being developed based upon these discoveries. Areas covered in this review This review examines the experimental therapies currently under investigation as of late 2009 for a major class of lung fibrosis called idiopathic pulmonary fibrosis (IPF). What the reader will gain The reader will gain an overview of current experimental therapies for IPF. Take home message With the recent approval of Pirfenidone in Japan for use in IPF, and a rich pipeline of experimental therapies in various stages of clinical development, the future looks bright for new treatment options. PMID:20443753

  20. Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis.

    PubMed

    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.

  1. 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

  2. Intrapulmonary concentration of levofloxacin in patients with idiopathic pulmonary fibrosis.

    PubMed

    Huang, Hui; Wang, Yanxun; Jiang, Chunguo; Lang, Liwei; Wang, Hongyun; Chen, Yong; Zhao, Yang; Xu, Zuojun

    2014-06-01

    Patients with idiopathic pulmonary fibrosis (IPF) have significantly impaired pulmonary diffusion, which may affect the pulmonary concentration of many drugs, including antibiotics. In this study, we compared the difference in pulmonary levofloxacin (LVFX) concentration between patients with normal lung function and IPF. The IPF group included 10 patients with a proven diagnosis of IPF and a diffusing capacity for carbon monoxide ranging from 40% to 70% of predicted values. The control group included 10 patients with normal pulmonary function. Blood and bronchoalveolar lavage fluid (BALF) were taken at 3-3.5 h after fasting. LVFX (500 mg) was administered orally. LVFX concentrations in the serum and BALF were determined using HPLC-MS/MC. The level of LVFX in alveolar epithelial lining fluid (ELF) was calculated using the following formula: LVFX ELF = LVFX BALF × (Urea serum/Urea BALF). No significant differences in age, body weight, height, and calculated creatinine clearance and BALF retrieval rate were observed between groups. LVFX serum concentrations in the IPF and control groups were (5.97 ± 1.28) μg/ml and (6.84 ± 3.43) μg/ml, respectively (P = 0.4727). ELF concentration of LVFX in the control group was (27.81 ± 21.36) μg/ml, while the concentration in the IPF group was (10.17 ± 2.46) μg/ml, less than half of that in the controls (P = 0.0058). The intrapulmonary concentration of LVFX in IPF patients was lower than those with normal lung function. Notably, however, the ELF LVFX concentration following 500 mg once-daily exceeded the MIC90 of common respiratory pathogens. Excellent antibacterial efficacy of LVFX can be expected for IPF patients in the treatment of respiratory tract infections.

  3. Self-Eating: Friend or Foe? The Emerging Role of Autophagy in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Margaritopoulos, George A.; Tsitoura, Eliza; Tzanakis, Nikos; Spandidos, Demetrios A.; Siafakas, Nikos M.; Sourvinos, George; Antoniou, Katerina M.

    2013-01-01

    Idiopathic pulmonary fibrosis is the most common and severe form of idiopathic interstitial pneumonias. Despite an exponential increase in our understanding of potentially important mediators and mechanisms, the pathogenesis remains elusive, and little therapeutic progress has been made in the last few years. Mortality in 3–5 years is still 50%. Autophagy, a highly conserved homeostatic mechanism necessary for cell survival, has been recently implicated in the pathogenesis of pulmonary disorders. In this paper we aim to highlight some key issues regarding the process of autophagy and its possible association with the pathogenesis of idiopathic pulmonary fibrosis. PMID:23691501

  4. Patient-reported outcomes in idiopathic pulmonary fibrosis research.

    PubMed

    Swigris, Jeffrey J; Fairclough, Diane

    2012-08-01

    Patient-reported outcomes (PROs) include questionnaires or surveys that ask patients for their perceptions about things like symptoms they are experiencing or quality of life. For incurable, morbid, life-shortening conditions like idiopathic pulmonary fibrosis (IPF), PROs are particularly germane: They elucidate for clinicians and researchers what it is like for patients to live with such a disease, and they may detect important treatment effects not captured by other metrics (eg, pulmonary physiology). However, a relative paucity of research on PROs in IPF has left significant knowledge gaps in this area and contributed to the timidity investigators have about using PROs as prominent outcomes in IPF drug trials. Additional research on existing instruments is needed to establish or bolster their basic psychometric properties in IPF. When PROs are used as end points in therapeutic trials, analyzing PRO response data can be challenging, but these challenges can be overcome with a transparent, thoughtful, and sophisticated statistical approach. In this article, we discuss some of the basics of PRO assessment, existing knowledge gaps in IPF-related PRO research, and the potential usefulness of using PROs in IPF trials and conclude by offering specific recommendations for an approach to analyzing repeated-measures PRO data from IPF trials.

  5. 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

  6. 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

  7. Determinants of 6-minute walk distance in patients with idiopathic pulmonary fibrosis undergoing lung transplant evaluation

    PubMed Central

    Rivera-Lebron, Belinda N.; Kreider, Maryl; Lee, James; Kawut, Steven M.

    2016-01-01

    Abstract Little is known about the physiologic determinants of 6-minute walk distance in idiopathic pulmonary fibrosis. We investigated the demographic, pulmonary function, echocardiographic, and hemodynamic determinants of 6-minute walk distance in patients with idiopathic pulmonary fibrosis evaluated for lung transplantation. We performed a cross-sectional analysis of 130 patients with idiopathic pulmonary fibrosis who completed a lung transplantation evaluation at the Hospital of the University of Pennsylvania between 2005 and 2010. Multivariable linear regression analysis was used to generate an explanatory model for 6-minute walk distance. After adjustment for age, sex, race, height, and weight, the presence of right ventricular dilation was associated with a decrease of 50.9 m (95% confidence interval [CI], 8.4–93.3) in 6-minute walk distance (P=0.02). For each 200-mL reduction in forced vital capacity, the walk distance decreased by 15.0 m (95% CI, 9.0–21.1; P<0.001). For every increase of 1 Wood unit in pulmonary vascular resistance, the walk distance decreased by 17.3 m (95% CI, 5.1–29.5; P=0.006). Six-minute walk distance in idiopathic pulmonary fibrosis depends in part on circulatory impairment and the degree of restrictive lung disease. Future trials that target right ventricular morphology, pulmonary vascular resistance, and forced vital capacity may potentially improve exercise capacity in patients with idiopathic pulmonary fibrosis. PMID:27076905

  8. TLR9 Differentiates Rapid from Slowly Progressive Forms of Idiopathic Pulmonary Fibrosis

    PubMed Central

    Trujillo, Glenda; Meneghin, Alessia; Flaherty, Kevin R.; Sholl, Lynette M.; Myers, Jeffrey L.; Kazerooni, Ella A.; Gross, Barry H.; Oak, Sameer R.; Coelho, Ana Lucia; Evanoff, Holly; Day, Elizabeth; Toews, Galen B.; Joshi, Amrita D.; Schaller, Matthew A.; Waters, Beatrice; Jarai, Gabor; Westwick, John; Kunkel, Steve L.; Martinez, Fernando J.; Hogaboam, Cory M.

    2011-01-01

    Idiopathic pulmonary fibrosis is a generally progressive disorder with highly heterogeneous disease progression. The most common of the idiopathic interstitial pneumonias, idiopathic pulmonary fibrosis is characterized by a steady worsening of lung function and gas exchange cause by diffuse alveolar damage and severe fibrosis. We examined clinical features of patients with idiopathic pulmonary fibrosis to classify them as exhibiting rapid or slowly progressive over the first year of follow-up. We identified differences between the two groups in order to investigate the mechanism of rapid progression. Previous work from our laboratory has demonstrated that Toll-like receptor 9, a pathogen recognition receptor, promotes myofibroblast differentiation in lung fibroblasts cultured from biopsies of patients with idiopathic pulmonary fibrosis. Therefore, we hypothesized that TLR9 functions as both a sensor of pathogenic molecules and a profibrotic signal in rapidly progressive idiopathic pulmonary fibrosis. TLR9 was present at higher concentrations in surgical lung biopsies from rapidly progressive patients than in tissue from normal controls. Fibroblasts from rapid progressors were more responsive to the TLR9 agonist, CpG, than were fibroblasts from control patients. We used a humanized SCID mouse and demonstrated that there was increased fibrosis in murine lungs receiving human lung fibroblasts from rapid progressors than in mice receiving normal fibroblasts. This fibrosis was exacerbated by intranasal CpG challenges. Furthermore, CpG induced the differentiation of blood monocytes into fibrocytes and the epithelial-to-mesenchymal transition of A549 lung epithelial cells. These data suggest that TLR9 may drive the pathogenesis of rapidly progressive idiopathic pulmonary fibrosis and is a potential indicator of this subset of the disease. PMID:21068441

  9. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define “slow” or “rapid” disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression. PMID:27159038

  10. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis.

    PubMed

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo; Cosio, Manuel G; Saetta, Marina

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define "slow" or "rapid" disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression.

  11. Sleep and respiratory sleep disorders in idiopathic pulmonary fibrosis.

    PubMed

    Milioli, Giulia; Bosi, Marcello; Poletti, Venerino; Tomassetti, Sara; Grassi, Andrea; Riccardi, Silvia; Terzano, Mario Giovanni; Parrino, Liborio

    2016-04-01

    Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) characterized by inflammation and progressive scarring of the lung parenchyma. IPF profoundly affects the quality of life (QoL) and fatigue is a frequently disabling symptom. The cause of fatigue is not well understood but patients with IPF often report extremely poor sleep quality and sleep-related breathing disorders (SRBD) that correlate with QoL. IPF patients present alterations in sleep architecture, including decreased sleep efficiency, slow wave sleep and rapid eye movement (REM) sleep, and increased sleep fragmentation. Moreover, sleep related hypoventilation during the vulnerable REM sleep period and obstructive sleep apnea-hypopnea syndrome (OSAHS) are frequent, but remain usually underdiagnosed. These SRBD in IPF are associated with alterations of the sleep structure, reduction of QoL and increased risk of mortality. In the absence of an effective therapy for IPF, optimizing the QoL could become the primary therapeutic goal. In this perspective the diagnosis and treatment of SRBD could significantly improve the QoL of IPF patients.

  12. MicroRNA regulatory networks in idiopathic pulmonary fibrosis.

    PubMed

    Pandit, Kusum V; Milosevic, Jadranka

    2015-04-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal scarring lung disease of unknown etiology, characterized by changes in microRNA expression. Activation of transforming growth factor (TGF-β) is a key event in the development of IPF. Recent reports have also identified epigenetic modification as an important player in the pathogenesis of IPF. In this review, we summarize the main results of studies that address the role of microRNAs in IPF and highlight the synergistic actions of these microRNAs in regulating TGF-β, the primary fibrogenic mediator. We outline epigenetic regulation of microRNAs by methylation. Functional studies identify microRNAs that alter proliferative and migratory properties of fibroblasts, and induce phenotypic changes in epithelial cells consistent with epithelial-mesenchymal transition. Though these studies were performed in isolation, we identify multiple co-operative actions after assembling the results into a network. Construction of such networks will help identify disease-propelling hubs that can be targeted for therapeutic purposes.

  13. Obstructive Sleep Apnea Is Common in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Lancaster, Lisa H.; Mason, Wendi R.; Parnell, James A.; Rice, Todd W.; Loyd, James E.; Milstone, Aaron P.; Collard, Harold R.; Malow, Beth A.

    2009-01-01

    Background: From 1984 to 2006, studies of sleep in patients with interstitial lung disease revealed disturbed sleep, frequent nocturnal desaturations, nocturnal cough, and obstructive sleep apnea (OSA). Our goal was to analyze OSA in an outpatient population of stable patients with idiopathic pulmonary fibrosis (IPF). Methods: Patients with IPF who had been followed up in the Vanderbilt Pulmonary Clinic were asked to participate. All patients were given a diagnosis of IPF by the 2000 American Thoracic Society consensus statement criteria. Subjects completed an Epworth sleepiness scale (ESS) questionnaire and a sleep apnea scale of sleep disorders questionnaire (SA-SDQ) before undergoing nocturnal polysomnography (NPSG). OSA was defined as an apnea-hypopnea index (AHI) of > 5 events per hour. Results: Fifty subjects enrolled and completed a NPSG. The mean age was 64.9 years, and the mean BMI was 32.3. OSA was diagnosed in 88% of subjects. Ten subjects (20%) had mild OSA (AHI, 5 to 15 events per hour), and 34 subjects (68%) had moderate-to-severe OSA (AHI, > 15 events per hour). Only 6 subjects (12%) had a normal AHI. One patient was asymptomatic as determined by ESS and SA-SDQ, but had an AHI of 24 events per hour. The sensitivity of the ESS was 75% with a specificity of 15%, whereas the SA-SDQ had a sensitivity of 88% with a specificity of 50%. BMI did not correlate strongly with AHI (r = 0.30; p = 0.05). Conclusions: OSA is prevalent in patients with IPF and may be underrecognized by primary care providers and specialists. Neither ESS nor SA-SDQ alone or in combination was a strong screening tool. Given the high prevalence found in our sample, formal sleep evaluation and polysomnography should be considered in patients with IPF. PMID:19567497

  14. Severity classification for idiopathic pulmonary fibrosis by using fuzzy logic

    PubMed Central

    Lopes, Agnaldo José; Capone, Domenico; Mogami, Roberto; Lanzillotti, Regina Serrão; de Melo, Pedro Lopes; Jansen, José Manoel

    2011-01-01

    OBJECTIVE: To set out a severity classification for idiopathic pulmonary fibrosis (IPF) based on the interaction of pulmonary function parameters with high resolution computed tomography (CT) findings. INTRODUCTION: Despite the contribution of functional and radiological methods in the study of IPF, there are few classification proposals for the disease based on these examinations. METHODS: A cross-sectional study was carried out, in which 41 non-smoking patients with IPF were evaluated. The following high resolution CT findings were quantified using a semi-quantitative scoring system: reticular abnormality, honeycombing and ground-glass opacity. The functional variables were measured by spirometry, forced oscillation technique, helium dilution method, as well as the single-breath method of diffusing capacity of carbon monoxide. With the interaction between functional indexes and high resolution CT scores through fuzzy logic, a classification for IPF has been built. RESULTS: Out of 41 patients studied, 26 were male and 15 female, with a mean age of 70.8 years. Volume measurements were the variables which showed the best interaction with the disease extension on high resolution CT, while the forced vital capacity showed the lowest estimative errors in comparison to total lung capacity. A classification for IPF was suggested based on the 95% confidence interval of the forced vital capacity %: mild group (≥92.7); moderately mild (76.9–92.6); moderate (64.3–76.8%); moderately severe (47.1–64.2); severe (24.3–47.0); and very severe (<24.3). CONCLUSION: Through fuzzy logic, an IPF classification was built based on forced vital capacity measurement with a simple practical application. PMID:21808868

  15. [Normal lung volumes in patients with idiopathic pulmonary fibrosis and emphysema].

    PubMed

    Casas, Juan Pablo; Abbona, Horacio; Robles, Adriana; López, Ana María

    2008-01-01

    Pulmonary function tests in idiopathic pulmonary fibrosis characteristically show a restrictive pattern, resulting from reduction of pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. Previous reports suggest that when both diseases coexist, pulmonary volumes are compensated and a smaller than expected reduction or even normal lung volumes can be found. We report 4 male patients of 64, 60, 73 and 70 years, all with heavy cigarette smoking history and progressive breathlessness. Three of them had severe limitation in their quality of life. All four showed advanced lung interstitial involvement, at high resolution CT scan, fibrotic changes predominantly in the subpleural areas of lower lung fields and concomitant emphysema in the upper lobes. Emphysema and pulmonary fibrosis was confirmed by open lung biopsy in one patient. The four patients showed normal spirometry and lung volumes with severe compromise of gas exchange and poor exercise tolerance evaluated by 6 minute walk test. Severe pulmonary arterial hypertension was also confirmed in three patients. Normal lung volumes does not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

  16. The Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet)

    PubMed Central

    de Andrade, Joao; Schwarz, Marvin; Collard, Harold R.; Gentry-Bumpass, Tedryl; Colby, Thomas; Lynch, David; Schwarz, M.; Zisman, D. A.; Hunninghake, G.; Chapman, J.; Olman, M.; Lubell, S.; Morrison, L. D.; Steele, M. P.; Haram, T.; Roman, J.; Perez, R.; Perez, T.; Ryu, J. H.; Utz, J. P.; Limper, A. H.; Daniels, C. E.; Meiras, K.; Walsh, S.; Brown, K. K.; Schwarz, M.; Bair, C.; Kervitsky, D.; Lasky, J. A.; Ditta, S.; deAndrade, J.; Thannickal, V. J.; Stewart, M.; Zisman, D. A.; Lynch, J.; Calahan, E.; Lopez, P.; King, T. E.; Collard, H. R.; Golden, J. A.; Wolters, P. J.; Jeffrey, R.; Noth, I.; Hogarth, D. K.; Sandbo, N.; Strek, M. E.; White, S. R.; Brown, C.; Garic, I.; Maleckar, S.; Martinez, F. J.; Flaherty, K. R.; Han, M.; Moore, B.; Toews, G. B.; Dahlgren, D.; Raghu, G.; Hayes, J.; Snyder, M.; Loyd, J. E.; Lancaster, L.; Lawson, W.; Greer, R.; Mason, W.; Kaner, R. J.; Monroy, V.; Wang, M.; Lynch, D. A.; Colby, T.; Anstrom, K. J.; Becker, R. C.; Eisenstein, E. L.; MacIntyre, N. R.; Morrison, L. D; Rochon, J.; Steele, M. P.; Sundy, J. S.; Davidson-Ray, L.; Dignacco, P.; Edwards, R.; Anderson, R.; Beci, R.; Calvert, S.; Cain, K.; Gentry-Bumpass, T.; Hill, D.; Ingham, M.; Kagan, E.; Kaur, J.; Matti, C.; McClelland, J.; Meredith, A.; Nguyen, T.; Pesarchick, J.; Roberts, R. S.; Tate, W.; Thomas, T.; Walker, J.; Whelan, D.; Winsor, J.; Yang, Q.; Yow, E.; Reynolds, H. Y.; Tian, X.; Kiley, J.; Noth, I.; Olman, M.; Schwarz, M.; Toews, G. B.; Hunninghake, G.; Culver, D. A.; Chapman, J.; Olman, M.; Lubell, S.; Wehrmann, R.; Morrison, L. D.; Steele, M. P.; Haram, T.; Kidd, R.; Kallay, M.; Lyda, E.; Ryu, J. H.; Utz, J. P.; Limper, A. H.; Daniels, C. E.; Meiras, K.; Walsh, S.; Sahn, S.; O’Banner, N.; Stokes, F.; Brown, K. K.; Bair, C.; Kervitsky, D.; Ettinger, N. A.; Merli, S.; de Andrade, J.; Thannickal, V. J.; Stewart, M.; Belperio, J.; Lynch, J. P.; Calahan, E.; Lopez, P.; King, T. E.; Collard, H. R.; Golden, J.; Wolters, P.; Eller, A.; Noth, I.; Hogarth, D. K.; Sandbo, N.; Strek, M. E.; Maleckar, S.; Rahimova, G.; Sardin, L.; Roman, J.; Perez, R.; Perez, T.; Glassberg, M.; Simonet, E.; Martinez, F. J.; Baumann, K.; Chan, K.; Chughtai, A.; Gross, B.; Flaherty, K. R.; Han, M. L.; Hyzy, R.; Kazerooni, E.; Moore, B.; Myers, J.; Toews, G. B.; White, E.; Dahlgren, D.; Rossman, M.; Kreider, M.; Le, K.; Fitzgerald, J.; Glazer, C.; Scholand, M. B.; Brewster, L.; Johnson, A.; Raghu, G.; Berry-Bell, P.; Snydsman, A.; Loyd, J. E.; Lancaster, L.; Lawson, W.; Greer, R.; Kinser, K.; Richardson, R.; Mason, W.; Kaner, R. J.; Bandong, K.; Antin-Ozerkis, D.; Holm, C.; Estrom, J.; Lynch, D. A.; Colby, T.; Anstrom, K. J.; Eisenstein, E. L.; Sundy, J. S.; Davidson-Ray, L.; Dignacco, P.; Edwards, R.; Beci, R.; Calvert, S.; Gentry-Bumpass, T.; Hill, D.; Hofmann, P. V.; Hwang, K.; Kaur, J.; Matti, C.; Meredith, A.; Pesarchick, J.; Ramey, S.; Roberts, R. S.; Sharlow, A.; Winsor, J.; Yang, Q.; Yow, E.; Weinmann, G. G.; Reynolds, H.; Schmetter, B.; Tian, X.; Kiley, J.; Martinez, F. J.; Raghu, G.; Schwarz, M.; Toews, G. B.; Zibrak, J.; Demersky, A.; Vey, M.; Rosas, I. O.; Debrosse, P.; Culver, D. A.; Chapman, J.; Olman, M.; Lubell, S.; Wehrmann, R.; Morrison, L. D.; Steele, M. P.; Haram, T.; Kidd, R.; Kallay, M.; Lyda, E.; Ryu, J. H.; Utz, J. P.; Limper, A. H.; Daniels, C. E.; Meiras, K.; Walsh, S.; Sahn, S.; O’Banner, N.; Stokes, F.; Padilla, M.; Berhanu, G.; Brown, K. K.; Bair, C.; Kervitsky, D.; Ettinger, N. A.; Merli, S.; Criner, G. J.; Swift, I. Q.; Satti, A.; Cordova, F.; Patel, N.; West, K.; Jones, G.; Lasky, J. A.; Ditta, S.; de Andrade, J.; Thannickal, V. J.; Stewart, M.; Belperio, J.; Lynch, J. P.; Calahan, E.; Lopez, P.; King, T. E.; Collard, H. R.; Golden, J.; Wolters, P.; Eller, A.; Noth, I.; Hogarth, D. K.; Sandbo, N.; Strek, M. E.; Maleckar, S.; Rahimova, G.; Sardin, L.; Roman, J.; Perez, R.; Perez, T.; Glassberg, M.; Simonet, E.; Martinez, F. J.; Baumann, K.; Chan, K.; Chughtai, A.; Gross, B.; Flaherty, K. R.; Han, M. L.; Hyzy, R.; Kazerooni, E.; Moore, B.; Myers, J.; Toews, G. B.; White, E.; Dahlgren, D.; Rossman, M.; Kreider, M.; Le, K.; Fitzgerald, J.; Glazer, C.; Scholand, M. B.; Brewster, L.; Johnson, A.; Raghu, G.; Berry-Bell, P.; Snydsman, A.; Loyd, J. E.; Lancaster, L.; Lawson, W.; Greer, R.; Mason, W.; Kaner, R. J.; Bandong, K.; Antin-Ozerkis, D.; Holm, C.; Estrom, J.; Lynch, D. A.; Colby, T.; Anstrom, K. J.; Becker, R. C.; Eisenstein, E. L.; Sundy, J. S.; Davidson-Ray, L.; Dignacco, P.; Edwards, R.; Beci, R.; Calvert, S.; Cain, K.; Gentry-Bumpass, T.; Hill, D.; Huang, K.; Kaur, J.; Matti, C.; Meredith, A.; Pesarchick, J.; Ramey, S.; Roberts, R. S.; Sharlow, A.; Winsor, J.; Yow, E.; Weinmann, G. G.; Reynolds, H.; Schmetter, B.; Tian, X.; Kiley, J.

    2015-01-01

    BACKGROUND: The National Heart, Lung, and Blood Institute-sponsored IPF Clinical Research Network (IPFnet) studies enrolled subjects with idiopathic pulmonary fibrosis (IPF) to evaluate drug therapies in treatment trials. An adjudication committee (AC) provided a structured review of cases in which there was uncertainty or disagreement regarding diagnosis or clinical event classification. This article describes the diagnosis and adjudication processes. METHODS: The diagnostic process was based on review of clinical data and high-resolution CT scans with central review of lung biopsies when available. The AC worked closely with the data coordinating center to obtain clinical, radiologic, and histologic data and to communicate with the clinical centers. The AC used a multidisciplinary discussion model with four clinicians, one radiologist, and one pathologist to adjudicate diagnosis and outcome measures. RESULTS: The IPFnet trials screened 1,015 subjects; of these, 23 cases required review by the AC to establish eligibility. The most common diagnosis for exclusion was suspected chronic hypersensitivity pneumonitis. The AC reviewed 88 suspected acute exacerbations (AExs), 93 nonelective hospitalizations, and 16 cases of bleeding. Determination of AEx presented practical challenges to adjudicators, as necessary clinical data were often not collected, particularly when subjects were evaluated outside of the primary study site. CONCLUSIONS: The IPFnet diagnostic process was generally efficient, but a multidisciplinary adjudication committee was critical to assure correct phenotype for study enrollment. The AC was key in adjudicating all adverse outcomes in two IPFnet studies terminated early because of safety issues. Future clinical trials in IPF should consider logistical and cost issues as they incorporate AExs and hospitalizations as outcome measures. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00517933, NCT00650091, NCT00957242; URL: www.clinicaltrials.gov PMID

  17. Role of Sonic Hedgehog in idiopathic pulmonary fibrosis.

    PubMed

    Bolaños, Alfredo Lozano; Milla, Criselda Mendoza; Lira, José Cisneros; Ramírez, Remedios; Checa, Marco; Barrera, Lourdes; García-Alvarez, Jorge; Carbajal, Verónica; Becerril, Carina; Gaxiola, Miguel; Pardo, Annie; Selman, Moisés

    2012-12-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease of unknown etiology and uncertain pathogenic mechanisms. Recent studies indicate that the pathogenesis of the disease may involve the abnormal expression of certain developmental pathways. Here we evaluated the expression of Sonic Hedgehog (SHH), Patched-1, Smoothened, and transcription factors glioma-associated oncogene homolog (GLI)1 and GLI2 by RT-PCR, as well as their localization in IPF and normal lungs by immunohistochemistry. The effects of SHH on fibroblast proliferation, migration, collagen and fibronectin production, and apoptosis were analyzed by WST-1, Boyden chamber chemotaxis, RT-PCR, Sircol, and annexin V-propidium iodide binding assays, respectively. Our results showed that all the main components of the Sonic signaling pathway were overexpressed in IPF lungs. With the exception of Smoothened, they were also upregulated in IPF fibroblasts. SHH and GLI2 localized to epithelial cells, whereas Patched-1, Smoothened, and GLI1 were observed mainly in fibroblasts and inflammatory cells. No staining was detected in normal lungs. Recombinant SHH increased fibroblast proliferation (P < 0.05), collagen synthesis, (2.5 ± 0.2 vs. 4.5 ± 1.0 μg of collagen/ml; P < 0.05), fibronectin expression (2-3-fold over control), and migration (190.3 ± 12.4% over control, P < 0.05). No effect was observed on α-smooth muscle actin expression. SHH protected lung fibroblasts from TNF-α/IFN-γ/Fas-induced apoptosis (14.5 ± 3.2% vs. 37.3 ± 7.2%, P < 0.0001). This protection was accompanied by modifications in several apoptosis-related proteins, including increased expression of X-linked inhibitor of apoptosis. These findings indicate that the SHH pathway is activated in IPF lungs and that SHH may contribute to IPF pathogenesis by increasing the proliferation, migration, extracellular matrix production, and survival of fibroblasts.

  18. A rare case of cor pulmonale secondary to idiopathic pulmonary fibrosis in Nigeria.

    PubMed

    Anakwue, Raphael Chinedu; Chijioke, Chioli Paschal; Iloanusi, Nneka Ifeyinwa

    2011-06-29

    Idiopathic pulmonary fibrosis (IPF) is a rarely reported disease in Nigeria. Cor pulmonale, one of the complications of this type of diffuse parenchymal lung disease is even rarer. The authors present a Nigerian patient with IPF with a classical high-resolution CT features, managed in our centre together with associated problems.

  19. IDENTIFICATION AND CHARACTERIZATION OF AN IDIOPATHIC PULMONARY FIBROSIS-LIKE CONDITION IN CATS

    EPA Science Inventory

    Interstitial lung diseases are a heterogeneous group of disorders due to a variety of causes. In veterinary medicine, those with a prominent fibrotic component of unknown etiology are often called idiopathic pulmonary fibrosis (IPF). In human medicine, this term is reserved for ...

  20. Genomic phenotype of non-cultured pulmonary fibroblasts in idiopathic pulmonary fibrosis.

    PubMed

    Emblom-Callahan, Margaret C; Chhina, Mantej K; Shlobin, Oksana A; Ahmad, Shahzad; Reese, Erika S; Iyer, Eswar P R; Cox, Daniel N; Brenner, Renee; Burton, Nelson A; Grant, Geraldine M; Nathan, Steven D

    2010-09-01

    Activated fibroblasts are the central effector cells of the progressive fibrotic process in idiopathic pulmonary fibrosis (IPF). Characterizing the genomic phenotype of isolated fibroblasts is essential to understanding IPF pathogenesis. Comparing the genomic phenotype of non-cultured pulmonary fibroblasts from advanced IPF patients' and normal lungs revealed novel genes, biological processes and concomitant pathways previously unreported in IPF fibroblasts. We demonstrate altered expression in proteasomal constituents, ubiquitination-mediators, Wnt, apoptosis and vitamin metabolic pathways and cell cycle regulators, suggestive of loss of cellular homeostasis. Specifically, FBXO32, CXCL14, BDKRB1 and NMNAT1 were up-regulated, while RARA and CDKN2D were down-regulated. Paradoxically, pro-apoptotic inducers TNFSF10, BAX and CASP6 were also found to be increased. This comprehensive description of altered gene expression in isolated IPF fibroblasts underscores the complex biological processes characteristic of IPF and may provide a foundation for future research into this devastating disease.

  1. Pulmonary Hypertension Associated with Idiopathic Pulmonary Fibrosis: Current and Future Perspectives

    PubMed Central

    Collum, Scott D.; Amione-Guerra, Javier; Cruz-Solbes, Ana S.; DiFrancesco, Amara; Hernandez, Adriana M.; Hanmandlu, Ankit; Youker, Keith; Guha, Ashrith

    2017-01-01

    Pulmonary hypertension (PH) is commonly present in patients with chronic lung diseases such as Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF) where it is classified as Group III PH by the World Health Organization (WHO). PH has been identified to be present in as much as 40% of patients with COPD or IPF and it is considered as one of the principal predictors of mortality in patients with COPD or IPF. However, despite the prevalence and fatal consequences of PH in the setting of chronic lung diseases, there are limited therapies available for patients with Group III PH, with lung transplantation remaining as the most viable option. This highlights our need to enhance our understanding of the molecular mechanisms that lead to the development of Group III PH. In this review we have chosen to focus on the current understating of PH in IPF, we will revisit the main mediators that have been shown to play a role in the development of the disease. We will also discuss the experimental models available to study PH associated with lung fibrosis and address the role of the right ventricle in IPF. Finally we will summarize the current available treatment options for Group III PH outside of lung transplantation. PMID:28286407

  2. Ultramicronized palmitoylethanolamide (PEA-um(®)) in the treatment of idiopathic pulmonary fibrosis.

    PubMed

    Di Paola, Rosanna; Impellizzeri, Daniela; Fusco, Roberta; Cordaro, Marika; Siracusa, Rosalba; Crupi, Rosalia; Esposito, Emanuela; Cuzzocrea, Salvatore

    2016-09-01

    Pulmonary fibrosis is a chronic condition characterized by progressive scarring of lung parenchyma. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (PEA-um(®)), an endogenous fatty acid amide, in mice subjected to idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis was induced in male mice by a single intratracheal administration of saline with bleomycin sulphate (1mg/kg body weight) in a volume of 100μL. PEA-um(®) was injected intraperitoneally at 1, 3 or 10mg/kg 1h after bleomycin instillation and daily thereafter. Animals were sacrificed after 7 and 21days by pentobarbitone overdose. One cohort of mice was sacrificed after seven days of bleomycin administration, followed by bronchoalveloar lavage and determination of myeloperoxidase activity, lung edema and histopathology features. In the 21-day cohort, mortality was assessed daily, and surviving mice were sacrificed followed by the above analyses together with immunohistochemical localization of CD8, tumor necrosis factor-α, CD4, interleukin-1β, transforming growth factor-β, inducible nitric oxide synthase and basic fibroblast growth factor. Compared to bleomycin-treated mice, animals that received also PEA-um(®) (3 or 10mg/kg) had significantly decreased weight loss, mortality, inflammation, lung damage at the histological level, and lung fibrosis at 7 and 21days. PEA-um(®) (1mg/kg) did not significantly inhibit the inflammation response and lung fibrosis. This study demonstrates that PEA-um(®) (3 and 10mg/kg) reduces the extent of lung inflammation in a mouse model of idiopathic pulmonary fibrosis.

  3. NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease.

    PubMed

    Szema, Anthony M; Forsyth, Edward; Ying, Benjamin; Hamidi, Sayyed A; Chen, John J; Hwang, Sonya; Li, Jonathan C; Sabatini Dwyer, Debra; Ramiro-Diaz, Juan M; Giermakowska, Wieslawa; Gonzalez Bosc, Laura V

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The % of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells, expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In

  4. NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease

    PubMed Central

    Szema, Anthony M.; Forsyth, Edward; Ying, Benjamin; Hamidi, Sayyed A.; Chen, John J.; Hwang, Sonya; Li, Jonathan C.; Sabatini Dwyer, Debra; Ramiro-Diaz, Juan M.; Giermakowska, Wieslawa; Gonzalez Bosc, Laura V.

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The % of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells, expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In

  5. Kallistatin protects against bleomycin-induced idiopathic pulmonary fibrosis by inhibiting angiogenesis and inflammation

    PubMed Central

    Huang, Xiaoping; Wang, Xiao; Xie, Xiaolan; Zeng, Shulan; Li, Zhaofa; Xu, Xianxiang; Yang, Huiyong; Qiu, Fei; Lin, Junsheng; Diao, Yong

    2017-01-01

    Aberrant angiogenesis and vascular remodeling are the main features of idiopathic pulmonary fibrosis. Kallistatin is an anti-angiogenic peptide with known effects on endothelial cells. This study aimed to demonstrate that kallistatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in a rat model by inhibiting angiogenesis. Twenty-five rats were randomly divided into five experimental groups: (A) Saline only (SA)-as the negative control, (B) BLM only (BLM)-as the model group, (C) BLM and 0.1 mg/kg kallistatin (L-Kal), (D) BLM and 0.5 mg/kg kallistatin (M-Kal), and (E) BLM and 2.5 mg/kg kallistatin (H-Kal). Fibrillar collagen was quantified by Masson’s trichrome and hematoxylin-eosin staining. Transforming growth factor-β1 (TGF-β1), α-smooth-muscle-actin (α-SMA) and microvascular density (MVD) were measured by immunohistochemistry. Vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), and tumor necrosis factor-α (TNF-α) were assayed by Western immunoblotting or ELISA. Daily administration of kallistatin attenuated fibrosis in BLM-induced pulmonary fibrosis, as shown by histology. During inflammation from BLM-induced pulmonary fibrosis, kallistatin reduced the number of inflammatory cells infiltrating the bronchoalveolar lavage fluid. Kallistatin also inhibited VEGF expression and phosphorylation of VEGFR2 (Flk-1). In vitro, kallistatin blocked tube formation by inhibiting Flk-1 and GSK-3β phosphorylation. The results demonstrated that continuous administration of kallistatin attenuated BLM-induced pulmonary fibrosis and improved survival of BLM rats. Reducing pulmonary fibrosis was achieved by partial inhibition of pulmonary inflammation and angiogenesis. PMID:28386328

  6. 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

  7. Surgical treatment for primary lung cancer combined with idiopathic pulmonary fibrosis.

    PubMed

    Watanabe, Atsushi; Miyajima, Masayoshi; Mishina, Taijiro; Nakazawa, Junji; Harada, Ryo; Kawaharada, Nobuyoshi; Higami, Tetsuya

    2013-05-01

    Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause. IPF is associated with an increased risk of lung cancer, and lung cancer patients with IPF undergoing pulmonary resection for non-small cell lung cancer have increased postoperative morbidity and mortality. Especially, postoperative acute exacerbation of IPF (AEIPF) causes fatal status and long-term outcomes are worse than for patients without IPF, although certain subgroups have a good long-term outcome. A comprehensive review of the current literature pertaining to AEIPF and the late phase outcome after the context of a surgical intervention was performed.

  8. Herpes Virus Infection Is Associated with Vascular Remodeling and Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Calabrese, Fiorella; Kipar, Anja; Lunardi, Francesca; Balestro, Elisabetta; Perissinotto, Egle; Rossi, Emanuela; Nannini, Nazarena; Marulli, Giuseppe; Stewart, James P.; Rea, Federico

    2013-01-01

    Background Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed. Methods Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. Results A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p = 0.01), poorer performance in the six minute walking test (6MWT; p = 0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p = 0.02). Increased arterial thickening, particularly of the intimal layer (p = 0.002 and p = 0.004) and higher TGF-β expression (p = 0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p = 0.03), poorer performance in the 6MWT (p = 0.008) and PGD (p = 0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. Conclusion

  9. IDENTIFICATION OF SPONTANEOUS FELINE IDIOPATHIC PULMONARY FIBROSIS: MORPHOLOGY AND ULTRASTRUCTURAL EVIDENCE FOR A TYPE II PNEUMOCYTE DEFECT

    EPA Science Inventory

    Abstract
    Idiopathic pulmonary fibrosis currently lacks an animal model that develops the persistent, progressive lung fibrosis characteristic of the disease. Sixteen domestic cats developed dyspnea that was not responsive to therapy and which rapidly progressed until death/eu...

  10. Burden of Idiopathic Pulmonary Fibrosis Progression: A 5-Year Longitudinal Follow-Up Study

    PubMed Central

    Cottin, Vincent; Schmidt, Aurélie; Catella, Laura; Porte, Fanny; Fernandez-Montoya, Céline; Le Lay, Katell; Bénard, Stève

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with an unpredictable course. An observational study was set up using the French hospital discharge database to describe the reasons, outcomes and costs of hospitalisations related to this disease. Patients newly hospitalised for idiopathic pulmonary fibrosis (ICD-10 code: J84.1) in 2008 were identified and followed for 5 years. As J84.1 includes other fibrotic pulmonary diseases, an algorithm excluding age<50 years and presence of a differential diagnosis in the following year was defined. Overall, 6,476 patients were identified; of whom 30% were admitted through the emergency unit and 12% died during their first hospitalisation. Most of patients were hospitalised at least once for one or several acute events (n = 5,635; 87.0% of patients), of whom 36.5% of patients with an acute respiratory worsening (in-hospital mortality of 17.0% and median cost of €3,224; interquartile range (IQR €889–6,092)), 43.7% of patients with a respiratory infection (in-hospital mortality of 29.5% and median cost of €5,432 (IQR, €3,620–9,115)) and 51.7% of patients with a cardiac event (in-hospital mortality of 35.7% and median cost of €4,584 (IQR, €2,803–6,399)); 30.2% of these events occurred during the first hospitalisation. Finally, the 3-year in-hospital mortality crude rate was 36.8%. This study is the first providing extensive data on hospitalisations in patients with pulmonary fibrosis, mostly idiopathic, in France, demonstrating high burden and hospital cost. PMID:28099456

  11. Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients

    PubMed Central

    Porat, Ziv; Budovsky, Arie; Braiman, Alex; Zeische, Rolf; Fraifeld, Vadim E.

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with unknown etiology and no effective treatment. In this study, we show that primary cultures of fibroblasts derived from lung biopsies of IPF patients exhibited (i) accelerated replicative cellular senescence (CS); (ii) high resistance to oxidative-stress-induced cytotoxicity or CS; (iii) a CS-like morphology (even at the proliferative phase); and (iv) rapid accumulation of senescent cells expressing the myofibroblast marker α-SMA. Our findings suggest that CS could serve as a bridge connecting lung aging and its quite frequent outcome -- pulmonary fibrosis, and be an important player in the disease progression. Consequently, targeting senescent cells offers the potential of being a promising therapeutic approach. PMID:26399448

  12. Pulmonary Fibrosis

    MedlinePlus

    Pulmonary fibrosis is a condition in which the tissue deep in your lungs becomes scarred over time. This tissue ... may not get enough oxygen. Causes of pulmonary fibrosis include environmental pollutants, some medicines, some connective tissue ...

  13. The antifibrotic effects and mechanisms of microRNA-26a action in idiopathic pulmonary fibrosis.

    PubMed

    Liang, Haihai; Xu, Chaoqian; Pan, Zhenwei; Zhang, Ying; Xu, Zhidan; Chen, Yingzhun; Li, Tianyu; Li, Xuelian; Liu, Ying; Huangfu, Longtao; Lu, Ying; Zhang, Zhihua; Yang, Baofeng; Gitau, Samuel; Lu, Yanjie; Shan, Hongli; Du, Zhimin

    2014-06-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high-lethality fibrotic lung disease characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, loss of lung function. Although dysregulation of some microRNAs (miRs) has been shown to play important roles in the pathophysiological processes of IPF, the role of miRs in fibrotic lung diseases is not well understood. In this study, we found downregulation of miR-26a in the lungs of mice with experimental pulmonary fibrosis and in IPF, which resulted in posttranscriptional derepression of connective tissue growth factor (CTGF), and induced collagen production. More importantly, inhibition of miR-26a in the lungs caused pulmonary fibrosis in vivo, whereas overexpression of miR-26a repressed transforming growth factor (TGF)-β1-induced fibrogenesis in MRC-5 cells and attenuated experimental pulmonary fibrosis in mice. Our study showed that miR-26a was downregulated by TGF-β1-mediated phosphorylation of Smad3. Moreover, miR-26a inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4, which determines the nuclear translocation of p-Smad2/Smad3. Taken together, our experiments demonstrated the antifibrotic effects of miR-26a in fibrotic lung diseases and suggested a new strategy for the prevention and treatment of IPF using miR-26a. The current study also uncovered a novel positive feedback loop between miR-26a and p-Smad3, which is involved in pulmonary fibrosis.

  14. 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.

  15. Bronchoalveolar lavage in idiopathic pulmonary fibrosis: what does it tell us?

    PubMed

    Pesci, A; Ricchiuti, E; Ruggiero, R; De Micheli, A

    2010-07-01

    Bronchoalveolar lavage (BAL) has only a limited role in diagnosis of idiopathic pulmonary fibrosis (IPF). A finding of raised neutrophils (>5%) and eosinophils (>2%) is characteristic but not diagnostic of IPF. BAL cell count does not clearly differentiate between fibrotic non-specific interstitial pneumonia and IPF either diagnostically or prognostically. BAL in IPF should be considered in all patients with suspected infection, malignancy or acute exacerbations. In such cases, it may be diagnostic. Because of few and conflicting results BAL fluid analysis has very little clinical relevance determining prognosis and response to treatment in IPF.

  16. Sex Steroid Receptor Expression in Idiopathic Pulmonary Fibrosis.

    PubMed

    Mehrad, Mitra; Trejo Bittar, Humberto E; Yousem, Samuel A

    2017-03-11

    Usual interstitial pneumonia (UIP) is characterized by progressive scarring of the lungs and is associated with high morbidity and mortality despite therapeutic interventions. Sex steroid receptors have been demonstrated to play an important role in chronic lung conditions; however, their significance is unknown in patients with UIP. We retrospectively reviewed 40 idiopathic UIP cases for the expression of hormonal receptors. Forty cases including 10 normal lung, 10 cryptogenic organizing pneumonia (COP), 10 idiopathic organizing diffuse alveolar damage (DAD), 7 hypersensitivity pneumonitis (HP) and 3 nonspecific interstitial pneumonitis (NSIP) served as controls. Immunohistochemistry for estrogen receptor alpha (ER-α), progesterone receptor (PR) and androgen receptor (AR) was performed in all groups. Expression of these receptors was assessed in four anatomic/pathologic compartments: alveolar and bronchiolar epithelium, arteries/veins, fibroblastic foci/airspace organization, and old scar. All UIPs (100%) stained positive for PR in myofibroblasts in the scarred areas, while among the control cases only one NSIP case stained focally positive and the rest were negative. PR was positive in myocytes of the large-sized arteries within the fibrotic areas in 31 cases (77.5%). PR was negative within the alveolar and bronchial epithelium, airspace organization and center of fibroblastic foci, however, weak PR positivity was noted in the peripheral fibroblasts of the fibroblastic foci where they merged with dense fibrous connective tissue scar. All UIP and control cases were negative for AR and ER-α. This is the first study to show the expression of PR within the established fibrotic areas of UIP, indicating that progesterone may have profibrotic effects in UIP patients. Hormonal therapy by targeting PR could be of potential benefit in patients with UIP/IPF.

  17. Alteration of Aging-dependent MicroRNAs in Idiopathic Pulmonary Fibrosis (IPF)

    PubMed Central

    Nho, Richard Seonghun

    2015-01-01

    Idiopathic Pulmonary Fibrosis (IPF) is the most severe fibrotic lung disease and characterized by the accumulation of (myo)fibroblasts and collagen within the alveolar wall resulting in obliteration of the gas-exchange surface. Although the detailed pathogenesis is not understood, recent studies have found that several microRNAs (miRNAs) are associated with the progression of lung diseases including IPF. IPF is an age-associated disease and, accordingly, frequently found in an aged population. In this review, the functional roles of miRNAs that are deregulated in IPF progression are discussed together with how aging affects the miRNA signature, altering the fibroblast phenotype and promoting lung fibrosis. Finally, the possibility of targeting miRNAs as a therapeutic approach for the treatment of IPF is discussed. PMID:26303294

  18. Development of a non-infectious rat model of acute exacerbation of idiopathic pulmonary fibrosis

    PubMed Central

    Chen, Shan-Shan; Yin, Zhao-Fang; Chen, Tao; Qiu, Hui; Wei, Ya-Ru; Du, Shan-Shan; Jin, Yue-Ping; Zhao, Meng-Meng; Wu, Qin

    2017-01-01

    Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with severe pulmonary fibrosis. The main cause of IPF-associated death is acute exacerbation of IPF (AE-IPF). This study aims to develop a rat model of AE-IPF by two intratracheal perfusions with bleomycin (BLM). Methods Ninety male Sprague Dawley (SD) rats were randomized into three groups: an AE-IPF model group (BLM + BLM group), an IPF model group (BLM group), and a normal control group. Rats in the BLM + BLM group underwent a second perfusion with BLM on day 28 after the first perfusion with BLM. Rats in the other two groups received saline as the second perfusion. Six rats in each group were sacrificed on day 31, day 35, and day 42 after the first perfusion, respectively. Additional 18 rats in each group were observed for survival. Results Rats in the BLM + BLM group had significantly worse pulmonary alveolar inflammation and fibrosis than rats in the BLM group. Rats in the BLM + BLM group also developed large amounts of hyaline membrane, showed high levels of albumin (ALB) and various inflammatory factors in the bronchoalveolar lavage fluid (BALF), and had markedly increased lung water content. Furthermore, rat survival was reduced in the BLM + BLM group. The pathophysiological characteristics of rats in the BLM + BLM group resemble those of patients with AE-IPF. Conclusions A second perfusion with BLM appears to induce acute exacerbation of pulmonary fibrosis and may be used to model AE-IPF in rats. PMID:28203411

  19. 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

  20. Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis.

    PubMed

    Andersson-Sjöland, Annika; de Alba, Carolina García; Nihlberg, Kristian; Becerril, Carina; Ramírez, Remedios; Pardo, Annie; Westergren-Thorsson, Gunilla; Selman, Moisés

    2008-01-01

    Idiopathic pulmonary fibrosis is characterized by the accumulation of fibroblasts/myofibroblasts and aberrant remodeling of the lung parenchyma. However, the sources of fibroblasts in IPF lungs are unclear. Fibrocytes are circulating progenitors of fibroblasts implicated in wound healing and fibrosis. In this study we evaluated evidence for the presence of fibrocytes in the lung of patients with idiopathic pulmonary fibrosis by immunofluorescence and confocal microscopy. Fibrocytes were identified in tissues in 8 out of 9 fibrotic lungs. Combinations including CXCR4 and a mesenchymal marker stained significantly more fibrocytes/mm(2) of tissue compared with combinations using CD34 or CD45RO with mesenchymal markers: CXCR4/procollagen-I (10.3+/-2.9fibrocytes/mm(2)) and CXCR4/prolyl-4-hydroxylase (4.1+/-3.1), versus CD34/procollagen-I (2.8+/-3.0), CD34/alphaSMA (2.2+/-1.6) and CD45RO/prolyl-4-hydroxylase (1.3+/-1.6); p<0.003. There was a positive correlation between the abundance of fibroblastic foci and the amount of lung fibrocytes (r=0.79; p<0.02). No fibrocytes were identified in normal lungs. The fibrocyte attractant chemokine CXCL12 increased in plasma [median: 2707.5pg/ml (648.1-4884.7) versus 1751.5pg/ml (192.9-2686.0) from healthy controls; p<0.003)] and was detectable in the bronchoalveolar lavage fluid of 40% of the patients but not in controls. In the lung CXCL12 was strongly expressed by alveolar epithelial cells. A negative correlation between plasma levels of CXCL12 with lung diffusing capacity for carbon monoxide (DLCO) (r=-0.56; p<0.03) and oxygen saturation on exercise was found (r=-0.41; p<0.04). These findings indicate that circulating fibrocytes, likely recruited through the CXCR4/CXCL12 axis, may contribute to the expansion of the fibroblast/myofibroblast population in idiopathic pulmonary fibrosis.

  1. Non-invasive Imaging of Idiopathic Pulmonary Fibrosis Using Cathepsin Protease Probes.

    PubMed

    Withana, Nimali P; Ma, Xiaowei; McGuire, Helen M; Verdoes, Martijn; van der Linden, Wouter A; Ofori, Leslie O; Zhang, Ruiping; Li, Hao; Sanman, Laura E; Wei, Ke; Yao, Shaobo; Wu, Peilin; Li, Fang; Huang, Hui; Xu, Zuojun; Wolters, Paul J; Rosen, Glenn D; Collard, Harold R; Zhu, Zhaohui; Cheng, Zhen; Bogyo, Matthew

    2016-01-22

    Idiopathic pulmonary fibrosis (IPF) is a lethal, chronic, progressive disease characterized by formation of scar tissue within the lungs. Because it is a disease of unknown etiology, it is difficult to diagnose, to predict disease course and to devise treatment strategies. Recent evidence suggests that activated macrophages play key roles in the pathology of IPF. Therefore, imaging probes that specifically recognize these pools of activated immune cells could provide valuable information about how these cells contribute to the pathobiology of the disease. Here we demonstrate that cysteine cathepsin-targeted imaging probes can be used to monitor the contribution of macrophages to fibrotic disease progression in the bleomycin-induced murine model of pulmonary fibrosis. Furthermore, we show that the probes highlight regions of macrophage involvement in fibrosis in human biopsy tissues from IPF patients. Finally, we present first-in-human results demonstrating non-invasive imaging of active cathepsins in fibrotic lesions of patients with IPF. Together, our findings validate small molecule cysteine cathepsin probes for clinical PET imaging and suggest that they have the potential to be used to generate mechanistically-informative molecular information regarding cellular drivers of IPF disease severity and progression.

  2. Pathogenesis pathways of idiopathic pulmonary fibrosis in bleomycin-induced lung injury model in mice.

    PubMed

    Shi, Keyun; Jiang, Jianzhong; Ma, Tieliang; Xie, Jing; Duan, Lirong; Chen, Ruhua; Song, Ping; Yu, Zhixin; Liu, Chao; Zhu, Qin; Zheng, Jinxu

    2014-01-01

    Our objective was to investigate the pathogenesis pathways of idiopathic pulmonary fibrosis (IPF). Bleomycin (BLM) induced animal models of experimental lung fibrosis were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-β1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-β1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-β1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-β, IL-31 and JAKs/STATs pathway.

  3. 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

  4. [Idiopathic lung fibrosis].

    PubMed

    Leonhardt, L; Geldszus, R; Molitor, S J

    1990-02-01

    In a 39-year-old patient with chronic progressive idiopathic pulmonary fibrosis, the genetic aspects, course and therapeutic possibilities of the disease are discussed. In February, 1987, the English-born patient, Anthony V., attended for initial examination on account of progressive dyspnoea, on which occasion radiology and pulmonary function analysis revealed advanced pulmonary fibrosis. The patient's family history revealed a familial genesis, since both his father (?) and his sister had died of this disease. A comparative of the patient's chest films with original chest films of his sister revealed almost identical findings. Within the previous twelve months, follow-up examinations done on A.V. revealed an increase in the restrictive component (reduction of vital capacity from 2,400 ml to 1,500 ml), development of partial respiratory failure at rest, and global respiratory failure in response to mild ergometric exercise despite intermittent high-dose steroid administrations superimposed on long-term, low-dose steroid therapy. The unfavourable evolution observed over the past 12 months is underscored by an increase in mean pulmonary arterial pressure from 18 mmHg initially to a present 34 mmHg at rest, and 46 mmHg under submaximal ergometric loading. The only option still left to the patient is the possibility of a lung transplantation, which - probably initially unilateral - is scheduled to be carried out in the near future at the Chest Surgery Department of the Medical University at Hannover.

  5. Endoplasmic reticulum stress, a new wrestler, in the pathogenesis of idiopathic pulmonary fibrosis

    PubMed Central

    Zhang, Lei; Wang, Yi; Pandupuspitasari, Nuruliarizki Shinta; Wu, Guorao; Xiang, Xudong; Gong, Quan; Xiong, Weining; Wang, Cong-Yi; Yang, Ping; Ren, Boxu

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) has attracted extensive attention for its unexplained progressive lung scarring, short median survival and its unresponsiveness to traditional therapies. Despite extensive studies, the mechanisms underlying IPF pathoetiologies, however, remain poorly understood. Recent advances delineated a potential function of endoplasmic reticulum (ER) stress in meeting the need of fibrotic response, which pinpointed a critical role for the unfolded protein response (UPR) pathways in IPF pathogenesis. In this review, we highlight the effect of ER stress and the activation of UPR on the survival, differentiation, function and proliferation of major profibrotic cells in lung tissues during the course of IPF, and discuss the feasibility whether targeting UPR components could be an orientation for developing effective therapeutic strategies against this devastating disorder in clinical settings. PMID:28337301

  6. Idiopathic pulmonary fibrosis and sleep disorders: no longer strangers in the night.

    PubMed

    Schiza, Sophia; Mermigkis, Charalampos; Margaritopoulos, George A; Daniil, Zoi; Harari, Sergio; Poletti, Venerino; Renzoni, Elizabetta A; Torre, Olga; Visca, Dina; Bouloukaki, Isolde; Sourvinos, George; Antoniou, Katerina M

    2015-06-01

    The prevalence of obstructive sleep apnoea (OSA) is continuously increasing in patients with idiopathic pulmonary fibrosis (IPF) and, for the first time, the recent IPF guidelines recognise OSA as an important associated comorbidity that can affect patient's survival. Thus, it becomes conceivable that clinicians should refer patients with newly diagnosed IPF to sleep centres for the diagnosis and treatment of OSA as well as for addressing issues regarding the reduced compliance of patients with continuous positive airway pressure therapy. The discovery of biomarkers common to both disorders may help early diagnosis, institution of the most appropriate treatment and follow-up of patients. Better understanding of epigenetic changes may provide useful information about pathogenesis and, possibly, development of new drugs for a dismal disease like IPF.

  7. Assessing health status and quality of life in idiopathic pulmonary fibrosis: which measure should be used?

    PubMed

    De Vries, J; Seebregts, A; Drent, M

    2000-03-01

    Many studies conducted on the health status and quality of life (QOL) of patients with certain chronic diseases have demonstrated that their disease had an impact on their lives. However, less is known about the QOL and health status of patients suffering from idiopathic pulmonary fibrosis (IPF). In the present study, three focus groups of IPF patients (n=10) were run to identify the aspects of QOL or health status that are relevant to this population and to establish which measure is preferable to assess these aspects. The patients completed and discussed the St. George's Respiratory Questionnaire (SGRQ) and the World Health Organization Quality of Life assessment instrument (WHOQOL-100). Results indicated that hobbies/leisure activities, mobility, transport, social relationships, working capacity, energy and doing things slower were aspects relevant to IPF patients' QOL. The WHOQOL-100, with an additional social support questionnaire, appeared to be preferable.

  8. Treatment of idiopathic pulmonary fibrosis: a position paper from a Nordic expert group.

    PubMed

    Sköld, C M; Bendstrup, E; Myllärniemi, M; Gudmundsson, G; Sjåheim, T; Hilberg, O; Altraja, A; Kaarteenaho, R; Ferrara, G

    2017-02-01

    Idiopathic pulmonary fibrosis (IPF) is a fatal progressive lung disease occurring in adults. In the last decade, the results of a number of clinical trials based on the updated disease classification have been published. The registration of pirfenidone and nintedanib, the first two pharmacological treatment options approved for IPF, marks a new chapter in the management of patients with this disease. Other nonpharmacological treatments such as lung transplantation, rehabilitation and palliation have also been shown to be beneficial for these patients. In this review, past and present management is discussed based on a comprehensive literature search. A treatment algorithm is presented based on available evidence and our overall clinical experience. In addition, unmet needs with regard to treatment are highlighted and discussed. We describe the development of various treatment options for IPF from the first consensus to recent guidelines based on evidence from large-scale, multinational, randomized clinical trials, which have led to registration of the first drugs for IPF.

  9. 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.

  10. 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

  11. The role of club cell phenoconversion and migration in idiopathic pulmonary fibrosis

    PubMed Central

    Fukumoto, Jutaro; Soundararajan, Ramani; Leung, Joseph; Cox, Ruan; Mahendrasah, Sanjay; Muthavarapu, Neha; Herrin, Travis; Czachor, Alexander; Tan, Lee C.; Hosseinian, Nima; Patel, Priyanshi; Gone, Jayanthraj; Breitzig, Mason T.; Cho, Young; Cooke, Andrew J.; Galam, Lakshmi; Narala, Venkata Ramireddy; Pathak, Yashwant; Lockey, Richard F.; Kolliputi, Narasaiah

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is an age-related multifactorial disease featuring non-uniform lung fibrosis. The decisive cellular events at early stages of IPF are poorly understood. While the involvement of club cells in IPF pathogenesis is unclear, their migration has been associated with lung fibrosis. In this study, we labeled club cells immunohistochemically in IPF lungs using a club cell marker Claudin-10 (Cldn10), a unique protein based on the recent report which demonstrated that the appearance of Cldn10 in developing and repairing lungs precedes other club cell markers including club cell secretory protein (CCSP). Cldn10-positive cells in IPF lungs displayed marked pleomorphism and were found in varied arrangements, suggesting their phenoconversion. These results were corroborated by immunogold labeling for Cldn10. Further, immunohistochemical double-labeling for Cldn10 and α-smooth muscle actin (α-SMA) demonstrated that aberrant α-SMA signals are frequently encountered near disorganized Cldn10-positive cells in hyperplastic bronchiolar epithelium and thickened interstitium of IPF lungs. Collectively, these data indicate that club cells actively participate in the initiation and progression of IPF through phenoconversion involving the acquisition of proliferative and migratory abilities. Thus, our new findings open the possibility for club cell-targeted therapy to become a strategic option for the treatment of IPF. PMID:27899769

  12. Idiopathic pulmonary fibrosis: current treatment options and critical appraisal of nintedanib

    PubMed Central

    Bonella, Francesco; Stowasser, Susanne; Wollin, Lutz

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and is characterized by a poor prognosis, with an estimated 5-year survival of approximately 20%. Progressive and irreversible lung functional impairment leads to chronic respiratory insufficiency with a severely impaired quality of life. In the last 2 decades, novel treatments for IPF have been developed as a consequence of an increasing understanding of disease pathogenesis and pathobiology. In IPF, injured dysfunctional alveolar epithelial cells promote fibroblast recruitment and proliferation, resulting in scarring of the lung tissue. Recently, pirfenidone and nintedanib have been approved for the treatment of IPF, having shown efficacy to slow functional decline and disease progression. This article focuses on the pharmacologic characteristics and clinical evidence supporting the use of nintedanib, a potent small-molecule tyrosine kinase inhibitor, as therapy for IPF. After introducing the mechanism of action and pharmacokinetics, an overview of the safety and efficacy results from the most recent clinical trials of nintedanib in IPF is presented. PMID:26715838

  13. Developmental Reprogramming in Mesenchymal Stromal Cells of Human Subjects with Idiopathic Pulmonary Fibrosis

    PubMed Central

    Chanda, Diptiman; Kurundkar, Ashish; Rangarajan, Sunad; Locy, Morgan; Bernard, Karen; Sharma, Nirmal S.; Logsdon, Naomi J.; Liu, Hui; Crossman, David K.; Horowitz, Jeffrey C.; De Langhe, Stijn; Thannickal, Victor J.

    2016-01-01

    Cellular plasticity and de-differentiation are hallmarks of tissue/organ regenerative capacity in diverse species. Despite a more restricted capacity for regeneration, humans with age-related chronic diseases, such as cancer and fibrosis, show evidence of a recapitulation of developmental gene programs. We have previously identified a resident population of mesenchymal stromal cells (MSCs) in the terminal airways-alveoli by bronchoalveolar lavage (BAL) of human adult lungs. In this study, we characterized MSCs from BAL of patients with stable and progressive idiopathic pulmonary fibrosis (IPF), defined as <5% and ≥10% decline, respectively, in forced vital capacity over the preceding 6-month period. Gene expression profiles of MSCs from IPF subjects with progressive disease were enriched for genes regulating lung development. Most notably, genes regulating early tissue patterning and branching morphogenesis were differentially regulated. Network interactive modeling of a set of these genes indicated central roles for TGF-β and SHH signaling. Importantly, fibroblast growth factor-10 (FGF-10) was markedly suppressed in IPF subjects with progressive disease, and both TGF-β1 and SHH signaling were identified as critical mediators of this effect in MSCs. These findings support the concept of developmental gene re-activation in IPF, and FGF-10 deficiency as a potentially critical factor in disease progression. PMID:27869174

  14. Impact of Comorbidities on Mortality in Patients with Idiopathic Pulmonary Fibrosis

    PubMed Central

    Kreuter, Michael; Ehlers-Tenenbaum, Svenja; Palmowski, Karin; Bruhwyler, Jacques; Oltmanns, Ute; Muley, Thomas; Heussel, Claus Peter; Warth, Arne; Kolb, Martin; Herth, Felix J. F.

    2016-01-01

    Introduction Comorbidities significantly influence the clinical course of idiopathic pulmonary fibrosis (IPF). However, their prognostic impact is not fully understood. We therefore aimed to determine the impact of comorbidities, as individual and as whole, on survival in IPF. Methods The database of a tertiary referral centre for interstitial lung diseases was reviewed for comorbidities, their treatments, their frequency and survival in IPF patients. Results 272 patients were identified of which 12% had no, 58% 1–3 and 30% 4–7 comorbidities, mainly cardiovascular, pulmonary and oncologic comorbidities. Median survival according to the frequency of comorbidities differed significantly with 66 months for patients without comorbidities, 48 months when 1–3 comorbidities were reported and 35 months when 4–7 comorbidities were prevalent (p = 0.004). A multivariate Cox proportional hazard analyses identified other cardiac diseases and lung cancer as significant predictors of death, gastro-oesophageal reflux disease (GERD) and diastolic dysfunction had a significant positive impact on survival. A significant impact of comorbidities associated therapies on survival was not discovered. This included the use of proton pump inhibitors at baseline, which was not associated with a survival benefit (p = 0.718). We also established a predictive tool for highly prevalent comorbidities, termed IPF comorbidome which demonstrates a new relationship of IPF and comorbidities. Conclusion Comorbidities are frequent in IPF patients. Some comorbidities, especially lung cancer, mainly influence survival in IPF, while others such as GERD may inherit a more favourable effect. Moreover, their cumulative incidence impacts survival. PMID:27023440

  15. A comparison of published multidimensional indices to predict outcome in idiopathic pulmonary fibrosis

    PubMed Central

    Sharp, Charles; Adamali, Huzaifa I.

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) has an unpredictable course and prognostic factors are incompletely understood. We aimed to identify prognostic factors, including multidimensional indices from a significant IPF cohort at the Bristol Interstitial Lung Disease Centre in the UK. Patients diagnosed with IPF between 2007 and 2014 were identified. Longitudinal pulmonary physiology and exercise testing results were collated, with all-cause mortality used as the primary outcome. Factors influencing overall, 12- and 24-month survival were identified using Cox proportional hazards modelling and receiver operating characteristic curve analysis. We found in this real-world cohort of 167 patients, diffusing capacity for carbon monoxide (DLCO) and initiation of long-term oxygen were independent markers of poor prognosis. Exercise testing results predicted 12-month mortality as well as DLCO, but did not perform as well for overall survival. The Composite Physiological Index was the best performing multidimensional index, but did not outperform DLCO. Our data confirmed that patients who experienced a fall in forced vital capacity (FVC) >10% had significantly worse survival after that point (p=0.024). Our data from longitudinal follow-up in IPF show that DLCO is the best individual prognostic marker, outperforming FVC. Exercise testing is important in predicting early poor outcome. Regular and complete review should be conducted to ensure appropriate care is delivered in a timely fashion. PMID:28326312

  16. FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

    PubMed Central

    Staab-Weijnitz, Claudia A.; Fernandez, Isis E.; Knüppel, Larissa; Maul, Julia; Heinzelmann, Katharina; Juan-Guardela, Brenda M.; Hennen, Elisabeth; Preissler, Gerhard; Winter, Hauke; Neurohr, Claus; Hatz, Rudolf; Lindner, Michael; Behr, Jürgen; Kaminski, Naftali

    2015-01-01

    Rationale: Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta). Objectives: To assess the expression and function of FKBP10 in IPF. Methods: We assessed FKBP10 expression in bleomycin-induced lung fibrosis (using quantitative reverse transcriptase–polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U.S. cohort, and performed Western blot analysis from 6 patients with IPF and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by endoplasmic reticulum stress or transforming growth factor-β1, was analyzed by small interfering RNA–mediated loss-of-function experiments, quantitative reverse transcriptase–polymerase chain reaction, Western blot, and quantification of secreted collagens in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF. Measurements and Main Results: FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68+ macrophages. Transforming growth factor-β1, but not endoplasmic reticulum stress, induced FKBP10 expression in phLF. The small interfering RNA–mediated knockdown of FKBP10 attenuated expression of profibrotic mediators and effectors, including collagens I and V and α-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen

  17. Rheumatoid Arthritis-Associated Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis: Shared Mechanistic and Phenotypic Traits Suggest Overlapping Disease Mechanisms.

    PubMed

    Paulin, Francisco; Doyle, Tracy J; Fletcher, Elaine A; Ascherman, Dana P; Rosas, Ivan O

    2015-01-01

    The prevalence of clinically evident interstitial lung disease in patients with rheumatoid arthritis is approximately 10%. An additional 33% of undiagnosed patients have interstitial lung abnormalities that can be detected with high-resolution computed tomography. Rheumatoid arthritis-interstitial lung disease patients have three times the risk of death compared to those with rheumatoid arthritis occurring in the absence of interstitial lung disease, and the mortality related to interstitial lung disease is rising. Rheumatoid arthritis-interstitial lung disease is most commonly classified as the usual interstitial pneumonia pattern, overlapping mechanistically and phenotypically with idiopathic pulmonary fibrosis, but can occur in a non-usual interstitial pneumonia pattern, mainly nonspecific interstitial pneumonia. Based on this, we propose two possible pathways to explain the coexistence of rheumatoid arthritis and interstitial lung disease: (i) Rheumatoid arthritis-interstitial lung disease with a non-usual interstitial pneumonia pattern may come about when an immune response against citrullinated peptides taking place in another site (e.g. the joints) subsequently affects the lungs; (ii) Rheumatoid arthritis-interstitial lung disease with a usual interstitial pneumonia pattern may represent a disease process in which idiopathic pulmonary fibrosis-like pathology triggers an immune response against citrullinated proteins that promotes articular disease indicative of rheumatoid arthritis. More studies focused on elucidating the basic mechanisms leading to different sub-phenotypes of rheumatoid arthritis-interstitial lung disease and the overlap with idiopathic pulmonary fibrosis are necessary to improve our understanding of the disease process and to define new therapeutic targets.

  18. 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

  19. Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials

    PubMed Central

    2013-01-01

    Background Acute exacerbation of idiopathic pulmonary fibrosis has become an important outcome measure in clinical trials. This study aimed to explore the concept of suspected acute exacerbation as an outcome measure. Methods Three investigators retrospectively reviewed subjects enrolled in the Sildenafil Trial of Exercise Performance in IPF who experienced a respiratory serious adverse event during the course of the study. Events were classified as definite acute exacerbation, suspected acute exacerbation, or other, according to established criteria. Results Thirty-five events were identified. Four were classified as definite acute exacerbation, fourteen as suspected acute exacerbation, and seventeen as other. Definite and suspected acute exacerbations were clinically indistinguishable. Both were most common in the winter and spring months and were associated with a high risk of disease progression and short-term mortality. Conclusions In this study one half of respiratory serious adverse events were attributed to definite or suspected acute exacerbations. Suspected acute exacerbations are clinically indistinguishable from definite acute exacerbations and represent clinically meaningful events. Clinical trialists should consider capturing both definite and suspected acute exacerbations as outcome measures. PMID:23848435

  20. Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry.

    PubMed

    Behr, Jürgen; Kreuter, Michael; Hoeper, Marius M; Wirtz, Hubert; Klotsche, Jens; Koschel, Dirk; Andreas, Stefan; Claussen, Martin; Grohé, Christian; Wilkens, Henrike; Randerath, Winfried; Skowasch, Dirk; Meyer, F Joachim; Kirschner, Joachim; Gläser, Sven; Herth, Felix J F; Welte, Tobias; Huber, Rudolf Maria; Neurohr, Claus; Schwaiblmair, Martin; Kohlhäufl, Martin; Höffken, Gert; Held, Matthias; Koch, Andrea; Bahmer, Thomas; Pittrow, David

    2015-07-01

    After introduction of the new international guidelines on idiopathic pulmonary fibrosis (IPF) in 2011, we investigated clinical management practices for patients with IPF according to physicians' diagnoses. A prospective, multicenter, noninterventional study with comprehensive quality measures including on-site source data verification was performed in Germany. 502 consecutive patients (171 newly diagnosed, 331 prevalent; mean±SD age 68.7±9.4 years, 77.9% males) with a mean disease duration of 2.3±3.5 years were enrolled. IPF diagnosis was based on clinical assessments and high-resolution computed tomography (HRCT) in 90.2%, and on surgical lung biopsy combined with histology in 34.1% (lavage in 61.8%). The median 6-min walk distance was 320 m (mean 268±200 m). The mean forced vital capacity was 72±20% pred and diffusing capacity of the lung for carbon monoxide was 35±15% pred. No drugs were administered in 17.9%, oral steroids in 23.7%, N-acetylcysteine in 33.7%, pirfenidone in 44.2% and other drugs in 4.6% of patients. Only 2.8% of the cohort was listed for lung transplantation. IPF patients were diagnosed in line with the new guidelines. They had more severe disease than those enrolled in recent randomised controlled trials. In addition to HRCT, the frequency of lung biopsies was surprisingly high. Treatment patterns varied substantially.

  1. 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.

  2. 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

  3. Patient considerations and drug selection in the treatment of idiopathic pulmonary fibrosis

    PubMed Central

    Trawinska, Maria A; Rupesinghe, Ruwani D; Hart, Simon P

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease of unknown cause. Approximately 5,000 people are diagnosed with IPF in the UK every year. People with IPF suffer significant morbidity and, without any curative treatment at present, survival rates remain poor with a median survival of 3 years. While treatment remains largely supportive, many drug therapies have been trialed in IPF over the years. Pirfenidone and nintedanib are newly licensed treatments for IPF and the first drugs to have shown convincing evidence of slowing disease progression. In addition to evaluating clinical evidence, we also discuss elements affecting drug choice from the viewpoint of patients and health care professionals. We discuss pharmacological and nonpharmacological aspects of providing best supportive care for patients with IPF. However, few good quality studies exist focusing on controlling symptoms specifically in patients with IPF, and recommendations are often extrapolated from evidence in other chronic diseases. In covering these topics, we hope to provide readers with a comprehensive review of the available evidence pertaining to all aspects of care for patients suffering with IPF. PMID:27114711

  4. Patient-centred management in idiopathic pulmonary fibrosis: similar themes in three communication models.

    PubMed

    Wuyts, Wim A; Peccatori, Fedro A; Russell, Anne-Marie

    2014-06-01

    The progressive and highly variable course of idiopathic pulmonary fibrosis (IPF) can present patients and their families with various challenges at different points of the disease. Structured communication between the healthcare professional and the patient is vital to ensure the best possible support and treatment for the patient. While research in this area has been limited, an increasing number of studies are emerging that support the role of communication in patients with debilitating and fatal lung diseases. Communication models used in other conditions that share many challenges with IPF, such as cancer, provide important insights for developing specifically designed patient support and communications models in IPF. Three communication models will be described: 1) the patient-centred care model (for oncology); 2) the three pillars of care model (for IPF); and 3) the Brompton model of care (for interstitial lung disease). Themes common to all three models include comprehensive patient education, encouraged patient participation and an accessible healthcare system, all supported by a collaborative provider-patient relationship. The development of effective communication skills is an on-going process and it is recommended to examine communication models used in other chronic diseases.

  5. 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

  6. 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

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

    PubMed Central

    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

  8. Danger-associated molecular patterns and danger signals in idiopathic pulmonary fibrosis.

    PubMed

    Ellson, Christian D; Dunmore, Rebecca; Hogaboam, Cory M; Sleeman, Matthew A; Murray, Lynne A

    2014-08-01

    The chronic debilitating lung disease, idiopathic pulmonary fibrosis (IPF), is characterized by a progressive decline in lung function, with a median mortality rate of 2-3 years after diagnosis. IPF is a disease of unknown cause and progression, and multiple pathways have been demonstrated to be activated in the lungs of these patients. A recent genome-wide association study of more than 1,000 patients with IPF identified genes linked to host defense, cell-cell adhesion, and DNA repair being altered due to fibrosis (Fingerlin, et al. Nat Genet 2013;45:613-620). Further emerging data suggest that the respiratory system may not be a truly sterile environment, and it exhibits an altered microbiome during fibrotic disease (Molyneaux and Maher. Eur Respir Rev 2013;22:376-381). These altered host defense mechanisms might explain the increased susceptibility of patients with IPF to microbial- and viral-induced exacerbations. Moreover, chronic epithelial injury and apoptosis are key features in IPF, which might be mediated, in part, by both pathogen-associated (PA) and danger-associated molecular patterns (MPs). Emerging data indicate that both PAMPs and danger-associated MPs contribute to apoptosis, but not necessarily in a manner that allows for the removal of dying cells, without further exacerbating inflammation. In contrast, both types of MPs drive cellular necrosis, leading to an exacerbation of lung injury and/or infection as the debris promotes a proinflammatory response. Thus, this Review focuses on the impact of MPs resulting from infection-driven apoptosis and necrosis during chronic fibrotic lung disease.

  9. Sildenafil Preserves Exercise Capacity in Patients With Idiopathic Pulmonary Fibrosis and Right-sided Ventricular Dysfunction

    PubMed Central

    Bach, David S.; Hagan, Peter G.; Yow, Eric; Flaherty, Kevin R.; Toews, Galen B.; Anstrom, Kevin J.; Martinez, Fernando J.

    2013-01-01

    Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with pulmonary vasculopathy. Objective: The purpose of this study was to determine whether sildenafil improves 6-min walk distance (6MWD) in subjects with IPF and right ventricular dysfunction. Methods: The IPFnet, a network of IPF research centers in the United States, conducted a randomized trial examining the effect of sildenafil on 6MWD in patients with advanced IPF, defined by carbon monoxide diffusing capacity < 35% predicted. A substudy examined 119 of 180 randomized subjects where echocardiograms were available for independent review by two cardiologists. Right ventricular (RV) hypertrophy (RVH), right ventricular systolic dysfunction (RVSD), and right ventricular systolic pressure (RVSP) were assessed. Multivariable linear regression models estimated the relationship between RV abnormality, sildenafil treatment, and changes in 6MWD, St. George’s Respiratory Questionnaire (SGRQ), the EuroQol instrument, and SF-36 Health Survey (SF-36) from enrollment to 12 weeks. Results: The prevalence of RVH and RVSD were 12.8% and 18.6%, respectively. RVSP was measurable in 71 of 119 (60%) subjects; mean RVSP was 42.5 mm Hg. In the subgroup of subjects with RVSD, subjects treated with sildenafil experienced less decrement in 6MWD (99.3 m; P = .01) and greater improvement in SGRQ (13.4 points; P = .005) and EuroQol visual analog scores (17.9 points; P = .04) than subjects receiving placebo. In the subgroup with RVH, sildenafil was not associated with change in 6MWD (P = .13), but was associated with greater relative improvement in SGRQ (14.8 points; P = .02) vs subjects receiving placebo. Sildenafil treatment in those with RVSD and RVH was not associated with change in SF-36. Conclusions: Sildenafil treatment in IPF with RVSD results in better preservation of exercise capacity as compared with placebo. Sildenafil also improves quality of life in subjects with RVH and RVSD. PMID:23732584

  10. Exercise training in idiopathic pulmonary fibrosis: is it of benefit?

    PubMed Central

    2016-01-01

    Key points Exercise training has been proven to be a safe and effective behavioural intervention for prevention and rehabilitation of chronic conditions. Despite the complexity of the signs and symptoms presented in IPF, supervised exercise training is a feasible and effective treatment for clinical improvement. Emerging data show significant enhancements in exercise capacity, dyspnoea and quality of life among IPF patients after exercise training interventions. Understanding of the principles of exercise training and the pathophysiology of IPF are essential for effective exercise programme delivery. Educational aims To describe the current evidence supporting exercise training for IPF. To highlight the importance of exercise physiology principles in rehabilitation treatment of patients with IPF. To introduce an effective practical exercise programme for IPF. To discuss the possible underlying physiological mechanisms of training effects in IPF. Exercise is a well-documented safe and effective intervention for prevention and rehabilitation of chronic diseases. Idiopathic pulmonary fibrosis (IPF) is a chronic deadly lung disease associated with severe signs and symptoms, exercise intolerance, diminished quality of life and poor prognosis. In the short term, supervised exercise training programmes have demonstrated clinical benefits in improving exercise capacity, dyspnoea and quality of life in patients with IPF. The underlying mechanisms of chronic adaption to a regular exercise regimen in IPF have yet to be well described and require further investigation. The available data underscore the importance of implementing training principles to target the pathophysiological impairments of IPF in order to optimise training adaption and enhance the outcomes. The current exercise training data in IPF provide sufficient evidence of clinical benefit for consideration to be given to recommending exercise-based pulmonary rehabilitation as standard of care for IPF. PMID

  11. 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

  12. 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.

  13. Inflammatory Leukocyte Phenotypes Correlate with Disease Progression in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Moore, Bethany B.; Fry, Chris; Zhou, Yueren; Murray, Susan; Han, MeiLan K.; Martinez, Fernando J.; Flaherty, Kevin R.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by progressive deposition of extracellular matrix, worsening dyspnea, and eventual mortality. Pathogenesis of IPF is poorly understood and the role inflammation and activated leukocytes play in the disease process is controversial. Previous studies demonstrated that activated leukocyte subsets characterize IPF patients. We sought to validate this observation in a well-defined cohort of 35 IPF patients and to correlate the observed leukocyte phenotypes with robust parameters of disease progression. We demonstrate that in univariate and multivariate analyses, increases in the CD14hi, CD16hi subset of monocytes measured at baseline correlated with disease progression, with a threshold value >0.5% of the total peripheral blood mononuclear cells being a significant predictor for worse outcome. In addition, several T cell subsets, including CD25 expressing CD4 cells, and CXCR3 expressing CD4 and CD8 subsets correlated with disease progression when found in increased percentages in the peripheral blood of IPF patients when sampled at baseline. Somewhat surprising in comparison to previous literature, the CD4 T cells did not appear to have lost expression of the co-stimulatory molecule, CD28, but the CD8 T cells did. Taken together, these results are consistent with the presence of an inflammatory process in IPF patients who eventually progress. However, when longitudinal measurements of these same markers were examined, there was significant heterogeneity of expression and these biomarkers did not necessarily remain elevated in IPF patients with progressive disease. We interpret this heterogeneity to suggest that IPF patients experience episodic inflammatory events that once triggered, may lead to disease progression. This longitudinal heterogeneity in biomarker analyses may explain why such markers are not consistently measured in all IPF cohorts. PMID:25580363

  14. Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry

    PubMed Central

    Kreuter, Michael; Hoeper, Marius M.; Wirtz, Hubert; Klotsche, Jens; Koschel, Dirk; Andreas, Stefan; Claussen, Martin; Grohé, Christian; Wilkens, Henrike; Randerath, Winfried; Skowasch, Dirk; Meyer, F. Joachim; Kirschner, Joachim; Gläser, Sven; Herth, Felix J.F.; Welte, Tobias; Huber, Rudolf Maria; Neurohr, Claus; Schwaiblmair, Martin; Kohlhäufl, Martin; Höffken, Gert; Held, Matthias; Koch, Andrea; Bahmer, Thomas; Pittrow, David

    2015-01-01

    After introduction of the new international guidelines on idiopathic pulmonary fibrosis (IPF) in 2011, we investigated clinical management practices for patients with IPF according to physicians' diagnoses. A prospective, multicenter, noninterventional study with comprehensive quality measures including on-site source data verification was performed in Germany. 502 consecutive patients (171 newly diagnosed, 331 prevalent; mean±sd age 68.7±9.4 years, 77.9% males) with a mean disease duration of 2.3±3.5 years were enrolled. IPF diagnosis was based on clinical assessments and high-resolution computed tomography (HRCT) in 90.2%, and on surgical lung biopsy combined with histology in 34.1% (lavage in 61.8%). The median 6-min walk distance was 320 m (mean 268±200 m). The mean forced vital capacity was 72±20% pred and diffusing capacity of the lung for carbon monoxide was 35±15% pred. No drugs were administered in 17.9%, oral steroids in 23.7%, N-acetylcysteine in 33.7%, pirfenidone in 44.2% and other drugs in 4.6% of patients. Only 2.8% of the cohort was listed for lung transplantation. IPF patients were diagnosed in line with the new guidelines. They had more severe disease than those enrolled in recent randomised controlled trials. In addition to HRCT, the frequency of lung biopsies was surprisingly high. Treatment patterns varied substantially. PMID:25837040

  15. Increased Expression of CC16 in Patients with Idiopathic Pulmonary Fibrosis

    PubMed Central

    Buendía-Roldán, Ivette; Ruiz, Víctor; Sierra, Patricia; Montes, Eduardo; Ramírez, Remedios; Vega, Anita; Salgado, Alfonso; Vargas, Mario H.; Mejía, Mayra; Pardo, Annie; Selman, Moisés

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology. The pathogenic mechanisms are unclear, but evidence indicates that aberrantly activated alveolar epithelial cells secrete a variety of mediators which induce the migration, proliferation and activation of fibroblasts and finally the excessive accumulation of extracellular matrix with the consequent destruction of the lung parenchyma. CC16 (approved symbol SCGB1A1), a putative anti-inflammatory protein produced by “club” cells in the distal airways, has not been evaluated in IPF lungs. In this study, we determined the serum and bronchoalveolar lavage (BAL) levels as well as the lung cell localization of this protein. Also, we explored the usefulness of serum levels of CC16 for the differential diagnosis of IPF (n = 85), compared with non-IPF interstitial lung diseases [chronic hypersensitivity pneumonitis (cHP; n = 85) and connective tissue diseases (CTD-ILD; n = 85)]. CC16 was significantly increased in serum and BAL fluids of IPF patients and was found not only in club cells but also in alveolar epithelial cells. When compared with non-IPF patients and controls, serum levels were significantly increased (p<0.0001). Sensitivity and specificity for CC16 (cut-off 41ng/mL) were 24% and 90%, positive predictive value 56% and negative predictive value 69%. These findings demonstrate that CC16 is upregulated in IPF patients suggesting that may participate in its pathogenesis. Although higher than the serum levels of non-IPF patients it shows modest sensitivity to be useful as a potential biomarker for the differential diagnosis. PMID:27977812

  16. Immunoglobulin Free Light Chains Are Increased in Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis

    PubMed Central

    Groot Kormelink, Tom; Pardo, Annie; Knipping, Karen; Buendía-Roldán, Ivette; García-de-Alba, Carolina; Blokhuis, Bart R.; Selman, Moises; Redegeld, Frank A.

    2011-01-01

    Background Idiopathic pulmonary fibrosis (IPF), a devastating lung disorder of unknown aetiology, and chronic hypersensitivity pneumonitis (HP), a disease provoked by an immunopathologic reaction to inhaled antigens, are two common interstitial lung diseases with uncertain pathogenic mechanisms. Previously, we have shown in other upper and lower airway diseases that immunoglobulin free light chains (FLCs) are increased and may be involved in initiating a local inflammation. In this study we explored if such a mechanism may also apply to HP and IPF. Methods In this study we examined the presence of FLC in serum and BAL fluid from 21 IPF and 22 HP patients and controls. IgG, IgE and tryptase concentrations were measured in BAL fluid only. The presence of FLCs, plasma cells, B cells and mast cells in lung tissue of 3 HP and 3 IPF patients and 1 control was analyzed using immunohistochemistry. Results FLC concentrations in serum and BAL fluid were increased in IPF and HP patients as compared to control subjects. IgG concentrations were only increased in HP patients, whereas IgE concentrations were comparable to controls in both patient groups. FLC-positive cells, B cells, plasma cells, and large numbers of activated mast cells were all detected in the lungs of HP and IPF patients, not in control lung. Conclusion These results show that FLC concentrations are increased in serum and BAL fluid of IPF and HP patients and that FLCs are present within affected lung tissue. This suggests that FLCs may be involved in mediating pathology in both diseases. PMID:21980441

  17. Apoptosis induction by thalidomide: critical for limb teratogenicity but therapeutic potential in idiopathic pulmonary fibrosis?

    PubMed

    Knobloch, Jürgen; Jungck, David; Koch, Andrea

    2011-01-01

    Thalidomide is a powerful treatment for inflammatory and cancer-based diseases. However, its clinical use remains limited due to its teratogenic properties, which primarily affect limb development. A prerequisite for overcoming these limitations is to understand the cellular and molecular mechanisms underlying thalidomide teratogenicity, which involve induction of oxidative stress, suppression of ubiquitin-mediated protein degradation and disruption of angiogenesis. Here, we discuss the hypothesis that thalidomide-induced limb teratogenicity is primarily based on the generation of nuclear oxidative stress with subsequent induction of transient apoptosis in the outgrowing limb bud. To this end, we establish a model of the signaling network regulating cell proliferation, survival and endogenous apoptosis-induction required for correct limb outgrowth and patterning. We then summarize data showing how thalidomide interferes with this signaling network: thalidomide inhibits the activity of the redox-sensitive transcription factor NF-κB, shifts the balance of fibroblast growth factors and bone morphogenetic proteins (Bmps) towards pro-apoptotic Bmps, and suppresses Wnt/β-catenin- and Akt-dependent survival signaling in the limb bud. Consequently, prechondrogenic precursor cells that determine skeletal elements are eliminated leading to the development of truncated limbs. We further discuss the involvement of thalidomide effects on ubiquitin-mediated protein degradation and angiogenesis in the induction of apoptosis in the limb bud. Finally, we discuss the paradox that the embryonic molecular pathology induced by thalidomide suggests this drug as a candidate for therapeutic application in idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung disease characterized by downregulation of Bmp signaling, increased Wnt and Akt activity, and apoptosis resistance.

  18. Idiopathic pulmonary fibrosis - a systematic review on methodology for the collection of epidemiological data

    PubMed Central

    2013-01-01

    Background Recent studies suggest that the incidence of idiopathic pulmonary fibrosis (IPF) is rising. Accurate epidemiological data on IPF, however, are sparse and the results of previous studies are contradictory. This study was undertaken to gain insight into the various methods used in the epidemiological research of IPF, and to get accurate and comparable data on these different methodologies. Methods A systematic database search was performed in order to identify all epidemiological studies on IPF after the previous guidelines for diagnosis and treatment were published in 2000. Medline (via Pubmed), Science Sitation Index (via Web of Science) and Embase databases were searched for original epidemiological articles published in English in international peer-reviewed journals starting from 2001. After pre-screening and a full-text review, 13 articles were accepted for data abstraction. Results Three different methodologies of epidemiological studies were most commonly used, namely: 1) national registry databases, 2) questionnaire-based studies, and 3) analysis of the health care system’s own registry databases. The overall prevalence and incidence of IPF varied in these studies between 0.5–27.9/100,000 and 0.22–8.8/100,000, respectively. According to four studies the mortality and incidence of IPF are rising. Conclusions We conclude that there are numerous ways to execute epidemiological research in the field of IPF. This review offers the possibility to compare the different methodologies that have been used, and this information could form a basis for future studies investigating the prevalence and incidence of IPF. PMID:23962167

  19. Dehydroepiandrosterone has strong antifibrotic effects and is decreased in idiopathic pulmonary fibrosis.

    PubMed

    Mendoza-Milla, Criselda; Valero Jiménez, Ana; Rangel, Claudia; Lozano, Alfredo; Morales, Violeta; Becerril, Carina; Chavira, Roberto; Ruiz, Víctor; Barrera, Lourdes; Montaño, Martha; Pardo, Annie; Selman, Moisés

    2013-11-01

    Idiopathic pulmonary fibrosis (IPF) is an ageing-related lung disorder characterised by expansion of the myofibroblast population and aberrant lung remodelling. Dehydroepiandrosterone (DHEA), a steroid pro-hormone, decreases with age but an exaggerated decline has been associated with chronic degenerative diseases. We quantified the plasma levels of DHEA and its sulfated form (DHEA-S) in 137 IPF patients and 58 controls and examined the effects of DHEA on human lung fibroblasts. Plasma DHEA/DHEA-S was significantly decreased in male IPF patients (median (range) DHEA: 4.4 (0.2-29.2) versus 6.7 (2.1-15.2) ng · mL(-1), p<0.01; DHEA-S: 47 (15.0-211) versus 85.2 (37.6-247.0) μg · dL(-1), p<0.001), while in females only DHEA-S was significantly decreased (32.6 (15.0-303.0) versus 68.3 (16.4-171) μg · dL(-1), p<0.001). DHEA caused a decrease in fibroblast proliferation and an approximately two-fold increase in fibroblast apoptosis, probably through the intrinsic pathway with activation of caspase-9. This effect was accompanied by upregulation of several pro-apoptotic proteins (Bax and cyclin-dependent kinase-inhibitor CDNK1A) and downregulation of anti-apoptotic proteins, such as cellular inhibitor of apoptosis (c-IAP)1 and c-IAP2. DHEA also caused a significant decrease of transforming growth factor-β1-induced collagen production and fibroblast to myofibroblast differentiation, and inhibited platelet-derived growth factor-induced fibroblast migration. These findings demonstrate a disproportionate decrease of DHEA/DHEA-S in IPF patients and indicate that this molecule has multiple antifibrotic properties.

  20. The usefulness of monomeric periostin as a biomarker for idiopathic pulmonary fibrosis

    PubMed Central

    Fujimoto, Kiminori; Sakamoto, Noriho; Takahashi, Koichiro; Yamamoto, Hiroshi; Kushima, Hisako; Ishii, Hiroshi; Akasaka, Keiichi; Ono, Junya; Kamei, Ayami; Azuma, Yoshinori; Matsumoto, Hisako; Yamaguchi, Yukie; Aihara, Michiko; Johkoh, Takeshi; Kawaguchi, Atsushi; Ichiki, Masao; Sagara, Hironori; Kadota, Jun-ichi; Hanaoka, Masayuki; Hayashi, Shin-ichiro; Kohno, Shigeru; Hoshino, Tomoaki; Izuhara, Kenji

    2017-01-01

    The natural course of idiopathic pulmonary fibrosis (IPF) is variable. Predicting disease progression and survival in IPF is important for treatment. We previously demonstrated that serum periostin has the potential to be a prognostic biomarker for IPF. Our aim was to use monomeric periostin in a multicenter study to evaluate its efficacy in diagnosing IPF and predicting its progression. To do so, we developed a new periostin kit to detect only monomeric periostin. The subjects consisted of 60 IPF patients in a multicenter cohort study. We applied monomeric periostin, total periostin detected by a conventional kit, and the conventional biomarkers—KL-6, SP-D, and LDH—to diagnose IPF and to predict its short-term progression as estimated by short-term changes of %VC and % DL, CO. Moreover, we compared the fraction ratios of monomeric periostin to total periostin in IPF with those in other periostin-high diseases: atopic dermatitis, systemic scleroderma, and asthma. Monomeric periostin showed the greatest ability to identify IPF comparable with KL-6 and SP-D. Both monomeric and total periostin were well correlated with the decline of %VC and % DL, CO. Clustering of IPF patients into high and low periostin groups proved useful for predicting the short-term progression of IPF. Moreover, the relative ratio of monomeric periostin was higher in IPF than in other periostin-high diseases. Measuring monomeric periostin is useful for diagnosing IPF and predicting its short-term progression. Moreover, the ratio of monomeric periostin to total periostin is elevated in IPF compared to other periostin-high diseases. PMID:28355256

  1. Thiopurine S- methyltransferase [corrected] testing in idiopathic pulmonary fibrosis: a pharmacogenetic cost-effectiveness analysis.

    PubMed

    Hagaman, Jared T; Kinder, Brent W; Eckman, Mark H

    2010-04-01

    Azathioprine in combination with N-acetylcysteine (NAC) and steroids is a standard therapy for idiopathic pulmonary fibrosis (IPF). Its use, however, is limited by its side effects, principally leukopenia. A genotypic assay, thiopurine S-methyltransferase (TPMT), has been developed that can potentially identify those at risk for developing leukopenia with azathioprine, and thereby limit its toxicity. In those with abnormal TPMT activity, azathioprine can be started at lower dose or an alternate regimen selected. Determine the cost-effectiveness of a treatment strategy using TPMT testing before initiation of azathioprine, NAC, and steroids in IPF by performing a computer-based simulation. We developed a decision analytic model comparing three strategies: azathioprine, NAC and steroids with and without prior TPMT testing, and conservative therapy, consisting of only supportive measures. Prevalence of abnormal TPMT alleles and complication rates of therapy were taken from the literature. We assumed a 12.5% incidence of abnormal TPMT alleles, 4% overall incidence of leukopenia while taking azathioprine, and that azathioprine, NAC, and steroids in combination reduced IPF disease progression by 14% during 12 months. TPMT testing before azathioprine, NAC, and steroids was the most effective and most costly strategy. The marginal cost-effectiveness of the TPMT testing strategy was $49,156 per quality adjusted life year (QALY) gained versus conservative treatment. Compared with azathioprine, NAC and steroids without prior testing, the TPMT testing strategy cost only $29,662 per QALY gained. In sensitivity analyses, when the prevalence of abnormal TPMT alleles was higher than our base case, TPMT was "cost-effective." At prevalence rates lower than our base case, it was not. TPMT testing before initiating therapy with azathioprine, NAC, and steroids is a cost-effective treatment strategy for IPF.

  2. 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

  3. Relationship between survival and age in patients with idiopathic pulmonary fibrosis

    PubMed Central

    Koo, So-My; Kim, Dong Soon; Kim, Young Whan; Chung, Man Pyo; 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; Hwangbo, Young

    2016-01-01

    Background There is a debate that older patients with idiopathic pulmonary fibrosis (IPF) have a worse prognosis. We evaluated whether age affects the survival of patients with IPF. Methods The Korean Interstitial Lung Disease (ILD) Research Group conducted a national survey to evaluate the clinical, physiological, radiological, and survival characteristics of patients with IPF. A total of 1,663 patients with IPF were stratified into three groups according to age: (I) <60 years (n=309); (II) 60–69 years (n=613); and (III) ≥70 years (n=741). Results The 1-, 3- and 5-year observed survival rates were 83.0%, 62.6%, and 49.2% in the total population, respectively. The 1-, 3-, and 5-year relative survival rates were 85.7%, 69.1%, and 58.0% in all patients, respectively. The observed survival rate of the group ≥70 years of age was significantly lower than those of the other groups (P<0.001). In contrast, no significant difference in relative survival rate was detected among the three age groups. Compared with patients less than 60 years of age, patients with above 70 years of age had not increased risk of worse relative survival [P=0.252; hazard ratio (HR), 1.11; 95% confidence interval (CI), 0.76–1.64]. Conclusions The prognosis of patients above 70 years of age with IPF was not different to that of patients less than 60 years of age, using relative survival rate. Age may not affect survival in patients with IPF. PMID:28066605

  4. COMPARISON BETWEEN SEDATION AND GENERAL ANESTHESIA FOR HIGH RESOLUTION COMPUTED TOMOGRAPHIC CHARACTERIZATION OF CANINE IDIOPATHIC PULMONARY FIBROSIS IN WEST HIGHLAND WHITE TERRIERS.

    PubMed

    Roels, Elodie; Couvreur, Thierry; Farnir, Frédéric; Clercx, Cécile; Verschakelen, Johny; Bolen, Géraldine

    2017-02-23

    Canine idiopathic pulmonary fibrosis is a progressive interstitial lung disease mainly affecting West Highland white terriers. Thoracic high-resolution computed tomographic (T-HRCT) findings for Canine idiopathic pulmonary fibrosis acquired under general anesthesia have been described previously. However, the use of general anesthesia may be contraindicated for some affected dogs. Sedation may allow improved speed and safety, but it is unknown whether sedation would yield similar results in identification and grading of Canine idiopathic pulmonary fibrosis lesions. The aim of this prospective, observational, method-comparison, case-control study was to compare findings from T-HRCT images acquired under sedation versus general anesthesia for West Highland white terriers affected with Canine idiopathic pulmonary fibrosis (n = 11) and age-matched controls (n = 9), using the glossary of terms of the Fleischner Society and a scoring system. Ground-glass opacity was identified in all affected West Highland white terriers for both sedation and general anesthesia acquisitions, although the Ground-glass opacity extent varied significantly between the two acquisitions (P < 0.001). Ground-glass opacity was the sole lesion observed in control dogs (n = 6), but was less extensive compared with affected West Highland white terriers. Identification and grading of a mosaic attenuation pattern differed significantly between acquisitions (P < 0.001). Identification of lesions such as consolidations, nodules, parenchymal and subpleural bands, bronchial wall thickening, and bronchiectasis did not differ between acquisitions. The present study demonstrated that T-HRCT obtained under sedation may provide different information than T-HRCT obtained under general anesthesia for identification and grading of some Canine idiopathic pulmonary fibrosis lesions, but not all of them. These differences should be taken into consideration when general anesthesia is contraindicated and sedation is

  5. Efficacy of antioxidant in idiopathic pulmonary fibrosis: A systematic review and meta-analysis

    PubMed Central

    Kandhare, Amit D.; Mukherjee, Anwesha; Ghosh, Pinaki; Bodhankar, Subhash L.

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic oxido-inflammatory disorder of the lung. Oxidative stress is widely recognized as a central feature of IPF. Antioxidant therapy has been proposed as an effective treatment for IPF. An array of clinical trials describing the therapeutic impact of these drugs have been reporting albeit with conflicting evidence points. We performed a meta-analysis of trials in which efficacy of antioxidant therapy was compared with control in IPF. Systematic literature search was conducted in PubMed, EMBASE, the Cochrane Library, CPCI-S (Conference Proceedings Citation Index-Science), ICTRP (International Clinical Trials Registry Platform), and Google Scholar till June 2016 by two independent researchers. Various outcomes such as changes in pulmonary function tests (change in vital capacity [ΔVC], change in forced vital capacity [ΔFVC], change in percentage of predicted vital capacity [Δ%VC], and change in percentage of predicted carbon monoxide diffusing capacity [Δ%DLco]), changes in 6 minutes walking test distance (Δ6MWT), rates of adverse events, and rates of death, were included. All statistical analyses were performed using RevMan V.5.3. Twelve studies (n = 1062) were identified that used antioxidants (N-acetylcysteine and lecithinized superoxide dismutase) as a treatment for IPF. Overall, there was no association of antioxidant therapy with ΔFVC (SMD = 0.27, 95% CI:-0.07 to 0.61; P = 0.12), ΔFVC (%) (SMD = -0.10, 95% CI:-0.56 to 0.36; P = 0.66) and 6MWT (SMD = -0.04, 95% CI:-0.11 to 0.20; P = 0.59) in IPF patients. However, combined antioxidant therapy was found to be associated with %VC (SMD = 0.37, 95% CI: 0.09 to 0.64; P = 0.008) and Δ%DLco (SMD = 0.15, 95% CI: 0.00 to 0.29; P = 0.05) in IPF patients. Strong evidence was obtained that the antioxidants increased adverse effects adverse events (OR = 1.56, 95% CI: 0.75 to 3.24; P = 0.23) but it did not associate mortality (OR = 0.96, 95% CI: 0.44 to 2.11; P = 0.92). The

  6. Efficacy of antioxidant in idiopathic pulmonary fibrosis: A systematic review and meta-analysis.

    PubMed

    Kandhare, Amit D; Mukherjee, Anwesha; Ghosh, Pinaki; Bodhankar, Subhash L

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic oxido-inflammatory disorder of the lung. Oxidative stress is widely recognized as a central feature of IPF. Antioxidant therapy has been proposed as an effective treatment for IPF. An array of clinical trials describing the therapeutic impact of these drugs have been reporting albeit with conflicting evidence points. We performed a meta-analysis of trials in which efficacy of antioxidant therapy was compared with control in IPF. Systematic literature search was conducted in PubMed, EMBASE, the Cochrane Library, CPCI-S (Conference Proceedings Citation Index-Science), ICTRP (International Clinical Trials Registry Platform), and Google Scholar till June 2016 by two independent researchers. Various outcomes such as changes in pulmonary function tests (change in vital capacity [ΔVC], change in forced vital capacity [ΔFVC], change in percentage of predicted vital capacity [Δ%VC], and change in percentage of predicted carbon monoxide diffusing capacity [Δ%DLco]), changes in 6 minutes walking test distance (Δ6MWT), rates of adverse events, and rates of death, were included. All statistical analyses were performed using RevMan V.5.3. Twelve studies (n = 1062) were identified that used antioxidants (N-acetylcysteine and lecithinized superoxide dismutase) as a treatment for IPF. Overall, there was no association of antioxidant therapy with ΔFVC (SMD = 0.27, 95% CI:-0.07 to 0.61; P = 0.12), ΔFVC (%) (SMD = -0.10, 95% CI:-0.56 to 0.36; P = 0.66) and 6MWT (SMD = -0.04, 95% CI:-0.11 to 0.20; P = 0.59) in IPF patients. However, combined antioxidant therapy was found to be associated with %VC (SMD = 0.37, 95% CI: 0.09 to 0.64; P = 0.008) and Δ%DLco (SMD = 0.15, 95% CI: 0.00 to 0.29; P = 0.05) in IPF patients. Strong evidence was obtained that the antioxidants increased adverse effects adverse events (OR = 1.56, 95% CI: 0.75 to 3.24; P = 0.23) but it did not associate mortality (OR = 0.96, 95% CI: 0.44 to 2.11; P = 0.92). The

  7. Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis

    PubMed Central

    Donahoe, Michael; Valentine, Vincent G.; Chien, Nydia; Gibson, Kevin F.; Raval, Jay S.; Saul, Melissa; Xue, Jianmin; Zhang, Yingze; Duncan, Steven R.

    2015-01-01

    Background Severe acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are medically untreatable and often fatal within days. Recent evidence suggests autoantibodies may be involved in IPF progression. Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments. We conducted a pilot trial to test the hypothesis that autoantibody-targeted therapies may also benefit AE-IPF patients. Methods Eleven (11) critically-ill AE-IPF patients with no evidence of conventional autoimmune diseases were treated with therapeutic plasma exchanges (TPE) and rituximab, supplemented in later cases with intravenous immunoglobulin (IVIG). Plasma anti-epithelial (HEp-2) autoantibodies and matrix metalloproteinase-7 (MMP7) were evaluated by indirect immunofluorescence and ELISA, respectively. Outcomes among the trial subjects were compared to those of 20 historical control AE-IPF patients treated with conventional glucocorticoid therapy prior to this experimental trial. Results Nine (9) trial subjects (82%) had improvements of pulmonary gas exchange after treatment, compared to one (5%) historical control. Two of the three trial subjects who relapsed after only five TPE responded again with additional TPE. The three latest subjects who responded to an augmented regimen of nine TPE plus rituximab plus IVIG have had sustained responses without relapses after 96-to-237 days. Anti-HEp-2 autoantibodies were present in trial subjects prior to therapy, and were reduced by TPE among those who responded to treatment. Conversely, plasma MMP7 levels were not systematically affected by therapy nor correlated with clinical responses. One-year survival of trial subjects was 46+15% vs. 0% among historical controls. No serious adverse events were attributable to the experimental medications. Conclusion This pilot trial indicates specific treatments that reduce autoantibodies

  8. Effect of statins on disease-related outcomes in patients with idiopathic pulmonary fibrosis

    PubMed Central

    Kreuter, Michael; Bonella, Francesco; Costabel, Ulrich; Spagnolo, Paolo; Weycker, Derek; Kirchgaessler, Klaus-Uwe; Kolb, Martin

    2017-01-01

    Background 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. Methods 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). Results 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). Conclusions 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. Trial registration numbers NCT01366209, NCT00287729 and NCT00287716. PMID:27708114

  9. Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses

    PubMed Central

    Kahloon, Rehan A.; Xue, Jianmin; Bhargava, Arpit; Csizmadia, Eva; Otterbein, Leo; Kass, Daniel J.; Bon, Jessica; Soejima, Makoto; Levesque, Marc C.; Lindell, Kathleen O.; Gibson, Kevin F.; Kaminski, Naftali; Banga, Gunjan; Oddis, Chester V.; Pilewski, Joseph M.; Sciurba, Frank C.; Donahoe, Michael; Zhang, Yingze

    2013-01-01

    Rationale: Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations. Objectives: To identify clinically relevant, antigen-specific immune responses in patients with IPF. Methods: Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti–heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies. Measurements and Main Results: HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 ± 10% vs. 80 ± 5%; hazard ratio = 4.2; 95% confidence interval, 2.0–8.6; P < 0.0001). HSP70 protein, antigen–antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression. Conclusions: Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in

  10. Accelerated Variant of Idiopathic Pulmonary Fibrosis: Clinical Behavior and Gene Expression Pattern

    PubMed Central

    Selman, Moisés; Carrillo, Guillermo; Estrada, Andrea; Mejia, Mayra; Becerril, Carina; Cisneros, José; Gaxiola, Miguel; Pérez-Padilla, Rogelio; Navarro, Carmen; Richards, Thomas; Dauber, James; King, Talmadge E.; Pardo, Annie; Kaminski, Naftali

    2007-01-01

    Background Idiopathic pulmonary fibrosis (IPF) is characterized by the insidious onset of dyspnea or cough. However, a subset of patients has a short duration of symptoms with rapid progression to end-stage disease. In this study, we evaluated clinical and molecular features of “rapid” and “slow” progressors with IPF. Methods and Findings 26 patients with <6 months of symptoms before first presentation [rapid progressors] and 88 patients with >24 months of symptoms [slow progressors] were studied. Survival was analyzed by the Kaplan-Meyer method and proportional hazard's model. Lung microarrays and tissue proteins were measured in a subset of patients. No differences were found in age, physiologic impairment and bronchoalveolar lavage (BAL) cellular profile. There were more males (OR = 6.5; CI:1.4-29.5; p = 0.006) and smokers (OR = 3.04; CI:1.1-8.3; p = 0.04) in the rapid progressors group. Survival from the beginning of symptoms was significantly reduced in rapid progressors (HR = 9.0; CI:4.48-18.3; p<0.0001) and there was a tendency for decreased survival from the time of diagnosis (HR = 1.5; CI:0.81-2.87; p = 0.18). We identified 437 differentially expressed genes. Lungs of rapid progressors overexpressed genes involved in morphogenesis, oxidative stress, migration/proliferation, and genes from fibroblasts/smooth muscle cells. Upregulation of two of these genes, adenosine-2B receptor and prominin-1/CD133, was validated by immunohistochemistry and were expressed by alveolar epithelial cells. BAL from rapid progressors showed a >2-fold increase of active matrix metalloproteinase-9, and induced a higher fibroblast migration compared with slow progressors and controls [238±98% versus 123±29% (p<0.05) and 30±17% (p<0.01)]. Conclusions/Significance A subgroup of IPF patients, predominantly smoking males, display an accelerated clinical course and have a gene expression pattern that is different from those with slower progression

  11. CD8+ T lymphocytes in lung tissue from patients with idiopathic pulmonary fibrosis

    PubMed Central

    Daniil, Zoe; Kitsanta, Panagiota; Kapotsis, George; Mathioudaki, Maria; Kollintza, Androniki; Karatza, Marilena; Milic-Emili, Joseph; Roussos, Charis; Papiris, Spyros A

    2005-01-01

    Background Several studies have implicated a role of inflammation in the pathogenesis of lung damage in idiopathic pulmonary fibrosis (IPF). Parenchymal lung damage leads to defects in mechanics and gas exchange and clinically manifests with exertional dyspnea. Investigations of inflammatory cells in IPF have shown that eosinophils, neutrophils and CD8+ TLs may be associated with worse prognosis. We wished to investigate by quantitative immunohistochemistry infiltrating macrophages, neutrophils and T lymphocytes (TLs) subpopulations (CD3+, CD4+ and CD8+) in lung tissue of patients with IPF and their correlation with lung function indices and grade of dyspnoea. Methods Surgical biopsies of 12 patients with IPF were immunohistochemically stained with mouse monoclonal antibodies (anti-CD68 for macrophages, anti-elastase for neutrophils, and anti-CD3, anti-CD4, anti-CD8 for CD3+TLs, CD4+TLs, and CD8+TLs respectively). The number of positively stained cells was determined by observer-interactive computerized image analysis (SAMBA microscopic image processor). Cell numbers were expressed in percentage of immunopositive nuclear surface in relation to the total nuclear surface of infiltrative cells within the tissue (labeling Index). Correlations were performed between cell numbers and physiological indices [FEV1, FVC, TLC, DLCO, PaO2, PaCO2 and P(A-a)O2)] as well as dyspnoea scores assessed by the Medical Research Council (MRC) scale. Results Elastase positive cells accounted for the 7.04% ± 1.1 of total cells, CD68+ cells for the 16.6% ± 2, CD3+ TLs for the 28.8% ± 7, CD4+ TLs for the 14.5 ± 4 and CD8+ TLs for the 13.8 ± 4. CD8+TLs correlated inversely with FVC % predicted (rs = -0.67, p = 0.01), TLC % predicted (rs = -0.68, p = 0.01), DLCO % predicted (rs = -0.61, p = 0.04), and PaO2 (rs = -0.60, p = 0.04). Positive correlations were found between CD8+TLs and P(A-a)O2 (rs = 0.65, p = 0.02) and CD8+TLs and MRC score (rs = 0.63, p = 0.02). Additionally, CD68+ cells

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

    PubMed Central

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

    2015-01-01

    Abstract 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

  13. Understanding and optimizing health-related quality of life and physical functional capacity in idiopathic pulmonary fibrosis

    PubMed Central

    Olson, Amy L; Brown, Kevin K; Swigris, Jeffrey J

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive pulmonary disease characterized by the insidious onset of shortness of breath due to parenchymal scarring. As IPF progresses, breathlessness worsens, physical functional capacity declines, and health-related quality of life (HRQL) – the impact of health or disease on a person’s satisfaction with their overall station in life – deteriorates. These two inextricably linked variables – breathlessness and physical functional capacity – are strong drivers of HRQL. With the emergence of new and prospective therapies for IPF, it is more important than ever to be able to accurately and reliably assess how IPF patients feel and function. Doing so will promote the development of novel interventions to target impairments in these areas and ensure that the field is capable of assessing the effect of therapeutics interventions on these critically important patient-centered outcomes. PMID:27274328

  14. 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

  15. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema.

    PubMed

    Chilosi, Marco; Carloni, Angelo; Rossi, Andrea; Poletti, Venerino

    2013-09-01

    Different anatomic and physiological changes occur in the lung of aging people that can affect pulmonary functions, and different pulmonary diseases, including deadly diseases such as chronic obstructive pulmonary disease (COPD)/emphysema and idiopathic pulmonary fibrosis (IPF), can be related to an acceleration of the aging process. The individual genetic background, as well as exposure to a variety of toxic substances (cigarette smoke in primis) can contribute significantly to accelerating pulmonary senescence. Premature aging can impair lung function by different ways: by interfering specifically with tissue repair mechanisms after damage, thus perturbing the correct crosstalk between mesenchymal and epithelial components; by inducing systemic and/or local alteration of the immune system, thus impairing the complex mechanisms of lung defense against infections; and by stimulating a local and/or systemic inflammatory condition (inflammaging). According to recently proposed pathogenic models in COPD and IPF, premature cellular senescence likely affects distinct progenitors cells (mesenchymal stem cells in COPD, alveolar epithelial precursors in IPF), leading to stem cell exhaustion. In this review, the large amount of data supporting this pathogenic view are discussed, with emphasis on the possible molecular and cellular mechanisms leading to the severe parenchymal remodeling that characterizes, in different ways, these deadly diseases.

  16. 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.

  17. Bleomycin Induces Molecular Changes Directly Relevant to Idiopathic Pulmonary Fibrosis: A Model for “Active” Disease

    PubMed Central

    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 MT.; 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. PMID:23565148

  18. TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis

    PubMed Central

    Ma, Shwu-Fan; Martinez, Fernando J.; Anstrom, Kevin J.; Raghu, Ganesh; Schwartz, David A.; Valenzi, Eleanor; Witt, Leah; Lee, Cathryn; Vij, Rekha; Huang, Yong; Strek, Mary E.; Noth, Imre

    2015-01-01

    Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown. Objectives: To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial. Methods: SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of ≥10% in FVC. Measurements and Main Results: Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (Pinteraction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02–0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79–13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort. Conclusions: NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF. PMID:26331942

  19. Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis

    PubMed Central

    Karki, Suman; Surolia, Ranu; Hock, Thomas David; Guroji, Purusotham; Zolak, Jason S.; Duggal, Ryan; Ye, Tong; Thannickal, Victor J.; Antony, Veena B.

    2014-01-01

    Pleural mesothelial cells (PMCs), which are derived from the mesoderm, exhibit an extraordinary capacity to undergo phenotypic changes during development and disease. PMC transformation and trafficking has a newly defined role in idiopathic pulmonary fibrosis (IPF); however, the contribution of Wilms' tumor 1 (Wt1)-positive PMCs to the generation of pathognomonic myofibroblasts remains unclear. PMCs were obtained from IPF lung explants and healthy donor lungs that were not used for transplantation. Short hairpin Wt1-knockdown PMCs (sh Wt1) were generated with Wt1 shRNA, and morphologic and functional assays were performed in vitro. Loss of Wt1 abrogated the PMC phenotype and showed evidence of mesothelial-to-mesenchymal transition (MMT), with a reduced expression of E-cadherin and an increase in the profibrotic markers α-smooth muscle actin (α-SMA) and fibronectin, along with increased migration and contractility, compared with that of the control. Migration of PMCs in response to active transforming growth factor (TGF)-β1 was assessed by live-cell imaging with 2-photon microscopy and 3D imaging, of Wt1-EGFP transgenic mice. Lineage-tracing experiments to map the fate of Wt1+ PMCs in mouse lung in response to TGF-β1 were also performed by using a Cre-loxP system. Our results, for the first time, demonstrate that Wt1 is necessary for the morphologic integrity of pleural membrane and that loss of Wt1 contributes to IPF via MMT of PMCs into a myofibroblast phenotype.—Karki, S., Surolia, R., Hock, T. D., Guroji, P., Zolak, J. S., Duggal, R., Ye, T., Thannickal, V., J., Antony, V. B. Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis. PMID:24265486

  20. 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

  1. Pulmonary Fibrosis Foundation

    MedlinePlus

    ... for a friend. Ways to Give Announcements CHICAGO BEAR JORDAN HOWARD BRINGS HIS FIGHT TO PULMONARY FIBROSIS ... 22-year-old lead rusher for the Chicago Bears, will announce his commitment to fight pulmonary fibrosis ( ...

  2. Idiopathic pulmonary artery aneurysm.

    PubMed

    Kotwica, Tomasz; Szumarska, Joanna; Staniszewska-Marszalek, Edyta; Mazurek, Walentyna; Kosmala, Wojciech

    2009-05-01

    Pulmonary artery aneurysm (PAA) is an uncommon lesion, which may be associated with different etiologies including congenital cardiovascular diseases, systemic vasculitis, connective tissue diseases, infections, and trauma. Idiopathic PAA is sporadically diagnosed by exclusion of concomitant major pathology. We report a case of a 56-year-old female with an idiopathic pulmonary artery dilatation identified fortuitously by echocardiography and confirmed by contrast-enhanced computed tomography. Neither significant pulmonary valve dysfunction nor pulmonary hypertension and other cardiac abnormalities which might contribute to the PAA development were found. Here, we describe echocardiographic and computed tomography findings and review the literature on PAA management.

  3. Ambroxol hydrochloride in the management of idiopathic pulmonary fibrosis: Clinical trials are the need of the hour

    PubMed Central

    Gupta, P. R.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease of unknown etiology. Its pathogenesis remains poorly elucidated but aberrant wound healing is central to its pathology. It has a median survival time of 3 to 5 years. None of the treatment modality or drugs tried in its management has so far changed the overall outcome. Recent in vitro and experimental studies have shown that ambroxol hydrochloride exerts several newer actions, namely the surfactant stimulatory, anti-imflammatory and anti-oxidant actions, in addition to its being a secrrtolytic and mucokinetic agent. The anti inflammatory and anti-fibrotic properties of the drug are due to its ability to block the release of oxidant stress markers, cytokines, leukotrienes, MPO activity, hydroxyproline content, nitic oxide and/or collagen I & III mRNA in the local milieu while preserving the SOD and GSH-PX activities. In human studies also, the agent was able to block the expression of TGF-beta and TNF-alpha in plasma and preserving the carbon monoxide diffusion capacity of the lungs in lung cancer patients on radiation therapy. Thus, ambroxol may have the potential to check the dysregulated healing process that is typical of IPF. This, coupled with its safety profile for human use, warrants clinical trials of the drug in the management of IPF. PMID:24669082

  4. Idiopathic pulmonary fibrosis in Sweden: report from the first year of activity of the Swedish IPF-Registry

    PubMed Central

    Ferrara, Giovanni; Carlson, Lisa; Palm, Andreas; Einarsson, Jonas; Olivesten, Cecilia; Sköld, Magnus; for the Swedish Idiopathic Pulmonary Fibrosis Registry Group

    2016-01-01

    Background Idiopathic pulmonary fibrosis (IPF) is an emerging problem in the western world, being related to increasing age and implying significant costs for the diagnosis and management of affected patients. The epidemiology of IPF is not well understood. Methods To allow estimates of the problem and eventually to evaluate quality of the care of IPF patients in Sweden, a national IPF Registry was started in the autumn of 2014. Data on criteria used to diagnose IPF, demographics, lung function, and quality of life (measured with the King's Brief Interstitial Lung Disease Questionnaire, K-BILD) were reported directly to the registry, based at the coordinating centre (Karolinska University Hospital, Stockholm, Sweden) via a web-based platform. Results During the first year, the registry was implemented in 11 (33%) of the 33 respiratory units in the country. Seventy-one patients were registered between October 2014 and October 2015, 50 (70.4%) males and 21 (29.6%) females. Median age was 70 (range 47–86). The mean K-BILD score at the first inclusion in the registry was 54.3+9.5. Conclusions The main features of IPF patients in this first Swedish cohort were consistent with data published in the literature in main multinational randomized controlled trials. The K-BILD questionnaire showed that quality of life of patients with IPF and their perception of the disease are quite poor at the time of inclusion in the registry. PMID:27105945

  5. A Systematic Review of the Role of Dysfunctional Wound Healing in the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis

    PubMed Central

    Betensley, Alan; Sharif, Rabab; Karamichos, Dimitrios

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disorder showcasing an interaction between genetic predisposition and environmental risks. This usually involves the coaction of a mixture of cell types associated with abnormal wound healing, leading to structural distortion and loss of gas exchange function. IPF bears fatal prognosis due to respiratory failure, revealing a median survival of approximately 2 to 3 years. This review showcases the ongoing progress in understanding the complex pathophysiology of IPF and it highlights the latest potential clinical treatments. In IPF, various components of the immune system, particularly clotting cascade and shortened telomeres, are highly involved in disease pathobiology and progression. This review also illustrates two US Food and Drug Administration (FDA)-approved drugs, nintedanib (OFEV, Boehringer Ingelheim, Ingelheim am Rhein, Germany) and pirfenidone (Esbriet, Roche, Basel, Switzerland), that slow IPF progression, but unfortunately neither drug can reverse the course of the disease. Although the mechanisms underlying IPF remain poorly understood, this review unveils the past and current advances that encourage the detection of new IPF pathogenic pathways and the development of effective treatment methods for the near future. PMID:28035951

  6. Myriad Functions of Stanniocalcin-1 (STC1) Cover Multiple Therapeutic Targets in the Complicated Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF)

    PubMed Central

    Ohkouchi, Shinya; Ono, Manabu; Kobayashi, Makoto; Hirano, Taizou; Tojo, Yutaka; Hisata, Shu; Ichinose, Masakazu; Irokawa, Toshiya; Ogawa, Hiromasa; Kurosawa, Hajime

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is an intractable disease for which the pathological findings are characterized by temporal and spatial heterogeneity. The pathogenesis is composed of myriad factors, including repetitive injuries to epithelial cells, alterations in immunity, the formation of vascular leakage and coagulation, abnormal wound healing, fibrogenesis, and collagen accumulation. Therefore, the molecular target drugs that are used or attempted for treatment or clinical trials may not cover the myriad therapeutic targets of IPF. In addition, the complicated pathogenesis results in a lack of informative biomarkers to diagnose accurately the status of IPF. These facts point out the necessity of using a combination of drugs, that is, each single drug with molecular targets or a single drug with multiple therapeutic targets. In this review, we introduce a humoral factor, stanniocalcin-1 (STC1), which has myriad functions, including the maintenance of calcium homeostasis, the promotion of early wound healing, uncoupling respiration (aerobic glycolysis), reepithelialization in damaged tissues, the inhibition of vascular leakage, and the regulation of macrophage functions to keep epithelial and endothelial homeostasis, which may adequately cover the myriad therapeutic targets of IPF. PMID:26740747

  7. Retrospective observational study of trends in hospital admissions for idiopathic pulmonary fibrosis in Spain (2004–2013) using administrative data

    PubMed Central

    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

    2017-01-01

    Objective 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). Methods We identified patients hospitalised with IPF in Spain from 2004 to 2013. Data were collected from the National Hospital Discharge Database. Results 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). Conclusions The frequency of hospital admissions for IPF increased during the study period, as did healthcare costs. However, IHM and LOHS decreased. PMID:28193850

  8. Plasma B-Lymphocyte Stimulator (BLyS) and B-cell Differentiation in Idiopathic Pulmonary Fibrosis Patients*

    PubMed Central

    Xue, Jianmin; Kass, Daniel J.; Bon, Jessica; Vuga, Louis; Tan, Jiangning; Csizmadia, Eva; Otterbein, Leo; Soejima, Makoto; Levesque, Marc C.; Gibson, Kevin F.; Kaminski, Naftali; Pilewski, Joseph M.; Donahoe, Michael; Sciurba, Frank C.; Duncan, Steven R.

    2013-01-01

    We hypothesized B-cells are involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a progressive, restrictive lung disease that is refractory to glucocorticoids and other nonspecific therapies, and almost invariably lethal. Accordingly, we sought to identify clinically-associated B-cell-related abnormalities in these patients. Phenotypes of circulating B-cells were characterized by flow cytometry. Intrapulmonary processes were evaluated by immunohistochemistry. Plasma B-lymphocyte stimulating factor (BLyS) was assayed by ELISA. Circulating B-cells of IPF subjects were more antigen-differentiated, with greater plasmablast proportions (3.1±0.8%) than in normal controls (1.3±0.3%) (p<0.03), and the extent of this differentiation correlated with IPF patient lung volumes (r=0.44, p<0.03). CD20+ B-cell aggregates, diffuse parenchymal and perivascular immune complexes, and complement depositions were all prevalent in IPF lungs, but much less prominent or absent in normal lungs. Plasma concentrations of BLyS, an obligate factor for B-cell survival and differentiation, were significantly greater (p<0.0001) in 110 IPF (2.05±0.05 ng/ml) than among 53 normal (1.40±0.04 ng/ml) and 90 chronic obstructive pulmonary disease (COPD) subjects (1.59±0.05 ng/ml). BLyS levels were uniquely correlated among IPF patients with pulmonary artery pressures (r=0.58, p<0.0001). The 25% of IPF subjects with the greatest BLyS values also had diminished one-year survival (46±11%), compared to those with lesser BLyS concentrations (81±5%) (HR=4.0, 95%CI=1.8-8.7, p=0.0002). Abnormalities of B-cells and BLyS are common in IPF patients, and highly associated with disease manifestations and patient outcomes. These findings have implications regarding IPF pathogenesis, and illuminate the potential for novel treatment regimens that specifically target B-cells in patients with this lung disease. PMID:23872052

  9. Expression analysis of angiogenic growth factors and biological axis CXCL12/CXCR4 axis in idiopathic pulmonary fibrosis.

    PubMed

    Antoniou, Katerina M; Soufla, Giannoula; Lymbouridou, Rena; Economidou, Foteini; Lasithiotaki, Ismini; Manousakis, Manolis; Drositis, Ioannis; Spandidos, Demetrios A; Siafakas, Nikolaos M

    2010-01-01

    Idiopathic pulmonary fibrosis (IPF) is associated with aberrant repair, persistence of collagen deposition, and the development of vascular remodeling. However, the role of angiogenesis in the pathogenesis of IPF is still undetermined. The aim of this study was to evaluate the combined mRNA expression of vascular endothelial growth factor A (VEGFA), fibroblast growth factor 2 (FGF2), insulin-like growth factor 1 (IGF1) epidermal growth factor (EGF), and its receptor (EGFR) in lung tissue obtained from IPF patients. We have also investigated the expression of chemokine CXCL12/stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, to identify alterations that maybe implicated in the pathogenesis of IPF. The subjects studied consisted of two distinct groups: patients with IPF (n = 25) and subjects (control) undergoing thoracic surgery for reasons other than interstitial lung disease (n = 10). Expression analysis of the aforementioned growth factors and biological axis CXCL12/CXR4 analysis were performed using real-time RT-PCR. IGF-1, EGF, and FGF2 mRNA levels are significantly decreased in the patients compared to the controls (p = 0.028, p = 0.023 and p = 0.009, respectively). SDF1-TR1 and SDF1-TR2 transcript levels were significantly lower in patients compared to controls (p = 0.017 and p = 0.001). Significant coexpression of VEGF mRNA with IGF mRNA was observed in the group of the patients (p = 0.017). An additional coexpression of VEGF mRNA with SDF1-TR1 mRNA was demonstrated(p = 0.030). Our results show a downregulation in angiogenetic mechanisms in IPF. However, our results should be further verified by measuring other angiogenetic pathways in more samples.

  10. Clinical Course and Changes in High-Resolution Computed Tomography Findings in Patients with Idiopathic Pulmonary Fibrosis without Honeycombing

    PubMed Central

    Bando, Masashi; Baba, Tomohisa; Kataoka, Kensuke; Yamada, Yoshihito; Yamamoto, Hiroshi; Miyamoto, Atsushi; Ikushima, Soichiro; Johkoh, Takeshi; Sakai, Fumikazu; Terasaki, Yasuhiro; Hebisawa, Akira; Kawabata, Yoshinori; Sugiyama, Yukihiko; Ogura, Takashi

    2016-01-01

    Some patients with idiopathic pulmonary fibrosis (IPF) do not have honeycombing on high-resolution computed tomography (HRCT) at their initial evaluation. The clinical course and sequential changes in HRCT findings in these patients are not fully understood. We reviewed the cases of 43 patients with IPF without honeycombing on initial HRCT from institutions throughout Japan. All patients were diagnosed with IPF based on a surgical lung biopsy. Multidisciplinary discussions were held five times between 2011 and 2014, to exclude alternative etiologies. We evaluated the sequential changes in HRCT findings in 30 patients with IPF. We classified these 30 patients into three groups based on their HRCT patterns and clarified the clinical characteristics and prognosis among the groups. The patterns of all 30 patients on initial HRCT corresponded to a possible usual interstitial pneumonia (UIP) pattern which was described in the 2011 International Statement. On long-term follow-up (71.0±38.7 standard deviation [SD] months), honeycombing was seen in 16 patients (53%, the HoneyCo group); traction bronchiectasis or cysts without honeycombing was observed in 12 patients (40%, the NoHoneyCo group), and two patients showed no interval change (7%, the NoChange group) on HRCT. The mean survival periods of the HoneyCo and NoHoneyCo groups were 67.1 and 61.2 months, respectively (p = 0.76). There are some patients with IPF whose conditions chronically progress without honeycombing on HRCT. The appearance of honeycombing on HRCT during the follow-up might not be related to prognosis. PMID:27829068

  11. Corticosteroid and cyclophosphamide in acute exacerbation of idiopathic pulmonary fibrosis: a single center experience and literature review.

    PubMed

    Novelli, Luca; Ruggiero, Roberto; De Giacomi, Federica; Biffi, Alice; Faverio, Paola; Bilucaglia, Luca; Gamberini, Silvia; Messinesi, Grazia; Pesci, Alberto

    2016-12-23

    Acute Exacerbation (AEx) is a frequent and severe complication of Idiopathic Pulmonary Fibrosis (IPF). In the absence of consensus regarding treatment, studies evaluating the efficacy of specific therapies, such as corticosteroids and immunosuppresant agents, are needed. In this case series we evaluated the outcome in terms of survival of intravenous pulse doses of high-dose corticosteroid (methylprednisolone 1000 mg per day for 3 consecutive days) followed by montlhy cyclophosphamide administration (maximum 6 doses) in a cohort of patients with AEx-IPF referred to the Respiratory Unit, San Gerardo University Hospital, Monza, Italy, from 2009 to 2013. A total of 11 patients (7 males, median age 65 years) were enrolled. A median of five monthly pulse doses of cyclophosphamide were administered, with four patients receiving all 6 doses. Four patients died before completion. Three patients developed adverse events. Overall survival at 3 months was 73%, at 6 months 63%, at 12 months 55%, at 18 months 45% and at 2 years 27%. In-hospital mortality was 9%. Causes of death were: six respiratory failures from disease progression, one lung cancer and one breast cancer. Two patients received lung transplantation and were excluded from the Kaplan-Meier analysis. In conclusion, combined intravenous pulse doses of high-dose corticosteroid and cyclophosphamide could be a reasonable add-on therapy for AEx-IPF, considering the few side effects and safe profile. A complete and rapid diagnostic work-up associated to the proper management (e.g. support of respiratory failure with non-invasive ventilation) in the right setting, may also have a positive effect on patients' outcome.

  12. Lung dust content in idiopathic pulmonary fibrosis: a study with scanning electron microscopy and energy dispersive x ray analysis.

    PubMed Central

    Monsó, E; Tura, J M; Pujadas, J; Morell, F; Ruiz, J; Morera, J

    1991-01-01

    Examination with an optical microscope and polarised light is not sensitive enough to detect low diameter asbestos fibres. This limitation implies that some cases of asbestosis can be erroneously diagnosed as idiopathic pulmonary fibrosis (IPF) if asbestos bodies are not found in the standard examination of abnormal tissue. To determine whether IPF is over-diagnosed, a study was carried out with scanning electron microscopy (SEM) and energy dispersive x ray analysis (EDXA) on 25 samples previously diagnosed as IPF at the standard examination. Scanning electron microscopy will show the presence of low diameter fibres in the lung without tissue destruction, and these fibres can be identified using EDXA. The quantitative and qualitative results for lung tissue from patients diagnosed as having IPF were compared with the results of the examination of 25 samples of normal lung. Most of the samples from patients diagnosed as having IPF showed only occasional inorganic particles (less than 10 particles/SEM field at 160 x), results equivalent to the results obtained in normal lung. Two cases of IPF, however, showed innumerable asbestos fibres (greater than 100 fibres/SEM field). One of these two patients had an antecedent of brief exposure to asbestos. No environmental antecedent was found in the second patient. Asbestosis was the final diagnosis for these two patients. The examination of inorganic particles in normal lungs showed mainly non-fibrous silicates (61.4%) and particles of heavy elements (34.9%). Only one asbestos fibre was found (0.9%). It is concluded that standard pathological techniques overdiagnose IPF in a few cases in which asbestos bodies are not found with the optical microscope. Images PMID:2039745

  13. Recommendations for the management of idiopathic pulmonary fibrosis in South Africa: a position statement of the South African Thoracic Society

    PubMed Central

    Ainslie, Gillian M.; Dheda, Keertan; Allwood, Brian W.; Wong, Michelle L.; Lalloo, Umesh G.; Abdool-Gaffar, Mohamed S.; Khalfey, Hoosain; Irusen, Elvis M.

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a very specific form of a chronic, progressive fibroproliferative interstitial pneumonia of unknown aetiology. The disease is generally associated with a poor prognosis. Several international evidence-based guidelines on the diagnosis and management of IPF and other interstitial lung diseases (ILDs) have been published and updated in the last decade, and while the body of evidence for the use of some treatment modalities has grown, others have been shown to be futile and even harmful to patients. In a patient who presents with the classic clinical features, restrictive ventilatory impairment with impaired diffusion and a high resolution computed tomography (HRCT) scan of the lungs showing a usual interstitial pneumonia (UIP) pattern, a definitive diagnosis of IPF can be made, provided all other causes of a radiological UIP pattern are excluded. Patients who present with atypical clinical features or an HRCT pattern classified as “possible” UIP, should be referred for a surgical lung biopsy. Once the diagnosis of IPF is confirmed, a patient-centred approached should be followed, as the stage of the disease, degree of impairment, rate of disease progression, comorbid illnesses and patient preferences all impact on long-term management. The South African Thoracic Society (SATS) suggests that anti-fibrotic treatment should be offered to appropriate candidates [confirmed IPF with a forced vital capacity (FVC) of 50–80%], but discontinued should there be evidence of disease progression (a decline in FVC of ≥10% within any 12-month period). The routine use of high dose oral steroids, immunosuppressive drugs and anticoagulants is not recommended whilst anti-acid therapy may be considered in patients without advanced disease. PMID:28149568

  14. 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.

  15. Body mass index—percent forced vital capacity—respiratory hospitalization: new staging for idiopathic pulmonary fibrosis patients

    PubMed Central

    Nagano, Hiroaki; Nei, Yuichiro; Yamashiro, Shin

    2016-01-01

    Background Idiopathic pulmonary fibrosis (IPF) is relentless progressive interstitial lung disease. Evaluating predictor of mortality for IPF patients is crucial. The aim of this study was to evaluate the serial trend of important indicators of prognosis and create a useful staging method for IPF patients. Methods We retrospectively searched medical records, pulmonary function tests (PFTs), and chest high resolution computed tomography (HRCT) scans from January 1, 2008 through June 30, 2015 at our hospital. We also evaluated the same parameters 1-year later. Results We identified 65 IPF patients. The mean age was 71.9±1.8 years (range, 22–85 years). In terms of PFTs, mean percent predicted forced vital capacity (%FVC) was 69.8±2.7. Baseline mean body mass index (BMI) was 24.3±0.6 kg/mm2. Mean survival was 39.2 months (range, 0.9–158.9 months). Cox proportional hazard ratios (HRs) showed the following to be predictors of mortality in IPF patients: 1-year BMI (HR: 0.899; 95% CI: 0.825–0.979; P=0.021); 1-year %FVC (HR: 0.932; 95% CI: 0.887–0.979; P=0.005) and 1-year respiratory hospitalization (HR: 3.307; 95% CI: 2.149–5.090; P<0.001). On the basis of these date, we created a new staging method for predicting mortality for IPF patients, consisting of delta BMI, delta %FVC and respiratory hospitalization within a year following diagnosis of IPF (BFR staging). We stratified patients into one of three groups according to the composite points. Mean survival of stages 1, 2, and 3 was 77.9 (30.8–158.9), 43.9 (0.9–145.2) and 14.8 (3.5–32) months (P<0.001), respectively. Conclusions In our cohort of IPF patients, this new staging method, including delta BMI and delta %FVC and respiratory hospitalization within 1-year showed a clear survival difference. PMID:28149554

  16. Guidelines for the diagnosis and treatment of idiopathic pulmonary fibrosis. Sociedad Española de Neumología y Cirugía Torácica (SEPAR) Research Group on Diffuse Pulmonary Diseases.

    PubMed

    Xaubet, Antoni; Ancochea, Julio; Bollo, Elena; Fernández-Fabrellas, Estrella; Franquet, Tomás; Molina-Molina, Maria; Montero, Maria Angeles; Serrano-Mollar, Anna

    2013-08-01

    Idiopathic pulmonary fibrosis is defined as a chronic fibrosing interstitial pneumonia limited to the lung, of unknown cause, with poor prognosis and few treatment options. In recent years there has been an increase in their prevalence, probably due to the optimization of diagnostic methods and increased life expectancy. The ATS/ERS Consensus (2000) established the diagnostic criteria and recommendations for the assessment of the disease course and treatment. Later studies have helped to redefine diagnostic criteria and treatment options. In 2011, an international consensus was published, establishing diagnostic criteria and new treatment strategies. These guidelines have been updated with the newest aspects of diagnosis and treatment of idiopathic pulmonary fibrosis. A level of evidence has been identified for the most relevant questions, particularly with regard to treatment options.

  17. Consensus document for the diagnosis and treatment of idiopathic pulmonary fibrosis: Joint Consensus of Sociedade Portuguesa de Pneumologia, Sociedade Portuguesa de Radiologia e Medicina Nuclear e Sociedade Portuguesa de Anatomia Patológica.

    PubMed

    Robalo Cordeiro, C; Campos, P; Carvalho, L; Campainha, S; Clemente, S; Figueiredo, L; Jesus, J M; Marques, A; Souto-Moura, C; Pinto Basto, R; Ribeiro, A; Serrado, M; Morais, A

    2016-01-01

    Idiopathic pulmonary fibrosis is a rare interstitial lung disease included in the Idiopathic Interstitial Pneumonias group. Although several potential risk factors have been described, it is a progressive fibrosing disease of unknown cause affecting mainly adults over 50 years and associated with a poor prognosis, reflected in a median survival of 2-3 years after diagnosis. The concept of a multidisciplinary working group for the diagnosis of idiopathic pulmonary fibrosis is based on the need to have experienced pulmonologists, radiologists and pathologists in the evaluation and correct treatment of the disease, and requires the use of all available data about individual patients, standardized (largely through High Resolution Computed Tomography and pathology when needed) as well as non-standardized data (laboratory, serology and biomarkers). This approach helps to increase diagnostic accuracy and is an internationally accepted recommendation. In regard to therapy, the situation has changed radically since the publication of the ATS/ERS/JRS/ALAT 2011 guidelines on the diagnosis and management of idiopathic pulmonary fibrosis where it was stressed that no proven therapy exists for this disease. Currently besides non-pharmacological treatment, therapy of complications and comorbidities and palliative care, nintedanib and pirfenidone, two compounds with pleiotropic mechanisms of action, are to date, the two drugs with confirmed efficacy in slowing functional decline and disease progression in idiopathic pulmonary fibrosis patients.

  18. Idiopathic pulmonary fibrosis

    MedlinePlus

    ... be asked whether you have been exposed to asbestos or other toxins and if you have been ... include the following: Bronchoscopy Chest CT scan Chest x-ray Echocardiogram Measurements of blood oxygen level (arterial blood ...

  19. Pulmonary Rehabilitation

    MedlinePlus

    ... Topics Bronchitis COPD Cystic Fibrosis Idiopathic Pulmonary Fibrosis Sarcoidosis Send a link to NHLBI to someone by ... people who have COPD (chronic obstructive pulmonary disease), sarcoidosis (sar-koy-DOE-sis), idiopathic pulmonary fibrosis , or ...

  20. [Idiopathic pulmonary hemosiderosis with dendriform pulmonary ossification].

    PubMed

    Barrera, Ana Madeleine; Vargas, Leslie

    2016-12-01

    Pulmonary ossification is a rare and usually asymptomatic finding reported as incidental in lung biopsies. Similarly, idiopathic pulmonary hemosiderosis is a rare cause of pulmonary infiltrates. We report the case of a 64-year old man with chronic respiratory symptoms in whom these two histopathological findings converged.

  1. Molecular Endotyping of Pulmonary Fibrosis.

    PubMed

    Goodwin, Amanda T; Jenkins, Gisli

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a devastating and incurable progressive fibrotic lung condition associated with a significant disease burden. In recent years there has been an exponential increase in the number of preclinical and clinical studies performed in IPF. IPF is defined according to rigid diagnostic criteria; hence, a significant subset of patients with unclassifiable disease has been excluded from these studies. The traditional diagnostic classification of all progressive fibrotic lung diseases uses specific clinical, radiological, and histopathological features to define each condition. However, the considerable heterogeneity within each form of pulmonary fibrosis has raised the possibility of distinct pathophysiological mechanisms culminating in a common phenotype. Thus, the classification of fibrotic lung diseases according to the driving molecular mechanisms rather than specific user-defined histopathological and radiological features could improve several aspects of clinical care. Discoveries from basic science research have defined multiple complex molecular pathways involved in the pathogenesis of pulmonary fibrosis that may provide markers for the molecular endotyping of this disease. In addition, these molecular pathways have revealed potential therapeutic targets. Reclassifying progressive fibrotic lung diseases according to molecular endotypes may allow for more accurate assessment of prognosis and individualized treatment. Furthermore, recent developments that have been applied to a narrow group of patients with IPF may be applicable to those with other progressive fibrotic lung diseases. This review presents the latest developments from translational research in this area and explains how molecular endotyping could revolutionize the diagnosis, stratification, and treatment of pulmonary fibrosis.

  2. Diagnosis: to biopsy or not to biopsy: assessing the role of surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis.

    PubMed

    Fishbein, Michael C

    2005-11-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic disorder that is associated with a poorer prognosis than subacute idiopathic interstitial pneumonias (IIPs). IPF can be differentiated from other IIPs on the basis of its histologic pattern of usual interstitial pneumonia (UIP). Although a surgical lung biopsy specimen showing a UIP pattern is required for the definitive diagnosis of IPF, clinical criteria can be used in the absence of a lung biopsy specimen to make a likely diagnosis of IPF. The predictive value of these criteria largely depends on the expertise of the clinician and radiologist, but considerable interobserver variability exists even when evaluations are performed by experts in the field. Moreover, these criteria lead to misdiagnosis in about 25 to 35% of cases. Interobserver variability is reduced and diagnostic accuracy is improved in cases in which a diagnosis is made with a high degree of confidence. Diagnostic accuracy is also higher when the diagnosis is made by a core group of experts rather than by a referring center. The decision on whether or not to perform a surgical lung biopsy is difficult. It is clearly indicated in cases in which clinical or radiologic findings are atypical or when the diagnosis is made with a low degree of certainty.

  3. 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

  4. Plasma Vascular Endothelial Growth Factor Concentration and Alveolar Nitric Oxide as Potential Predictors of Disease Progression and Mortality in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Kotecha, Jalpa; Shulgina, Ludmila; Sexton, Darren W.; Atkins, Christopher P.; Wilson, Andrew M.

    2016-01-01

    Background: Declining lung function signifies disease progression in idiopathic pulmonary fibrosis (IPF). Vascular endothelial growth factor (VEGF) concentration is associated with declining lung function in 6 and 12-month studies. Alveolar nitric oxide concentration (CANO) is increased in patients with IPF, however its significance is unclear. This study investigated whether baseline plasma VEGF concentration and CANO are associated with disease progression or mortality in IPF. Methods: 27 IPF patients were studied (maximum follow-up 65 months). Baseline plasma VEGF concentration, CANO and pulmonary function tests (PFTs) were measured. PFTs were performed the preceding year and subsequent PFTs and data regarding mortality were collected. Disease progression was defined as one of: death, relative decrease of ≥10% in baseline forced vital capacity (FVC) % predicted, or relative decrease of ≥15% in baseline single breath diffusion capacity of carbon monoxide (TLCO-SB) % predicted. Results: Plasma VEGF concentration was not associated with progression-free survival or mortality. There was a trend towards shorter time to disease progression and death with higher CANO. CANO was significantly higher in patients with previous declining versus stable lung function. Conclusion: The role of VEGF in IPF remains uncertain. It may be of value to further investigate CANO in IPF. PMID:27618114

  5. Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

    PubMed Central

    Saketkoo, Lesley Ann; Mittoo, Shikha; Huscher, Dörte; Khanna, Dinesh; Dellaripa, Paul F; Distler, Oliver; Flaherty, Kevin R; Frankel, Sid; Oddis, Chester V; Denton, Christopher P; Fischer, Aryeh; Kowal-Bielecka, Otylia M; LeSage, Daphne; Merkel, Peter A; Phillips, Kristine; Pittrow, David; Swigris, Jeffrey; Antoniou, Katerina; Baughman, Robert P; Castelino, Flavia V; Christmann, Romy B; Christopher-Stine, Lisa; Collard, Harold R; Cottin, Vincent; Danoff, Sonye; Highland, Kristin B; Hummers, Laura; Shah, Ami A; Kim, Dong Soon; Lynch, David A; Miller, Frederick W; Proudman, Susanna M; Richeldi, Luca; Ryu, Jay H; Sandorfi, Nora; Sarver, Catherine; Wells, Athol U; Strand, Vibeke; Matteson, Eric L; Brown, Kevin K; Seibold, James R

    2014-01-01

    Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field. PMID:24368713

  6. Lactic Acid is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation Via pH-Dependent Activation of Transforming Growth Factor-β

    SciTech Connect

    Kottman, R. M.; 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.; Sime, Patricia J.

    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 were 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.

  7. Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension

    PubMed Central

    Carrick, Ryan P.; McConaha, Melinda E.; Jones, Brittany R.; Shay, Sheila D.; Moore, Christy S.; Blackwell, Thomas R.; Gladson, Santhi; Penner, Niki L.; Burman, Ankita; Tanjore, Harikrishna; Hemnes, Anna R.; Karwandyar, Ayub K.; Polosukhin, Vasiliy V.; Talati, Megha A.; Dong, Hui-Jia; Gleaves, Linda A.; Carrier, Erica J.; Gaskill, Christa; Scott, Edward W.; Majka, Susan M.; Fessel, Joshua P.; West, James D.; Blackwell, Timothy S.; Lawson, William E.

    2015-01-01

    Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions. PMID:26637636

  8. Who Needs Pulmonary Rehabilitation?

    MedlinePlus

    ... Topics Bronchitis COPD Cystic Fibrosis Idiopathic Pulmonary Fibrosis Sarcoidosis Send a link to NHLBI to someone by ... other symptoms. Examples of interstitial lung diseases include sarcoidosis and idiopathic pulmonary fibrosis . Cystic fibrosis (CF). CF ...

  9. Pulmonary fibrosis: pathogenesis, etiology and regulation

    PubMed Central

    Wilson, MS; Wynn, TA

    2009-01-01

    Pulmonary fibrosis and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary fibrotic diseases is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, idiopathic pulmonary fibrosis (IPF), is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following lung injury, and highlights the pathogenesis of some of the most widespread pulmonary fibrotic diseases. A three phase model of wound repair is reviewed that includes; (1) injury; (2) inflammation; and (3) repair. In most pulmonary fibrotic conditions dysregulation at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFβ1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis. PMID:19129758

  10. Advanced glycation end-products and receptor for advanced glycation end-products expression in patients with idiopathic pulmonary fibrosis and NSIP.

    PubMed

    Kyung, Sun Young; Byun, Kyung Hee; Yoon, Jin Young; Kim, Yu Jin; Lee, Sang Pyo; Park, Jeong-Woong; Lee, Bong Hee; Park, Jong Sook; Jang, An Soo; Park, Choon Sik; Jeong, Sung Hwan

    2014-01-01

    Advanced glycation end products (AGEs) are associated with the pathogenesis of various diseases. AGEs induce excess accumulation of extracellular matrix and expression of profibrotic cytokines. In addition, studies on receptor for advanced glycation end products (RAGE) have shown that the ligand-RAGE interaction activates several intracellular signaling cascades associated with several fibrotic diseases. We investigated the expression of AGEs and RAGE in samples from patients with idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP). Lung tissues and plasma samples from patients with IPF (n=10), NSIP (n=10), and control subjects (n=10) were obtained. Expression of AGEs and RAGE was determined by immunofluorescence assay of lung tissue. Circulating AGEs were measured by Western blot and enzyme-linked immunosorbent assay. Lungs with IPF showed strong expression for both AGEs and RAGE compared to that in NSIP and controls. However, no difference in AGE or RAGE expression was observed in lungs with NSIP compared to that in the controls. Levels of circulating AGEs also increased significantly in lungs of patients with IPF compared to those with NSIP and normal control. Increased AGE-RAGE interaction may play an important role in the pathogenesis of IPF.

  11. Preoperative physiotherapy in subjects with idiopathic pulmonary fibrosis qualified for lung transplantation: implications on hospital length of stay and clinical outcomes

    PubMed Central

    Polastri, Massimiliano; Zagnoni, Giulia; Nava, Stefano

    2016-01-01

    Background Lung transplantation (LTx) candidates with chronic disease are more prone to exercise limitations. Preoperative physiotherapy (PP) can improve exercise tolerance, which in some patients, is severely impaired, often leaving them housebound. The aim of this study was to answer this question: In patients with idiopathic pulmonary fibrosis (IPF) qualifying for LTx, is PP effective in improving postoperative outcomes and reducing length of stay (LOS) after transplantation? Methods Six major databases were searched up to December 2015. We did not apply limits to publication date, date, gender, or language. Citations were accepted if they discussed preoperative physiotherapeutic treatment in patients with IPF waiting for LTx. Results After the full texts were read, three papers met the inclusion criteria and were included. All of these papers had an observational design. In total, 55 subjects with IPF and awaiting LTx were observed. Conclusions The effectiveness of PP in improving postoperative outcomes and reducing LOS following LTx remains unclear, although it appears to benefit IPF patients who qualify for LTx by improving their health status, physical activity levels, and respiratory-related symptoms. PMID:27162679

  12. Advanced glycation end-products and receptor for advanced glycation end-products expression in patients with idiopathic pulmonary fibrosis and NSIP

    PubMed Central

    Kyung, Sun Young; Byun, Kyung Hee; Yoon, Jin Young; Kim, Yu Jin; Lee, Sang Pyo; Park, Jeong-Woong; Lee, Bong Hee; Park, Jong Sook; Jang, An Soo; Park, Choon Sik; Jeong, Sung Hwan

    2014-01-01

    Advanced glycation end products (AGEs) are associated with the pathogenesis of various diseases. AGEs induce excess accumulation of extracellular matrix and expression of profibrotic cytokines. In addition, studies on receptor for advanced glycation end products (RAGE) have shown that the ligand-RAGE interaction activates several intracellular signaling cascades associated with several fibrotic diseases. We investigated the expression of AGEs and RAGE in samples from patients with idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP). Lung tissues and plasma samples from patients with IPF (n=10), NSIP (n=10), and control subjects (n=10) were obtained. Expression of AGEs and RAGE was determined by immunofluorescence assay of lung tissue. Circulating AGEs were measured by Western blot and enzyme-linked immunosorbent assay. Lungs with IPF showed strong expression for both AGEs and RAGE compared to that in NSIP and controls. However, no difference in AGE or RAGE expression was observed in lungs with NSIP compared to that in the controls. Levels of circulating AGEs also increased significantly in lungs of patients with IPF compared to those with NSIP and normal control. Increased AGE-RAGE interaction may play an important role in the pathogenesis of IPF. PMID:24427342

  13. Comparative Study of Circulating MMP-7, CCL18, KL-6, SP-A, and SP-D as Disease Markers of Idiopathic Pulmonary Fibrosis

    PubMed Central

    Hamai, Kosuke; Iwamoto, Hiroshi; Ishikawa, Nobuhisa; Horimasu, Yasushi; Masuda, Takeshi; Miyamoto, Shintaro; Nakashima, Taku; Ohshimo, Shinichiro; Fujitaka, Kazunori; Hamada, Hironobu; Hattori, Noboru; Kohno, Nobuoki

    2016-01-01

    Background. Recent reports indicate that matrix metalloproteinase-7 (MMP-7) and CC-chemokine ligand 18 (CCL18) are potential disease markers of idiopathic pulmonary fibrosis (IPF). The objective of this study was to perform direct comparisons of these two biomarkers with three well-investigated serum markers of IPF, Krebs von den Lungen-6 (KL-6), surfactant protein-A (SP-A), and SP-D. Methods. The serum levels of MMP-7, CCL18, KL-6, SP-A, and SP-D were evaluated in 65 patients with IPF, 31 patients with bacterial pneumonia, and 101 healthy controls. The prognostic performance of these five biomarkers was evaluated in patients with IPF. Results. The serum levels of MMP-7, KL-6, and SP-D in patients with IPF were significantly elevated compared to those in patients with bacterial pneumonia and in the healthy controls. Multivariate survival analysis showed that serum MMP-7 and KL-6 levels were independent predictors in IPF patients. Moreover, elevated levels of both KL-6 and MMP-7 were associated with poorer survival rates in IPF patients, and the combination of both markers provided the best risk discrimination using the C statistic. Conclusions. The present results indicated that MMP-7 and KL-6 were promising prognostic markers of IPF, and the combination of the two markers might improve survival prediction in patients with IPF. PMID:27293304

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

    PubMed Central

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

    2016-01-01

    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. PMID:27983601

  15. miR-30a as Potential Therapeutics by Targeting TET1 through Regulation of Drp-1 Promoter Hydroxymethylation in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Zhang, Songzi; Liu, Huizhu; Liu, Yuxia; Zhang, Jie; Li, Hongbo; Liu, Weili; Cao, Guohong; Xv, Pan; Zhang, Jinjin; Lv, Changjun; Song, Xiaodong

    2017-01-01

    Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in idiopathic pulmonary fibrosis (IPF) regulation is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 is yet to be investigated. Additionally, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual-luciferase reporter assay system were used to identify the target gene of miR-30a, and cell transfection was utilized to confirm this relationship. Ten–eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and miR-30a mimic and inhibitor transfection significantly reduced and increased the TET1 protein expression, respectively. Further experimentation verified that the TET1 siRNA interference could inhibit Drp-1 promoter hydroxymethylation. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit TET1 expression through base pairing with complementary sites in the 3′untranslated region to regulate Drp-1 promoter hydroxymethylation. Furthermore, miR-30a could act as a potential therapeutic target for IPF. PMID:28294974

  16. miR-30a as Potential Therapeutics by Targeting TET1 through Regulation of Drp-1 Promoter Hydroxymethylation in Idiopathic Pulmonary Fibrosis.

    PubMed

    Zhang, Songzi; Liu, Huizhu; Liu, Yuxia; Zhang, Jie; Li, Hongbo; Liu, Weili; Cao, Guohong; Xv, Pan; Zhang, Jinjin; Lv, Changjun; Song, Xiaodong

    2017-03-15

    Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in idiopathic pulmonary fibrosis (IPF) regulation is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 is yet to be investigated. Additionally, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual-luciferase reporter assay system were used to identify the target gene of miR-30a, and cell transfection was utilized to confirm this relationship. Ten-eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and miR-30a mimic and inhibitor transfection significantly reduced and increased the TET1 protein expression, respectively. Further experimentation verified that the TET1 siRNA interference could inhibit Drp-1 promoter hydroxymethylation. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit TET1 expression through base pairing with complementary sites in the 3'untranslated region to regulate Drp-1 promoter hydroxymethylation. Furthermore, miR-30a could act as a potential therapeutic target for IPF.

  17. 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.

  18. 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

  19. 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

  20. Lung Fibroblasts from Patients with Idiopathic Pulmonary Fibrosis Exhibit Genome-Wide Differences in DNA Methylation Compared to Fibroblasts from Nonfibrotic Lung

    PubMed Central

    Huang, Steven K.; Scruggs, Anne M.; McEachin, Richard C.; White, Eric S.; Peters-Golden, Marc

    2014-01-01

    Excessive fibroproliferation is a central hallmark of idiopathic pulmonary fibrosis (IPF), a chronic, progressive disorder that results in impaired gas exchange and respiratory failure. Fibroblasts are the key effector cells in IPF, and aberrant expression of multiple genes contributes to their excessive fibroproliferative phenotype. DNA methylation changes are critical to the development of many diseases, but the DNA methylome of IPF fibroblasts has never been characterized. Here, we utilized the HumanMethylation 27 array, which assays the DNA methylation level of 27,568 CpG sites across the genome, to compare the DNA methylation patterns of IPF fibroblasts (n = 6) with those of nonfibrotic patient controls (n = 3) and commercially available normal lung fibroblast cell lines (n = 3). We found that multiple CpG sites across the genome are differentially methylated (as defined by P value less than 0.05 and fold change greater than 2) in IPF fibroblasts compared to fibroblasts from nonfibrotic controls. These methylation differences occurred both in genes recognized to be important in fibroproliferation and extracellular matrix generation, as well as in genes not previously recognized to participate in those processes (including organ morphogenesis and potassium ion channels). We used bisulfite sequencing to independently verify DNA methylation differences in 3 genes (CDKN2B, CARD10, and MGMT); these methylation changes corresponded with differences in gene expression at the mRNA and protein level. These differences in DNA methylation were stable throughout multiple cell passages. DNA methylation differences may thus help to explain a proportion of the differences in gene expression previously observed in studies of IPF fibroblasts. Moreover, significant variability in DNA methylation was observed among individual IPF cell lines, suggesting that differences in DNA methylation may contribute to fibroblast heterogeneity among patients with IPF. These

  1. 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.

  2. Survival from an Acute Exacerbation of Idiopathic Pulmonary Fibrosis with or without Direct Hemoperfusion with a Polymyxin B-immobilized Fiber Column: A Retrospective Analysis

    PubMed Central

    Oishi, Keiji; Aoe, Keisuke; Mimura, Yusuke; Murata, Yoriyuki; Sakamoto, Kenji; Koutoku, Wataru; Matsumoto, Tsuneo; Ueoka, Hiroshi; Yano, Masafumi

    2016-01-01

    Objective Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are fatal episodes of acute respiratory worsening of unknown etiology. Previous studies on acute respiratory distress syndrome have shown that direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) can have a beneficial effect on the respiratory status. This retrospective study investigated the prognosis and survival outcome of patients with AE-IPF who underwent PMX-DHP. Methods We examined the records of 50 patients with AE-IPF treated in our hospital. All patients received corticosteroid pulse therapy. We compared the disease outcome between 27 patients who underwent PMX-DHP (PMX group) and 23 patients who did not (non-PMX group). The independent predictors of survival were determined using Cox proportional hazards analyses. Results A multivariate analysis of all patients revealed that PMX-DHP therapy was a significant predictor of survival (HR=0.442, 95% CI 0.223-0.873; p=0.019). The 12-month survival rate was significantly higher in the PMX group than in the non-PMX group (41.7% vs. 9.8%; p=0.040). According to a subanalysis of the PMX group, the time from AE-IPF onset to PMX-DHP was a significant predictor of survival (HR=1.080, 95% CI 1.001-1.166; p=0.049). Conclusion PMX-DHP improved the prognosis of AE-IPF. The time from AE-IPF onset to PMX-DHP may therefore be informative for predicting the patient outcome. PMID:27980253

  3. Tissue remodelling in pulmonary fibrosis.

    PubMed

    Knudsen, Lars; Ruppert, Clemens; Ochs, Matthias

    2017-03-01

    Many lung diseases result in fibrotic remodelling. Fibrotic lung disorders can be divided into diseases with known and unknown aetiology. Among those with unknown aetiology, idiopathic pulmonary fibrosis (IPF) is a common diagnosis. Because of its progressive character leading to a rapid decline in lung function, it is a fatal disease with poor prognosis and limited therapeutic options. Thus, IPF has motivated many studies in the last few decades in order to increase our mechanistic understanding of the pathogenesis of the disease. The current concept suggests an ongoing injury of the alveolar epithelium, an impaired regeneration capacity, alveolar collapse and, finally, a fibroproliferative response. The origin of lung injury remains elusive but a diversity of factors, which will be discussed in this article, has been shown to be associated with IPF. Alveolar epithelial type II (AE2) cells play a key role in lung fibrosis and their crucial role for epithelial regeneration, stabilisation of alveoli and interaction with fibroblasts, all known to be responsible for collagen deposition, will be illustrated. Whereas mechanisms of collagen deposition and fibroproliferation are the focus of many studies in the field, the awareness of other mechanisms in this disease is currently limited to biochemical and imaging studies including quantitative assessments of lung structure in IPF and animal models assigning alveolar collapse and collapse induration crucial roles for the degradation of the lung resulting in de-aeration and loss of surface area. Dysfunctional AE2 cells, instable alveoli and mechanical stress trigger remodelling that consists of collapsed alveoli absorbed by fibrotic tissue (i.e., collapse induration).

  4. Oxidative Stress and Pulmonary Fibrosis

    PubMed Central

    Cheresh, Paul; Kim, Seok-Jo; Tulasiram, Sandhya; Kamp, David W.

    2012-01-01

    Oxidative stress is implicated as an important molecular mechanism underlying fibrosis in a variety of organs, including the lungs. However, the causal role of reactive oxygen species (ROS) released from environmental exposures and inflammatory / interstitial cells in mediating fibrosis as well as how best to target an imbalance in ROS production in patients with fibrosis are not firmly established. We focus on the role of ROS in pulmonary fibrosis and, where possible, highlight overlapping molecular pathways in other organs. The key origins of oxidative stress in pulmonary fibrosis (e.g. environmental toxins, mitochondria / NADPH oxidase of inflammatory and lung target cells, and depletion of antioxidant defenses) are reviewed. The role of alveolar epithelial cell (AEC) apoptosis by mitochondria- and p53-regulated death pathways are examined. We emphasize an emerging role for the endoplasmic reticulum (ER) in pulmonary fibrosis. After briefly summarizing how ROS trigger a DNA damage response, we concentrate on recent studies implicating a role for mitochondrial DNA (mtDNA) damage and repair mechanisms focusing on 8-oxoguanine DNA glycosylase (Ogg1) as well as crosstalk between ROS production, mtDNA damage, p53, Ogg1, and mitochondrial aconitase (ACO2). Finally, the association between ROS and TGF-β1-induced fibrosis is discussed. Novel insights into the molecular basis of ROS-induced pulmonary diseases and, in particular, lung epithelial cell death may promote the development of unique therapeutic targets for managing pulmonary fibrosis as well as fibrosis in other organs and tumors, and in aging; diseases for which effective management is lacking. PMID:23219955

  5. [Hepatitis C virus and pulmonary fibrosis].

    PubMed

    Manganelli, Paolo; Salaffi, Fausto; Pesci, Alberto

    2002-05-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease characterized by an accumulation of alveolar macrophages and neutrophils in the lower respiratory tract, parenchymal injury, and interstitial fibrosis. Although the etiology of IPF is unknown, it has been suggested that viral agents, among which hepatitis C virus (HCV), may be involved in inducing the disease. In patients with chronic hepatitis HCV+ and in those with mixed cryoglobulinemia HCV-associated, HCV may trigger a subclinical lymphocyte alveolitis. Furthermore, pulmonary fibrosis associated with a variety of rheumatic disorders has been reported in 8/300 patients with active chronic hepatitis HCV+. Bronchoalveolar lavage, carried out in 4/8 patients, showed an increased percentage of neutrophils in all of them and a mild increase of lymphocytes in 2 patients. Thoracoscopic lung biopsy was carried out in 2 patients and showed a desquamative interstitial pneumonia; in one case HCV-RNA was found in the pulmonary parenchyma. Although the above observations seem indicate a role for HCV in IFP, further studies are required to define its true importance in the etiopathogenesis of the interstitial lung disease.

  6. Amine oxidase activity regulates the development of pulmonary fibrosis.

    PubMed

    Marttila-Ichihara, Fumiko; Elima, Kati; Auvinen, Kaisa; Veres, Tibor Z; Rantakari, Pia; Weston, Christopher; Miyasaka, Masayuki; Adams, David; Jalkanen, Sirpa; Salmi, Marko

    2017-03-01

    In pulmonary fibrosis, an inflammatory reaction and differentiation of myofibroblasts culminate in pathologic deposition of collagen. Amine oxidase copper containing-3 (AOC3) is a cell-surface expressed oxidase that regulates leukocyte extravasation. Here we analyzed the potential role of AOC3 using gene-modified and inhibitor-treated mice in a bleomycin-induced pulmonary fibrosis model. Inflammation and fibrosis of lungs were assessed by histologic, flow cytometric, and quantitative PCR analysis. AOC3-deficient mice showed a 30-50% reduction in fibrosis, collagen synthesis, numbers of myofibroblasts, and accumulation of CD4(+) lymphocytes, NK T cells, macrophages, and type 2 innate lymphoid cells compared with wild-type control mice. AOC3 knock-in mice, which express a catalytically inactive form of AOC3, were also protected from lung fibrosis. In wild-type mice, a small-molecule AOC3 inhibitor treatment reduced leukocyte infiltration, myofibroblast differentiation, and fibrotic injury both in prophylactic and early therapeutic settings by about 50% but was unable to reverse the established fibrosis. AOC3 was also induced in myofibroblasts in human idiopathic pulmonary fibrosis. Thus, the oxidase activity of AOC3 contributes to the development of lung fibrosis mainly by regulating the accumulation of pathogenic leukocyte subtypes, which drive the fibrotic response.-Marttila-Ichihara, F., Elima, K., Auvinen, K., Veres, T. Z., Rantakari, P., Weston, C., Miyasaka, M., Adams, D., Jalkanen, S., Salmi, M. Amine oxidase activity regulates the development of pulmonary fibrosis.

  7. Living with Idiopathic Pulmonary Fibrosis

    MedlinePlus

    ... this page with Gmail. Bookmark this page with Google. Share this page from the NHLBI on LinkedIn. ... NEXT >> Updated: September 20, 2011 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ...

  8. Pulmonary fibrosis is associated with an elevated risk of thromboembolic disease

    PubMed Central

    Sprunger, D.B.; Olson, A.L.; Huie, T.J.; Fernandez-Perez, E.R.; Fischer, A.; Solomon, J.J.; Brown, K.K.; Swigris, J.J.

    2013-01-01

    Recent epidemiological studies have suggested an increased risk of venous thromboembolism (VTE) in lung fibrosis. Large-scale epidemiological data regarding the risk of VTE in pulmonary fibrosis-associated mortality have not been published. Using data from the National Center for Health Statistics from 1988–2007, we determined the risk of VTE in decedents with pulmonary fibrosis in the USA. We analysed 46,450,489 records, of which 218,991 met our criteria for idiopathic pulmonary fibrosis. Among these, 3,815 (1.74%) records also contained a diagnostic code for VTE. The risk of VTE in pulmonary fibrosis decedents was 34% higher than in the background population, and 44% and 54% greater than among decedents with chronic obstructive pulmonary disease and lung cancer, respectively. Those with VTE and pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone (females: 74.3 versus 77.4 yrs (p<0.0001); males: 72.0 versus 74.4 yrs (p<0.0001)). Decedents with pulmonary fibrosis had a significantly greater risk of VTE. Those with VTE and pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone. These data suggest a link between a pro-fibrotic and a pro-coagulant state. PMID:21737559

  9. Lung tissues in systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension

    PubMed Central

    Hsu, Eileen; Shi, Haiwen; Jordan, Rick M.; Lyons-Weiler, James; Pilewski, Joseph M.; Feghali-Bostwick, Carol A.

    2010-01-01

    Objective Pulmonary complications in systemic sclerosis (SSc), including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality. We compared the molecular fingerprint of SSc lung tissues and matching primary lung fibroblasts to those of normal donors, and patients with idiopathic pulmonary fibrosis (IPF) and idiopathic pulmonary arterial hypertension (IPAH). Methods Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively. Results We identified a consensus of 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. Enriched function groups in SSc-PF and IPF lungs included fibrosis, insulin-like growth factor signaling and caveolin-mediated endocytosis. Functional groups shared by SSc-PAH and IPAH lungs included antigen presentation, chemokine activity, and IL-17 signaling. Conclusion Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts of patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease- (SSc) and phenotype- (PF vs PAH) specific. These signatures provide new insights into pathogenesis and potential therapeutic targets for SSc lung disease. PMID:21360508

  10. Expression and mechanism of BRP-39 in bleomycin-induced pulmonary fibrosis in rat.

    PubMed

    Du, Chunxian; Yang, Yibing; Lin, Yuhui; Yang, Jiong

    2014-09-01

    The purpose of the study was to explore the effects of breast regression protein 39 (BRP-39) in bleomycin-induced pulmonary fibrosis and its mechanism in pulmonary fibrosis by studying change in BRP-39 to provide a novel direction for the treatment of idiopathic pulmonary fibrosis. SPF grade male C57BL/6 rats were randomly divided into three groups, including bleomycin group, bleomycin+ BRP-39 recombinant protein group and control group. HE and Masson staining were applied to test the change in lung tissue after being treated by BRP-39, ELISA was applied to test the expression of TGF-β1 in different groups, and Western blot was used to test the expression of BRP-39 in rat lung tissue. Expression of BRP-39 increased, the fibrosis was obvious, and lung tissue collagen increased in bleomycin-induced pulmonary fibrosis in rat lung tissue. Increasing BRP-39 protein level and intratracheal bleomycin medication to establish pulmonary fibrosis model can aggravate pulmonary fibrosis. Along with the increase in BRP-39 protein level, TGF-β1 expression level also increased in lung tissue. Western blot results showed the expression of BRP-39, and TGF-β1 had the same trend in different groups. BRP-39 has effects in bleomycin-induced rat pulmonary fibrosis. Change in BRP-39 can affect the process of bleomycin-induced pulmonary fibrosis. The mechanism of BRP-3 in pulmonary fibrosis may work by regulating TGF-β1.

  11. Extracellular adenosine levels are associated with the progression and exacerbation of pulmonary fibrosis.

    PubMed

    Luo, Fayong; Le, Ngoc-Bao; Mills, Tingting; Chen, Ning-Yuan; Karmouty-Quintana, Harry; Molina, Jose G; Davies, Jonathan; Philip, Kemly; Volcik, Kelly A; Liu, Hong; Xia, Yang; Eltzschig, Holger K; Blackburn, Michael R

    2016-02-01

    Idiopathic pulmonary fibrosis is a devastating lung disease with limited treatment options. The signaling molecule adenosine is produced in response to injury and serves a protective role in early stages of injury and is detrimental during chronic stages of disease such as seen in lung conditions such as pulmonary fibrosis. Understanding the association of extracellular adenosine levels and the progression of pulmonary fibrosis is critical for designing adenosine based approaches to treat pulmonary fibrosis. The goal of this study was to use various models of experimental lung fibrosis to understand when adenosine levels are elevated during pulmonary fibrosis and whether these elevations were associated with disease progression and severity. To accomplish this, extracellular adenosine levels, defined as adenosine levels found in bronchioalveolar lavage fluid, were determined in mouse models of resolvable and progressive pulmonary fibrosis. We found that relative bronchioalveolar lavage fluid adenosine levels are progressively elevated in association with pulmonary fibrosis and that adenosine levels diminish in association with the resolution of lung fibrosis. In addition, treatment of these models with dipyridamole, an inhibitor of nucleoside transporters that potentiates extracellular adenosine levels, demonstrated that the resolution of lung fibrosis is blocked by the failure of adenosine levels to subside. Furthermore, exacerbating adenosine levels led to worse fibrosis in a progressive fibrosis model. Increased adenosine levels were associated with elevation of IL-6 and IL-17, which are important inflammatory cytokines in pulmonary fibrosis. These results demonstrate that extracellular adenosine levels are closely associated with the progression of experimental pulmonary fibrosis and that this signaling pathway may mediate fibrosis by regulating IL-6 and IL-17 production.

  12. Combined Pulmonary Fibrosis and Emphysema Syndrome

    PubMed Central

    Rounds, Sharon I. S.

    2012-01-01

    There is increasing clinical, radiologic, and pathologic recognition of the coexistence of emphysema and pulmonary fibrosis in the same patient, resulting in a clinical syndrome known as combined pulmonary fibrosis and emphysema (CPFE) that is characterized by dyspnea, upper-lobe emphysema, lower-lobe fibrosis, and abnormalities of gas exchange. This syndrome frequently is complicated by pulmonary hypertension, acute lung injury, and lung cancer. The CPFE syndrome typically occurs in male smokers, and the mortality associated with this condition, especially if pulmonary hypertension is present, is significant. In this review, we explore the current state of the literature and discuss etiologic factors and clinical characteristics of the CPFE syndrome. PMID:22215830

  13. Cadherin-11 Regulation of Fibrosis through Modulation of Epithelial-to-Mesenchymal Transition: Implications for Pulmonary Fibrosis in Scleroderma

    DTIC Science & Technology

    2015-10-01

    SUPPLEMENTARY NOTES 14. ABSTRACT Systemic sclerosis is a potentially devastating multisystem disorder characterized inflammation and autoimmunity...expression is increased in fibrotic tissues from lungs of patients with idiopathic pulmonary fibrosis and skin of patients with systemic sclerosis...mouse (red) Cad-11 Figure 3. Serum cadherin-11 levels are increased in certain autoantibody subsets of systemic sclerosis using a commercial

  14. Emodin alleviates bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Guan, Ruijuan; Zhao, Xiaomei; Wang, Xia; Song, Nana; Guo, Yuhong; Yan, Xianxia; Jiang, Liping; Cheng, Wenjing; Shen, Linlin

    2016-11-16

    Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with few treatment options and poor prognosis. Emodin, extracted from Chinese rhubarb, was found to be able to alleviate bleomycin (BLM)-induced pulmonary fibrosis, yet the underlying mechanism remains largely unknown. This study aimed to further investigate the effects of emodin on the inflammation and fibrosis of BLM-induced pulmonary fibrosis and the mechanism involved in rats. Our results showed that emodin improved pulmonary function, reduced weight loss and prevented death in BLM-treated rats. Emodin significantly relieved lung edema and fibrotic changes, decreased collagen deposition, and suppressed the infiltration of myofibroblasts [characterized by expression of α-smooth muscle actin (α-SMA)] and inflammatory cells (mainly macrophages and lymphocytes). Moreover, emodin reduced levels of TNF-α, IL-6, TGF-β1 and heat shock protein (HSP)-47 in the lungs of BLM-treated rats. In vitro, emodin profoundly inhibited TGF-β1-induced α-SMA, collagen IV and fibronectin expression in human embryo lung fibroblasts (HELFs). Emodin also inhibited TGF-β1-induced Smad2/3 and STAT3 activation, indicating that Smad2/3 and STAT3 inactivation mediates emodin-induced effects on TGF-β1-induced myofibroblast differentiation. These results suggest that emodin can exert its anti-fibrotic effect via suppression of TGF-β1 signaling and subsequently inhibition of inflammation, HSP-47 expression, myofibroblast differentiation and extracellular matrix (ECM) deposition.

  15. Tissue inhibitor of metalloproteinase-3 is up-regulated by transforming growth factor-beta1 in vitro and expressed in fibroblastic foci in vivo in idiopathic pulmonary fibrosis.

    PubMed

    García-Alvarez, Jorge; Ramirez, Remedios; Checa, Marco; Nuttall, Robert K; Sampieri, Clara L; Edwards, Dylan R; Selman, Moisés; Pardo, Annie

    2006-05-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by fibroblast expansion and extracellular matrix accumulation. However, the mechanisms involved in matrix remodeling have not been elucidated. In this study, the authors aimed to evaluate the expression of the tissue inhibitors of matrix metalloproteinases (TIMPs) in human fibroblasts and whole tissues from IPF and normal lungs. They also determined the role of mitogen-activated protein kinase (MAPK) in TIMP3 expression. TIMP1, TIMP2, and TIMP3 were highly expressed in lung fibroblasts. Transforming growth factor (TGF)-beta1, a profibrotic mediator, induced strong up-regulation of TIMP3 at the mRNA and protein levels. The authors examined whether the MAPK pathway was involved in TGF-beta1-induced TIMP3 expression. TGF-beta1 induced the phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2. Biochemical blockade of p38 by SB203580, but not of the ERK MAPK pathway, inhibited the effect of this factor. The effect was also blocked by the tyrosine kinase inhibitor genistein and by antagonizing TGF-beta1 receptor type I (activin-linked kinase [ALK5]). In IPF tissues TIMP3 gene expression was significantly increased and the protein was localized to fibroblastic foci and extracellular matrix. Our findings suggest that TGF-beta1-induced TIMP3 may be an important mediator in lung fibrogenesis.

  16. Yin Yang 1 Is a Novel Regulator of Pulmonary Fibrosis

    PubMed Central

    Lin, Xin; Sime, Patricia J.; Xu, Haodong; Williams, Marc A.; LaRussa, Larry; Georas, Steve N.; Guo, Jia

    2011-01-01

    Rationale: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known. Objectives: To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis. Methods: Lung fibroblasts were cultured with transforming growth factor (TGF)-β or tumor necrosis factor-α. Nuclear factor (NF)-κB, YY1, and α-smooth muscle actin (SMA) were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1f/f conditional knockout mouse after being exposed to silica or bleomycin. Measurements and Main Results: TGF-β and tumor necrosis factor-α up-regulated YY1 expression in lung fibroblasts. TGF-β–induced YY1 expression was dramatically decreased by an inhibitor of NF-κB, which blocked I-κB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate α-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1+/−) mice were significantly protected from lung fibrosis, which was associated with attenuated α-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1f/f mice reduced lung fibrosis. Conclusions: YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-κB–dependent manner, and YY1 regulates fibrogenesis at least in part by increasing α-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis. PMID:21169469

  17. Therapeutic Targeting of CC Ligand 21 or CC Chemokine Receptor 7 Abrogates Pulmonary Fibrosis Induced by the Adoptive Transfer of Human Pulmonary Fibroblasts to Immunodeficient Mice

    PubMed Central

    Pierce, Elizabeth M.; Carpenter, Kristin; Jakubzick, Claudia; Kunkel, Steven L.; Flaherty, Kevin R.; Martinez, Fernando J.; Hogaboam, Cory M.

    2007-01-01

    Idiopathic interstitial pneumonias (IIPs) are a collection of pulmonary fibrotic diseases of unknown etiopathogenesis. CC chemokine receptor 7 (CCR7) is expressed in IIP biopsies and primary fibroblast lines, but its role in pulmonary fibrosis was not previously examined. To study the in vivo role of CCR7 in a novel model of pulmonary fibrosis, 1.0 × 106 primary fibroblasts grown from idiopathic pulmonary fibrosis/usual interstitial pneumonia, nonspecific interstitial pneumonia, or histologically normal biopsies were injected intravenously into C.B-17 severe combined immunodeficiency (SCID)/beige (bg) mice. At days 35 and 63 after idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblast injection, patchy interstitial fibrosis and increased hydroxyproline were present in the lungs of immunodeficient mice. Adoptively transferred nonspecific interstitial pneumonia fibroblasts caused a more diffuse interstitial fibrosis and increased hydroxyproline levels at both times, but injected normal human fibroblasts did not induce interstitial remodeling changes in C.B-17SCID/bg mice. Systemic therapeutic immunoneutralization of either human CCR7 or CC ligand 21, its ligand, significantly attenuated the pulmonary fibrosis in groups of C.B-17SCID/bg mice that received either type of IIP fibroblasts. Thus, the present study demonstrates that pulmonary fibrosis is initiated by the intravenous introduction of primary human fibroblast lines into immunodeficient mice, and this fibrotic response is dependent on the interaction between CC ligand 21 and CCR7. PMID:17392156

  18. Erdosteine prevents bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Sogut, Sadik; Ozyurt, Huseyin; Armutcu, Ferah; Kart, Levent; Iraz, Mustafa; Akyol, Omer; Ozen, Suleyman; Kaplan, Suleyman; Temel, Ismail; Yildirim, Zeki

    2004-06-28

    Oxidative stress plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. Therefore, erdosteine, an antioxidant, is expected to have an inhibitor potential against the disease. Rats were given one dose of bleomycin in pulmonary fibrosis groups and saline in controls. The first dose of oral erdosteine (10 mg/kg/day) was given 2 days before the bleomycin injection to achieve the plateau level in blood and continued until killing. At day 14, fibrotic changes were evaluated, using Aschoft's criteria and lung hydroxyproline content. Bleomycin produced a fivefold increase in fibrosis score that was decreased by 87% by erdosteine (P>0.001) and almost twofold increases in hydroxyproline content which were completely prevented by erdosteine. Myeloperoxidase activities and MDA levels, which were significantly higher in the bleomycin group, were then significantly attenuated by erdosteine. These results revealed that oral erdosteine may prevent the development of acute pulmonary inflammation caused by bleomycin injection via the repression of neutrophil accumulation and lipid peroxidation, resulting in the inhibition of subsequent lung fibrosis.

  19. Pulmonary haemosiderosis with juvenile idiopathic arthritis in a Malaysian child.

    PubMed

    Wong, A R; Noor, A S Siti; Rasool, A H G; Quah, B S; Roberton, D

    2007-10-01

    A rare case of childhood pulmonary haemosiderosis with juvenile idiopathic arthritis is discussed, with particular reference to treatment with hydroxychloroquine and sildenafil for pulmonary hypertension which occurs secondary to this disease.

  20. [Combined pulmonary fibrosis and emphysema syndrome].

    PubMed

    Alilović, Marija; Peroš-Golubićić, Tatjana; Tekavec Trkanjec, Jasna; Hećimović, Ana; Smojver-Ježek, Silvana

    2015-01-01

    CPFE-combined pulmonary fibrosis and emphysema is a new term for a syndrome whose main characteristic is fibrosis in lower pulmonary lobes with simultaneous emphysema in upper pulmonary lobes. CPFE patients have well preserved pulmonary test values for unexpectedly long period, but extremely lowered carbon monoxide diffusion capacity and significant arterial hypertension. All CPFE studies indicate that CPFE occurs predominately in older male population. Smoking is considered main cause in developing CPFE. Reduced survival rate is linked with arterial hypertension extent, and mortality rate is greater than that for patients with isolated pulmonary fibrosis or emphysema. This study is focused on characteristics of twelve CPFE patients. This paper describes cases of 12 patients with the syndrome of pulmonary fibrosis associated with emphysema. All patients were male, mean age of 68 years. At the certain period of life they all were smokers, but most of them were also exposed to air pollution due to their profession. Shortness of breath on exertion was present in all patients. All patients had neat pulmonary function tests with significantly reduced diffusing capacity for carbon mon- oxide (average 39%). Pulmonary arterial hypertension (PAH) averaged 56 mmHg (range 25-75 mmHg) was present in 75% of patients. Four patients died during the period of four months, of which three patients had PAH greater than 70 mmHg. The fourth patient died of lung cancer.

  1. Immunolocalization of SPARC, tenascin, and thrombospondin in pulmonary fibrosis.

    PubMed Central

    Kuhn, C.; Mason, R. J.

    1995-01-01

    Several biochemically unrelated multifunctional extracellular proteins, SPARC, thrombospondin 1, and tenascin-C (TN), have been grouped as antiadhesive glycoproteins because they inhibit the spreading of cells on extracellular matrix in vitro. Migration of fibroblasts and epithelial cells into the air spaces to organize inflammatory exudate is a feature common to several fibrosing lung diseases. We hypothesized that migration would be facilitated by loosening the adhesive interactions between cells and the pericellular matrix components of the alveolar wall and that one or more of the anti-adhesive glycoproteins could be involved. Immunohistochemistry was used to localize SPARC, TN, and thrombospondin 1 in biopsies of organizing pneumonia, idiopathic pulmonary fibrosis (nine cases of usual interstitial pneumonia, one of desquamative interstitial pneumonia), and control lungs. Each antigen had a distinctive distribution. Only TN was expressed in control lungs, where it strongly stained the basement membrane of large bronchi and weakly stained alveolar entrance rings and small veins. In organizing pneumonia, TN was heavily stained through the entire extracellular matrix of the Masson bodies. In idiopathic pulmonary fibrosis, TN was abundant in the fibroblast foci of active fibrosis but was also present in the basement membrane regions beneath the metaplastic epithelium lining honeycomb cysts. TN was abundant in the interstitium in desquamative interstitial pneumonia. SPARC was observed only intracellularly where it occurred in the fibroblasts of Masson bodies of organizing pneumonia and the fibroblast foci of usual interstitial pneumonia. In desquamative interstitial pneumonia, expression of SPARC was minimal, in rare interstitial fibroblasts. Thrombospondin 1 was found consistently in organizing pneumonia but only infrequently in idiopathic pulmonary fibrosis. In both, it was localized in the extracellular matrix immediately beneath reparative epithelium. These

  2. "End-stage" pulmonary fibrosis in sarcoidosis.

    PubMed

    Teirstein, Alvin T; Morgenthau, Adam S

    2009-02-01

    Pulmonary fibrosis is an unusual "end stage" in patients with sarcoidosis. Fibrosis occurs in a minority of patients, and presents with a unique physiologic combination of airways dysfunction (obstruction) superimposed on the more common restrictive dysfunction. Imagin techniques are essential to the diagnosis, assessment and treatment of pulmonary fibrosis. Standard chest radiographs and CT scans may reveal streaks, bullae, cephalad retraction of the hilar areas, deviation of the trachea and tented diaphragm. Positive gallium and PET scans indicate residual reversible granulomatous disease and are important guides to therapy decisions. Treatment, usually with corticosteroids, is effective in those patients with positive scans, but fibrosis does not improve with any treatment. With severe functional impariment and patient disability, pulmonary hypertension and right heart failure may supervene for which the patient will require treatment. Oxygen, careful diuresis, sildenafil and bosentan may be salutary. These patients are candidates for lung transplantation.

  3. Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis.

    PubMed

    Huang, Long Shuang; Berdyshev, Evgeny; Mathew, Biji; Fu, Panfeng; Gorshkova, Irina A; He, Donghong; Ma, Wenli; Noth, Imre; Ma, Shwu-Fan; Pendyala, Srikanth; Reddy, Sekhar P; Zhou, Tong; Zhang, Wei; Garzon, Steven A; Garcia, Joe G N; Natarajan, Viswanathan

    2013-04-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease, wherein transforming growth factor β (TGF-β) and sphingosine-1-phosphate (S1P) contribute to the pathogenesis of fibrosis. However, the in vivo contribution of sphingosine kinase (SphK) in fibrotic processes has not been documented. Microarray analysis of blood mononuclear cells from patients with IPF and SphK1- or SphK2-knockdown mice and SphK inhibitor were used to assess the role of SphKs in fibrogenesis. The expression of SphK1/2 negatively correlated with lung function and survival in patients with IPF. Also, the expression of SphK1 was increased in lung tissues from patients with IPF and bleomycin-challenged mice. Knockdown of SphK1, but not SphK2, increased survival and resistance to pulmonary fibrosis in bleomycin-challenged mice. Administration of SphK inhibitor reduced bleomycin-induced mortality and pulmonary fibrosis in mice. Knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-β secretion in a bleomycin-induced lung fibrosis mouse model that was accompanied by reduced phosphorylation of Smad2 and MAPKs in lung tissue. In vitro, bleomycin-induced expression of SphK1 in lung fibroblast was found to be TGF-β dependent. Taken together, these data indicate that SphK1 plays a critical role in the pathology of lung fibrosis and is a novel therapeutic target.

  4. Diffuse interstitial pulmonary fibrosis: pulmonary fibrosis in mice induced by treatment with butylated hydroxytoluene and oxygen

    SciTech Connect

    Haschek, W.M.; Brody, A.R.; Klein-Szanto, A.J.P.; Witschi, H.

    1981-12-01

    It is proposed that the pulmonary fibrosis induced in mice by treatment with BHT and oxygen is a good experimental model for human pulmonary fibrosis. The mechanism of synergistic and additive effects of various agents on pulmonary injury and the epithelial mesenchymal interactions occurring during the early and late phases of lung repair could be studied. This model could be used for study of the effects of various concentrations of oxygen on diffusely damaged lung and assessment of the efficacy of drugs in preventing or resolving excessive collagen accumulation in lung. In addition, the relationship between pulmonary fibrosis and emphysema could be studied.

  5. Idiopathic pulmonary haemosiderosis. Epidemiology, pathogenic aspects and diagnosis.

    PubMed

    Milman, N; Pedersen, F M

    1998-07-01

    Idiopathic pulmonary haemosiderosis (IPH) is a rare clinical entity characterized by recurrent episodes of diffuse alveolar haemorrhage, often presenting with haemoptysis. Many patients have iron deficiency anaemia due to deposition of haemosiderin iron in the alveoli, and eventually develop moderate pulmonary fibrosis. Typically, intensive search for an aetiology ends up negative. There is no evidence of pulmonary vasculitis or capillaritis. The aetiology is obscure, but may be an immunological or toxic mechanism causing a defect in the basement membrane of the pulmonary capillary. IPH affects both children and adults. During an acute episode, a chest X-ray demonstrates bilateral, alveolar infiltrates. Sputum examination discloses haemosiderin-laden alveolar macrophages. Diagnosis is established by lung biopsy (fiber-optic or thoracoscopic), showing large numbers of haemosiderin-laden macrophages in the alveoli and without evidence of capillaritis or deposition of immunoglobulins. Corticosteroids and/or immunosuppressive drugs may be effective during an acute bleeding episode, and may in some patients improve symptoms and prognosis on the long-term, but the response to treatment displays great interindividual variation.

  6. Identification of Clinical Phenotypes in Idiopathic Interstitial Pneumonia with Pulmonary Emphysema.

    PubMed

    Sato, Suguru; Tanino, Yoshinori; Misa, Kenichi; Fukuhara, Naoko; Nikaido, Takefumi; Uematsu, Manabu; Fukuhara, Atsuro; Wang, Xintao; Ishida, Takashi; Munakata, Mitsuru

    2016-01-01

    Objective Since the term "combined pulmonary fibrosis and emphysema" (CPFE) was first proposed, the co-existence of pulmonary fibrosis and pulmonary emphysema (PE) has drawn considerable attention. However, conflicting results on the clinical characteristics of patients with both pulmonary fibrosis and PE have been published because of the lack of an exact definition of CPFE. The goal of this study was thus to clarify the clinical characteristics and phenotypes of idiopathic interstitial pneumonia (IIP) with PE. Methods We retrospectively analyzed IIP patients who had been admitted to our hospital. Their chest high-resolution computed tomography images were classified into two groups according to the presence of PE. We then performed a cluster analysis to identify the phenotypes of IIP patients with PE. Results Forty-four (53.7%) out of 82 patients had at least mild emphysema in their bilateral lungs. The cluster analysis separated the IIP patients with PE into three clusters. The overall survival rate of one cluster that consisted of mainly idiopathic pulmonary fibrosis (IPF) patients was significantly worse than those of the other clusters. Conclusion Three different phenotypes can be identified in IIP patients with PE, and IPF with PE is a distinct clinical phenotype with a poor prognosis.

  7. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations.

    PubMed

    Flume, Patrick A; Mogayzel, Peter J; Robinson, Karen A; Goss, Christopher H; Rosenblatt, Randall L; Kuhn, Robert J; Marshall, Bruce C

    2009-11-01

    The natural history of cystic fibrosis lung disease is one of chronic progression with intermittent episodes of acute worsening of symptoms frequently called acute pulmonary exacerbations These exacerbations typically warrant medical intervention. It is important that appropriate therapies are recommended on the basis of available evidence of efficacy and safety. The Cystic Fibrosis Foundation therefore established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians. It is hoped that these guidelines will be helpful to clinicians in the treatment of individuals with cystic fibrosis.

  8. "Nocturnal seizures" in idiopathic pulmonary arterial hypertension.

    PubMed

    Izzo, Anthony; McSweeney, Julia; Kulik, Thomas; Khatwa, Umakanth; Kothare, Sanjeev V

    2013-10-15

    The usual differential diagnoses of nocturnal events in children include parasomnias, nocturnal seizures, nocturnal reflux (Sandifer syndrome), hypnic jerks, periodic limb movements of sleep, and sleep disordered breathing. We report a previously healthy young girl who presented to the sleep clinic for evaluation of nocturnal events which were diagnosed as medically refractory nocturnal seizures. It was not until a syncopal event occurred in the daytime, which prompted referral for cardiac evaluation, the diagnosis of idiopathic pulmonary arterial hyper-tension (IPAH) was made. Sleep physicians should consider IPAH in the differential diagnosis of nocturnal events in children.

  9. Idiopathic pulmonary hemosiderosis - a diagnostic challenge

    PubMed Central

    2014-01-01

    Idiopathic pulmonary hemosiderosis is a rare disorder that can occur at any age and is characterized by the triad of hemoptysis, iron deficiency anemia and diffuse pulmonary infiltrates. The clinical course is exceedingly variable especially in children and a substantial proportion of this age group is undiagnosed. It is probably due to the fact that iron deficiency anemia may be the first and the only manifestation of IPH, preceding other symptoms and signs by several months and IPH is not considered as a rare cause of anemia, unless the typical triad is present. We present a case of IPH in a 13-year-old girl, treated for several months with persistent iron deficiency anemia, without response to therapy. PMID:24708654

  10. Effect of Pistacia lentiscus oil on experimental pulmonary fibrosis.

    PubMed

    Abidi, Anouar; Serairi Beji, Raja; Kourda, Nadia; Ennigrou, Samir; Ksouri, Riadh; Jameleddine, Saloua

    2016-07-01

    Background - Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by histopathological lesions in lung tissue. This is the most common and most severe idiopathic interstitial pneumonias. Current treatments are based on the combination of corticosteroids and immunosuppressants, but their effectiveness is still debated. Purpose of work - Testing the preventive effect of Pistacia Lentiscus oil, known for its antioxidant, anti-mutagenic and anti-proliferative effects, on a model of experimental lung fibrosis. Methods - Two groups of rats received an intratracheal injection of bleomycin (4.5 mg / kg). The first group, control (n = 20 rats), has received no treatment. The second group was treated with Pistacia Lentiscus oil (n = 20 rats) for 30 days before fibrosis induction, by daily gavage oil Pistacia Lentiscus oil (3,33ml / kg). This treatment was continued for 10 days. At the end of the experimental period, all rats were sacrificed and the lung tissue was examined histopathologically and immunostained for TGFβ. Results - The chromatographic profile oil Pistacia Lentiscus oil shows the dominance of two fatty acids that are linoleic acid and palmitic acid representing respectively 70.57 and 24.67%. Our results also show a decrease in the distribution of TGFβ both at the level of the inflammatory infiltrate and at the level of the pulmonary parenchyma histiocytes of rats treated with Pistacia Lentiscus oil compared with control rats. However, these changes are not accompanied by statistically significant changes of fibrosis score and inflammatory index. Conclusion - Our results are interesting to consider. Further studies using higher doses of Pistacia Lentiscus oil are important to conduct.

  11. Carbon monoxide-bound hemoglobin-vesicles for the treatment of bleomycin-induced pulmonary fibrosis.

    PubMed

    Nagao, Saori; Taguchi, Kazuaki; Sakai, Hiromi; Tanaka, Ryota; Horinouchi, Hirohisa; Watanabe, Hiroshi; Kobayashi, Koichi; Otagiri, Masaki; Maruyama, Toru

    2014-08-01

    Carbon monoxide (CO) has potent anti-inflammatory and anti-oxidant effects. We report herein on the preparation of a nanotechnology-based CO donor, CO-bound hemoglobin-vesicles (CO-HbV). We hypothesized that CO-HbV could have a therapeutic effect on idiopathic pulmonary fibrosis (IPF), an incurable lung fibrosis, that is thought to involve inflammation and the production of reactive oxygen species (ROS). Pulmonary fibril formation and respiratory function were quantitatively evaluated by measuring hydroxyproline levels and forced vital capacity, respectively, using a bleomycin-induced pulmonary fibrosis mice model. CO-HbV suppressed the progression of pulmonary fibril formation and improved respiratory function compared to saline and HbV. The suppressive effect of CO-HbV on pulmonary fibrosis can be attributed to a decrease in ROS generation by inflammatory cells, NADPH oxidase 4 and the production of inflammatory cells, cytokines and transforming growth factor-β in the lung. This is the first demonstration of the inhibitory effect of CO-HbV on the progression of pulmonary fibrosis via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced pulmonary fibrosis mice model. CO-HbV has the potential for use in the treatment of, not only IPF, but also a variety of other ROS and inflammation-related disorders.

  12. Hsp90 regulation of fibroblast activation in pulmonary fibrosis

    PubMed Central

    Sontake, Vishwaraj; Wang, Yunguan; Kasam, Rajesh K.; Sinner, Debora; Reddy, Geereddy B.; Naren, Anjaparavanda P.; McCormack, Francis X.; Jegga, Anil G.; Madala, Satish K.

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease associated with fibroblast activation that includes excessive proliferation, tissue invasiveness, myofibroblast transformation, and extracellular matrix (ECM) production. To identify inhibitors that can attenuate fibroblast activation, we queried IPF gene signatures against a library of small-molecule-induced gene-expression profiles and identified Hsp90 inhibitors as potential therapeutic agents that can suppress fibroblast activation in IPF. Although Hsp90 is a molecular chaperone that regulates multiple processes involved in fibroblast activation, it has not been previously proposed as a molecular target in IPF. Here, we found elevated Hsp90 staining in lung biopsies of patients with IPF. Notably, fibroblasts isolated from fibrotic lesions showed heightened Hsp90 ATPase activity compared with normal fibroblasts. 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a small-molecule inhibitor of Hsp90 ATPase activity, attenuated fibroblast activation and also TGF-β–driven effects on fibroblast to myofibroblast transformation. The loss of the Hsp90AB, but not the Hsp90AA isoform, resulted in reduced fibroblast proliferation, myofibroblast transformation, and ECM production. Finally, in vivo therapy with 17-AAG attenuated progression of established and ongoing fibrosis in a mouse model of pulmonary fibrosis, suggesting that targeting Hsp90 represents an effective strategy for the treatment of fibrotic lung disease. PMID:28239659

  13. A translational preclinical model of interstitial pulmonary fibrosis and pulmonary hypertension: mechanistic pathways driving disease pathophysiology

    PubMed Central

    Jarman, Elizabeth R.; Khambata, Valerie S.; Yun Ye, Li; Cheung, Kenneth; Thomas, Matthew; Duggan, Nicholas; Jarai, Gabor

    2014-01-01

    Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease, in which a decline in patient prognosis is frequently associated with the onset of pulmonary hypertension (PH). Animal models exhibiting principle pathophysiological features of IPF and PH could provide greater insight into mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches for intervention. Here, we describe an in vivo disease model, in which animals develop progressive interstitial pulmonary fibrosis and associated PH, as defined by the presence of fibrotic foci adjacent to areas of alveolar injury and remodeling of the pulmonary vasculature. Associated changes in physiological parameters included a decline in lung function and increase in mean pulmonary arterial pressure (mPAP) >25 mmHg. The early fibrotic pathology is associated with a profibrogenic microenvironment, elevated levels of the matrix metalloproteases, MMP‐2, MMP‐7, and MMP‐12, TIMP‐1, the chemoattractant and mitogen, PDGF‐β, and the chemokines CCL2 and CXCL12, that are associated with the recruitment of macrophages, mast cells, and fibrocytes. Principle mechanistic pathways associated with disease pathogenesis are upregulated in the lungs and pulmonary arteries, with sustained increases in gene transcripts for the profibrotic mediator TGF‐β1 and components of the TGF‐β signaling pathway; PAI‐1, Nox‐4, and HIF‐1α. Therapeutic treatment with the ALK‐5/TGF‐β RI inhibitor SB‐525334 reversed established pulmonary fibrosis and associated vascular remodeling, leading to normalization in clinically translatable physiological parameters including lung function and hemodynamic measurements of mPAP. These studies highlight the application of this model in validating potential approaches for targeting common mechanistic pathways driving disease pathogenesis. PMID:25214520

  14. Matrix Remodeling in Pulmonary Fibrosis and Emphysema.

    PubMed

    Kulkarni, Tejaswini; O'Reilly, Philip; Antony, Veena B; Gaggar, Amit; Thannickal, Victor J

    2016-06-01

    Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-β1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema.

  15. Interstitial pulmonary fibrosis and progressive massive fibrosis related to smoking methamphetamine with talc as filler.

    PubMed

    Baylor, Peter A; Sobenes, Juan R; Vallyathan, Val

    2013-05-01

    We present a case of interstitial pulmonary fibrosis accompanied by radiographic evidence of progressive massive fibrosis in a patient who had a 15-20 year history of almost daily recreational inhalation of methamphetamine. Mineralogical analysis confirmed the presence of talc on biopsy of the area of progressive massive fibrosis. The coexistence of interstitial pulmonary fibrosis and progressive massive fibrosis suggests that prolonged recreational inhalation of methamphetamine that has been "cut" with talc can result in sufficient amount of talc being inhaled to result in interstitial pulmonary fibrosis and progressive massive fibrosis in the absence of other causes.

  16. Idiopathic retroperitoneal fibrosis causing unilateral ureteral and sigmoid colon obstruction

    PubMed Central

    Yan, Ting; Wang, Yujuan; Liu, Zhijun; Zhang, Xiaolei; Wu, Qian; Xi, Mingrong

    2017-01-01

    Abstract Objective: The present report aimed to present a unique case of idiopathic retroperitoneal fibrosis (RPF) presenting features of unilateral ureteral and sigmoid colon obstruction. RPF is a rare disorder with unclear etiology. Case report: A 43-year-old female had a 10-day history of lower right abdominal and lumbar pain. Gynecological examination, ultrasound, and computed tomography (CT) were all suggestive of right ovarian tumor. An enhanced CT showed right-sided hydronephrosis. The patient was diagnosed as having ovarian cancer. Ten days after hospitalization, a right intraureteral stent with a double-J catheter was inserted. Upon exploring the abdomen, unyielding RPF was encountered. A partial sigmoidectomy and colostomy were performed. Postoperative pathological results suggested idiopathic RPF. She received steroid treatments. Conclusion: RPF is a rare disease that can be misdiagnosed. Our understanding about its presentation has to be improved and it should be considered as a differential diagnosis for patients presenting with abdominal diseases. PMID:28207528

  17. How Is Idiopathic Pulmonary Fibrosis Treated?

    MedlinePlus

    ... doctor may keep you on them longer. N-acetylcysteine N-acetylcysteine is an antioxidant that may help prevent lung ... is a combination of prednisone, azathioprine, and N-acetylcysteine. However, this treatment was recently found harmful in ...

  18. How Is Idiopathic Pulmonary Fibrosis Diagnosed?

    MedlinePlus

    ... infection is causing your symptoms. Skin Test for Tuberculosis For this test, your doctor injects a substance ... one of your arms. This substance reacts to tuberculosis (TB). If you have a positive reaction, a ...

  19. The Mitochondrial Cardiolipin Remodeling Enzyme Lysocardiolipin Acyltransferase Is a Novel Target in Pulmonary Fibrosis

    PubMed Central

    Huang, Long Shuang; Mathew, Biji; Zhao, Yutong; Noth, Imre; Reddy, Sekhar P.; Harijith, Anantha; Usatyuk, Peter V.; Berdyshev, Evgeny V.; Kaminski, Naftali; Zhou, Tong; Zhang, Wei; Zhang, Yanmin; Rehman, Jalees; Kotha, Sainath R.; Gurney, Travis O.; Parinandi, Narasimham L.; Lussier, Yves A.; Garcia, Joe G. N.

    2014-01-01

    Rationale: Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis. Objectives: To define a role for LYCAT in human and murine models of pulmonary fibrosis. Methods: We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge. Measurements and Main Results: LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection. Conclusions: This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis. PMID

  20. Novelty in treatment of pulmonary fibrosis: pulmonary hypertension drugs and others.

    PubMed

    Correale, Michele; Totaro, Antonio; Lacedonia, Donato; Montrone, Deodata; Di Biase, Matteo; Barbaro Foschino, Maria Pia; Brunetti, Natale Daniele

    2013-09-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic condition of unknown etiology with deteriorating respiratory function leading to respiratory failure. Corticosteroids, alone or in combination with immunosuppressive drugs such as azathioprine, colchicine, and cyclophosphamide, have been used with limited success. Interferon-gamma-1b showed a significant improvement in pulmonary function only in one study. Pirfenidone, cyclosporine and acetylcysteine may also be of benefit but data from studies are limited. Novel drugs, mainly antifibrotic, anticytokine and immunoregulatory, are currently being investigated in various trial phases. Endothelin receptor antagonists have been shown to have possible beneficial effects in early stages of IPF. However, most recently, the so-called triple combination therapy, anticoagulation therapy and endothelin receptor antagonists, especially ambrisentan, are either harmful or ineffective in IPF and are not recommended. We report a brief review on the present and possible future therapeutic options in IPF.

  1. Tadalafil as treatment for idiopathic pulmonary arterial hypertension.

    PubMed

    de Carvalho, Adriana Castro; Hovnanian, André Luiz; Fernandes, Caio Julio César dos Santos; Lapa, Mônica; Jardim, Carlos; Souza, Rogério

    2006-11-01

    Phosphodiesterase inhibitors like sildenafil have already been shown to improve functional capacity and hemodynamics in the treatment of pulmonary arterial hypertension. Few studies address the effects of new phosphodiesterase inhibitors as tadalafil. We report a case of a patient with idiopathic pulmonary arterial hypertension in functional class IV (New York Heart Association) with significant response to treatment with tadalafil.

  2. B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.

    PubMed

    François, Antoine; Gombault, Aurélie; Villeret, Bérengère; Alsaleh, Ghada; Fanny, Manoussa; Gasse, Paméla; Adam, Sylvain Marchand; Crestani, Bruno; Sibilia, Jean; Schneider, Pascal; Bahram, Seiamak; Quesniaux, Valérie; Ryffel, Bernhard; Wachsmann, Dominique; Gottenberg, Jacques-Eric; Couillin, Isabelle

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.

  3. The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

    PubMed Central

    Kim, Seok-Jo; Cheresh, Paul; Jablonski, Renea P.; Williams, David B.; Kamp, David W.

    2015-01-01

    Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) that may contribute to aging-related lung diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos exposure). The mammalian mitochondrial DNA (mtDNA) encodes for 13 proteins, including several essential for oxidative phosphorylation. We review the evidence implicating that oxidative stress-induced mtDNA damage promotes AEC apoptosis and pulmonary fibrosis. We focus on the emerging role for AEC mtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1) and mitochondrial aconitase (ACO-2) in maintaining mtDNA integrity which is important in preventing AEC apoptosis and asbestos-induced pulmonary fibrosis in a murine model. We then review recent studies linking the sirtuin (SIRT) family members, especially SIRT3, to mitochondrial integrity and mtDNA damage repair and aging. We present a conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function. The emerging insights into the pathobiology underlying AEC mtDNA damage and apoptosis is suggesting novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer. PMID:26370974

  4. MiR-338* targeting smoothened to inhibit pulmonary fibrosis by epithelial-mesenchymal transition

    PubMed Central

    Zhuang, Yi; Dai, Jinghong; Wang, Yongsheng; Zhang, Huan; Li, Xinxiu; Wang, Chunli; Cao, Mengshu; Liu, Yin; Ding, Jingjing; Cai, Hourong; Zhang, Deping; Wang, Yaping

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. Recent studies indicate that some microRNAs (miRNAs) may play critical roles in the pathogenesis of pulmonary fibrosis. In this study, we aim to investigate whether miR-338* (miR-338-5p), which has been found to be associated with tumor progression, is associated with pathological process of pulmonary fibrosis. Balb/c mice were treated with bleomycin (BLM) to establish IPF models. Targtscan was used to predict the downstream target of miR-338*. Morphological changes were observed with light microscope and epithelial to mesenchymal transition (EMT) markers were detected by western blot. The expression of miR-338* or downstream target SMO was analyzed by real-time quantitative RT-PCR, northern blot or western blot. MiR-338* was down-regulated in the lung tissue from mice with bleomycin-induced pulmonary fibrosis. The smoothened (SMO) is a direct target of miR-338*, and knocking-down the expression of SMO could partially rescue the fibrotic phenotype of TGF-β-induced NuLi-1 cells. Over-expression of SMO led to the fibrotic phenotype of NuLi-1 cells even without TGF-β treatment. These findings showed that the over-expression of SMO contributed to the fibrotic phenotype of NuLi-1 cells by affecting the epithelial-to-mesenchymal transition (EMT) procedure. Furthermore, in vivo, lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. In conclusion, our results suggest that miR-338* can target SMO to reduce the EMT procedure and thus postpone the development of pulmonary fibrosis. PMID:27508042

  5. Pulmonary arterial hypertension in idiopathic inflammatory myopathies

    PubMed Central

    Sanges, Sébastien; Yelnik, Cécile M.; Sitbon, Olivier; Benveniste, Olivier; Mariampillai, Kuberaka; Phillips-Houlbracq, Mathilde; Pison, Christophe; Deligny, Christophe; Inamo, Jocelyn; Cottin, Vincent; Mouthon, Luc; Launay, David; Lambert, Marc; Hatron, Pierre-Yves; Rottat, Laurence; Humbert, Marc; Hachulla, Eric

    2016-01-01

    Abstract Occurrence of pulmonary arterial hypertension (PAH) in idiopathic inflammatory myopathies (IIMs) without extensive interstitial lung disease (ILD) has rarely been described in the medical literature. This study aimed to report all cases with association of PAH and IIM in the French Pulmonary Hypertension (PH) Registry, to identify IIM features associated with the presence of PAH, and to describe treatment modalities of these patients. All cases of IIM-PAH were retrieved from the French PH Registry, which gathers PH patients prospectively enrolled by 27 referral hospital centers across France. Patients were excluded if they had an extensive ILD or overlap syndrome. Characteristics of IIM-PAH patients were compared with a control group of IIM patients without PH. Among the 5223 PH patients in the Registry, 34 had a diagnosis of IIM. Among them, 3 IIM-PAH patients (2 females and 1 male) had no evidence of extensive ILD or overlap syndrome, and were included in this study. In these 3 patients, dermatomyositis (DM) was the only identified IIM. One patient had autoantibodies classically associated with IIM (anti-Ku). PAH had always developed after IIM onset, was severe in all cases, and led to a marked functional impairment. By pooling our cases with 6 patients previously reported in the literature, and comparing them with a control cohort of 35 IIM patients without PH, we identify several IIM characteristics possibly associated with PAH occurrence, including DM subtype (78% vs 46%; P = 0.02), skin involvement (P = 0.04), anti-SSA antibodies (P = 0.05), and peripheral microangiopathy (P = 0.06). Overall, IIM-PAH patients were managed by corticosteroids and/or immunosuppressants, either alone or combined with PAH therapy. Patients did not seem to respond to IIM treatment alone. Our study reports for the first time the rare but possible association of PAH and IIM in a large prospective PH Registry. In that setting, PAH seems associated with DM, skin involvement

  6. MiR-338* suppresses fibrotic pathogenesis in pulmonary fibrosis through targeting LPA1

    PubMed Central

    Zhuang, Yi; Dai, Jinghong; Wang, Yongsheng; Zhang, Huan; Li, Xinxiu; Wang, Chunli; Cao, Mengshu; Liu, Yin; Cai, Hourong; Zhang, Deping; Wang, Yaping

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. MicroRNAs (miRNAs), as gene regulators, are assumed to regulate about one third of genes and thus play important roles in cellular functions including proliferation, growth, differentiation and apoptosis. Recent studies have indicated that some miRNAs may play critical roles in the pathogenesis of pulmonary fibrosis. In this study, we found that miR-338*(miR-338-5p), which has been found to be associated with tumor progression, was down-regulated in fibroblasts and TGF-β-induced lung fibrotic tissues. Over-expression of miR-338* can partly prevent the fibrotic process induced by TGF-β. Moreover, LPA1 was proven to be a downstream target of miR-338*. Lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. Taken together, our results suggest that miR-338* attenuates the pathogenesis of pulmonary fibrosis through targeting LPA1. Thus, miR-338* can be a potential therapeutic target for the treatment of IPF. PMID:27508041

  7. Contribution of Fetal, but Not Adult, Pulmonary Mesothelium to Mesenchymal Lineages in Lung Homeostasis and Fibrosis.

    PubMed

    von Gise, Alexander; Stevens, Sean M; Honor, Leah B; Oh, Jin Hee; Gao, Chi; Zhou, Bin; Pu, William T

    2016-02-01

    The lung is enveloped by a layer of specialized epithelium, the pulmonary mesothelium. In other organs, mesothelial cells undergo epithelial-mesenchymal transition and contribute to organ stromal cells. The contribution of pulmonary mesothelial cells (PMCs) to the developing lung has been evaluated with differing conclusions. PMCs have also been indirectly implicated in lung fibrosis in the progressive, fatal lung disease idiopathic pulmonary fibrosis. We used fetal or postnatal genetic pulse labeling of PMCs to assess their fate in murine development, normal lung homeostasis, and models of pulmonary fibrosis. We found that most fetal PMC-derived mesenchymal cells (PMCDCs) expressed markers of pericytes and fibroblasts, only a small minority expressed smooth muscle markers, and none expressed endothelial cell markers. Postnatal PMCs did not contribute to lung mesenchyme during normal lung homeostasis or in models of lung fibrosis. However, fetal PMCDCs were abundant and actively proliferating within fibrotic regions in lung fibrosis models, suggesting that they actively participate in the fibrotic process. These data clarify the role of fetal and postnatal PMCDCs in lung development and disease.

  8. Molecular targets in pulmonary fibrosis: the myofibroblast in focus.

    PubMed

    Scotton, Chris J; Chambers, Rachel C

    2007-10-01

    Idiopathic pulmonary fibrosis (IPF) is one of a group of interstitial lung diseases that are characterized by excessive matrix deposition and destruction of the normal lung architecture. Long-term survival of IPF patients is poor, with a 5-year survival rate of only 20%. Despite a lack of evidence-based benefit, IPF has historically been treated with corticosteroids and/or cytotoxic agents such as prednisone. Given the poor efficacy of these drugs, novel therapeutic strategies are required for the management of IPF. This demands a better understanding of the molecular mechanisms underlying the pathogenesis and progression of this disease. The primary effector cell in fibrosis is the myofibroblast; these cells are highly synthetic for collagen, have a contractile phenotype, and are characterized by the presence of alpha-smooth muscle actin stress fibers. They may be derived by activation/proliferation of resident lung fibroblasts, epithelial-mesenchymal differentiation, or recruitment of circulating fibroblastic stem cells (fibrocytes). From a therapeutic viewpoint, interfering with the pathways that lead to myofibroblast expansion should be of considerable benefit in the treatment of IPF. This review will highlight some of the key molecules involved in this process and the clinical trials that have ensued.

  9. Hiatal hernia on thoracic computed tomography in pulmonary fibrosis.

    PubMed

    Tossier, Céline; Dupin, Clairelyne; Plantier, Laurent; Leger, Julie; Flament, Thomas; Favelle, Olivier; Lecomte, Thierry; Diot, Patrice; Marchand-Adam, Sylvain

    2016-09-01

    Gastro-oesophageal reflux has long been suspected of implication in the genesis and progression of idiopathic pulmonary fibrosis (IPF). We hypothesised that hiatal hernia may be more frequent in IPF than in other interstitial lung disease (ILD), and that hiatal hernia may be associated with more severe clinical characteristics in IPF.We retrospectively compared the prevalence of hiatal hernia on computed tomographic (CT) scans in 79 patients with IPF and 103 patients with other ILD (17 scleroderma, 54 other connective tissue diseases and 32 chronic hypersensitivity pneumonitis). In the IPF group, we compared the clinical, biological, functional, CT scan characteristics and mortality of patients with hiatal hernia (n=42) and without hiatal hernia (n=37).The prevalence of hiatal hernia on CT scan at IPF diagnosis was 53%, similar to ILD associated with scleroderma, but significantly higher than in the two other ILD groups. The size of the hiatal hernia was not linked to either fibrosis CT scan scores, or reduction in lung function in any group. Mortality from respiratory causes was significantly higher among IPF patients with hiatal hernia than among those without hiatal hernia (p=0.009).Hiatal hernia might have a specific role in IPF genesis, possibly due to pathological gastro-oesophageal reflux.

  10. Prostaglandin F(2alpha) receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta.

    PubMed

    Oga, Toru; Matsuoka, Toshiyuki; Yao, Chengcan; Nonomura, Kimiko; Kitaoka, Shiho; Sakata, Daiji; Kita, Yoshihiro; Tanizawa, Kiminobu; Taguchi, Yoshio; Chin, Kazuo; Mishima, Michiaki; Shimizu, Takao; Narumiya, Shuh

    2009-12-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta (TGF-beta) functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A(2) (cPLA(2)) suppresses bleomycin-induced pulmonary fibrosis, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-beta stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-beta signaling additively decrease fibrosis. Furthermore, PGF(2alpha) is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-beta. These findings show that PGF(2alpha)-FP signaling facilitates pulmonary fibrosis independently of TGF-beta and suggests this signaling pathway as a therapeutic target for IPF.

  11. Tumor necrosis factor superfamily 14 (LIGHT) controls TSLP to drive pulmonary fibrosis

    PubMed Central

    Herro, Rana; Da Silva Antunes, Ricardo; Aguilera, Amelia Roman; Tamada, Koji; Croft, Michael

    2015-01-01

    Background Pulmonary fibrosis is characterized by excessive accumulation of collagen and α-smooth muscle actin (aSMA) in the lung. The key molecules that promote these phenotypes are of clinical interest. Objectives TSLP has been found at high levels in patients with asthma and idiopathic pulmonary fibrosis, and TSLP has been proposed as a primary driver of lung fibrotic disease. We asked whether TNFSF14 (aka LIGHT) controls TSLP production to initiate fibrosis. Methods Expression of TSLP and initiation of pulmonary fibrosis induced by bleomycin were assessed in mice deficient in LIGHT. The ability of recombinant LIGHT, given intratracheally to naïve mice, to promote TSLP and fibrosis was also determined. Results Genetic deletion of LIGHT abolished lung TSLP expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and aSMA. Furthermore, recombinant LIGHT administered in vivo induced lung expression of TSLP in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a TSLP-dependent manner. Blockade of LIGHT binding to either of its receptors, HVEM and LTβR, inhibited clinical symptoms of pulmonary fibrosis, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of TSLP. Moreover, LIGHT induced TSLP directly in human bronchial epithelial cells and synergized with IL-13 and TGF-β in vivo to promote TSLP in the lungs and drive fibrosis. Conclusions These results show that LIGHT is a profibrogenic cytokine that may be a key driver of TSLP production during the initiation and development of lung fibrotic disease. PMID:25680454

  12. Simvastatin impairs the induction of pulmonary fibrosis caused by a western style diet: a preliminary study

    PubMed Central

    Kruzliak, Peter; Hare, David L; Zvonicek, Vaclav; Klimas, Jan; Zulli, Anthony

    2015-01-01

    The role of an atherogenic diet in causing pulmonary fibrosis has received little attention and simvastatin has been shown to reduce pulmonary fibrosis in animal models. To determine if an atherogenic diet can induce pulmonary fibrosis and whether simvastatin treatment is beneficial by up-regulating heat shock protein 70 and 90. New Zealand white rabbits (n = 15) were divided: Group 1 (control); Group 2 (MC) received a normal rabbit diet with 1% methionine plus 0.5% cholesterol (atherogenic diet). Group 3 received the same diet as the MC group plus 5 mg/kg/day simvastatin orally (MCS). After 4 weeks, the lungs were collected and analysed. Picrosirus red staining of lung interstitial collagen content showed that the atherogenic diet increased fibrosis 2.9-fold (P < 0.05), bronchiole adventitial collagen was increased 2.3-fold (P < 0.05) and bronchiole epithelium was increased 34-fold (P < 0.05), and simvastatin treatment severely reduced this effect (P < 0.05). Western blot analysis showed that the atherogenic diet significantly reduced lung Hsp70 protein by 22% (P < 0.05) and Hsp90 protein by 18% (P < 0.05) and simvastatin treatment did not affect this result. However, aortic hyper-responsiveness to vasoconstrictors (angiotensin II and phenylephrine) were markedly reduced by simvastatin treatment. We report that an atherogenic diet stimulates pulmonary fibrosis and reduces lung Hsp70/Hsp90 protein concentration. Simvastatin impairs this by mechanisms unrelated to Hsp70/Hsp90, but possibly a reduction in angiotensin II receptor or alpha adrenergic receptor pathways. These results could have implications in idiopathic pulmonary fibrosis. PMID:26304628

  13. Protective role of andrographolide in bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Zhu, Tao; Zhang, Wei; Xiao, Min; Chen, Hongying; Jin, Hong

    2013-12-03

    Idiopathic pulmonary fibrosis (IPF) is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT), apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB) is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced pulmonary fibrosis. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-α in bronchoalveolar lavage fluid (BALF) were measured. HE staining and Masson's trichrome (MT) staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-β1 and α-SMA mRNA and protein were analyzed. Activation of NF-κB was determined by western blotting and electrophoretic mobility shift assay (EMSA). On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-α in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-β1 and α-SMA mRNA and protein expression in bleomycin-induced pulmonary fibrosis. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-κB p65/total NF-κB p65 and NF-κB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-κB. Andrographolide holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

  14. Idiopathic Pulmonary Hemosiderosis in a Child with Recurrent Macrophage Activation Syndrome Secondary to Systemic Juvenile Idiopathic Arthritis

    PubMed Central

    Barut, Kenan; Sahin, Sezgin; Adrovic, Amra

    2017-01-01

    Macrophage activation syndrome, a severe complication of systemic juvenile idiopathic arthritis and other inflammatory diseases, represents one of the most important rheumatological emergencies. Delayed diagnosis could lead to life-threatening complications. Pulmonary hemosiderosis has been classically characterized by a triad of anemia, hemoptysis, and lung infiltrates on chest radiogram. Although the majority of patients of pulmonary hemosiderosis are considered idiopathic, secondary hemosiderosis associated with known diseases could be seen. In this case report, we aimed to present gradually increased pulmonary manifestations due to pulmonary hemosiderosis with recurrent macrophage activation syndrome attacks in a child with systemic juvenile idiopathic arthritis. PMID:28251009

  15. Post-mortem evidence of idiopathic left ventricular hypertrophy and idiopathic interstitial myocardial fibrosis: is exercise the cause?

    PubMed Central

    Whyte, Gregory; Sheppard, Mary; George, Keith; Shave, Robert; Prasad, Sanjay; O’Hanlon, Rory; Sharma, Sanjay

    2009-01-01

    We report the case of an experienced, highly trained marathon runner who died suddenly while running. On post-mortem examination, left ventricle hypertrophy and idiopathic interstitial myocardial fibrosis was found. We believe that life-long, repetitive bouts of arduous physical activity resulted in fibrous replacement of the myocardium, causing a pathological substrate for the propagation of fatal arrhythmias. PMID:21686644

  16. Treatment of idiopathic/hereditary pulmonary arterial hypertension.

    PubMed

    Matsubara, Hiromi; Ogawa, Aiko

    2014-10-01

    Treatment of pulmonary hypertension has progressed by recently developed pulmonary arterial hypertension-targeted drugs. However, long-term survival of the patients with idiopathic/heritable pulmonary arterial hypertension is still suboptimal. To improve the outcomes, treatment goals of pulmonary hypertension were proposed at the 5th World Symposium on Pulmonary Hypertension held at Nice, France in 2013; parameters were obtained from cardiopulmonary exercise test, blood tests, echocardiography, and magnetic resonance imaging. In particular, parameters evaluating right ventricular function have been highlighted because survival of the patients with pulmonary arterial hypertension is closely related to right ventricular function. However, treatment specifically targeted to improve right ventricular function in pulmonary hypertension is not yet established. In this setting, we need to maintain or improve right ventricular function with available vasodilators. In this review, we focus on the following two points: (1) Why can pulmonary arterial hypertension-targeted drugs improve right ventricular function without an apparent decrease in pulmonary artery pressure? (2) Are proposed goals sufficient to improve long-term prognosis of the patients? Further, we will discuss what would be the appropriate goal in treating patients with pulmonary arterial hypertension.

  17. Targeting of Discoidin Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation During Pulmonary Fibrosis.

    PubMed

    Zhao, Hu; Bian, Huan; Bu, Xin; Zhang, Shuya; Zhang, Pan; Yu, Jiangtian; Lai, Xiaofeng; Li, Di; Zhu, Chuchao; Yao, Libo; Su, Jin

    2016-10-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal human disease with short survival time and few treatment options. Herein, we demonstrated that discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase that predominantly transduces signals from fibrillar collagens, plays a critical role in the induction of fibrosis and angiogenesis in the lung. In vitro cell studies showed that DDR2 can synergize the actions of both transforming growth factor (TGF)-β and fibrillar collagen to stimulate lung fibroblasts to undergo myofibroblastic changes and vascular endothelial growth factor (VEGF) expression. In addition, we confirmed that late treatment of the injured mice with specific siRNA against DDR2 or its kinase inhibitor exhibited therapeutic efficacy against lung fibrosis. Thus, this study not only elucidated novel mechanisms by which DDR2 controls the development of pulmonary fibrosis, but also provided candidate target for the intervention of this stubborn disease.

  18. Deregulation of selective autophagy during aging and pulmonary fibrosis: the role of TGFβ1.

    PubMed

    Sosulski, Meredith L; Gongora, Rafael; Danchuk, Svitlana; Dong, Chunmin; Luo, Fayong; Sanchez, Cecilia G

    2015-10-01

    Aging constitutes a significant risk factor for fibrosis, and idiopathic pulmonary fibrosis (IPF) is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to pulmonary fibrosis. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to lung injury in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to lung injury are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy (mitophagy). Fibroblast to myofibroblast differentiation (FMD) is an important feature of pulmonary fibrosis in which the profibrotic cytokine TGFβ1 plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts' fate. On the contrary, FMD mediated by TGFβ1 is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a TGFβ1-adenoviral model of lung fibrosis. PINK1 expression is also reduced in the aging murine lung and biopsies from IPF patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to lung injury may contribute to the promotion and/or perpetuation of pulmonary fibrosis. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases.

  19. Exome Sequencing Links Mutations in PARN and RTEL1 with Familial Pulmonary Fibrosis and Telomere Shortening

    PubMed Central

    Stuart, Bridget D.; Choi, Jungmin; Zaidi, Samir; Xing, Chao; Holohan, Brody; Chen, Rui; Choi, Mihwa; Dharwadkar, Pooja; Torres, Fernando; Girod, Carlos E.; Weissler, Jonathan; Fitzgerald, John; Kershaw, Corey; Klesney-Tait, Julia; Mageto, Yolanda; Shay, Jerry W.; Ji, Weizhen; Bilguvar, Kaya; Mane, Shrikant; Lifton, Richard P.; Garcia, Christine Kim

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial pulmonary fibrosis kindreds. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no prior connection to telomere biology or disease, with five novel heterozygous damaging mutations in unrelated cases and none in controls (P-value = 1.3 × 10−8); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more novel damaging and missense variants at conserved residues in cases than controls (P = 1.6 × 10−6). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths and epigenetic inheritance of short telomeres was seen in family members. Together these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction. PMID:25848748

  20. 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

  1. Inhibitory effects of amines from Citrus reticulata on bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Zhou, Xian-Mei; Cao, Zhen-Dong; Xiao, Na; Shen, Qi; Li, Jian-Xin

    2016-02-01

    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.

  2. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension.

    PubMed

    Karmouty-Quintana, Harry; Philip, Kemly; Acero, Luis F; Chen, Ning-Yuan; Weng, Tingting; Molina, Jose G; Luo, Fayong; Davies, Jonathan; Le, Ngoc-Bao; Bunge, Isabelle; Volcik, Kelly A; Le, Thanh-Thuy T; Johnston, Richard A; Xia, Yang; Eltzschig, Holger K; Blackburn, Michael R

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2B(f/f)-LysM(Cre)) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO2, bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2B(f/f)-LysM(Cre) mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH.

  3. Mast Cells: A Pivotal Role in Pulmonary Fibrosis

    PubMed Central

    Veerappan, Arul; O'Connor, Nathan J.; Brazin, Jacqueline; Reid, Alicia C.; Jung, Albert; McGee, David; Summers, Barbara; Branch-Elliman, Dascher; Stiles, Brendon; Worgall, Stefan; Kaner, Robert J.

    2013-01-01

    Pulmonary fibrosis is characterized by an inflammatory response that includes macrophages, neutrophils, lymphocytes, and mast cells. The purpose of this study was to evaluate whether mast cells play a role in initiating pulmonary fibrosis. Pulmonary fibrosis was induced with bleomycin in mast-cell-deficient WBB6F1-W/Wv (MCD) mice and their congenic controls (WBB6F1-+/+). Mast cell deficiency protected against bleomycin-induced pulmonary fibrosis, but protection was reversed with the re-introduction of mast cells to the lungs of MCD mice. Two mast cell mediators were identified as fibrogenic: histamine and renin, via angiotensin (ANG II). Both human and rat lung fibroblasts express the histamine H1 and ANG II AT1 receptor subtypes and when activated, they promote proliferation, transforming growth factor β1 secretion, and collagen synthesis. Mast cells appear to be critical to pulmonary fibrosis. Therapeutic blockade of mast cell degranulation and/or histamine and ANG II receptors should attenuate pulmonary fibrosis. PMID:23570576

  4. “Denervation” of autonomous nervous system in idiopathic pulmonary arterial hypertension by low-dose radiation: a case report with an unexpected outcome

    PubMed Central

    Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Paul; Oezkan, Filiz; Mahnkopf, Christian; Grabenbauer, Gerhard; Kreczy, Alfons; Bartunek, Rudolf; Darwiche, Kaid; Freitag, Lutz; Li, Qiang; Huang, Haidong; Vogl, Thomas; LePilvert, Patrick; Tsiouda, Theodora; Tsakiridis, Kosmas; Zarogoulidis, Konstantinos; Brachmann, Johannes

    2014-01-01

    Vasointestinal peptide metabolism plays a key physiological role in multimodular levels of vasodilatory, smooth muscle cell proliferative, parenchymal, and inflammatory lung reactions. In animal studies, vasointestinal peptide relaxes isolated pulmonary arterial segments from several mammalian species in vitro and neutralizes the pulmonary vasoconstrictor effect of endothelin. In some animal models, it reduces pulmonary vascular resistance in vivo and in monocrotaline-induced pulmonary hypertension. A 58-year-old woman presented with dyspnea and mild edema of the lower extremities. A bronchoscopy was performed without any suspicious findings suggesting a central tumor or other infiltrative disease. Endobronchial ultrasound revealed enlarged pulmonary arteries containing thrombi, a few enlarged lymph nodes, and enlarged mediastinal tissue anatomy with suspicion for mediastinal infiltration of a malignant process. We estimated that less than 10% of the peripheral vascular bed of the lung was involved in direct consolidated fibrosis as demonstrated in the left upper lobe apex. Further, direct involvement of fibrosis around the main stems of the pulmonary arteries was assumed to be low from positron emission tomography and magnetic resonance imaging scans. Assuming a positive influence of low-dose radiation, it was not expected that this could have reduced pulmonary vascular resistance by over two thirds of the initial result. However; it was noted that this patient had idiopathic pulmonary arterial hypertension mixed with “acute” (mediastinal) fibrosis which could have contributed to the unexpected success of reduction of pulmonary vascular resistance. To the best of our knowledge, this is the first report of successful treatment of idiopathic pulmonary arterial hypertension, probably as a result of low-dose radiation to the pulmonary arterial main stems. The patient continues to have no specific complaints concerning her idiopathic pulmonary arterial hypertension

  5. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers.

    PubMed

    Cohn, Jonathan A; Neoptolemos, John P; Feng, Jinong; Yan, Jin; Jiang, Zefei; Greenhalf, William; McFaul, Christopher; Mountford, Roger; Sommer, Steve S

    2005-10-01

    Cystic fibrosis (CF) is a recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. The risk of idiopathic chronic pancreatitis (ICP) is increased in individuals who have CFTR genotypes containing a CF-causing mutation plus a second pathogenic allele. It is unknown whether the risk of ICP is increased in CF carriers who have one CF-causing mutation plus one normal allele. In this study, 52 sporadic cases of ICP were ascertained through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen mutations were excluded. DNA was comprehensively tested for CFTR mutations using a robotically enhanced, multiplexed, and highly redundant form of single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing. Fifteen subjects had a total of 18 pathogenic CFTR alleles. Eight subjects had common CF-causing mutations. This group included seven CF carriers in whom the second CFTR allele was normal (4.3 times the expected frequency, P=0.0002). Three subjects had compound heterozygotes genotypes containing two pathogenic alleles (31 times the expected frequency, P<0.0001). A variant allele of uncertain significance (p.R75Q) was detected in eight of the 52 ICP subjects and at a similar frequency (13/96) in random donors. ICP differs from other established CFTR-related conditions in that ICP risk is increased in CF carriers who have one documented normal CFTR allele. Having two CFTR mutations imparts a higher relative risk, while having only one mutation imparts a higher attributable risk.

  6. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension

    PubMed Central

    Karmouty-Quintana, Harry; Philip, Kemly; Acero, Luis F.; Chen, Ning-Yuan; Weng, Tingting; Molina, Jose G.; Luo, Fayong; Davies, Jonathan; Le, Ngoc-Bao; Bunge, Isabelle; Volcik, Kelly A.; Le, Thanh-Thuy T.; Johnston, Richard A.; Xia, Yang; Eltzschig, Holger K.; Blackburn, Michael R.

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2Bf/f-LysMCre) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO2, bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2Bf/f-LysMCre mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH.—Karmouty-Quintana, H., Philip, K., Acero, L. F., Chen, N.-Y., Weng, T., Molina, J. G., Luo, F., Davies, J., Le, N.-B., Bunge, I., Volcik, K. A., Le, T.-T. T., Johnston, R. A., Xia, Y., Eltzschig, H. K., Blackburn, M. R. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension. PMID:25318478

  7. IRON HOMEOSTASIS DURING CYSTIC FIBROSIS PULMONARY EXACERBATION

    PubMed Central

    Gifford, Alex H.; Moulton, Lisa A.; Dorman, Dana B.; Olbina, Gordana; Westerman, Mark; Parker, H. Worth; Stanton, Bruce A.; O’Toole, George A.

    2012-01-01

    Hypoferremia is a marker of disease severity in cystic fibrosis (CF). The effect of systemic antibiotics on iron homeostasis during CF pulmonary exacerbation (CFPE) is unknown. Our central hypotheses were that, by the completion of treatment, serum iron would increase, serum concentrations of interleukin-6 (IL-6) and hepcidin-25, two mediators of hypoferremia, would decrease, and sputum iron would decrease. Methods: Blood and sputum samples were collected from 12 subjects with moderate-to-severe CF (median percent-predicted forced expiratory volume in one second (FEV1%) = 29%; median weight = 56 kg) within 24 hours of starting and completing a course of systemic antibiotics. Results: After treatment, subjects showed median FEV1% and body weight improvements of 4.5% and 2.0 kg, respectively (p <0.05). Median serum iron rose by 2.4 μmol/l (p <0.05), but 75% of patients remained hypoferremic. Median serum IL-6 and hepcidin-25 levels fell by 12.1 pg/ml and 37.5 ng/ml, respectively (p <0.05). Median serum erythropoietin (EPO) and hemoglobin levels were unaffected by treatment. We observed a trend toward lower sputum iron content after treatment. Conclusions: Hypoferremia is a salient characteristic of CFPE that improves with waning inflammation. Despite antibiotic treatment, many patients remain hypoferremic and anemic due to ineffective erythropoiesis. PMID:22883617

  8. Sirtuin 3 Deregulation Promotes Pulmonary Fibrosis.

    PubMed

    Sosulski, Meredith L; Gongora, Rafael; Feghali-Bostwick, Carol; Lasky, Joseph A; Sanchez, Cecilia G

    2016-08-13

    Oxidative stress leads to alveolar epithelial cell injury and fibroblast-myofibroblast differentiation (FMD), key events in the pathobiology of pulmonary fibrosis (PF). Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase regulator of antioxidant response and mitochondrial homeostasis. Here, we demonstrate reduced SIRT3 expression in the lungs of old mice compared to young mice, as well as in two murine models of PF. The analysis of the pattern of SIRT3 expression in the lungs of patients with PF revealed low SIRT3 staining within the fibrotic regions. We also demonstrated, using murine models of PF and human lung fibroblasts, that reduced SIRT3 expression in response to transforming growth factor beta 1 (TGFβ1) promotes acetylation (inactivation) of major oxidative stress response regulators, such as SOD2 and isocitrate dehydrogenase 2. Reduction of SIRT3 in human lung fibroblasts promoted FMD. By contrast, overexpression of SIRT3 attenuated TGFβ1-mediated FMD and significantly reduced the levels of SMAD family member 3 (SMAD3). Resveratrol induced SIRT3 expression and ameliorated acetylation changes induced by TGFβ1. We demonstrated that SIRT3-deficient mice are more susceptible to PF compared to control mice, and concomitantly exhibit enhanced SMAD3 expression. Collectively, these data define a SIRT3/TGFβ1 interaction during aging that may play a significant role in the pathobiology of PF.

  9. The significance of nanoparticles in particle-induced pulmonary fibrosis

    PubMed Central

    Byrne, James D; Baugh, John A

    2008-01-01

    Exposure to airborne nanoparticles contributes to many chronic pulmonary diseases. Nanoparticles, classified as anthropogenic and natural particles, and fibers of diameters less than 100 nm, have unrestricted access to most areas of the lung due to their size. Size relates to the deposition efficiency of the particle, with particles in the nano-range having the highest efficiencies. The deposition of nanoparticles in the lung can lead to chronic inflammation, epithelial injury, and further to pulmonary fibrosis. Cases of particle-induced pulmonary fibrosis, namely pneumoconiosis, are mostly occupationally influenced, and continue to be documented around the world. The tremendous growth of nanotechnology, however, has spurred fears of increased rates of pulmonary diseases, especially fibrosis. The severity of toxicological consequences warrants further examination of the effects of nanoparticles in humans, possible treatments and increased regulatory measures. PMID:18523535

  10. Pulmonary talcosis as a result of massive aspiration of baby powder.

    PubMed

    Cruthirds, T P; Cole, F H; Paul, R N

    1977-05-01

    Progressive diffuse pulmonary fibrosis as a sequel to massive aspiration of baby powder (talc) is documented. The diagnosis should be considered in "idiopathic" pulmonary fibrosis in childhood and adult life.

  11. Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

    SciTech Connect

    Fukunaga, Satoki; Kakehashi, Anna; Sumida, Kayo; Kushida, Masahiko; Asano, Hiroyuki; Gi, Min; Wanibuchi, Hideki

    2015-08-01

    To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.

  12. Novel form of miR-29b suppresses bleomycin-induced pulmonary fibrosis

    PubMed Central

    Yamada, Yuko; Takanashi, Masakatsu; Sudo, Katsuko; Ueda, Shinobu; Ohno, Shin-ichiro; Kuroda, Masahiko

    2017-01-01

    MicroRNA 29b (miR-29b) replacement therapy is effective for suppressing fibrosis in a mouse model. However, to develop clinical applications for miRNA mimics, the side effects of nucleic acid drugs have to be addressed. In this study, we focused on miRNA mimics in order to develop therapies for idiopathic pulmonary fibrosis. We developed a single-stranded RNA, termed “miR-29b Psh-match,” that has a unique structure to avoid problems associated with the therapeutic uses of miRNAs. A comparison of miR-29b Psh-match and double-stranded one, termed “miR-29b mimic” indicated that the single-stranded form was significantly effective towards fibrosis according to both in vivo and in vitro experiments. This novel form of miR-29b may become the foundation for developing an effective therapeutic drug for pulmonary fibrosis. PMID:28234907

  13. Challenges in pulmonary fibrosis · 2 : Bronchiolocentric fibrosis

    PubMed Central

    Cordier, Jean‐François

    2007-01-01

    Bronchiolocentric fibrosis is essentially represented by the pathological pattern of constrictive fibrotic bronchiolitis obliterans. The corresponding clinical condition (obliterative bronchiolitis) is characterised by dyspnoea, airflow obstruction at lung function testing and air trapping with characteristic mosaic features on expiratory high resolution CT scans. Bronchiolitis obliterans may result from many causes including acute diffuse bronchiolar damage after inhalation of toxic gases or fumes, alloimmune chronic processes after lung or haematopoietic stem cell transplantation, or connective tissue disease (especially rheumatoid arthritis). Airway‐centred interstitial fibrosis and bronchiolar metaplasia are other features of bronchiolocentric fibrosis. PMID:17600295

  14. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis

    NASA Astrophysics Data System (ADS)

    Kaminski, Naftali; Allard, John D.; Pittet, Jean F.; Zuo, Fengrong; Griffiths, Mark J. D.; Morris, David; Huang, Xiaozhu; Sheppard, Dean; Heller, Renu A.

    2000-02-01

    The molecular mechanisms of pulmonary fibrosis are poorly understood. We have used oligonucleotide arrays to analyze the gene expression programs that underlie pulmonary fibrosis in response to bleomycin, a drug that causes lung inflammation and fibrosis, in two strains of susceptible mice (129 and C57BL/6). We then compared the gene expression patterns in these mice with 129 mice carrying a null mutation in the epithelial-restricted integrin 6 subunit (6/-), which develop inflammation but are protected from pulmonary fibrosis. Cluster analysis identified two distinct groups of genes involved in the inflammatory and fibrotic responses. Analysis of gene expression at multiple time points after bleomycin administration revealed sequential induction of subsets of genes that characterize each response. The availability of this comprehensive data set should accelerate the development of more effective strategies for intervention at the various stages in the development of fibrotic diseases of the lungs and other organs.

  15. What to Expect After Pulmonary Rehabilitation

    MedlinePlus

    ... Expect After Benefits & Risks Links Related Topics Bronchitis COPD Cystic Fibrosis Idiopathic Pulmonary Fibrosis Sarcoidosis Send a ... answer questions. Some of these tests, such as exercise tests, will be the same ones you had ...

  16. What to Expect Before Pulmonary Rehabilitation

    MedlinePlus

    ... Expect After Benefits & Risks Links Related Topics Bronchitis COPD Cystic Fibrosis Idiopathic Pulmonary Fibrosis Sarcoidosis Send a ... how well you're able to breathe and exercise. You'll have lung function tests to check ...

  17. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis.

    PubMed

    Dadrich, Monika; Nicolay, Nils H; Flechsig, Paul; Bickelhaupt, Sebastian; Hoeltgen, Line; Roeder, Falk; Hauser, Kai; Tietz, Alexandra; Jenne, Jürgen; Lopez, Ramon; Roehrich, Manuel; Wirkner, Ute; Lahn, Michael; Huber, Peter E

    2016-05-01

    Background : Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods : C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion : Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined inhibition of

  18. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis

    PubMed Central

    Dadrich, Monika; Nicolay, Nils H.; Flechsig, Paul; Bickelhaupt, Sebastian; Hoeltgen, Line; Roeder, Falk; Hauser, Kai; Tietz, Alexandra; Jenne, Jürgen; Lopez, Ramon; Roehrich, Manuel; Wirkner, Ute; Lahn, Michael; Huber, Peter E.

    2016-01-01

    ABSTRACT Background: Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods: C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results: Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion: Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement: RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined

  19. Immune complexes, gallium lung scans, and bronchoalveolar lavage in idiopathic interstitial pneumonitis-fibrosis

    SciTech Connect

    Gelb, A.F.; Dreisen, R.B.; Epstein, J.D.; Silverthorne, J.D.; Bickel, Y.; Fields, M.; Border, W.A.; Taylor, C.R.

    1983-08-01

    We obtained results of lung immune complexes (LIC), circulating immune complexes (CIC), 48-hour gallium lung scans (scans), bronchoalveolar lavage (BAL), and pulmonary function tests in 20 patients with idiopathic interstitial pneumonitis-fibrosis. Sixteen patients had predominantly interstitial (13 cases UIP) and/or intraalveolar (3 cases DIP) cellular disease (group 1). Prior to corticosteroid therapy in group 1, scans were positive in 75 percent, CIC were elevated in 86 percent, LIC were present in 64 percent, and BAL was abnormal in 90 percent. Duration of follow-up after treatment was 3.5 +/- 1.0 year. In group 1 after treatment with corticosteroids in 13 patients and corticosteroids and penicillamine (three patients) and plasmapheresis (one patient), only four patients remain stable or improved. After corticosteroid therapy, elevated CIC returned to normal values despite progressive patient deterioration. In three patients, lung immune complexes were still detected after circulating immune complexes had returned to normal after corticosteroid therapy. In group 2 were four patients with fibrotic disease; scans and CIC were uniformly negative, LIC were weakly present in only one patient, and BAL was abnormal in all. Despite corticosteroid therapy, all have died or deteriorated. These results suggest that positive gallium lung scans, BAL, circulating immune complexes, and to a lesser extent, lung immune complexes are associated with the cellular phase of interstitial pneumonia, but do not reliably identify a corticosteroid-responsive group.

  20. Protective effect of dexpanthenol on bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Ermis, Hilal; Parlakpinar, Hakan; Gulbas, Gazi; Vardi, Nigar; Polat, Alaadin; Cetin, Asli; Kilic, Talat; Aytemur, Zeynep Ayfer

    2013-12-01

    Despite extensive studies, there is no effective treatment currently available other than pirfenidone for idiopathic pulmonary fibrosis. A protective effect of pantothenic acid and its derivatives on cell damage produced by oxygen radicals has been reported, but it has not been tested in bleomycin (BLM)--induced pulmonary fibrosis in rats. Therefore, we aimed to investigate the preventive effect of dexpanthenol (Dxp) on pulmonary fibrosis. Thirty-two rats were assigned to four groups as follows: (1) control group, (2) dexpanthenol (Dxp) group; 500 mg/kg Dxp continued intraperitoneally for 14 days, (3) bleomycin (BLM) group; a single intratracheal injection of BLM (2.5 mg/kg body weight in 0.25-ml phosphate buffered saline), and (4) BLM + Dxp-treated group; 500 mg/kg Dxp was administered 1 h before the intratracheal BLM injection and continued for 14 days i.p. The histopathological grades of lung inflammation and collagen deposition, tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and myeloperoxidase (MPO) were measured. BLM provoked inflammation and collagen deposition (p < 0.0001), with a marked increase in myeloperoxidase (MPO) activity resembling increased inflammatory activity (p < 0.0001), which was prevented by Dxp (p < 0.0001, p = 0.02). BLM reduced tissue activities of SOD, GPx, and CAT compared to controls (p = 0.01, 0.03, 0.009). MDA was increased with BLM (p = 0.003). SOD (p = 0.001) and MDA (p = 0.016) levels were improved in group 4. The CAT levels in the BLM + Dxp group were close to those in the control group (p > 0.05). We showed that Dxp significantly prevents BLM-induced lung fibrosis in rats. Further studies are required to evaluate the role of Dxp in the treatment of lung fibrosis.

  1. Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension.

    PubMed

    Meyer, F J; Lossnitzer, D; Kristen, A V; Schoene, A M; Kübler, W; Katus, H A; Borst, M M

    2005-01-01

    Idiopathic pulmonary arterial hypertension (IPAH) is a pulmonary vasculopathy of unknown aetiology. Dyspnoea, peripheral airway obstruction and inefficient ventilation are common in IPAH. Data on respiratory muscle function are lacking. This prospective single-centre study included 26 female and 11 male patients with IPAH in World Health Organization functional classes II-IV. Mean+/-SD pulmonary artery pressure was 48.6+/-16.9 in females and 53.1+/-22.9 mmHg in males; cardiac output was 3.7+/-1.3 and 4.2+/-1.7 L x min(-1). Maximal inspiratory pressure (PI,max) was lower in the female patients than in 20 controls (5.3+/-2.0 versus 8.2+/-2.0 kPa). In the male patients, PI,max was lower than in 25 controls (6.8+/-2.2 versus 10.5+/-3.7 kPa). Maximal expiratory pressure (PE,max) was lower in the female patients than in controls (6.2+/-2.6 versus 9.5+/-2.1 kPa), and in male patients as compared to controls (7.1+/-1.6 versus 10.3+/-3.9 kPa). There was no correlation between PI,max or PE,max and parameters of pulmonary haemodynamics or exercise testing. The ratio of mouth occlusion pressure within the first 0.1 s of inspiration and PI,max was higher in IPAH than in controls (females 0.067+/-0.066 versus 0.021+/-0.008; males 0.047+/-0.061 versus 0.023+/-0.016). In conclusion, this study provides the first evidence of inspiratory and expiratory muscle weakness in idiopathic pulmonary arterial hypertension. The pathomechanisms and the prognostic significance should be further investigated.

  2. Pulmonary Hypertension in Patients with Chronic Fibrosing Idiopathic Interstitial Pneumonias

    PubMed Central

    Hoeper, Marius M.; Behr, Juergen; Held, Matthias; Grunig, Ekkehard; Vizza, C. Dario; Vonk-Noordegraaf, Anton; Lange, Tobias J.; Claussen, Martin; Grohé, Christian; Klose, Hans; Olsson, Karen M.; Zelniker, Thomas; Neurohr, Claus; Distler, Oliver; Wirtz, Hubert; Opitz, Christian; Huscher, Doerte; Pittrow, David; Gibbs, J. Simon R.

    2015-01-01

    Background Pulmonary hypertension (PH) is a common finding in patients with chronic fibrosing idiopathic interstitial pneumonias (IIP). Little is known about the response to pulmonary vasodilator therapy in this patient population. COMPERA is an international registry that prospectively captures data from patients with various forms of PH receiving pulmonary vasodilator therapies. Methods We retrieved data from COMPERA to compare patient characteristics, treatment patterns, response to therapy and survival in newly diagnosed patients with idiopathic pulmonary arterial hypertension (IPAH) and PH associated with IIP (PH-IIP). Results Compared to patients with IPAH (n = 798), patients with PH-IIP (n = 151) were older and predominantly males. Patients with PH-IIP were treated predominantly with phosphodiesterase-5 inhibitors (88% at entry, 87% after 1 year). From baseline to the first follow-up visit, the median improvement in 6MWD was 30 m in patients with IPAH and 24.5 m in patients with PH-IIP (p = 0.457 for the difference between both groups). Improvements in NYHA functional class were observed in 22.4% and 29.5% of these patients, respectively (p = 0.179 for the difference between both groups). Survival rates were significantly worse in PH-IIP than in IPAH (3-year survival 34.0 versus 68.6%; p<0.001). Total lung capacity, NYHA class IV, and mixed-venous oxygen saturation were independent predictors of survival in patients with PH-IIP. Conclusions Patients with PH-IIP have a dismal prognosis. Our results suggest that pulmonary vasodilator therapy may be associated with short-term functional improvement in some of these patients but it is unclear whether this treatment affects survival. Trial Registration clinicaltrials.gov NCT01347216 PMID:26630396

  3. Losartan attenuates paraquat-induced pulmonary fibrosis in rats.

    PubMed

    Guo, F; Sun, Y B; Su, L; Li, S; Liu, Z F; Li, J; Hu, X T; Li, J

    2015-05-01

    Paraquat (PQ) is one of the most widely used herbicides in the world and can cause pulmonary fibrosis in the cases with intoxication. Losartan, an angiotensin II type 1 receptor antagonist, has beneficial effects on the treatment of fibrosis. The aim of this study was to examine the effect of losartan on pulmonary fibrosis in PQ-intoxicated rats. Adult male Sprague Dawley rats (n = 32, 180-220 g) were randomly assigned to four groups: (i) control group; (ii) PQ group; (iii) PQ + losartan 7d group; and (iv) PQ + losartan 14d group. Losartan treatment (intragastrically (i.g.), 10 mg/kg) was performed for 7 and 14 days after a single i.g. dose of 40 mg/kg PQ. All rats were killed on the 16th day, and hematoxylin-eosin and Masson's trichrome staining were used to examine lung injury and fibrosis. The levels of hydroxyproline and transforming growth factor β1 (TGF-β1), matrix metallopeptidase 9 (Mmp9), and tissue inhibitor of metalloproteinase 1 (TIMP-1) messenger RNA (mRNA) expression and relative expression levels of collagen type I and III were also detected. PQ caused a significant increase in hydroxyproline content, mRNA expression of TGF-β1, Mmp9, and TIMP-1, and relative expression levels of collagen type I and III ( p < 0.05), while losartan significantly decreased the amount of hydroxyproline and downregulated TGF-β1, Mmp9, and TIMP-1 mRNA and collagen type I and III expressions ( p < 0.05). Histological examination of PQ-treated rats showed lung injury and widespread inflammatory cell infiltration in the alveolar space and pulmonary fibrosis, while losartan could markedly reduce such damage and prevent pulmonary fibrosis. The results of this study indicated that losartan could reduce lung damage and prevent pulmonary fibrosis induced by PQ.

  4. Centrilobular emphysema combined with pulmonary fibrosis results in improved survival: a response.

    PubMed

    Cottin, Vincent; Cordier, Jean-François; Wells, Athol U

    2011-07-25

    Better survival in combined pulmonary fibrosis and emphysema than in lone pulmonary fibrosis: bias or reality? A response to Centrilobular emphysema combined with pulmonary fibrosis results in improved survival by Todd et al., Fibrogenesis & Tissue Repair 2011, 4:6.Please see related letter http://fibrogenesis.com/content/4/1/17.

  5. Cadherin-11 Regulation of Fibrosis through Modulation of Epithelial-to-Mesenchymal Transition: Implications for Pulmonary Fibrosis in Scleroderma

    DTIC Science & Technology

    2013-10-01

    bleomycin displayed a reduction in lung inflammation and pulmonary fibrosis . Scale bars: 200 mm (H&E), 100 mm (MT); n= 8 mice per group Progress...the process of EMT. This proposal builds on these recent observations and utilizes the IP bleomycin pulmonary fibrosis model. We hypothesize that...Cad11 regulates the EMT in AEC during the development of pulmonary fibrosis and that cadherin-11 is therapeutic target in the intraperitoneal bleomycin

  6. [Successful pregnancy in a patient with idiopathic pulmonary arterial hypertension. Case report].

    PubMed

    Szenczi, Orsolya; Karlócai, Kristóf; Bucsek, László; Rigó, János

    2016-04-10

    Idiopathic pulmonary arterial hypertension is characterized by progressive increase in pulmonary arterial pressure and pulmonary vascular resistance which lead to right ventricular failure and death. Pregnancy in patients with idiopathic pulmonary arterial hypertension is contraindicated because of the high maternal and fetal mortality. The authors present a case of successful pregnancy and delivery of a patient with idiopathic pulmonary arterial hypertension in Hungary for the first time. The aim of the report was to demonstrate that management and treatment of idiopathic pulmonary arterial hypertension in a pregnant woman is a complex and multidisciplinary task that should involve obstetrician, cardiologist and anesthesiologist. Those patients who become pregnant and do not wish to terminate the pregnancy must be referred to obstetric centers where a multidiciplinary approach is taken.

  7. Carvedilol inhibits proliferation of cultured pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension.

    PubMed

    Fujio, Hideki; Nakamura, Kazufumi; Matsubara, Hiromi; Kusano, Kengo Fukushima; Miyaji, Katsumasa; Nagase, Satoshi; Ikeda, Tetsuya; Ogawa, Aiko; Ohta-Ogo, Keiko; Miura, Daiji; Miura, Aya; Miyazaki, Masahiro; Date, Hiroshi; Ohe, Tohru

    2006-02-01

    Idiopathic pulmonary arterial hypertension (IPAH) is associated with proliferation of smooth muscle cells (SMCs) in small pulmonary arteries. Inhibition of proliferation of pulmonary artery smooth muscle cells (PASMCs) may be an effective treatment of patients with idiopathic pulmonary arterial hypertension. Recent studies have shown that carvedilol, an alpha- and beta-blocker with antioxidant and calcium channel blocking properties, inhibits the proliferation of cultured normal human pulmonary artery smooth muscle cells. In this study, we tested the hypothesis that carvedilol has antiproliferative effects on pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension. Pulmonary artery smooth muscle cells from six idiopathic pulmonary arterial hypertension patients who had undergone lung transplantation were cultured. To determine cell proliferation, H-thymidine incorporation was measured. Platelet-derived growth factor-induced proliferation of IPAH-PASMCs was significantly greater than that of normal control pulmonary artery smooth muscle cells. Carvedilol (0.1 microM to 10 microM) inhibited the proliferation of idiopathic pulmonary arterial hypertension-pulmonary artery smooth muscle cells in a concentration-dependent manner. Prazosin (an alpha-blocker) and N-acetyl L cysteine (an antioxidant agent) (0.1 microM to 10 microM) did not inhibit their proliferation, but the high concentration of propranolol (a beta-blocker) and nifedipine (a calcium channel blocker) (10 microM) inhibited the proliferation. The combination of propranolol and nifedipine inhibited the proliferation but only at a high concentration (10 microM) combination. Cell cycle analysis revealed that carvedilol (10 microM) significantly decreased the number of cells in S and G2/M phases. These results indicate that carvedilol inhibits the exaggerated proliferation of pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension

  8. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.

    PubMed

    Cottin, V; Nunes, H; Brillet, P-Y; Delaval, P; Devouassoux, G; Tillie-Leblond, I; Israel-Biet, D; Court-Fortune, I; Valeyre, D; Cordier, J-F

    2005-10-01

    The syndrome resulting from combined pulmonary fibrosis and emphysema has not been comprehensively described. The current authors conducted a retrospective study of 61 patients with both emphysema of the upper zones and diffuse parenchymal lung disease with fibrosis of the lower zones of the lungs on chest computed tomography. Patients (all smokers) included 60 males and one female, with a mean age of 65 yrs. Dyspnoea on exertion was present in all patients. Basal crackles were found in 87% and finger clubbing in 43%. Pulmonary function tests were as follows (mean+/-sd): total lung capacity 88%+/-17, forced vital capacity (FVC) 88%+/-18, forced expiratory volume in one second (FEV1) 80%+/-21 (% predicted), FEV1/FVC 69%+/-13, carbon monoxide diffusion capacity of the lung 37%+/-16 (% predicted), carbon monoxide transfer coefficient 46%+/-19. Pulmonary hypertension was present in 47% of patients at diagnosis, and 55% during follow-up. Patients were followed for a mean of 2.1+/-2.8 yrs from diagnosis. Survival was 87.5% at 2 yrs and 54.6% at 5 yrs, with a median of 6.1 yrs. The presence of pulmonary hypertension at diagnosis was a critical determinant of prognosis. The authors hereby individualise the computer tomography-defined syndrome of combined pulmonary fibrosis and emphysema characterised by subnormal spirometry, severe impairment of gas exchange, high prevalence of pulmonary hypertension, and poor survival.

  9. Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis

    PubMed Central

    Ryan, Alan J.; Shi, Lei; Glogauer, Michael; Neighbors, Jeffrey D.; Hohl, Raymond; Carter, A. Brent

    2015-01-01

    Fibrotic remodeling in lung injury is a major cause of morbidity. The mechanism that mediates the ongoing fibrosis is unclear, and there is no available treatment to abate the aberrant repair. Reactive oxygen species (ROS) have a critical role in inducing fibrosis by modulating extracellular matrix deposition. Specifically, mitochondrial hydrogen peroxide (H2O2) production by alveolar macrophages is directly linked to pulmonary fibrosis as inhibition of mitochondrial H2O2 attenuates the fibrotic response in mice. Prior studies indicate that the small GTP-binding protein, Rac1, directly mediates H2O2 generation in the mitochondrial intermembrane space. Geranylgeranylation of the C-terminal cysteine residue (Cys189) is required for the for Rac1 activation and mitochondrial import. We hypothesized that impairment of geranylgeranylation would limit mitochondrial oxidative stress, and, thus, abrogate progression of pulmonary fibrosis. By targeting the isoprenoid pathway with a novel agent, digeranyl bisphosphonate (DGBP), which impairs geranylgeranylation, we demonstrate that Rac1 mitochondrial import, mitochondrial oxidative stress, and progression of the fibrotic response to lung injury are significantly attenuated. These observations reveal that targeting the isoprenoid pathway to alter Rac1 geranylgeranylation halts the progression of pulmonary fibrosis after lung injury. PMID:25958207

  10. Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis

    PubMed Central

    Cabrera, Sandra; Maciel, Mariana; Herrera, Iliana; Nava, Teresa; Vergara, Fabián; Gaxiola, Miguel; López-Otín, Carlos; Selman, Moisés; Pardo, Annie

    2015-01-01

    Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic pulmonary fibrosis suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in lung fibrosis is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced lung fibrosis in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the ATG4B protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses. PMID:25906080

  11. Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis.

    PubMed

    Cabrera, Sandra; Maciel, Mariana; Herrera, Iliana; Nava, Teresa; Vergara, Fabián; Gaxiola, Miguel; López-Otín, Carlos; Selman, Moisés; Pardo, Annie

    2015-04-03

    Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic pulmonary fibrosis suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in lung fibrosis is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced lung fibrosis in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the ATG4B protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses.

  12. Vaccinia vaccine–based immunotherapy arrests and reverses established pulmonary fibrosis

    PubMed Central

    Collins, Samuel L.; Chan-Li, Yee; Oh, MinHee; Vigeland, Christine L.; Mitzner, Wayne; Powell, Jonathan D.; Horton, Maureen R.

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a fatal disease without any cure. Both human disease and animal models demonstrate dysregulated wound healing and unregulated fibrogenesis in a background of low-grade chronic T lymphocyte infiltration. Tissue-resident memory T cells (Trm) are emerging as important regulators of the immune microenvironment in response to pathogens, and we hypothesized that they might play a role in regulating the unremitting inflammation that promotes lung fibrosis. Herein, we demonstrate that lung-directed immunotherapy, in the form of i.n. vaccination, induces an antifibrotic T cell response capable of arresting and reversing lung fibrosis. In mice with established lung fibrosis, lung-specific T cell responses were able to reverse established pathology — as measured by decreased lung collagen, fibrocytes, and histologic injury — and improve physiologic function. Mechanistically, we demonstrate that this effect is mediated by vaccine-induced lung Trm. These data not only have implications for the development of immunotherapeutic regimens to treat IPF, but also suggest a role for targeting tissue-resident memory T cells to treat other tissue-specific inflammatory/autoimmune disorders. PMID:27158671

  13. The ethical Kampo formulation Sho-seiryu-to (TJ-19) prevents bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Yang, Chang-qing; Sun, Peng-yuan; Ding, Da-zhi; Moriuchi, Hiroshi; Ishitsuka, Yoichi; Irikura, Mitsuru; Irie, Tetsumi

    2010-01-01

    The effects of Sho-seiryu-to (TJ-19), an ethical Kampo formulation, on bleomycin (BLM)-induced pulmonary fibrosis in rats was examined. Pulmonary fibrosis was induced by intratracheal instillation of a single dose of BLM (5 mg/kg). The TJ-19 used consisted of at least 21 constituents, as determined by three-dimensional HPLC analysis, and was administered orally twice a day at a dose of 1.5 g/kg until the end of the study period. Changes in general appearance and body weight were monitored. Twenty-eight days after BLM instillation, the animals were sacrificed and the study parameters were measured. TJ-19 attenuated the loss in body weight, increase in lung/body weight ratio and concentration of hydroxyproline and malondialdehyde in the lung tissues induced by BLM administration. TJ-19 also prevented BLM-induced fibrotic changes in the lung histology. These protective effects of TJ-19 were observed when administration was started 1 week before and simultaneously with the instillation of BLM. These results suggest that TJ-19 has prophylactic potential against BLM-induced pulmonary fibrosis, and may therefore be a promising drug candidate and medicinal resource for preventing BLM-induced and idiopathic pulmonary fibrosis.

  14. Combined pulmonary fibrosis and emphysema: an increasingly recognized condition* **

    PubMed Central

    Dias, Olívia Meira; Baldi, Bruno Guedes; Costa, André Nathan; Carvalho, Carlos Roberto Ribeiro

    2014-01-01

    Combined pulmonary fibrosis and emphysema (CPFE) has been increasingly recognized in the literature. Patients with CPFE are usually heavy smokers or former smokers with concomitant lower lobe fibrosis and upper lobe emphysema on chest HRCT scans. They commonly present with severe breathlessness and low DLCO, despite spirometry showing relatively preserved lung volumes. Moderate to severe pulmonary arterial hypertension is common in such patients, who are also at an increased risk of developing lung cancer. Unfortunately, there is currently no effective treatment for CPFE. In this review, we discuss the current knowledge of the pathogenesis, clinical characteristics, and prognostic factors of CPFE. Given that most of the published data on CPFE are based on retrospective analysis, more studies are needed in order to address the role of emphysema and its subtypes; the progression of fibrosis/emphysema and its correlation with inflammation; treatment options; and prognosis. PMID:25029654

  15. Idiopathic retroperitoneal fibrosis and its overlap with IgG4-related disease.

    PubMed

    Rossi, Giovanni Maria; Rocco, Rossana; Accorsi Buttini, Eugenia; Marvisi, Chiara; Vaglio, Augusto

    2017-04-01

    Retroperitoneal fibrosis (RPF) is a rare disease characterised by fibrous tissue proliferation in the retroperitoneum, with encasement of the ureters and large vessels of the abdomen as the most destructive of potentially severe complications. It can either be idiopathic, or secondary to infections, malignancies, or the use of certain drugs. The idiopathic form accounts for approximately 75% of the cases, and is usually responsive to immunosuppressive therapy. In recent years, the emergence of a new clinical entity, IgG4-related disease (IgG4-RD), shed light on many fibro-inflammatory disorders once thought to be separate clinical entities, although frequently associated in the so-called multifocal fibrosclerosis. Among these, together with sclerosing pancreatitis and cholangitis, pseudotumour of the orbit, idiopathic mediastinal fibrosis and other conditions, is idiopathic retroperitoneal fibrosis (IRF). Both IRF and IgG4-RD can be associated with a wide variety of disorders, usually governed by immune-mediated (and particularly auto-immune) mechanisms. In our review, we discuss the clinical and therapeutic challenges IRF presents to the internist, as well as the meaning of its recent inclusion in the IgG4-RD spectrum from a clinical practice standpoint.

  16. Pulmonary artery aneurysm in an adult patient with idiopathic dilatation of the pulmonary artery

    PubMed Central

    Betkier-Lipińska, Katarzyna; Czarkowski, Sebastian; Hendzel, Piotr; Cwetsch, Andrzej

    2015-01-01

    Idiopathic dilatation of the pulmonary artery (IDPA) is a rare congenital heart disease. It has been described for almost one hundred years, and numerous definitions have been proposed. The IDPA diagnostic criteria have not been updated for years. Secondary to primary disease, pulmonary artery aneurism was recognised as a lethal defect; however, long-term follow-up of patients with IDPA has not been well researched. Thus, indications to medical or surgical treatment are not evidence based. Here, we present a rare case of a 54-year-old patient with IDPA, who remained under observation for 36 years without surgical intervention. PMID:26855651

  17. Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5)

    PubMed Central

    Walters, Dianne M.; White, Kevin M.; Patel, Ushma; Davis, Martin J.; Veluci-Marlow, Roberta M.; Bhupanapadu Sunkesula, Solomon Raju; Bonner, James C.; Martin, Jessica R.; Gladwell, Wes; Kleeberger, Steven R.

    2014-01-01

    Interstitial lung diseases (ILDs) are characterized by injury, inflammation, and scarring of alveoli, leading to impaired function. The etiology of idiopathic forms of ILD is not understood, making them particularly difficult to study due to the lack of appropriate animal models. Consequently, few effective therapies have emerged. We developed an inbred mouse model of ILD using vanadium pentoxide (V2O5), the most common form of a transition metal found in cigarette smoke, fuel ash, mineral ores, and steel alloys. Pulmonary responses to V2O5, including dose-dependent increases in lung permeability, inflammation, collagen content, and dysfunction, were significantly greater in DBA/2J mice compared to C57BL/6J mice. Inflammatory and fibrotic responses persisted for 4 mo in DBA/2J mice, while limited responses in C57BL/6J mice resolved. We investigated the genetic basis for differential responses through genetic mapping of V2O5-induced lung collagen content in BXD recombinant inbred (RI) strains and identified significant linkage on chromosome 4 with candidate genes that associate with V2O5-induced collagen content across the RI strains. Results suggest that V2O5 may induce pulmonary fibrosis through mechanisms distinct from those in other models of pulmonary fibrosis. These findings should further advance our understanding of mechanisms involved in ILD and thereby aid in identification of new therapeutic targets.—Walters, D. M., White, K. M., Patel, U., Davis, M. J., Veluci-Marlow, R. M., Bhupanapadu Sunkesula, S. R., Bonner, J. C., Martin, J. R., Gladwell, W., Kleeberger, S. R. Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5). PMID:24285090

  18. Expression of 150-kDa oxygen-regulated protein (ORP150) stimulates bleomycin-induced pulmonary fibrosis and dysfunction in mice.

    PubMed

    Tanaka, Ken-Ichiro; Shirai, Ayano; Ito, Yosuke; Namba, Takushi; Tahara, Kayoko; Yamakawa, Naoki; Mizushima, Tohru

    2012-09-07

    Idiopathic pulmonary fibrosis (IPF) involves pulmonary injury associated with inflammatory responses, fibrosis and dysfunction. Myofibroblasts and transforming growth factor (TGF)-β1 play major roles in the pathogenesis of this disease. Endoplasmic reticulum (ER) stress response is induced in the lungs of IPF patients. One of ER chaperones, the 150-kDa oxygen-regulated protein (ORP150), is essential for the maintenance of cellular viability under stress conditions. In this study, we used heterozygous ORP150-deficient mice (ORP150(+/-) mice) to examine the role of ORP150 in bleomycin-induced pulmonary fibrosis. Treatment of mice with bleomycin induced the expression of ORP150 in the lung. Bleomycin-induced inflammatory responses were slightly exacerbated in ORP150(+/-) mice compared to wild-type mice. On the other hand, bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction was clearly ameliorated in the ORP150(+/-) mice. Bleomycin-induced increases in pulmonary levels of both active TGF-β1 and myofibroblasts were suppressed in ORP150(+/-) mice. These results suggest that although ORP150 is protective against bleomycin-induced lung injury, this protein could stimulate bleomycin-induced pulmonary fibrosis by increasing pulmonary levels of TGF-β1 and myofibroblasts.

  19. Peripheral airways obstruction in idiopathic pulmonary artery hypertension (primary).

    PubMed

    Fernandez-Bonetti, P; Lupi-Herrera, E; Martinez-Guerra, M L; Barrios, R; Seoane, M; Sandoval, J

    1983-05-01

    The mechanical properties of the lung were studied in ten nonsmokers with idiopathic pulmonary artery hypertension (IPAH) (mean pulmonary artery pressure 65.7 +/- 30 mm Hg). In the routine lung test, residual volume was found to be abnormal (greater than 120 percent of the predicted) in seven patients, and measured airway resistance was normal in eight out of the ten patients. A decreased FEF 75-85 percent, abnormal values for the helium-air flow ratios and increased closing capacities were documented in eight of ten patients in whom lung elastic recoil was normal (six of ten) or increased (four of ten). These features suggest peripheral airways obstruction (PAO) which was also supported by histopathologic findings in three cases (one biopsy and two necropsies). The observed changes in lung compliance could be related to the behavior of the coupling of the air-space and vascular compartments. The etiology of PAO in IPAH patients is not known, but our results indicate that both the peripheral airways and the pulmonary circulation are affected. The knowledge of PAO in IPAH patients could help to better understand the observed V/Q inequality in this entity.

  20. What Are the Benefits and Risks of Pulmonary Rehabilitation?

    MedlinePlus

    ... Expect After Benefits & Risks Links Related Topics Bronchitis COPD Cystic Fibrosis Idiopathic Pulmonary Fibrosis Sarcoidosis Send a ... in your daily life Increase your ability to exercise Decrease the symptoms of your disease or condition ...

  1. Pulmonary fibrosis and emphysema: Is the emphysema type associated with the pattern of fibrosis?

    PubMed Central

    Oikonomou, Anastasia; Mintzopoulou, Paraskevi; Tzouvelekis, Argyris; Zezos, Petros; Zacharis, George; Koutsopoulos, Anastasios; Bouros, Demosthenes; Prassopoulos, Panos

    2015-01-01

    AIM: To investigate whether the predominant emphysema type is associated with the high resolution computed tomography (HRCT) pattern of fibrosis in combined pulmonary fibrosis and emphysema (CPFE). METHODS: Fifty-three smokers with upper lobe emphysema and lower lobe pulmonary fibrosis on - HRCT - were retrospectively evaluated. Patients were stratified into 3 groups according to the predominant type of emphysema: Centrilobular (CLE), paraseptal (PSE), CLE = PSE. Patients were also stratified into 3 other groups according to the predominant type of fibrosis on HRCT: Typical usual interstitial pneumonia (UIP), probable UIP and nonspecific interstitial pneumonia (NSIP). HRCTs were scored at 5 predetermined levels for the coarseness of fibrosis (Coarseness), extent of emphysema (emphysema), extent of interstitial lung disease (TotExtILD), extent of reticular pattern not otherwise specified (RetNOS), extent of ground glass opacity with traction bronchiectasis (extGGOBx), extent of pure ground glass opacity and extent of honeycombing. HRCT mean scores, pulmonary function tests, diffusion capacity (DLCO) and systolic pulmonary arterial pressure were compared among the groups. RESULTS: The predominant type of emphysema was strongly correlated with the predominant type of fibrosis. The centrilobular emphysema group exhibited a significantly higher extent of emphysema (P < 0.001) and a lower extent of interstitial lung disease (P < 0.002), reticular pattern not otherwise specified (P < 0.023), extent of ground glass opacity with traction bronchiectasis (P < 0.002), extent of honeycombing (P < 0.001) and coarseness of fibrosis (P < 0.001) than the paraseptal group. The NSIP group exhibited a significantly higher extent of emphysema (P < 0.05), total lung capacity (P < 0.01) and diffusion capacity (DLCO) (P < 0.05) than the typical UIP group. The typical UIP group exhibited a significantly higher extent of interstitial lung disease, extent of reticular pattern not otherwise

  2. Smad3 signaling involved in pulmonary fibrosis and emphysema.

    PubMed

    Gauldie, Jack; Kolb, Martin; Ask, Kjetil; Martin, Gail; Bonniaud, Philippe; Warburton, David

    2006-11-01

    The incidence of finding evidence of both emphysema and pulmonary fibrosis in the same patient has received increased attention. Several investigators have found on biopsy the presence of emphysema of the upper zones and diffuse parenchymal disease with fibrosis of the lower zones of the lung, especially associated with current or previous heavy smokers. Believed previously to be two different disease mechanisms, there are now data to implicate some common pathways of cell and molecular activation leading to the different morphologic and physiologic outcomes. According to a current view, emphysema may originate from a protease/antiprotease imbalance, whereas a role for antiproteases has been proposed in the modulation of fibrosis. Overexpression of transforming growth factor beta (TGF-beta) in experimental rodent models leads to progressive pulmonary fibrosis, accompanied with marked up-regulation of protease inhibitors, such as tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator inhibitor-1 (PAI-1) genes, along with excessive matrix accumulation. It may be that a "matrix degrading" pulmonary microenvironment, one in which metalloproteinase activities prevail, favors the development of emphysema, whereas a "matrix nondegrading" microenvironment, with enhanced presence of TIMPs, would lead to matrix accumulation and fibrosis. Surprisingly, although Smad3 null mice, deficient in TGF-beta signal transmission, are resistant to bleomycin- and TGF-beta-mediated fibrosis, they develop spontaneous age-related airspace enlargement, consistent with emphysema, with a lack of ability to repair tissue damage appropriately. A common element is tissue damage and repair, with TGF-beta and the Smad signaling pathway playing prominent molecular roles. Both changes can be followed in experimental models with noninvasive imaging and physiologic measurements.

  3. Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis.

    PubMed

    Li, Min; Krishnaveni, Manda Sai; Li, Changgong; Zhou, Beiyun; Xing, Yiming; Banfalvi, Agnes; Li, Aimin; Lombardi, Vincent; Akbari, Omid; Borok, Zea; Minoo, Parviz

    2011-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments. Although the etiology of IPF is unknown, dysregulated TGF-β signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial TGF-β signaling via TGF-β receptor II (TβRII) and its contribution to fibrosis by generating mice in which TβRII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as TβRIINkx2.1-cre mice, were used to determine the impact of TβRII inactivation on (a) embryonic lung morphogenesis in vivo; and (b) the epithelial cell response to TGF-β signaling in vitro and in a bleomycin-induced, TGF-β-mediated mouse model of pulmonary fibrosis. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, TβRIINkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial TβRII in alveolar homeostasis. Absence of TβRII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic TGF-β. However, TβRIINkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced pulmonary fibrosis. To our knowledge, these findings are the first to demonstrate a specific role for TGF-β signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis.

  4. Is N-acetylcysteine effective in the treatment of pulmonary fibrosis?

    PubMed

    Jeldres Pulgar, Alejandro; Labarca, Gonzalo

    2016-09-29

    Idiopathic pulmonary fibrosis is a progressive chronic respiratory disease that in final stages carries high mortality. Several treatment options have been proposed, including N-acetylcysteine, but its role is not clearly established. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified eight systematic reviews including 16 trials addressing the question of this article. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded N-acetylcysteine might increase the risk of hospitalizations and exacerbations. While it is unclear whether this leads to increased mortality because the certainty of the evidence is very low, in general there is consensus that it should not be used except in the context of a new clinical trial.

  5. The Protective Effect of Naringin against Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats

    PubMed Central

    Turgut, Nergiz H.; Kara, Haki; Elagoz, Sahende; Deveci, Koksal; Gungor, Huseyin; Arslanbas, Emre

    2016-01-01

    The aim of the current study was to investigate the protective effect of naringin on bleomycin-induced pulmonary fibrosis in rats. Twenty-four Wistar rats randomly divided into four groups (control, bleomycin alone, bleomycin + naringin 40, and bleomycin + naringin 80) were used. Rats were administered a single dose of bleomycin (5 mg/kg; via the tracheal cannula) alone or followed by either naringin 40 mg/kg (orally) or naringin 80 mg/kg (orally) or water (1 mL, orally) for 14 days. Rats and lung tissue were weighed to determine the lung index. TNF-α and IL-1β levels, hydroxyproline content, and malondialdehyde (MDA) levels were assayed. Glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were determined. Tissue sections were stained with hematoxylin-eosin, Masson's trichrome, and 0.1% toluidine blue. TNF-α, IL-1β, and MDA levels and hydroxyproline content significantly increased (p < 0.01) and GPx and SOD activities significantly decreased in bleomycin group (p < 0.01). Naringin at a dose of 80 mg/kg body weight significantly decreased TNF-α and IL-1β activity, hydroxyproline content, and MDA level (p < 0.01) and increased GPx and SOD activities (p < 0.05). Histological evidence supported the results. These results show that naringin has the potential of reducing the toxic effects of bleomycin and may provide supportive therapy for conventional treatment methods for idiopathic pulmonary fibrosis. PMID:26977316

  6. Bone marrow-derived progenitor cells in pulmonary fibrosis.

    PubMed

    Hashimoto, Naozumi; Jin, Hong; Liu, Tianju; Chensue, Stephen W; Phan, Sem H

    2004-01-01

    The origin of fibroblasts in pulmonary fibrosis is assumed to be intrapulmonary, but their extrapulmonary origin and especially derivation from bone marrow (BM) progenitor cells has not been ruled out. To examine this possibility directly, adult mice were durably engrafted with BM isolated from transgenic mice expressing enhanced GFP. Induction of pulmonary fibrosis in such chimera mice by endotracheal bleomycin (BLM) injection caused large numbers of GFP(+) cells to appear in active fibrotic lesions, while only a few GFP(+) cells could be identified in control lungs. Flow-cytometric analysis of lung cells confirmed the BLM-induced increase in GFP(+) cells in chimera mice and revealed a significant increase in GFP(+) cells that also express type I collagen. GFP(+) lung fibroblasts isolated from chimera mice expressed collagen and telomerase reverse transcriptase but not alpha-smooth muscle actin. Treatment of isolated GFP(+) fibroblasts with TGF-beta failed to induce myofibroblast differentiation. Cultured lung fibroblasts expressed the chemokine receptors CXCR4 and CCR7 and responded chemotactically to their cognate ligands, stromal cell-derived factor-1 alpha and secondary lymphoid chemokine, respectively. Thus the collagen-producing lung fibroblasts in pulmonary fibrosis can also be derived from BM progenitor cells.

  7. Bone marrow–derived progenitor cells in pulmonary fibrosis

    PubMed Central

    Hashimoto, Naozumi; Jin, Hong; Liu, Tianju; Chensue, Stephen W.; Phan, Sem H.

    2004-01-01

    The origin of fibroblasts in pulmonary fibrosis is assumed to be intrapulmonary, but their extrapulmonary origin and especially derivation from bone marrow (BM) progenitor cells has not been ruled out. To examine this possibility directly, adult mice were durably engrafted with BM isolated from transgenic mice expressing enhanced GFP. Induction of pulmonary fibrosis in such chimera mice by endotracheal bleomycin (BLM) injection caused large numbers of GFP+ cells to appear in active fibrotic lesions, while only a few GFP+ cells could be identified in control lungs. Flow-cytometric analysis of lung cells confirmed the BLM-induced increase in GFP+ cells in chimera mice and revealed a significant increase in GFP+ cells that also express type I collagen. GFP+ lung fibroblasts isolated from chimera mice expressed collagen and telomerase reverse transcriptase but not α-smooth muscle actin. Treatment of isolated GFP+ fibroblasts with TGF-β failed to induce myofibroblast differentiation. Cultured lung fibroblasts expressed the chemokine receptors CXCR4 and CCR7 and responded chemotactically to their cognate ligands, stromal cell–derived factor-1α and secondary lymphoid chemokine, respectively. Thus the collagen-producing lung fibroblasts in pulmonary fibrosis can also be derived from BM progenitor cells. PMID:14722616

  8. Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats.

    PubMed

    Togami, Kohei; Chono, Sumio; Tada, Hitoshi

    2016-03-01

    Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.4, 10, 70, and 250 kDa) were administered to rat lungs using a MicroSprayer. Indocyanine green fluorescence signals were significantly weaker in fibrotic lungs than in control lungs and 6-CF and FD concentrations in the plasma of pulmonary fibrotic animals were markedly higher than in the plasma of control animals. Moreover, disrupted epithelial tight junctions, including claudins-1, -3, and -5, were observed in pulmonary fibrotic lesions using immunofluorescence microscopy. In addition, destruction of tight junctions on model alveolar epithelial cells (NCI-H441) by transforming growth factor-β1 treatment enhanced the permeability of 6-CF and FDs through NCI-H441 cell monolayers. These results indicate that aerosolized drugs are easily distributed into the plasma after leakage through damaged tight junctions of alveolar epithelium. Therefore, the development of delivery systems for anti-fibrotic agents to improve intrapulmonary pharmacokinetics may be necessary for effective idiopathic pulmonary fibrosis therapy.

  9. Autopsy confirmation of severe pulmonary interstitial fibrosis secondary to Munchausen syndrome presenting as cystic fibrosis.

    PubMed

    Croft, Philip R; Racz, Mark I; Bloch, John D; Palmer, Charles H

    2005-09-01

    Chronic factitious disorder with physical symptoms, or Munchausen syndrome, is a well-recognized but uncommonly diagnosed psychiatric condition characterized by the deliberate production of signs and symptoms of disease in order to receive medical attention. Clinical suspicion of this disease is rarely confirmed by autopsy, as the patients usually do not die as a consequence of feigning illness. Here we report the autopsy confirmation of a case of a suspected Munchausen syndrome patient who presented with a history of cystic fibrosis. Examination of the lungs demonstrated extensive severe interstitial fibrosis, and polariscopic examination revealed a large quantity of crystalline material throughout the tissue; X-ray diffraction identified the material as talc. Synopses of published cases of Munchausen syndrome presenting as cystic fibrosis, and cases of Munchausen syndrome with pulmonary talcosis are presented as part of the discussion.

  10. Modulation of pulmonary neuroendocrine cells in idiopathic interstitial pneumonia.

    PubMed

    Ito, T; Ogura, T; Ogawa, N; Udaka, N; Hayashi, H; Inayama, Y; Yazawa, T; Kitamura, H

    2002-10-01

    In order to reveal modulation of the number of pulmonary neuroendocrine cells (PNEC) in interstitial lung diseases and to clarify significance of cell proliferation activity in occurrence of PNEC, we counted airway PNEC of the patients of idiopathic interstitial pneumonia, secondary interstitial pneumonia and control lungs, and compared the number of PNEC with airway Ki-67 labeling. The lung tissue samples were obtained by video-assisted thoracoscopic surgery from 22 patients with usual interstitial pneumonia (UIP), 7 with non-specific interstitial pneumonia (NSIP), 8 with chronic hypersensitivity pneumonia (CHP), 13 with collagen vascular disease (CVD), and were compared with age-matched control lungs. The tissues were immunostained for chromogranin A and for Ki-67. Average incidence of bronchiolar PNEC in normal, UIP, NSIP, CHP, CVD lungs was 0.169%, 0.348%, 0.326%, 0.175% and 0.201%, respectively, and average Ki-67 labeling index in them was 0.241%, 1.186%, 1.605%, 1.058%, and 2.353%, respectively. And, in UIP lungs, PNEC incidence or Ki-67 labeling index was different according to pathological lesions. Thus, PNEC increase in the bronchiole of UIP, and the incidence of PNEC varies according to degree of activity of epithelial cell proliferation probably related to epithelial cell injury. Moreover, enhanced expression of human homolog of achaete-scute complex (hASH1) mRNA in UIP lungs suggests that hASH1 could play roles in the regulation of PNEC.

  11. Pulmonary fibrosis associated with psychotropic drug therapy: a case report

    PubMed Central

    2009-01-01

    Introduction Sertraline and Risperidone are commonly used psychotropic drugs. Sertraline has previously been associated with eosinopilic pneumonia. Neither drug is recognised as a cause of diffuse fibrotic lung disease. Our report represents the first such case. Case Presentation We describe the case of a 33 year old Asian male with chronic schizophrenia who had been treated for three years with sertraline and risperidone. He presented to hospital in respiratory failure following a six month history of progressive breathlessness. High resolution CT scan demonstrated diffuse pulmonary fibrosis admixed with patchy areas of consolidation. Because the aetiology of this man's diffuse parenchymal lung disease remained unclear a surgical lung biopsy was undertaken. Histological assessment disclosed widespread fibrosis with marked eosinophillic infiltration and associated organising pneumonia - features all highly suggestive of drug induced lung disease. Following withdrawal of both sertraline and risperidone and initiation of corticosteroid therapy the patient's respiratory failure resolved and three years later he remains well albeit limited by breathlessness on heavy exertion. Conclusion Drug induced lung disease can be rapidly progressive and if drug exposure continues may result in respiratory failure and death. Prompt recognition is critical as drug withdrawal may result in marked resolution of disease. This case highlights sertraline and risperidone as drugs that may, in susceptible individuals, cause diffuse pulmonary fibrosis. PMID:20062766

  12. Combined pulmonary fibrosis and emphysema (CPFE): what radiologist should know.

    PubMed

    Ciccarese, Federica; Attinà, Domenico; Zompatori, Maurizio

    2016-07-01

    Combined pulmonary fibrosis and emphysema is a relatively newly defined entity, which has been deeply studied in the recent years. Despite the wide numbers of papers on this topic, there are still several open questions about pathogenesis, epidemiology, natural history and prognosis. The diagnosis could be assessed only after HRCT scan as functional tests often result in an underestimation of this syndrome. What radiologists need to know about this syndrome consists in the heterogeneity of appearances: emphysema is mainly paraseptal and fibrotic pattern could be variable, including the variant of airspace enlargement with fibrosis which needs to be differentiated from honeycombing. A special attention must be paid on complications which could worsen the prognosis, such as pulmonary hypertension and lung cancer. Further studies are needed to address if the type of fibrotic pattern as well as fibrosis CT index could be considered as prognostic factors. Thus, the role of radiologists in the management of these patients is crucial as it involves diagnosis, detection of complications and could possible concerns the identification of patients at higher risk.

  13. Smoking-related idiopathic interstitial pneumonia: A review.

    PubMed

    Margaritopoulos, George A; Harari, Sergio; Caminati, Antonella; Antoniou, Katerina M

    2016-01-01

    For many years, cigarette smoking has been considered as the leading cause of chronic obstructive pulmonary disease and lung cancer. Recently, however, it has also been associated with the development of diffuse interstitial lung diseases. In the latest classification of the major idiopathic interstitial pneumonias (IIP), the term smoking-related IIP has been introduced, including two entities, namely desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-interstitial lung disease (RB-ILD). Other entities in which smoking has a definite or suggested role include pulmonary Langerhan's cell histiocytosis, smoking-related interstitial fibrosis, combined pulmonary fibrosis and emphysema syndrome and idiopathic pulmonary fibrosis. In this review, we will focus on the mechanisms of smoking-related lung damage and on the clinical aspects of these disorders with the exception of idiopathic pulmonary fibrosis, which will be reviewed elsewhere in this review series.

  14. Effects of leflunomide on inflamation and fibrosis in bleomycine induced pulmonary fibrosis in wistar albino rats

    PubMed Central

    Guzel, Aygul; Duran, Latif; Tutuncu, Serife; Guzel, Ahmet; Gunaydın, Mithat; Salis, Osman; Okuyucu, Ali; Selcuk, Mustafa Yasin

    2013-01-01

    Purposes Pulmonary fibrosis is a rare and progressive lung disease with a high mortality rate. The treatment regimens still fail to recover the disease. Leflunomide (LEF) is an immunomodulatory agent with antiproliferative activity that is used for the treatment of rheumatoid arthritis. The purpose of the study is to investigate the potential therapeutic efficacy of LEF in bleomycin (BLM) induced pulmonary fibrosis. Methods A total of 21 male, adult wistar albino rats were used. The animals were divided into three groups as control, BLM and BLM plus LEF groups (n=7). In BLM group, mice were treated with intratracheal instillation of BLM (2.5 U/kg). Control group received the same volume of saline instead of BLM. In LEF group, in addition to BLM, LEF (10 mg/kg, daily) was administrated by oral gavage. The effect of LEF on pulmonary inflammation and fibrosis was studied by measurements of serum clara cell protein-16 (CC-16), thiobarbituric acid reactive substance levels (TBARS), superoxide dismutase (SOD) and advanced oxidation protein products (AOPP) levels and lung tissue contents of IL-6, TNF-α and NF-κB by immunhistochemical examinations. Results LEF significantly increased the level of CC-16 and decreased the level of AOPP (P=0.042 and P=0.003 respectively). Lung tissue contents of IL-6, TNF-α and NF-κB significantly decreased in LEF group compared to BLM group by immunhistochemical examinations (P<0.001). Conclusions LEF reduces oxidative stress factors, alveolar inflammation and attenuates lung injury and fibrosis. PMID:24255778

  15. Pulmonary hypertension

    MedlinePlus

    Pulmonary arterial hypertension; Sporadic primary pulmonary hypertension; Familial primary pulmonary hypertension; Idiopathic pulmonary arterial hypertension; Primary pulmonary hypertension; PPH; Secondary pulmonary ...

  16. Diagnostic Values For Club Cell Secretory Protein (CC16) in Serum of Patients of Combined Pulmonary Fibrosis and Emphysema.

    PubMed

    Kokuho, Nariaki; Ishii, Takeo; Kamio, Koichiro; Hayashi, Hiroki; Kurahara, Misuzu; Hattori, Kumiko; Motegi, Takashi; Azuma, Arata; Gemma, Akihiko; Kida, Kozui

    2015-08-01

    Combined pulmonary fibrosis and emphysema (CPFE) is an under-recognized syndrome for which the diagnostic use of serum biomarkers is an attractive possibility. We hypothesized that CC16 and/or TGF-β1 or combinations with other biomarkers are useful for diagnosing CPFE. Patients with respiratory symptoms and a smoking history, with or without chronic obstructive pulmonary disease, were divided into the following three groups according to findings of high-resolution computed tomography of the chest: controls without either emphysema or fibrosis, patients with emphysema alone, and patients compatible with the diagnosis of CPFE. Serum concentrations of CC16, TGF-β1, SP-D, and KL-6 were measured in patients whose condition was stable for at least 3 months. To investigate changes in biomarkers of lung fibrosis in patients with a life-long smoking history, additional measurements were performed on the patients with idiopathic pulmonary fibrosis (IPF) of smoking history. The mean age of the first three groups was 68.0 years, whereas that of the IPF group was 71.8 years, and the groups contained 36, 115, 27, and 10 individuals, respectively. The serum concentration of CC16 in the four groups was 5.67 ± 0.42, 5.66 ± 0.35, 9.38 ± 1.04 and 22.15 ± 4.64 ng/ml, respectively, indicating that those patients with lung fibrosis had a significantly higher concentration. The combined use of CC16, SP-D, and KL-6 provided supportive diagnosis in conjunction with radiological imaging in diagnosis of CPFE. We conclude that a combination of biomarkers including CC16 could provide useful information to screen and predict the possible diagnosis of CPFE.

  17. TAZ contributes to pulmonary fibrosis by activating profibrotic functions of lung fibroblasts

    PubMed Central

    Noguchi, Satoshi; Saito, Akira; Mikami, Yu; Urushiyama, Hirokazu; Horie, Masafumi; Matsuzaki, Hirotaka; Takeshima, Hideyuki; Makita, Kosuke; Miyashita, Naoya; Mitani, Akihisa; Jo, Taisuke; Yamauchi, Yasuhiro; Terasaki, Yasuhiro; Nagase, Takahide

    2017-01-01

    Transcriptional coactivator with PDZ-binding motif (TAZ) regulates a variety of biological processes. Nuclear translocation and activation of TAZ are regulated by multiple mechanisms, including actin cytoskeleton and mechanical forces. TAZ is involved in lung alveolarization during lung development and Taz-heterozygous mice are resistant to bleomycin-induced lung fibrosis. In this study, we explored the roles of TAZ in the pathogenesis of idiopathic pulmonary fibrosis (IPF) through histological analyses of human lung tissues and cell culture experiments. TAZ was highly expressed in the fibroblastic foci of lungs from patients with IPF. TAZ controlled myofibroblast marker expression, proliferation, migration, and matrix contraction in cultured lung fibroblasts. Importantly, actin stress fibers and nuclear accumulation of TAZ were more evident when cultured on a stiff matrix, suggesting a feedback mechanism to accelerate fibrotic responses. Gene expression profiling revealed TAZ-mediated regulation of connective tissue growth factor (CTGF) and type I collagen. Clinical relevance of TAZ-regulated gene signature was further assessed using publicly available transcriptome data. These findings suggest that TAZ is involved in the pathogenesis of IPF through multifaceted effects on lung fibroblasts. PMID:28195168

  18. Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis.

    PubMed

    Kosanovic, Djuro; Luitel, Himal; Dahal, Bhola Kumar; Cornitescu, Teodora; Janssen, Wiebke; Danser, A H Jan; Garrelds, Ingrid M; De Mey, Jo G R; Fazzi, Gregorio; Schiffers, Paul; Iglarz, Marc; Fischli, Walter; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Grimminger, Friedrich; Seeger, Werner; Reiss, Irwin; Schermuly, Ralph Theo

    2015-10-01

    Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form.

  19. What Are the Signs and Symptoms of Idiopathic Pulmonary Fibrosis?

    MedlinePlus

    ... you may be short of breath only during exercise. Over time, you'll likely feel breathless even ... infections, blood clots in the lungs, and lung cancer. As the disease worsens, you may develop other potentially life-threatening ... This Content: NEXT >> ...

  20. Effect of sinus surgery on pulmonary function in patients with cystic fibrosis.

    PubMed

    Madonna, D; Isaacson, G; Rosenfeld, R M; Panitch, H

    1997-03-01

    The impact of sinus surgery on the pulmonary status of cystic fibrosis patients is unknown. This retrospective study reviewed the charts of the cystic fibrosis patients presenting to our institution's cystic fibrosis center with nasal obstruction, recurrent sinusitis, and nasal polyposis. This group subsequently underwent endoscopic ethmoidectomy and antrostomy. Fourteen of the 15 patients, ages 5-24 years, received preoperative and postoperative pulmonary function testing obtained by spirometry. The data were compiled and analyzed statistically. Our results suggested no significant improvement in the pulmonary function of cystic fibrosis patients after sinus surgery.

  1. Premature opening of the pulmonary valve in endomyocardial fibrosis.

    PubMed

    Okamoto, M; Amioka, H; Hashimoto, M; Shimamoto, H; Sakura, E; Yokote, Y; Yamagata, T; Tsuchioka, Y; Matsuura, H; Kajiyama, G

    1988-01-01

    Two-dimensional and Doppler echocardiographic findings in a 67-year-old man with endomyocardial fibrosis (EMF) are described. The two-dimensional echocardiogram showed typical features of EMF, right ventricular endomyocardial calcification, a thickened right ventricular wall, obliteration of the apex of the right ventricle and marked dilatation of the right atrium. In addition, premature opening of the pulmonary valve was observed during late diastole. The Doppler echocardiogram revealed forward flow from the right ventricle to the pulmonary artery, indicating the conduit state of the right ventricle. These findings were supported by cardiac catheterization and autopsy. Thus, two-dimensional and Doppler echocardiography are useful not only in making the diagnosis, but also in understanding the hemodynamic condition in EMF.

  2. ABCA3 mutations led to pulmonary fibrosis and emphysema with pulmonary hypertension in an 8-year-old girl.

    PubMed

    Ota, Chiharu; Kimura, Masato; Kure, Shigeo

    2016-06-01

    ABCA3 is highly expressed in alveolar epithelial type 2 cells and is associated with surfactant homeostasis. Patients with ABCA3 mutations develop various respiratory complications, such as fatal respiratory distress syndrome or interstitial lung disease. We describe a patient with pulmonary fibrosis and emphysema with pulmonary hypertension, associated with compound heterozygous mutations of the ABCA3 gene. This is the first report showing that mutations in the ABCA3 gene lead to pulmonary fibrosis and emphysema, including combined pulmonary fibrosis and emphysema, in childhood. Treatment with prostacyclin analogue, warfarin, and inhaled oxygen was effective to improve patient's hemodynamic condition as well as pulmonary fibrosis and emphysema. Pediatr Pulmonol. 2016;51:E21-E23. © 2016 Wiley Periodicals, Inc.

  3. The role of circulating mesenchymal progenitor cells (fibrocytes) in the pathogenesis of pulmonary fibrosis.

    PubMed

    Strieter, Robert M; Keeley, Ellen C; Hughes, Molly A; Burdick, Marie D; Mehrad, Borna

    2009-11-01

    Pulmonary fibrosis is associated with a number of disorders that affect the lung. Although there are several cellular types that are involved in the pathogenesis pulmonary fibrosis, the resident lung fibroblast has been viewed traditionally as the primary cell involved in promoting the deposition of ECM that culminates in pulmonary fibrosis. However, recent findings demonstrate that a circulating cell (i.e., the fibrocyte) can contribute to the evolution of pulmonary fibrosis. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that express a variety of cell-surface markers related to leukocytes, hematopoietic progenitor cells, and fibroblasts. Fibrocytes are unique in that they are capable of differentiating into fibroblasts and myofibroblasts, as well as adipocytes. In this review, we present data supporting the critical role these cells play in the pathogenesis of pulmonary fibrosis.

  4. The Chinese Herbal Medicine Formula mKG Suppresses Pulmonary Fibrosis of Mice Induced by Bleomycin.

    PubMed

    Gao, Ying; Yao, Li-Fu; Zhao, Yang; Wei, Li-Man; Guo, Peng; Yu, Meng; Cao, Bo; Li, Tan; Chen, Hong; Zou, Zhong-Mei

    2016-02-15

    Pulmonary fibrosis (PF) is a serious progressive lung disease and it originates from inflammation-induced parenchymal injury with excessive extracellular matrix deposition to result in the destruction of the normal lung architecture. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicine, has a prominent anti-inflammatory effect. The present study is to explore the inhibitory effects of mKG on bleomycin (BLM)-induced pulmonary fibrosis in mice. mKG significantly decreased pulmonary alveolitis, fibrosis scores, and interleukin-6 (IL-6), interleukin-17 (IL-17), transforming growth factor-β (TGF-β) and hydroxyproline (HYP) levels in lung tissue of mice compared with BLM treatment. It markedly alleviated the increase of HYP content in the lung tissues and pathologic changes of pulmonary fibrosis caused by BLM instillation. In conclusion, mKG has an anti-fibrotic effect and might be employed as a therapeutic candidate agent for attenuating pulmonary fibrosis.

  5. Protective roles of polysaccharides from Ganoderma lucidum on bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Chen, Jianhui; Shi, Yingying; He, Lian; Hao, Hairong; Wang, Baolan; Zheng, Yulong; Hu, Chengping

    2016-11-01

    The purpose of this paper was to investigate the protective effects of polysaccharides from (PGL) Ganoderma lucidum on bleomycin-induced pulmonary fibrosis in rats. Our study demonstrated that treatment with PGL of 100-300mg/kg for 28 days led to significant reduction in the pulmonary index, inflammatory cell infiltration and collagen deposition in rats with bleomycin-induced pulmonary fibrosis, which was associated with increased levels of glutathione, glutathione peroxidase, catalase and superoxide dismutase and decreased contents of malondialdehyde and hydroxyproline in the lung. These results indicated that PGL played a positive protective role in the pulmonary fibrosis and its possible mechanism was to improve lung antioxidant ability.

  6. Regulation of pulmonary fibrosis by chemokine receptor CXCR3

    PubMed Central

    Jiang, Dianhua; Liang, Jiurong; Hodge, Jennifer; Lu, Bao; Zhu, Zhou; Yu, Shuang; Fan, Juan; Gao, Yunfei; Yin, Zhinan; Homer, Robert; Gerard, Craig; Noble, Paul W.

    2004-01-01

    CXC chemokine receptor 3 (CXCR3) is the receptor for the IFN-γ–inducible C-X-C chemokines MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11. CXCR3 is expressed on activated immune cells and proliferating endothelial cells. The role of CXCR3 in fibroproliferation has not been investigated. We examined the role of CXCR3 in pulmonary injury and repair in vivo. CXCR3-deficient mice demonstrated increased mortality with progressive interstitial fibrosis relative to WT mice. Increased fibrosis occurred without increased inflammatory cell recruitment. CXCR3 deficiency resulted in both a reduced early burst of IFN-γ production and decreased expression of CXCL10 after lung injury. We identified a relative deficiency in lung NK cells in the unchallenged CXCR3-deficient lung and demonstrated production of IFN-γ by WT lung NK cells in vivo following lung injury. The fibrotic phenotype in the CXCR3-deficient mice was significantly reversed following administration of exogenous IFN-γ or restoration of endogenous IFN-γ production by adoptive transfer of WT lymph node and spleen cells. Finally, pretreatment of WT mice with IFN-γ–neutralizing Ab’s enhanced fibrosis following lung injury. These data demonstrate a nonredundant role for CXCR3 in limiting tissue fibroproliferation and suggest that this effect may be mediated, in part, by the innate production of IFN-γ following lung injury. PMID:15254596

  7. Metformin Reduces Bleomycin-induced Pulmonary Fibrosis in Mice.

    PubMed

    Choi, Sun Mi; Jang, An Hee; Kim, Hyojin; Lee, Kyu Hwa; Kim, Young Whan

    2016-09-01

    Metformin has anti-inflammatory and anti-fibrotic effects. We investigated whether metformin has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis in a murine model. A total of 62 mice were divided into 5 groups: control, metformin (100 mg/kg), BLM, and BLM with metformin (50 mg/kg or 100 mg/kg). Metformin was administered to the mice orally once a day from day 1. We sacrificed half of the mice on day 10 and collected the bronchoalveolar lavage fluid (BALF) from their left lungs. The remaining mice were sacrificed and analyzed on day 21. The right lungs were harvested for histological analyses. The messenger RNA (mRNA) levels of epithelial-mesenchymal transition markers were determined via analysis of the harvested lungs on day 21. The mice treated with BLM and metformin (50 mg/kg or 100 mg/kg) showed significantly lower levels of inflammatory cells in the BALF compared with the BLM-only mice on days 10 and 21. The histological examination revealed that the metformin treatment led to a greater reduction in inflammation than the treatment with BLM alone. The mRNA levels of collagen, collagen-1, procollagen, fibronectin, and transforming growth factor-β in the metformin-treated mice were lower than those in the BLM-only mice on day 21, although statistical significance was observed only in the case of procollagen due to the small number of live mice in the BLM-only group. Additionally, treatment with metformin reduced fibrosis to a greater extent than treatment with BLM alone. Metformin suppresses the inflammatory and fibrotic processes of BLM-induced pulmonary fibrosis in a murine model.

  8. Inhibition of Transglutaminase 2, a Novel Target for Pulmonary Fibrosis, by Two Small Electrophilic Molecules

    PubMed Central

    Olsen, Keith C.; Epa, Amali P.; Kulkarni, Ajit A.; Kottmann, R. Matthew; McCarthy, Claire E.; Johnson, Gail V.; Thatcher, Thomas H.; Phipps, Richard P.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrotic destruction of normal lung architecture. Due to a lack of effective treatment options, new treatment approaches are needed. We previously identified transglutaminase (TG)2, a multifunctional protein expressed by human lung fibroblasts (HLFs), as a positive driver of fibrosis. TG2 catalyzes crosslinking of extracellular matrix proteins, enhances cell binding to fibronectin and integrin, and promotes fibronectin expression. We investigated whether the small electrophilic molecules 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2) inhibit the expression and profibrotic functions of TG2. CDDO and 15d-PGJ2 reduced expression of TG2 mRNA and protein in primary HLFs from control donors and donors with IPF. CDDO and 15d-PGJ2 also decreased the in vitro profibrotic effector functions of HLFs including collagen gel contraction and cell migration. The decrease in TG2 expression did not occur through activation of the peroxisome proliferator activated receptor γ or generation of reactive oxidative species. CDDO and 15d-PGJ2 inhibited the extracellular signal–regulated kinase pathway, resulting in the suppression of TG2 expression. This is the first study to show that small electrophilic compounds inhibit the expression and profibrotic effector functions of TG2, a key promoter of fibrosis. These studies identify new and important antifibrotic activities of these two small molecules, which could lead to new treatments for fibrotic lung disease. PMID:24175906

  9. Inhibition of transglutaminase 2, a novel target for pulmonary fibrosis, by two small electrophilic molecules.

    PubMed

    Olsen, Keith C; Epa, Amali P; Kulkarni, Ajit A; Kottmann, R Matthew; McCarthy, Claire E; Johnson, Gail V; Thatcher, Thomas H; Phipps, Richard P; Sime, Patricia J

    2014-04-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrotic destruction of normal lung architecture. Due to a lack of effective treatment options, new treatment approaches are needed. We previously identified transglutaminase (TG)2, a multifunctional protein expressed by human lung fibroblasts (HLFs), as a positive driver of fibrosis. TG2 catalyzes crosslinking of extracellular matrix proteins, enhances cell binding to fibronectin and integrin, and promotes fibronectin expression. We investigated whether the small electrophilic molecules 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2) inhibit the expression and profibrotic functions of TG2. CDDO and 15d-PGJ2 reduced expression of TG2 mRNA and protein in primary HLFs from control donors and donors with IPF. CDDO and 15d-PGJ2 also decreased the in vitro profibrotic effector functions of HLFs including collagen gel contraction and cell migration. The decrease in TG2 expression did not occur through activation of the peroxisome proliferator activated receptor γ or generation of reactive oxidative species. CDDO and 15d-PGJ2 inhibited the extracellular signal-regulated kinase pathway, resulting in the suppression of TG2 expression. This is the first study to show that small electrophilic compounds inhibit the expression and profibrotic effector functions of TG2, a key promoter of fibrosis. These studies identify new and important antifibrotic activities of these two small molecules, which could lead to new treatments for fibrotic lung disease.

  10. Dramatic response of a patient with pregnancy induced idiopathic pulmonary arterial hypertension to sildenafil treatment.

    PubMed

    Taçoy, Gülten; Ekim, Numan Nadir; Cengel, Atiye

    2010-04-01

    Idiopathic pulmonary arterial hypertension (IPAH) is characterized by a progressive increase in pulmonary vascular resistance, which may lead to right ventricular failure and death. Major cardiovascular and pulmonary alterations occur during pregnancy and therefore worsen or increase the complications of pulmonary arterial hypertension (PAH). A patient diagnosed with IPAH after a successful full-term pregnancy and cesarean section with epidural anesthesia is presented. The postoperative course was complicated by progressive dyspnea, and lower limb edema. The outcome of treatment with sildenafil during puerperium was favorable in this patient. The clinical course was complicated by an unexpected spontaneous pregnancy after primary infertility.

  11. Intratracheal Bleomycin Aerosolization: The Best Route of Administration for a Scalable and Homogeneous Pulmonary Fibrosis Rat Model?

    PubMed Central

    Robbe, Alexandre; Tassin, Alexandra; Carpentier, Justine; Declèves, Anne-Emilie; Mekinda Ngono, Zita Léa; Nonclercq, Denis; Legrand, Alexandre

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic disease with a poor prognosis and is characterized by the accumulation of fibrotic tissue in lungs resulting from a dysfunction in the healing process. In humans, the pathological process is patchy and temporally heterogeneous and the exact mechanisms remain poorly understood. Different animal models were thus developed. Among these, intratracheal administration of bleomycin (BML) is one of the most frequently used methods to induce lung fibrosis in rodents. In the present study, we first characterized histologically the time-course of lung alteration in rats submitted to BLM instillation. Heterogeneous damages were observed among lungs, consisting in an inflammatory phase at early time-points. It was followed by a transition to a fibrotic state characterized by an increased myofibroblast number and collagen accumulation. We then compared instillation and aerosolization routes of BLM administration. The fibrotic process was studied in each pulmonary lobe using a modified Ashcroft scale. The two quantification methods were confronted and the interobserver variability evaluated. Both methods induced fibrosis development as demonstrated by a similar progression of the highest modified Ashcroft score. However, we highlighted that aerosolization allows a more homogeneous distribution of lesions among lungs, with a persistence of higher grade damages upon time. PMID:26064885

  12. Human Adipose-derived Mesenchymal Stem Cells Attenuate Early Stage of Bleomycin Induced Pulmonary Fibrosis: Comparison with Pirfenidone

    PubMed Central

    Reddy, Manoj; Fonseca, Lyle; Gowda, Shashank; Chougule, Basavraj; Hari, Aarya; Totey, Satish

    2016-01-01

    Background and Objectives Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, invariably fatal fibrotic lung disease with no lasting option for therapy. Mesenchymal stem cells (MSCs) could be a promising modality for the treatment of IPF. Aim of the study was to investigate improvement in survivability and anti-fibrotic efficacy of human adipose-derived mesenchymal stem cells (AD-MSCs) in comparison with pirfenidone in the bleomycin-induced pulmonary fibrosis model. Methods Human AD-MSCs were administered intravenously on day 3, 6 and 9 after an intra-tracheal challenge with bleomycin, whereas, pirfenidone was given orally in drinking water at the rate of 100 mg/kg body weight three times a day daily from day 3 onward. AD-MSCs were labelled with PKH-67 before administration to detect engraftment. Disease severity and improvement was assessed and compared between sham control and vehicle control groups using Kaplan-Meier survival analysis, biochemical and molecular analysis, histopathology and high resolution computed tomography (HRCT) parameters at the end of study. Results Results demonstrated that AD-MSCs significantly increase survivability; reduce organ weight and collagen deposition better than pirfenidone group. Histological analyses and HRCT of the lung revealed that AD-MSCs afforded protection against bleomycin induced fibrosis and protect architecture of the lung. Gene expression analysis revealed that AD-MSCs potently suppressed pro-fibrotic genes induced by bleomycin. More importantly, AD-MSCs were found to inhibit pro-inflammatory related transcripts. Conclusions Our results provided direct evidence that AD-MSC-mediated immunomodulation and anti-fibrotic effect in the lungs resulted in marked protection in pulmonary fibrosis, but at an early stage of disease. PMID:27871152

  13. Amniotic fluid stem cells inhibit the progression of bleomycin-induced pulmonary fibrosis via CCL2 modulation in bronchoalveolar lavage.

    PubMed

    Garcia, Orquidea; Carraro, Gianni; Turcatel, Gianluca; Hall, Marisa; Sedrakyan, Sargis; Roche, Tyler; Buckley, Sue; Driscoll, Barbara; Perin, Laura; Warburton, David

    2013-01-01

    The potential for amniotic fluid stem cell (AFSC) treatment to inhibit the progression of fibrotic lung injury has not been described. We have previously demonstrated that AFSC can attenuate both acute and chronic-fibrotic kidney injury through modification of the cytokine environment. Fibrotic lung injury, such as in Idiopathic Pulmonary Fibrosis (IPF), is mediated through pro-fibrotic and pro-inflammatory cytokine activity. Thus, we hypothesized that AFSC treatment might inhibit the progression of bleomycin-induced pulmonary fibrosis through cytokine modulation. In particular, we aimed to investigate the effect of AFSC treatment on the modulation of the pro-fibrotic cytokine CCL2, which is increased in human IPF patients and is correlated with poor prognoses, advanced disease states and worse fibrotic outcomes. The impacts of intravenous murine AFSC given at acute (day 0) or chronic (day 14) intervention time-points after bleomycin injury were analyzed at either day 3 or day 28 post-injury. Murine AFSC treatment at either day 0 or day 14 post-bleomycin injury significantly inhibited collagen deposition and preserved pulmonary function. CCL2 expression increased in bleomycin-injured bronchoalveolar lavage (BAL), but significantly decreased following AFSC treatment at either day 0 or at day 14. AFSC were observed to localize within fibrotic lesions in the lung, showing preferential targeting of AFSC to the area of fibrosis. We also observed that MMP-2 was transiently increased in BAL following AFSC treatment. Increased MMP-2 activity was further associated with cleavage of CCL2, rendering it a putative antagonist for CCL2/CCR2 signaling, which we surmise is a potential mechanism for CCL2 reduction in BAL following AFSC treatment. Based on this data, we concluded that AFSC have the potential to inhibit the development or progression of fibrosis in a bleomycin injury model during both acute and chronic remodeling events.

  14. Association of idiopathic retroperitoneal fibrosis, rapidly progressive glomerulonephritis and antiproteinase 3 antineutrophil cytoplasmic antibodies (anti PR3-ANCA).

    PubMed

    Martínez-Odriozola, P; Gutiérrez-Macías, A; Moina Eguren, I; Arrieta Lezama, J

    2008-09-01

    We report a case of idiopathic retroperitoneal fibrosis and rapidly progressive glomerulonephritis with serum antiproteinase 3 antineutrophil cytoplasmic antibodies (anti-PR3-ANCA), without clinical or histological signs of Wegener's granulomatosis, in a 46-year-old man. Our case and previously reported cases showing the same association support the hypothesis that the association is not fortuitous, but reflects a common immunological mechanism.

  15. Deficiency of developmental endothelial locus-1 (Del-1) aggravates bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Kang, Yoon-Young; Kim, Dong-Young; Lee, Seung-Hwan; Choi, Eun Young

    2014-03-07

    Pulmonary fibrosis is a lung disease wherein lung parenchyma is gradually and irreversibly replaced with collagen. The molecular pathogenesis of pulmonary fibrosis is not fully understood and the only effective treatment available is lung transplantation. To test if Del-1, an endogenous anti-inflammatory molecule, may be implicated in the development of pulmonary fibrosis, we induced pulmonary fibrosis in wild type (WT) and Del-1(-/-) mice by intratracheal administration of bleomycin. Del-1 expression in the lung was decreased in the WT mice treated with bleomycin compared to control mice. In addition, bleomycin-induced pulmonary fibrosis increased collagen deposition and TGF-β production in the lung of Del-1(-/-) mice. Finally, Del-1(-/-) mice treated with bleomycin displayed higher weight loss and greater mortality than did WT mice identically treated. These findings suggest that Del-1 may negatively regulate development of pulmonary fibrosis. Further delineation of a role for Del-1 in the development of pulmonary fibrosis will broaden our understanding of the molecular pathogenesis of this disease and hopefully help develop potential therapeutics.

  16. Loss of Matrix Metalloproteinase-13 Attenuates Murine Radiation-Induced Pulmonary Fibrosis

    SciTech Connect

    Flechsig, Paul; Hartenstein, Bettina; Teurich, Sybille; Dadrich, Monika; Hauser, Kai; Abdollahi, Amir; Groene, Hermann-Josef; Angel, Peter; Huber, Peter E.

    2010-06-01

    Purpose: Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMP13 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse. Methods and Materials: We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57Bl/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome. Results: We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5-6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival. Conclusions: Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis.

  17. 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

  18. The role of circulating mesenchymal progenitor cells, fibrocytes, in promoting pulmonary fibrosis.

    PubMed

    Strieter, Robert M; Keeley, Ellen C; Burdick, Marie D; Mehrad, Borna

    2009-01-01

    The resident fibroblast has been traditionally viewed as the primary cell involved in promoting pulmonary fibrosis. However, contemporary findings now support the concept of a circulating cell (fibrocyte) that also contributes to pulmonary fibrosis. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that express a variety of cell surface markers related to leukocytes, hematopoietic progenitor cells and fibroblasts. Fibrocytes are unique in that they are capable of differentiating into fibroblasts and myofibroblasts, as well as adipocytes. In this review, we present data supporting the critical role these cells play in the pathogenesis of pulmonary fibrosis.

  19. [The role of oxygen radicals in bleomycin-induced pulmonary fibrosis].

    PubMed

    Wang, X Z

    1992-06-01

    A model of pulmonary fibrosis in rat has been developed using intratracheal administration of bleomycin (BLM) A5 (5mg/kg). Histopathologic features and total lung collagen were studied. We found that type I pneumocytes detached, basement membrane denuded and endothelia edema were the earliest changes in BLM induced pulmonary fibrosis. Serum MDA (an index of lipid peroxidation) level in rats receiving intratracheal bleomycin were increased at earlier time after bleomycin administration. Meanwhile, MDA level in the lung homogenate was elevated too. Our results indicated that the injured type I pneumocytes and endothelia caused by oxygen radicles are the fundamental damages in bleomycin-induced pulmonary fibrosis.

  20. Combined Pulmonary Fibrosis and Emphysema Preceding Lupus Pleuritis.

    PubMed

    Kamiya, Yosuke; Toyoshima, Mikio; Akiyama, Norimichi; Suda, Takafumi

    2016-01-01

    An 83-year-old man, who was a former smoker, with anti-ribonucleoprotein (RNP) antibody-positive combined pulmonary fibrosis and emphysema presented with a cough and dyspnea. A chest radiograph showed bilateral pleural effusions. His laboratory data showed proteinuria and elevated levels of anti-nuclear antibodies, anti-double strand DNA antibodies, and CA125, with decreased serum complement levels. Thoracentesis showed an exudative pleural effusion with an increased lymphocyte count and elevated CA125 levels. A thoracoscopic biopsy specimen showed proliferation of CA125-positive mesothelial cells. Systemic lupus erythematosus was diagnosed. His symptoms and pleural effusion resolved after the initiation of systemic corticosteroid therapy. The detection of anti-RNP antibody and CA125 levels are helpful in the diagnosis of lupus pleuritis.

  1. Determinants of pulmonary fibrosis and lipidosis in the silica model.

    PubMed

    Heppleston, A G

    1986-12-01

    The conditions which might favour development of the fibrotic or the lipid component of the pulmonary reaction to inhaled quartz were examined in rats. Smaller particle size and freedom from surface contamination by amorphous silica or iron oxide, status of the animals whether specific pathogen-free or conventional, and the resistance of cell membranes to damage appeared to bear on fibrogenesis. Increased membrane stability by treatment with polyvinylpyridine-N-oxide abolished not only the fibrosis but also the response of type II cells and hence lipidosis. The rate and intensity of quartz deposition may also affect the response, a low concentration inhaled over a long period favouring nodulation. No other manipulations, environmental or pharmacological, succeeded in inhibiting lipidosis to the benefit of fibrosis. Guinea pigs, however, behaved differently, their reaction being characterized by massive alveolar accumulation of dust-bearing macrophages and type II cell hyperplasia but not by lipidosis. The species variation is unexplained but macrophage predominance may represent a phase that later transforms to lipidosis. The experimental findings may have implications for forms of pneumoconiosis other than silicosis.

  2. Genotype-phenotype correlation for pulmonary function in cystic fibrosis

    PubMed Central

    de Gracia, J; Mata, F; Alvarez, A; Casals, T; Gatner, S; Vendrell, M; de la Rosa, D; Guarner, L; Hermosilla, E

    2005-01-01

    Background: Since the CFTR gene was cloned, more than 1000 mutations have been identified. To date, a clear relationship has not been established between genotype and the progression of lung damage. A study was undertaken of the relationship between genotype, progression of lung disease, and survival in adult patients with cystic fibrosis (CF). Methods: A prospective cohort of adult patients with CF and two CFTR mutations followed up in an adult cystic fibrosis unit was analysed. Patients were classified according to functional effects of classes of CFTR mutations and were grouped based on the CFTR molecular position on the epithelial cell surface (I–II/I–II, I–II/III–V). Spirometric values, progression of lung disease, probability of survival, and clinical characteristics were analysed between groups. Results: Seventy four patients were included in the study. Patients with genotype I–II/I–II had significantly lower current spirometric values (p<0.001), greater loss of pulmonary function (p<0.04), a higher proportion of end-stage lung disease (p<0.001), a higher risk of suffering from moderate to severe lung disease (odds ratio 7.12 (95% CI 1.3 to 40.5)) and a lower probability of survival than patients with genotype I–II/III, I–II/IV and I–II/V (p<0.001). Conclusions: The presence of class I or II mutations on both chromosomes is associated with worse respiratory disease and a lower probability of survival. PMID:15994263

  3. Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4

    PubMed Central

    Jiang, Dianhua; Liang, Jiurong; Campanella, Gabriele S.; Guo, Rishu; Yu, Shuang; Xie, Ting; Liu, Ningshan; Jung, Yoosun; Homer, Robert; Meltzer, Eric B.; Li, Yuejuan; Tager, Andrew M.; Goetinck, Paul F.; Luster, Andrew D.; Noble, Paul W.

    2010-01-01

    Pulmonary fibrosis is a progressive, dysregulated response to injury culminating in compromised lung function due to excess extracellular matrix production. The heparan sulfate proteoglycan syndecan-4 is important in mediating fibroblast-matrix interactions, but its role in pulmonary fibrosis has not been explored. To investigate this issue, we used intratracheal instillation of bleomycin as a model of acute lung injury and fibrosis. We found that bleomycin treatment increased syndecan-4 expression. Moreover, we observed a marked decrease in neutrophil recruitment and an increase in both myofibroblast recruitment and interstitial fibrosis in bleomycin-treated syndecan-4–null (Sdc4–/–) mice. Subsequently, we identified a direct interaction between CXCL10, an antifibrotic chemokine, and syndecan-4 that inhibited primary lung fibroblast migration during fibrosis; mutation of the heparin-binding domain, but not the CXCR3 domain, of CXCL10 diminished this effect. Similarly, migration of fibroblasts from patients with pulmonary fibrosis was inhibited in the presence of CXCL10 protein defective in CXCR3 binding. Furthermore, administration of recombinant CXCL10 protein inhibited fibrosis in WT mice, but not in Sdc4–/– mice. Collectively, these data suggest that the direct interaction of syndecan-4 and CXCL10 in the lung interstitial compartment serves to inhibit fibroblast recruitment and subsequent fibrosis. Thus, administration of CXCL10 protein defective in CXCR3 binding may represent a novel therapy for pulmonary fibrosis. PMID:20484822

  4. Amplification of TGFβ Induced ITGB6 Gene Transcription May Promote Pulmonary Fibrosis

    PubMed Central

    Tatler, Amanda L.; Goodwin, Amanda T.; Gbolahan, Olumide; Saini, Gauri; Porte, Joanne; John, Alison E.; Clifford, Rachel L.; Violette, Shelia M.; Weinreb, Paul H.; Parfrey, Helen; Wolters, Paul J.; Gauldie, Jack; Kolb, Martin; Jenkins, Gisli

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive disease with poor survival rates and limited treatment options. Upregulation of αvβ6 integrins within the alveolar epithelial cells is a characteristic feature of IPF and correlates with poor patient survival. The pro-fibrotic cytokine TGFβ1 can upregulate αvβ6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated. We confirm that stimulation with exogenous TGFβ1 increases expression of the integrin β6 subunit gene (ITGB6) and αvβ6 integrin cell surface expression in a time- and concentration-dependent manner. TGFβ1-induced ITGB6 expression occurs via transcriptional activation of the ITGB6 gene, but does not result from effects on ITGB6 mRNA stability. Basal expression of ITGB6 in, and αvβ6 integrins on, lung epithelial cells occurs via homeostatic αvβ6-mediated TGFβ1 activation in the absence of exogenous stimulation, and can be amplified by TGFβ1 activation. Fundamentally, we show for the first time that TGFβ1-induced ITGB6 expression occurs via canonical Smad signalling since dominant negative constructs directed against Smad3 and 4 inhibit ITGB6 transcriptional activity. Furthermore, disruption of a Smad binding site at -798 in the ITGB6 promoter abolishes TGFβ1-induced ITGB6 transcriptional activity. Using chromatin immunoprecipitation we demonstrate that TGFβ1 stimulation of lung epithelial cells results in direct binding of Smad3, and Smad4, to the ITGB6 gene promoter within this region. Finally, using an adenoviral TGFβ1 over-expression model of pulmonary fibrosis we demonstrate that Smad3 is crucial for TGFβ1-induced αvβ6 integrin expression within the alveolar epithelium in vivo. Together, these data confirm that a homeostatic, autocrine loop of αvβ6 integrin activated TGFβ1-induced ITGB6 gene expression regulates epithelial basal αvβ6 integrin expression, and demonstrates that this occurs via Smad

  5. Induction of pulmonary fibrosis by cerium oxide nanoparticles

    SciTech Connect

    Ma, Jane Y.; Mercer, Robert R.; Barger, Mark; Schwegler-Berry, Diane; Scabilloni, James; Ma, Joseph K.; Castranova, Vincent

    2012-08-01

    Cerium compounds have been used as a diesel engine catalyst to lower the mass of diesel exhaust particles, but are emitted as cerium oxide (CeO{sub 2}) nanoparticles in the diesel exhaust. In a previous study, we have demonstrated a wide range of CeO{sub 2}-induced lung responses including sustained pulmonary inflammation and cellular signaling that could lead to pulmonary fibrosis. In this study, we investigated the fibrogenic responses induced by CeO{sub 2} in a rat model at various time points up to 84 days post-exposure. Male Sprague Dawley rats were exposed to CeO{sub 2} by a single intratracheal instillation. Alveolar macrophages (AM) were isolated by bronchial alveolar lavage (BAL). AM-mediated cellular responses, osteopontin (OPN) and transform growth factor (TGF)-β1 in the fibrotic process were investigated. The results showed that CeO{sub 2} exposure significantly increased fibrotic cytokine TGF-β1 and OPN production by AM above controls. The collagen degradation enzymes, matrix metalloproteinase (MMP)-2 and -9 and the tissue inhibitor of MMP were markedly increased in the BAL fluid at 1 day- and subsequently declined at 28 days after exposure, but remained much higher than the controls. CeO{sub 2} induced elevated phospholipids in BAL fluid and increased hydroxyproline content in lung tissue in a dose- and time-dependent manner. Immunohistochemical analysis showed MMP-2, MMP-9 and MMP-10 expressions in fibrotic regions. Morphological analysis noted increased collagen fibers in the lungs exposed to a single dose of 3.5 mg/kg CeO{sub 2} and euthanized at 28 days post-exposure. Collectively, our studies show that CeO{sub 2} induced fibrotic lung injury in rats, suggesting it may cause potential health effects. -- Highlights: ► Cerium oxide exposure significantly affected the following parameters in the lung. ► Induced fibrotic cytokine OPN and TGF-β1 production and phospholipidosis. ► Caused imbalance of the MMP-9/ TIMP-1 ratio that favors fibrosis

  6. Role of thioredoxin nitration in bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Wang, Lei; Song, Yimin; Li, Xiankui; Guo, Haizhou; Zhang, Guojun

    2016-01-01

    Oxidant stimulation has been suggested to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our study aimed to investigate the role and mechanisms of thioredoxin (Trx) nitration during the development of IPF. A rat model of IPF was established by intratracheal instillation of bleomycin (BLM). Male Wistar rats were randomly distributed among the control group and BLM-treated group, in which rats were intratracheally instilled with a single dose of BLM (5.0 mg/kg body mass in 1.0 mL phosphate-buffered saline). At 7 or 28 days after instillation the rats were euthanized. Histopathological and biochemical examinations were performed. The activity and protein level of thioredoxin were assessed. The thioredoxin nitration level was determined using immunoprecipitation and immunoblotting techniques. Our results demonstrated that protein tyrosine nitration increased in the BLM-treated group compared with the control group. Trx activity decreased in the BLM group compared with control group, whereas Trx expression and nitration level increased dramatically in the BLM group compared with the control group. Our results indicated that Trx nitration might be involved in the pathogenesis of IPF.

  7. Pulmonary Fibrosis in Response to Environmental Cues and Molecular Targets Involved in Its Pathogenesis

    PubMed Central

    Yoshida, Toshinori; Ohnuma, Aya; Horiuchi, Haruka; Harada, Takanori

    2011-01-01

    Chronic lung injury resulting from a variety of different causes is frequently associated with the develop ment of pulmonary fibrosis in humans. Although the etiology of pulmonary fibrosis is generally unknown, several sources of evidence support the hypothesis that a number of environmental and occupational agents play an etiologic role in the pathogenesis of this disease. The agents discussed in this review include beryllium, nylon flock, textile printing aerosols, polyvinyl chloride and didecyldimethylammonium chloride. The authors also describe a variety of animal models, including genetically modified mice, in order to investigate the molecular mechanism of pulmonary fibrosis, focusing on chemokine receptors, regulatory T cells and transforming growth factor-β and bone morphogenetic protein signaling. Overall, we propose the concept of toxicological pulmonary fibrosis as a lung disease induced in response to environmental cues. PMID:22272040

  8. Are physicians in primary health care able to recognize pulmonary fibrosis?

    PubMed Central

    Purokivi, Minna; Hodgson, Ulla; Myllärniemi, Marjukka; Salomaa, Eija-Riitta; Kaarteenaho, Riitta

    2017-01-01

    ABSTRACT Background: The early diagnosis of idiopathic pulmonary fibrosis (IPF) has become increasingly important due to evolving treatment options. IPF patients experience a significant delay in receiving an accurate diagnosis, thus delayed access to tertiary care is associated with higher mortality independently from disease severity. Objective: The aims were to evaluate whether there had been a delay in the referral process, and to determine whether the referring doctors had suspected IPF or other interstitial lung disease (ILD) already during the time of referral. Methods: Ninety-five referral letters of patients with IPF identified from the FinnishIPF registry were evaluated with respect to time of referral, referring unit, grounds for referral, symptoms, smoking status, occupational history, clinical examinations, co-morbidities, medication, radiological findings and lung function. Results: Fifty-nine percent of referral letters originated from primary public health care. The time from symptom onset to referral was reported in 60% of cases, mean time being 1.5 (0.8–2.3) (95%CI) years. The main reason for referral was a suspicion of interstitial lung disease (ILD) (63%); changes in chest X-ray were one reason for referring in 53% of cases. Lung auscultation was reported in 70% and inspiratory crackles in 52% of referral letters. Conclusions: Primary care doctors suspected lung fibrosis early in the course of disease. Lung auscultation and chest X-rays were the most common investigational abnormalities in the referrals. Providing general practitioners with more information of ILDs might shorten the delay from symptom onset to referral. PMID:28326180

  9. Are physicians in primary health care able to recognize pulmonary fibrosis?

    PubMed

    Purokivi, Minna; Hodgson, Ulla; Myllärniemi, Marjukka; Salomaa, Eija-Riitta; Kaarteenaho, Riitta

    2017-01-01

    Background: The early diagnosis of idiopathic pulmonary fibrosis (IPF) has become increasingly important due to evolving treatment options. IPF patients experience a significant delay in receiving an accurate diagnosis, thus delayed access to tertiary care is associated with higher mortality independently from disease severity. Objective: The aims were to evaluate whether there had been a delay in the referral process, and to determine whether the referring doctors had suspected IPF or other interstitial lung disease (ILD) already during the time of referral. Methods: Ninety-five referral letters of patients with IPF identified from the FinnishIPF registry were evaluated with respect to time of referral, referring unit, grounds for referral, symptoms, smoking status, occupational history, clinical examinations, co-morbidities, medication, radiological findings and lung function. Results: Fifty-nine percent of referral letters originated from primary public health care. The time from symptom onset to referral was reported in 60% of cases, mean time being 1.5 (0.8-2.3) (95%CI) years. The main reason for referral was a suspicion of interstitial lung disease (ILD) (63%); changes in chest X-ray were one reason for referring in 53% of cases. Lung auscultation was reported in 70% and inspiratory crackles in 52% of referral letters. Conclusions: Primary care doctors suspected lung fibrosis early in the course of disease. Lung auscultation and chest X-rays were the most common investigational abnormalities in the referrals. Providing general practitioners with more information of ILDs might shorten the delay from symptom onset to referral.

  10. Low-dose paclitaxel ameliorates pulmonary fibrosis by suppressing TGF-β1/Smad3 pathway via miR-140 upregulation.

    PubMed

    Wang, Congjie; Song, Xiaodong; Li, Youjie; Han, Fang; Gao, Shuyan; Wang, Xiaozhi; Xie, Shuyang; Lv, Changjun

    2013-01-01

    Abnormal TGF-β1/Smad3 activation plays an important role in the pathogenesis of pulmonary fibrosis, which can be prevented by paclitaxel (PTX). This study aimed to investigate an antifibrotic effect of the low-dose PTX (10 to 50 nM in vitro, and 0.6 mg/kg in vivo). PTX treatment resulted in phenotype reversion of epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs) with increase of miR-140. PTX resulted in an amelioration of bleomycin (BLM)-induced pulmonary fibrosis in rats with reduction of the wet lung weight to body weight ratios and the collagen deposition. Our results further demonstrated that PTX inhibited the effect of TGF-β1 on regulating the expression of Smad3 and phosphorylated Smad3 (p-Smad3), and restored the levels of E-cadherin, vimentin and α-SMA. Moreover, lower miR-140 levels were found in idiopathic pulmonary fibrosis (IPF) patients, TGF-β1-treated AECs and BLM-instilled rat lungs. Through decreasing Smad3/p-Smad3 expression and upregulating miR-140, PTX treatment could significantly reverse the EMT of AECs and prevent pulmonary fibrosis of rats. The action of PTX to ameliorate TGF-β1-induced EMT was promoted by miR-140, which increased E-cadherin levels and reduced the expression of vimentin, Smad3 and p-Smad3. Collectively, our results demonstrate that low-dose PTX prevents pulmonary fibrosis by suppressing the TGF-β1/Smad3 pathway via upregulating miR-140.

  11. Penetration of Ciprofloxacin and Amikacin into the Alveolar Epithelial Lining Fluid of Rats with Pulmonary Fibrosis.

    PubMed

    Ni, Wentao; Yang, Deqing; Mei, Hekun; Zhao, Jin; Liang, Beibei; Bai, Nan; Chai, Dong; Cui, Junchang; Wang, Rui; Liu, Youning

    2017-04-01

    We determined the concentration-time profiles of ciprofloxacin and amikacin in serum and alveolar epithelial lining fluid (ELF) of rats with or without pulmonary fibrosis and investigated the effect of pulmonary fibrosis on the capacity for penetration of antimicrobials into the ELF of rats. Pulmonary fibrosis was induced in rats with a single intratracheal instillation of bleomycin. After intravenous injection of ciprofloxacin or amikacin, blood and bronchoalveolar lavage fluid samples were collected. Urea concentrations in serum and lavage fluid were determined using an enzymatic assay. Ciprofloxacin and amikacin concentrations were determined by high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry, respectively. The mean ratio of ELF to plasma concentrations of ciprofloxacin at each time point in the normal group did not significantly differ from that in the pulmonary fibrosis group. However, the ratio of the ciprofloxacin area under the concentration-time curve from 0 to 24 h (AUC0-24) in ELF to the AUC0-24 in plasma was 1.02 in the normal group and 0.76 in the pulmonary fibrosis group. The mean ELF-to-plasma concentration ratios of amikacin at each time point in the normal group were higher than those in the pulmonary fibrosis group, reaching a statistically significant difference at 1, 2, and 4 h. The ratio of the AUC0-24 in ELF to the AUC0-24 in plasma was 0.49 in the normal group and 0.27 in the pulmonary fibrosis group. In conclusion, pulmonary fibrosis can influence the penetration of antimicrobials into the ELF of rats and may have a marked effect on the penetration of amikacin than that of ciprofloxacin.

  12. Innate immunity dictates cytokine polarization relevant to the development of pulmonary fibrosis

    PubMed Central

    Strieter, Robert M.; Keane, Michael P.

    2004-01-01

    New data support the importance of the innate immune response in the resolution or progression of pulmonary fibrosis. The presence of CXC chemokine receptor 3–expressing cells, specifically pulmonary NK cells, is necessary to produce IFN-γ. This is critical in the polarization of the immune response to injury toward a favorable Th1 response and resolution. In contrast, a Th2 response is associated with progressive fibrosis. PMID:15254582

  13. The Effects of Aerosolized STAT1 Antisense Oligodeoxynucleotides on Rat Pulmonary Fibrosis

    PubMed Central

    Wang, Wenjun; Liao, Bin; Zeng, Ming; Zhu, Chen; Fan, Xianming

    2009-01-01

    Previous study showed that aerosolized signal transducer and activator of transcription-1 (STAT1) antisense oligodeoxynucleotide (ASON) inhibited the expression of STAT1 and ICAM-1 mRNA and protein in alveolar macrophages (AMs) and decreased the concentrations of TGF-β, PDGF and TNF-α in bronchioalveolar lavage fluid (BALF) in bleomycin (BLM)-induced rat pulmonary fibrosis. Administration of STAT1 ASON ameliorated alveolitis in rat pulmonary fibrosis. However, further investigations are needed to determine whether there is an effect from administration of STAT1 ASON on fibrosis. This study investigated the effect of aerosolized STAT1 ASON on the expressions of inflammatory mediators, hydroxyproline and type I and type III collagen mRNA in BLM-induced rat pulmonary fibrosis. The results showed that STAT1 ASON applied by aerosolization could ameliorate alveolitis and fibrosis, inhibit the expressions of inflammatory mediators, decrease the content of hydroxyproline, and suppress the expressions of type I and type III collagen mRNA in lung tissue in BLM-induced rat pulmonary fibrosis. These results suggest that aerosolized STAT1 ASON might be considered as a promising new strategy in the treatment of pulmonary fibrosis. PMID:19254480

  14. Self-Efficacy, Pulmonary Function, Perceived Health and Global Quality of Life of Cystic Fibrosis Patients

    ERIC Educational Resources Information Center

    Wahl, Astrid K.; Rustoen ,Tone; Hanestad, Berit R.; Gjengedal, Eva; Moum, Torbjorn

    2005-01-01

    This study examined the extent that pulmonary function is related to perceived health status and global quality of life in adults suffering from cystic fibrosis, and the extent that self-efficacy modifies these relationships. Our sample comprised 86 adults (48% female; mean age, 29 years; age range, 18-54 years) with cystic fibrosis, recruited…

  15. Nitric Oxide Mediates Bleomycin-Induced Angiogenesis and Pulmonary Fibrosis via Regulation of VEGF

    PubMed Central

    Iyer, Anand Krishnan V.; Ramesh, Vani; Castro, Carlos A.; Kaushik, Vivek; Kulkarni, Yogesh M.; Wright, Clayton A.; Venkatadri, Rajkumar; Rojanasakul, Yon; Azad, Neelam

    2015-01-01

    Pulmonary fibrosis is a progressive lung disease hallmarked by increased fibroblast proliferation, amplified levels of extracellular matrix deposition and increased angiogenesis. Although dysregulation of angiogenic mediators has been implicated in pulmonary fibrosis, the specific rate-limiting angiogenic markers involved and their role in the progression of pulmonary fibrosis remains unclear. We demonstrate that bleomycin treatment induces angiogenesis, and inhibition of the central angiogenic mediator VEGF using anti-VEGF antibody CBO-P11 significantly attenuates bleomycin-induced pulmonary fibrosis in vivo. Bleomycin-induced nitric oxide (NO) was observed to be the key upstream regulator of VEGF via the PI3k/Akt pathway. VEGF regulated other important angiogenic proteins including PAI-1 and IL-8 in response to bleomycin exposure. Inhibition of NO and VEGF activity significantly mitigated bleomycin-induced angiogenic and fibrogenic responses. NO and VEGF are key mediators of bleomycin-induced pulmonary fibrosis, and could serve as important targets against this debilitating disease. Overall, our data suggests an important role for angiogenic mediators in the pathogenesis of bleomycin-induced pulmonary fibrosis. PMID:25919965

  16. A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Takemasa, Akihiro; Ishii, Yoshiki; Fukuda, Takeshi

    2012-12-01

    Neutrophil elastase plays pivotal roles in the pathogenesis of pulmonary fibrosis. The neutrophil elastase inhibitor, sivelestat, could alleviate pulmonary fibrosis; however, the antifibrotic mechanisms have not yet been clarified. We examined the antifibrotic mechanisms, mainly focusing on a key fibrotic cytokine, transforming growth factor (TGF)-β1, in this study. To elucidate the antifibrotic mechanisms of sivelestat, we examined a murine model of bleomycin-induced early-stage pulmonary fibrosis. After intratracheal instillation of bleomycin, sivelestat was administered intraperitoneally once a day for 7 or 14 days. Bronchoalveolar lavage fluid and lung samples were examined on day 7 or day 14 after bleomycin instillation. In the bleomycin-induced early-stage pulmonary fibrosis model, the neutrophil elastase level was increased in the lungs. Sivelestat significantly inhibited the increase in lung collagen content, fibrotic changes, the numbers of total cells (including macrophages, neutrophils and lymphocytes), the levels of the active form of TGF-β1 and phospho-Smad2 in bleomycin-induced early-stage pulmonary fibrosis. The total TGF-β1 levels and relative changes of TGF-β1 mRNA expression, however, were not decreased significantly by sivelestat. These results suggest that sivelestat alleviated bleomycin-induced pulmonary fibrosis via inhibition of both TGF-β activation and inflammatory cell recruitment in the lung.

  17. Nitric oxide mediates bleomycin-induced angiogenesis and pulmonary fibrosis via regulation of VEGF.

    PubMed

    Iyer, Anand Krishnan V; Ramesh, Vani; Castro, Carlos A; Kaushik, Vivek; Kulkarni, Yogesh M; Wright, Clayton A; Venkatadri, Rajkumar; Rojanasakul, Yon; Azad, Neelam

    2015-11-01

    Pulmonary fibrosis is a progressive lung disease hallmarked by increased fibroblast proliferation, amplified levels of extracellular matrix deposition and increased angiogenesis. Although dysregulation of angiogenic mediators has been implicated in pulmonary fibrosis, the specific rate-limiting angiogenic markers involved and their role in the progression of pulmonary fibrosis remains unclear. We demonstrate that bleomycin treatment induces angiogenesis, and inhibition of the central angiogenic mediator VEGF using anti-VEGF antibody CBO-P11 significantly attenuates bleomycin-induced pulmonary fibrosis in vivo. Bleomycin-induced nitric oxide (NO) was observed to be the key upstream regulator of VEGF via the PI3k/Akt pathway. VEGF regulated other important angiogenic proteins including PAI-1 and IL-8 in response to bleomycin exposure. Inhibition of NO and VEGF activity significantly mitigated bleomycin-induced angiogenic and fibrogenic responses. NO and VEGF are key mediators of bleomycin-induced pulmonary fibrosis, and could serve as important targets against this debilitating disease. Overall, our data suggests an important role for angiogenic mediators in the pathogenesis of bleomycin-induced pulmonary fibrosis.

  18. Vagotomy attenuates bleomycin-induced pulmonary fibrosis in mice

    PubMed Central

    Song, Nana; Liu, Jun; Shaheen, Saad; Du, Lei; Proctor, Mary; Roman, Jesse; Yu, Jerry

    2015-01-01

    The progression of pulmonary fibrosis (PF) entails a complex network of interactions between multiple classes of molecules and cells, which are closely related to the vagus nerve. Stimulation of the vagus nerve increases fibrogenic cytokines in humans, therefore, activation of the nerve may promote PF. The hypothesis was tested by comparing the extent and severity of fibrosis in lungs with and without vagal innervation in unilaterally vagotomized mice. The results show that in vagotomized lungs, there were less collagen staining, less severe fibrotic foci (subpleural, peri-vascular and peri-bronchiolar lesions) and destruction of alveolar architecture; decreased collagen deposition (denervated vs intact: COL1α1, 19.1 ± 2.2 vs 22.0 ± 2.6 ng/mg protein; COL1α2, 4.5 ± 0.3 vs 5.7 ± 0.5 ng/mg protein; p < 0.01, n = 21) and protein levels of transforming growth factor beta and interleukin 4; and fewer myofibroblast infiltration (denervated vs intact: 1.2 ± 0.2 vs 3.2 ± 0.6 cells/visual field; p < 0.05, n = 6) and M2 macrophages [though the infiltration of macrophages was increased (denervated vs intact: 112 ± 8 vs 76 ± 9 cells/visual field; p < 0.01, n = 6), the percentage of M2 macrophages was decreased (denervated vs intact: 31 ± 4 vs 57 ± 9%; p < 0.05, n = 5)]. It indicated that the vagus nerve may influence PF by enhancing fibrogenic factors and fibrogenic cells. PMID:26289670

  19. Pulmonary fibrosis: tissue characterization using late-enhanced MRI compared with unenhanced anatomic high-resolution CT

    PubMed Central

    Lavelle, Lisa P.; Brady, Darragh; McEvoy, Sinead; Murphy, David; Gibney, Brian; Gallagher, Annika; Butler, Marcus; Shortt, Fionnula; McMullen, Marie; Fabre, Aurelie; Lynch, David A.; Keane, Michael P.; Dodd, Jonathan D.

    2017-01-01

    PURPOSE We aimed to prospectively evaluate anatomic chest computed tomography (CT) with tissue characterization late gadolinium-enhanced magnetic resonance imaging (MRI) in the evaluation of pulmonary fibrosis (PF). METHODS Twenty patients with idiopathic pulmonary fibrosis (IPF) and twelve control patients underwent late-enhanced MRI and high-resolution CT. Tissue characterization of PF was depicted using a segmented inversion-recovery turbo low-angle shot MRI sequence. Pulmonary arterial blood pool nulling was achieved by nulling main pulmonary artery signal. Images were read in random order by a blinded reader for presence and extent of overall PF (reticulation and honeycombing) at five anatomic levels. Overall extent of IPF was estimated to the nearest 5% as well as an evaluation of the ratios of IPF made up of reticulation and honeycombing. Overall grade of severity was dependent on the extent of reticulation and honeycombing. RESULTS No control patient exhibited contrast enhancement on lung late-enhanced MRI. All IPF patients were identified with late-enhanced MRI. Mean signal intensity of the late-enhanced fibrotic lung was 31.8±10.6 vs. 10.5±1.6 for normal lung regions, P < 0.001, resulting in a percent elevation in signal intensity from PF of 204.8%±90.6 compared with the signal intensity of normal lung. The mean contrast-to-noise ratio was 22.8±10.7. Late-enhanced MRI correlated significantly with chest CT for the extent of PF (R=0.78, P = 0.001) but not for reticulation, honeycombing, or coarseness of reticulation or honeycombing. CONCLUSION Tissue characterization of IPF is possible using inversion recovery sequence thoracic MRI. PMID:28067202

  20. Cross Talk between Id1 and Its Interactive Protein Dril1 Mediate Fibroblast Responses to Transforming Growth Factor-β in Pulmonary Fibrosis

    PubMed Central

    Lin, Ling; Zhou, Zhihong; Zheng, Liang; Alber, Sean; Watkins, Simon; Ray, Prabir; Kaminski, Naftali; Zhang, Yingze; Morse, Danielle

    2008-01-01

    The presence of activated fibroblasts or myofibroblasts represents a hallmark of progressive lung fibrosis. Because the transcriptional response of fibroblasts to transforming growth factor-β1 (TGF-β1) is a determinant of disease progression, we investigated the role of the transcriptional regulator inhibitor of differentiation-1 (Id1) in the setting of lung fibrosis. Mice lacking the gene for Id1 had increased susceptibility to bleomycin-induced lung fibrosis, and fibroblasts lacking Id1 exhibited enhanced responses to TGF-β1. Because the effect of Id1 on fibrosis could not be explained by known mechanisms, we performed protein interaction screening and identified a novel binding partner for Id1, known as dead ringer-like-1 (Dril1). Dril1 shares structural similarities with Id1 and was recently implicated in TGF-β1 signaling during embryogenesis. To date, little is known about the function of Dril1 in humans. Although it has not been previously implicated in fibrotic disease, we found that Dril1 was highly expressed in lungs from patients with idiopathic pulmonary fibrosis and was regulated by TGF-β1 in human fibroblasts. Dril1 enhanced activation of TGF-β1 target genes, whereas Id1 decreased expression of these same molecules. Id1 inhibited DNA binding by Dril1, and the two proteins co-localized in vitro and in vivo, providing a potential mechanism for suppression of fibrosis by Id1 through inhibition of the profibrotic function of Dril1. PMID:18583319

  1. Idiopathic Mediastinal Fibrosis: a Systemic Immune-Mediated Disorder. A Case Series and a Review of the Literature.

    PubMed

    Rossi, Giovanni M; Emmi, Giacomo; Corradi, Domenico; Urban, Maria L; Maritati, Federica; Landini, Federica; Galli, Paola; Palmisano, Alessandra; Vaglio, Augusto

    2016-08-23

    Mediastinal fibrosis is a rare disease characterised by fibrous proliferation in the mediastinum. It can be idiopathic or secondary to several conditions such as infections and malignancies. Anecdotal reports have described idiopathic mediastinal fibrosis (IMF) in association with other fibro-inflammatory or autoimmune diseases. We report nine new IMF cases recently seen at our Fibro-Inflammatory Disease Clinic and reviewed the IMF cases reported in the English language literature throughout 2006-2016. The purposes of our literature search were to assess the frequency of the association between IMF and other immune-mediated disorders and to analyse which disorders most often coexist with IMF. Of our nine IMF cases, one was associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, one with large-vessel arteritis, three with idiopathic retroperitoneal fibrosis (one of which was IgG4-related), one with pancreatitis and one with IgG4-related seminal vesicle involvement. The remaining two cases, in which IMF was not associated with any other disease, were both classifiable as IgG4-related. The literature review showed that, of the 84 IMF cases identified, 27 (32 %) were associated with other idiopathic autoimmune or fibro-inflammatory disorders, particularly small-vessel vasculitis, Behçet disease, retroperitoneal fibrosis and other conditions belonging to the IgG4-related disease spectrum. Based on our own data and the literature review, we conclude that IMF is often associated with other autoimmune or fibro-inflammatory diseases; therefore, its clinical management requires an accurate screening of associated conditions. Immune-mediated mechanisms may be shared by these disorders.

  2. Protective Effect of Ginsenoside Rg1 on Bleomycin-Induced Pulmonary Fibrosis in Rats: Involvement of Caveolin-1 and TGF-β1 Signal Pathway.

    PubMed

    Zhan, Heqin; Huang, Feng; Ma, Wenzhuo; Zhao, Zhenghang; Zhang, Haifang; Zhang, Chong

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and high mortality rate. Panax Notoginseng Saponins (PNS), extracted from Panax Notoginseng as a traditional Asian medicine, displayed a significant anti-fibrosis effect in liver and lung. However, whether Ginsenoside Rg1 (Rg1), an important and active ingredient of PNS, exerts anti-fibrotic activity on IPF still remain unclear. In this study, we investigated the effect of Rg1 on bleomycin-induced pulmonary fibrosis in rats. Bleomycin (5 mg/kg body weight) was intratracheally administrated to male rats. Rg1 (18, 36 and 72 mg/kg) was orally administered on the next day after bleomycin. Lungs were harvested at day 7 and 28 for the further experiments. Histological analysis revealed that bleomycin successfully induced pulmonary fibrosis, and that Rg1 restored the histological alteration of bleomycin-induced pulmonary fibrosis (PF), significantly decreased lung coefficient, scores of alveolitis, scores of PF as well as contents of alpha smooth muscle actin (α-SMA) and hydroxyproline (Hyp) in a dose-dependent manner in PF rats. Moreover, Rg1 increased the expression levels of Caveolin-1 (Cav-1) mRNA and protein, lowered the expression of transforming growth factor-β1 (TGF-β1) mRNA and protein in the lung tissues of PF rats. These data suggest that Rg1 exhibits protective effect against bleomycin-induced PF in rats, which is potentially associated with the down-regulation of TGF-β1 and up-regulation of Cav-1.

  3. Preventive effects of vitamin D treatment on bleomycin-induced pulmonary fibrosis

    PubMed Central

    Zhang, Zongmei; Yu, Xiaoting; Fang, Xia; Liang, Aibin; Yu, Zhang; Gu, Pan; Zeng, Yu; He, Jian; Zhu, Hailong; Li, Shuai; Fan, Desheng; Han, Fei; Zhang, Lanjing; Yi, Xianghua

    2015-01-01

    Patients with pulmonary fibrosis often have low vitamin D levels, the effects of which are largely unknown. We here report that early vitamin D supplementation significantly reduced the severity of pulmonary fibrosis and inflammatory cell accumulationin in the bleomycin-induced pulmonary fibrosis mouse model on supplementary days 14, 21 and 28 (P < 0.001). Vitamin D supplementation also prevented some ultrastructural changes in response to bleomycin administration, including basement membrane thickening, interstitial fibrin deposition and microvilli flattening or disappearance on days 14, 21 and 28, and lamellar body swelling or vacuolation on days 21 and 28. The bleomycin group had rising hydroxyproline level on days 14, 21 and 28, whereas the vitamin D treatment group showed consistently lower hydroxyproline level but still higher than that of the control group (P < 0.001). Our immunohistochemistry and densitometry analyses showed less staining for α-smooth muscle actin, a myofibroblast marker, in the vitamin D group compared to the bleomycin group (P < 0.001). Thus, vitamin D treatment could prevent bleomycin-induced pulmonary fibrosis by delaying or suppressing ultrastructural changes, as well as attenuating hydroxyproline accumulation and inhibiting myofibroblastic proliferation. These data further our understanding of the roles of vitamin D in pulmonary fibrogenesis and in the treatment of pulmonary fibrosis. PMID:26627341

  4. Rupatadine Protects against Pulmonary Fibrosis by Attenuating PAF-Mediated Senescence in Rodents

    PubMed Central

    Lv, Xiao-xi; Wang, Xiao-xing; Li, Ke; Wang, Zi-yan; Li, Zhe; Lv, Qi; Fu, Xiao-ming; Hu, Zhuo-Wei

    2013-01-01

    A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF), in bleomycin- (BLM-) and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine’s anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the in vivo and in vitro activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis. PMID:23869224

  5. Increased deposition of chondroitin/dermatan sulfate glycosaminoglycan and upregulation of β1,3-glucuronosyltransferase I in pulmonary fibrosis.

    PubMed

    Venkatesan, Narayanan; Ouzzine, Mohamed; Kolb, Martin; Netter, Patrick; Ludwig, Mara S

    2011-02-01

    Pulmonary fibrosis (PF) is characterized by increased deposition of proteoglycans (PGs), in particular core proteins. Glycosaminoglycans (GAGs) are key players in tissue repair and fibrosis, and we investigated whether PF is associated with changes in the expression and structure of GAGs as well as in the expression of β1,3-glucuronosyltransferase I (GlcAT-I), a rate-limiting enzyme in GAG synthesis. Lung biopsies from idiopathic pulmonary fibrosis (IPF) patients and lung tissue from a rat model of bleomycin (BLM)-induced PF were immunostained for chondroitin sulfated-GAGs and GlcAT-I expression. Alterations in disaccharide composition and sulfation of chondroitin/dermatan sulfate (CS/DS) were evaluated by fluorophore-assisted carbohydrate electrophoresis (FACE) in BLM rats. Lung fibroblasts isolated from control (saline-instilled) or BLM rat lungs were assessed for GAG structure and GlcAT-I expression. Disaccharide analysis showed that 4- and 6-sulfated disaccharides were increased in the lungs and lung fibroblasts obtained from fibrotic rats compared with controls. Fibrotic lung fibroblasts and transforming growth factor-β(1) (TGF-β(1))-treated normal lung fibroblasts expressed increased amounts of hyaluronan and 4- and 6-sulfated chondroitin, and neutralizing anti-TGF-β(1) antibody diminished the same. TGF-β(1) upregulated GlcAT-I and versican expression in lung fibroblasts, and signaling through TGF-β type I receptor/p38 MAPK was required for TGF-β(1)-mediated GlcAT-I and CS-GAG expression in fibroblasts. Our data show for the first time increased expression of CS-GAGs and GlcAT-I in IPF, fibrotic rat lungs, and fibrotic lung fibroblasts. These data suggest that alterations of sulfation isomers of CS/DS and upregulation of GlcAT-I contribute to the pathological PG-GAG accumulation in PF.

  6. Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway.

    PubMed

    Liu, Qingmei; Chu, Haiyan; Ma, Yanyun; Wu, Ting; Qian, Feng; Ren, Xian; Tu, Wenzhen; Zhou, Xiaodong; Jin, Li; Wu, Wenyu; Wang, Jiucun

    2016-06-09

    Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-β-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-β-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-β signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis.

  7. Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway

    PubMed Central

    Liu, Qingmei; Chu, Haiyan; Ma, Yanyun; Wu, Ting; Qian, Feng; Ren, Xian; Tu, Wenzhen; Zhou, Xiaodong; Jin, Li; Wu, Wenyu; Wang, Jiucun

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-β-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-β-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-β signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis. PMID:27278104

  8. Role of curcumin in idiopathic pulmonary arterial hypertension treatment: a new therapeutic possibility.

    PubMed

    Bronte, Enrico; Coppola, Giuseppe; Di Miceli, Riccardo; Sucato, Vincenzo; Russo, Antonio; Novo, Salvatore

    2013-11-01

    The idiopathic pulmonary arterial hypertension is a complex disease that mainly affects pulmonary arterial circulation. This undergoes a remodeling with subsequent reduction of flow in the small pulmonary arteries. Because of this damage an increased vascular resistance gradually develops, and over time it carries out in heart failure. The inflammatory process is a key element in this condition, mediated by various cytokines. The inflammatory signal induces activation of NF-κB, and prompts TGF-β-related signaling pathway. Clinical evolution leads to progressive debilitation, greatly affecting the patient quality of life. The actual therapeutic approaches, are few and expensive, and include systemic drugs such as prostanoids, phosphodiesterase inhibitors and antagonists of endothelin-1 (ERBs). Some researchers have long investigated the anti-inflammatory effects of curcumin. It shows a role for inactivation of NF-κB-mediated inflammation. On the basis of these findings we propose a potential role of curcumin and its pharmacologically fit derivatives for treatment of idiopathic pulmonary arterial hypertension.

  9. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia of the Lung (DIPNECH): Current Best Evidence.

    PubMed

    Wirtschafter, Eric; Walts, Ann E; Liu, Sandy T; Marchevsky, Alberto M

    2015-10-01

    Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is recognized as a preneoplastic condition by the World Health Organization. We reviewed our experience with 30 patients and performed a systematic review of the English literature to collect best evidence on the clinical features and disease course in 169 additional patients. Some patients presented with one or more carcinoid tumors associated with multiple small pulmonary nodules on imaging studies and showed DIPNECH as a somewhat unexpected pathologic finding. Others presented with multiple small pulmonary nodules that raised suspicion of metastatic disease on imaging. A third subset was presented with previously unexplained respiratory symptoms. In most patients, DIPNECH was associated with a good prognosis, with chronological progression into a subsequent carcinoid tumor noted in only one patient and death attributed directly to DIPNECH in only two patients. There is no best evidence to support the use of octreotide, steroids, or bronchodilators in DIPNECH patients.

  10. Role of platelet-derived growth factor/platelet-derived growth factor receptor axis in the trafficking of circulating fibrocytes in pulmonary fibrosis.

    PubMed

    Aono, Yoshinori; Kishi, Masami; Yokota, Yuki; Azuma, Momoyo; Kinoshita, Katsuhiro; Takezaki, Akio; Sato, Seidai; Kawano, Hiroshi; Kishi, Jun; Goto, Hisatsugu; Uehara, Hisanori; Izumi, Keisuke; Nishioka, Yasuhiko

    2014-12-01

    Circulating fibrocytes have been reported to migrate into the injured lungs, and contribute to fibrogenesis via CXCL12-CXCR4 axis. In contrast, we report that imatinib mesylate prevented bleomycin (BLM)-induced pulmonary fibrosis in mice by inhibiting platelet-derived growth factor receptor (PDGFR), even when it was administered only in the early phase. The goal of this study was to test the hypothesis that platelet-derived growth factor (PDGF) might directly contribute to the migration of fibrocytes to the injured lungs. PDGFR expression in fibrocytes was examined by flow cytometry and RT-PCR. The migration of fibrocytes was evaluated by using a chemotaxis assay for human fibrocytes isolated from peripheral blood. The numbers of fibrocytes triple-stained for CD45, collagen-1, and CXCR4 were also examined in lung digests of BLM-treated mice. PDGFR mRNA levels in fibrocytes isolated from patients with idiopathic pulmonary fibrosis were investigated by real-time PCR. Fibrocytes expressed both PDGFR-α and -β, and migrated in response to PDGFs. PDGFR inhibitors (imatinib, PDGFR-blocking antibodies) suppressed fibrocyte migration in vitro, and reduced the number of fibrocytes in the lungs of BLM-treated mice. PDGF-BB was a stronger chemoattractant than the other PDGFs in vitro, and anti-PDGFR-β-blocking antibody decreased the numbers of fibrocytes in the lungs compared with anti-PDGFR-α antibody in vivo. Marked expression of PDGFR-β was observed in fibrocytes from patients with idiopathic pulmonary fibrosis compared with healthy subjects. These results suggest that PDGF directly functions as a strong chemoattractant for fibrocytes. In particular, the PDGF-BB-PDGFR-β biological axis might play a critical role in fibrocyte migration into the fibrotic lungs.

  11. [Functional respiratory evolution in two patients with emphysema and pulmonary fibrosis].

    PubMed

    Arce, Santiago C; Molinari, Luciana; De Vito, Eduardo L

    2009-01-01

    Combined pulmonary fibrosis and emphysema (CPFE) is a frequently under-diagnosed condition. Isolated pulmonary function tests (PFT) can give rise to misinterpretations. We have found no reports on these patients' spirometric progression. We describe two cases of CPFE, showing long-term functional evolution to have a more accurate understanding of current spirometric values. The most relevant findings are: 1) spirometry with discrete functional alterations in the presence of a marked dyspnea and the need, in one patient, for chronic oxygen therapy; and 2) functional evolution reflecting "pseudonormalisation" of the initial obstructive spirometric pattern, possibly as a result of fibrosis development. A mild obstructive defect in a patient with chronic airflow limitation and marked impairment of his/her clinical status and functional class should alert on the possibility of associated pulmonary fibrosis. A computed tomography (CT) and previous PFTs will allow a better understanding of this condition.

  12. Combined itraconazole-pentoxifylline treatment promptly reduces lung fibrosis induced by chronic pulmonary paracoccidioidomycosis in mice.

    PubMed

    Naranjo, Tonny W; Lopera, Damaris E; Diaz-Granados, Lucy R; Duque, Jhon J; Restrepo, Angela M; Cano, Luz E

    2011-02-01

    Fibrosis is a severe and progressive sequel of many pulmonary diseases, has no effective therapy at present and, consequently, represents a serious health problem. In Latin America, chronic pulmonary paracoccidioidomycosis (PCM) is one of the most important, prevalent and systemic fungal diseases that allows the development of lung fibrosis, with the additional disadvantage that this sequel may appear even after an apparently successful course of antifungal therapy. In this study, was propose the pentoxifylline as complementary treatment in the pulmonary PCM due to its immunomodulatory and anti-fibrotic properties demonstrated in vitro and in vivo in liver, skin and lung. Our objective was to investigate the possible beneficial effects that a combined antifungal (Itraconazole) and immunomodulatory (Pentoxifylline) therapy would have in the development of fibrosis in a model of experimental chronic pulmonary PCM in an attempt to simulate the naturally occurring events in human patients. Two different times post-infection (PI) were chosen for starting therapy, an "early time" (4 weeks PI) when fibrosis was still absent and a "late time" (8 weeks PI) when the fibrotic process had started. Infected mice received the treatments via gavage and were sacrificed during or upon termination of treatment; their lungs were then removed and processed for immunological and histopathologic studies in order to assess severity of fibrosis. When pulmonary paracoccidioidomycosis had evolved and reached an advanced stage of disease before treatment began (as normally occurs in many human patients when first diagnosed), the combined therapy (itraconazole plus pentoxifylline) resulted in a significantly more rapid reduction of granulomatous inflammation and pulmonary fibrosis, when compared with the results of classical antifungal therapy using itraconazole alone.

  13. Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

    SciTech Connect

    Zhang, Liang Ji, Yunxia Kang, Zechun Lv, Changjun Jiang, Wanglin

    2015-02-15

    An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

  14. Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice

    PubMed Central

    2014-01-01

    Background Increased expression of nitric oxide synthase (NOS) and an increase in plasma nitrite plus nitrate (NOx) have been reported in patients with pulmonary fibrosis, suggesting that nitric oxide (NO) plays an important role in its development. However, the roles of the entire NO and NOS system in the pathogenesis of pulmonary fibrosis still remain to be fully elucidated. The aim of the present study is to clarify the roles of NO and the NOS system in pulmonary fibrosis by using the mice lacking all three NOS isoforms. Methods Wild-type, single NOS knockout and triple NOS knockout (n/i/eNOS−/−) mice were administered bleomycin (BLM) intraperitoneally at a dose of 8.0 mg/kg/day for 10 consecutive days. Two weeks after the end of the procedure, the fibrotic and inflammatory changes of the lung were evaluated. In addition, we evaluated the effects of long-term treatment with isosorbide dinitrate, a NO donor, on the n/i/eNOS−/− mice with BLM-induced pulmonary fibrosis. Results The histopathological findings, collagen content and the total cell number in bronchoalveolar lavage fluid were the most severe/highest in the n/i/eNOS−/− mice. Long-term treatment with the supplemental NO donor in n/i/eNOS−/− mice significantly prevented the progression of the histopathological findings and the increase of the collagen content in the lungs. Conclusions These results provide the first direct evidence that a lack of all three NOS isoforms led to a deterioration of pulmonary fibrosis in a BLM-treated murine model. We speculate that the entire endogenous NO and NOS system plays an important protective role in the pathogenesis of pulmonary fibrosis. PMID:25092105

  15. Pulmonary function tests correlated with thoracic volumes in adolescent idiopathic scoliosis.

    PubMed

    Ledonio, Charles Gerald T; Rosenstein, Benjamin E; Johnston, Charles E; Regelmann, Warren E; Nuckley, David J; Polly, David W

    2017-01-01

    Scoliosis deformity has been linked with deleterious changes in the thoracic cavity that affect pulmonary function. The causal relationship between spinal deformity and pulmonary function has yet to be fully defined. It has been hypothesized that deformity correction improves pulmonary function by restoring both respiratory muscle efficiency and increasing the space available to the lungs. This research aims to correlate pulmonary function and thoracic volume before and after scoliosis correction. Retrospective correlational analysis between thoracic volume modeling from plain x-rays and pulmonary function tests was conducted. Adolescent idiopathic scoliosis patients enrolled in a multicenter database were sorted by pre-operative Total Lung Capacities (TLC) % predicted values from their Pulmonary Function Tests (PFT). Ten patients with the best and ten patients with the worst TLC values were included. Modeled thoracic volume and TLC values were compared before and 2 years after surgery. Scoliosis correction resulted in an increase in the thoracic volume for patients with the worst initial TLCs (11.7%) and those with the best initial TLCs (12.5%). The adolescents with the most severe pulmonary restriction prior to surgery strongly correlated with post-operative change in total lung capacity and thoracic volume (r(2)  = 0.839; p < 0.001). The mean increase in thoracic volume in this group was 373.1 cm(3) (11.7%) which correlated with a 21.2% improvement in TLC. Scoliosis correction in adolescents was found to increase thoracic volume and is strongly correlated with improved TLC in cases with severe restrictive pulmonary function, but no correlation was found in cases with normal pulmonary function. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:175-182, 2017.

  16. Atomized paclitaxel liposome inhalation treatment of bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Zhou, Y; Zhu, W P; Cai, X J; Chen, M

    2016-04-07

    We sought to determine the efficacy of atomized paclitaxel liposome inhalation treatment of pulmonary fibrosis in a bleomycin-induced rat model. Forty male Sprague-Dawley rats were randomly divided into four groups: healthy control, pulmonary fibrosis without treatment, paclitaxel liposome inhalation-treated, and intravenous paclitaxel liposome-treated. Fibrosis was induced by bleomycin injection. A total of 20 mg/kg paclitaxel liposome was administered by inhalation every other day for a total of 10 doses. The intravenous group received 5 mg/kg paclitaxel liposome on days 1, 7, 14, and 21. We observed the general condition, weight change, survival index, and pathological changes in the lung tissue of the rats. Quantitative analysis of collagen types I and III and transforming growth factor (TGF)-β1 expression in the lungs was also performed. The paclitaxel liposome inhalation and intravenous delivery methods improved survival index and pulmonary fibrosis Ashcroft score, and decreased the thickness of the alveolar interval. No obvious difference was found between the two groups. Compared with the untreated group, paclitaxel liposome inhalation and intravenous injection significantly reduced the levels of collagen types I and III and TGF-β1 expression equally. In conclusion, atomized paclitaxel liposome inhalation protects against severe pulmonary fibrosis in a bleomycin-induced rat model. This delivery method has less systemic side effects and increased safety over intravenous injection.

  17. Mesenchymal deficiency of Notch1 attenuates bleomycin-induced pulmonary fibrosis.

    PubMed

    Hu, Biao; Wu, Zhe; Bai, David; Liu, Tianju; Ullenbruch, Matthew R; Phan, Sem H

    2015-11-01

    Notch signaling pathway is involved in the regulation of cell fate, differentiation, proliferation, and apoptosis in development and disease. Previous studies suggest the importance of Notch1 in myofibroblast differentiation in lung alveogenesis and fibrosis. However, direct in vivo evidence of Notch1-mediated myofibroblast differentiation is lacking. In this study, we examined the effects of conditional mesenchymal-specific deletion of Notch1 on pulmonary fibrosis. Crossing of mice bearing the floxed Notch1 gene with α2(I) collagen enhancer-Cre-ER(T)-bearing mice successfully generated progeny with a conditional knockout (CKO) of Notch1 in collagen I-expressing (mesenchymal) cells on treatment with tamoxifen (Notch1 CKO). Because Notch signaling is known to be activated in the bleomycin model of pulmonary fibrosis, control and Notch1 CKO mice were analyzed for their responses to bleomycin treatment. The results showed significant attenuation of pulmonary fibrosis in CKO relative to control mice, as examined by collagen deposition, myofibroblast differentiation, and histopathology. However, there were no significant differences in inflammatory or immune cell influx between bleomycin-treated CKO and control mouse lungs. Analysis of isolated lung fibroblasts confirmed absence of Notch1 expression in cells from CKO mice, which contained fewer myofibroblasts and significantly diminished collagen I expression relative to those from control mice. These findings revealed an essential role for Notch1-mediated myofibroblast differentiation in the pathogenesis of pulmonary fibrosis.

  18. Association of growth and nutritional parameters with pulmonary function in cystic fibrosis: a literature review

    PubMed Central

    Mauch, Renan Marrichi; Kmit, Arthur Henrique Pezzo; Marson, Fernando Augusto de Lima; Levy, Carlos Emilio; Barros-Filho, Antonio de Azevedo; Ribeiro, José Dirceu

    2016-01-01

    Abstract Objective: To review the literature addressing the relationship of growth and nutritional parameters with pulmonary function in pediatric patients with cystic fibrosis. Data source: A collection of articles published in the last 15 years in English, Portuguese and Spanish was made by research in electronic databases - PubMed, Cochrane, Medline, Lilacs and Scielo - using the keywords cystic fibrosis, growth, nutrition, pulmonary function in varied combinations. Articles that addressed the long term association of growth and nutritional parameters, with an emphasis on growth, with pulmonary disease in cystic fibrosis, were included, and we excluded those that addressing only the relationship between nutritional parameters and cystic fibrosis and those in which the aim was to describe the disease. Data synthesis: Seven studies were included, with a total of 12,455 patients. Six studies reported relationship between growth parameters and lung function, including one study addressing the association of growth parameters, solely, with lung function, and all the seven studies reported relationship between nutritional parameters and lung function. Conclusions: The review suggests that the severity of the lung disease, determined by spirometry, is associated with body growth and nutritional status in cystic fibrosis. Thus, the intervention in these parameters can lead to the better prognosis and life expectancy for cystic fibrosis patients. PMID:27181343

  19. [Gastroesophageal reflux, pulmonary and gastric function in patients with cystic fibrosis. Results of a randomized trial].

    PubMed

    Escobar Castro, H; Perdomo Giraldi, M; Gimeno Benítez, R; Máiz Carro, L; Suárez Cortina, L

    1996-01-01

    We studied ten patients with Cystic fibrosis. The purposes of this study were to investigate the presence of gastroesophageal reflux and establish the probable association between gastroesophageal reflux and pulmonary and gastric involvement. All 10 patients underwent 24-hour esophageal pH recording, spirometry and gastric function. Abnormal reflux index was found in all these patients. Lung function was pathologic in the 3 older children. There were no relationship between the severity of the gastroesophageal reflux and the degree of pulmonary damage. No patient has gastric acid hypersecretion. Eight of 10 patients had steatorrhea. Our findings confirm the high frequence of gastroesophageal reflux in cystic fibrosis.

  20. Calcitonin gene-related peptide down-regulates bleomycin-induced pulmonary fibrosis.

    PubMed

    Li, Xian-Wei; Li, Xiao-Hui; Du, Jie; Li, Dai; Li, Yuan-Jian; Hu, Chang-Ping

    2016-12-01

    We have found that eIF3a plays an important role in bleomycin-induced pulmonary fibrosis, and up-regulation of eIF3a induced by TGF-β1 is mediated via the ERK1/2 pathway. Whether ERK1/2 - eIF3a signal pathway is involved in calcitonin gene-related peptide (CGRP)-mediated pathogenesis of bleomycin-induced pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. Sensory CGRP depletion by capsaicin exacerbated bleomycin-induced pulmonary fibrosis in rats, as shown by a significant disturbed alveolar structure, marked thickening of the interalveolar septa and dense interstitial infiltration by inflammatory cells and fibroblasts, accompanied with increased expression of TGF-β1, eIF3a, phosphorylated ERK1/2, α-SMA, collagen I, and collagen III. Exogenous application of CGRP significantly inhibited TGF-β1-induced proliferation and differentiation of pulmonary fibroblasts concomitantly with decreased expression of eIF3a, phosphorylated ERK1/2, α-SMA, collagen I, and collagen III. These effects of CGRP were abolished in the presence of CGRP8-37. These results suggest that endogenous CGRP is related to the development of pulmonary fibrosis induced by bleomycin, and the inhibitory effect of CGRP on proliferation of lung fibroblasts involves the ERK1/2 - eIF3a signaling pathway.

  1. Improved In vivo Assessment of Pulmonary Fibrosis in Mice using X-Ray Dark-Field Radiography

    NASA Astrophysics Data System (ADS)

    Yaroshenko, Andre; Hellbach, Katharina; Yildirim, Ali Önder; Conlon, Thomas M.; Fernandez, Isis Enlil; Bech, Martin; Velroyen, Astrid; Meinel, Felix G.; Auweter, Sigrid; Reiser, Maximilian; Eickelberg, Oliver; Pfeiffer, Franz

    2015-12-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with a median life expectancy of 4-5 years after initial diagnosis. Early diagnosis and accurate monitoring of IPF are limited by a lack of sensitive imaging techniques that are able to visualize early fibrotic changes at the epithelial-mesenchymal interface. Here, we report a new x-ray imaging approach that directly visualizes the air-tissue interfaces in mice in vivo. This imaging method is based on the detection of small-angle x-ray scattering that occurs at the air-tissue interfaces in the lung. Small-angle scattering is detected with a Talbot-Lau interferometer, which provides the so-called x-ray dark-field signal. Using this imaging modality, we demonstrate-for the first time-the quantification of early pathogenic changes and their correlation with histological changes, as assessed by stereological morphometry. The presented radiography method is significantly more sensitive in detecting morphological changes compared with conventional x-ray imaging, and exhibits a significantly lower radiation dose than conventional x-ray CT. As a result of the improved imaging sensitivity, this new imaging modality could be used in future to reduce the number of animals required for pulmonary research studies.

  2. Pulmonary fibrosis in asbestos insulation workers with lung cancer: a radiological and histopathological evaluation.

    PubMed Central

    Kipen, H M; Lilis, R; Suzuki, Y; Valciukas, J A; Selikoff, I J

    1987-01-01

    This study was undertaken to determine the relation between radiographic and histological manifestations of pulmonary asbestosis (interstitial fibrosis) in insulation workers who had died of lung cancer. Of 450 confirmed deaths from lung cancer a chest radiograph suitable for determining evidence of pneumoconiosis was obtained in 219. Of these cases, 138 also had a tissue specimen submitted that was suitable for histological study to determine the extent of histological fibrosis. There was a significant albeit limited correlation between the radiographic and histological findings (r = 0.27, p less than 0.0013). All 138 cases had histological evidence of parenchymal fibrosis; in 25 (18%), however, there was no radiographic evidence of parenchymal fibrosis. In 10 cases (7%) both parenchymal and pleural disease were undetectable on the radiograph. Thus a negative chest radiograph does not exclude the presence of interstitial fibrosis (asbestosis) in a substantial proportion of insulation workers previously exposed to asbestos who develop lung cancer. PMID:3814551

  3. Pulmonary lesion of idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia appears to be a cause of lymphoplasmacytic proliferation of the lung: a report of five cases.

    PubMed

    Kojima, Masaru; Nakamura, Naoya; Otuski, Yoshiro; Itoh, Hideaki; Ogawa, Yoshiyuki; Kobayashi, Hiroshi; Nakamura, Shigeo

    2008-01-01

    We report on pulmonary lesions seen in five cases of idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL). This group of five patients consisted of two Japanese men (age: 33 and 45 years), and three Japanese women (age: 25, 43, and 48 years). All five cases were detected incidentally on routine chest X-rays, and had multiple small nodular lesions in the bilateral lungs. These pulmonary lesions were the initial clinical presentation of IPL in three cases in which, at the onset of disease, no lymphadenopathy was detected. At the disease onset, all five cases showed prominent IPL. In three cases examined, serum interleukin-6 was elevated, and anti-human immunodeficiency type-1 antibody was negative in three cases. Clinically, autoimmune disease was suspected for all five cases, and the various autoantibodies were investigated. Although anti-Scl 70 antibody was positive in one case, this patient had no symptoms of systemic sclerosis. Pathologically, all five lesions were characterized by well-demarcated masses that consisted of abundant reactive germinal centers and a dense lymphoplasmacytic infiltrate in the interfollicular area with a variable degree of interfollicular fibrosis. The immunohistochemical study and polymerase chain reaction demonstrated the polytypic nature of the plasma cells and B-cells. IPL is rare in lymphoproliferative disorders. However, pulmonary involvement may frequently occur in IPL patients. Moreover, pulmonary involvement seems to represent the initial clinical manifestation of IPL. Therapeutically, it is important to discriminate between pulmonary involvement of IPL and pulmonary benign or malignant pulmonary lymphoplasmacytic proliferation, particularly marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type.

  4. Suppression of Expression of Heat Shock Protein 70 by Gefitinib and Its Contribution to Pulmonary Fibrosis

    PubMed Central

    Namba, Takushi; Tanaka, Ken-Ichiro; Hoshino, Tatsuya; Azuma, Arata; Mizushima, Tohru

    2011-01-01

    Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is of serious clinical concern. Gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is beneficial as a drug for treating non-small cell lung cancer; however, this drug induces ILD and the molecular mechanisms underpinning this condition remain unclear. We recently reported that expression of heat shock protein 70 (HSP70) protects against bleomycin-induced pulmonary fibrosis, an animal model of pulmonary fibrosis. In this study, we have examined the effects of drugs known to induce ILD clinically on the expression of HSP70 in cultured lung epithelial cells and have found that gefitinib has a suppressive effect. Results of a luciferase reporter assay, pulse-labelling analysis of protein and experiments using an inhibitor of translation or transcription suggest that gefitinib suppresses the expression of HSP70 at the level of translation. Furthermore, the results of experiments with siRNA for Dicer1, an enzyme responsible for synthesis of microRNA, and real-time RT-PCR analysis suggest that some microRNAs are involved in the gefitinib-induced translational inhibition of HSP70. Mutations in the EGFR affect the concentration of gefitinib required for suppressing the expression of HSP70. These results suggest that gefitinib suppresses the translation of HSP70 through an EGFR- and microRNA-mediated mechanism. In vivo, while oral administration of gefitinib suppressed the pulmonary expression of HSP70 and exacerbated bleomycin-induced pulmonary fibrosis in wild-type mice, these effects were not as distinct in transgenic mice expressing HSP70. Furthermore, oral co-administration of geranylgeranylacetone (GGA), an inducer of HSP70, suppressed gefitinib-induced exacerbation of bleomycin-induced pulmonary fibrosis. Taken together, these findings suggest that gefitinib-induced exacerbation of bleomycin-induced pulmonary fibrosis is mediated by suppression of

  5. Elastase modifies bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Trajano, Larissa Alexsandra Silva Neto; Trajano, Eduardo Tavares Lima; Lanzetti, Manuella; Mendonça, Morena Scopel Amorim; Guilherme, Rafael Freitas; Figueiredo, Rodrigo Tinoco; Benjamim, Cláudia Farias; Valenca, Samuel Santos; Costa, Andréa Monte Alto; Porto, Luís Cristóvão

    2016-04-01

    Pulmonary fibrosis (PF) is characterized by excessive accumulation of collagen in the lungs. Emphysema is characterized by loss of the extracellular matrix (ECM) and alveolar enlargement. We studied the co-participation of elastase-induced mild emphysema in bleomycin-induced PF in mice by analyzing oxidative stress, inflammation and lung histology. C57BL/6 mice were divided into four groups: control; bleomycin (0.1U/mouse); elastase (using porcine pancreatic elastase (PPE)+bleomycin (3U/mouse 14 days before 0.1U/mouse of bleomycin; PPE+B); elastase (3U/mouse). Mice were humanely sacrificed 7, 14 and 21 days after treatment with bleomycin or vehicle. PF was observed 14 days and 21 days after bleomycin treatment but was observed after 14 days only in the PPE+B group. In the PPE+B group at 21 days, we observed many alveoli and alveolar septa with few PF areas. We also observed marked and progressive increases of collagens 7, 14 and 21 days after bleomycin treatment whereas, in the PPE+B group, collagen deposition was observed only at 14 days. There was a reduction in activities of the antioxidant enzymes superoxide dismutase (p<0.05), catalase (p<0.01) and glutathione peroxidase (p<0.01) parallel with an increase in nitrite (p<0.01) 21 days after bleomycin treatment compared with the control group. These endpoints were also reduced (p<0.05, p<0.05 and p<0.01, respectively) and increased (p<0.01) in the PPE+B group at 21 days compared with the control group. Interleukin (IL)-1β expression was upregulated (p<0.01) whereas IL-6 was downregulated (p<0.05) in the PPE+B group at 21 days compared with the control group. PF and emphysema did not coexist in our model of lung disease and despite increased levels of oxidative stress and inflammatory markers after combined stimulus (elastase and bleomycin) overall histology was improved to that of the nearest control group.

  6. Inhibitory effect of emodin on bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Chen, Xiao-Hong; Sun, Ren-Shan; Hu, Jian-Ming; Mo, Zi-Yao; Yang, Zi-Feng; Jin, Guang-Yao; Guan, Wen-Da; Zhong, Nan-Shan

    2009-02-01

    1. Currently, there is no satisfactory treatment for pulmonary fibrosis. Emodin, a component in Chinese herbs, has been shown to have an antifibrotic effect on pancreatic fibrosis and liver fibrosis. In the present study, we tested the hypothesis that emodin may attenuate the development of pulmonary fibrosis. 2. Mice were randomly divided into five groups (n = 16 in each). One group was a control group; the remaining four groups were treated with intratracheal instillation of 3 mg/kg bleomycin (BLM). The following day, emodin (5, 10 or 20 mg/kg per day, p.o.) treatment was started for three of the BLM-treated groups and was continued for 21 days. The fourth BLM-treated group (and the control group) received daily 0.5% sodium carboxymethyl cellulose (placebo) by gavage over the same period. 3. Bleomycin challenge provoked severe pulmonary fibrosis, with marked increases in fibrosis fraction, hydroxyproline content and myeloperoxidase activity in lung tissue. Emodin treatment (10 and 20 mg/kg per day, p.o.) attenuated all these biochemical indices, as well as histopathological alterations induced by BLM. Furthermore, in mice injected with BLM, elevated levels of transforming growth factor-beta1, interleukin (IL)-4 and IL-13 were found in bronchoalveolar lavage fluid. These increases were significantly inhibited by 10 and 20 mg/kg per day emodin. 4. In cell culture, exposure of cells to 6.25, 12.5, 25 or 50 micromol/L emodin for 24 h decreased fibroblast proliferation. Treatment of cells with the same concentrations of emodin for 72 h decreased collagen production by fibroblasts. In addition, emodin (6.25, 12.5, 25 or 50 micromol/L) inhibited the steady state expression of alpha1 (I) procollagen and alpha2 (I) procollagen mRNA in a dose-dependent manner. 5. The results of the present study suggest that emodin may be effective in the treatment of pulmonary fibrosis.

  7. The role of all-trans retinoic acid in bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Dong, Zhaoxing; Tai, Wenlin; Yang, Yanni; Zhang, Tao; Li, Yongxia; Chai, Yanling; Zhong, Hong; Zou, Hua; Wang, Dianhua

    2012-03-01

    Much evidence suggests that immune imbalance in the lung plays a crucial role in the development of pulmonary fibrosis. Recently, all-trans retinoic acid (ATRA) shifting the regulatory T/T-helper 17 (Treg/Th17) profile had been proven in some diseases. However, to date, the effect of ARTA of pulmonary fibrosis has not been examined from this aspect. The objective of this study was to study the effect of ATRA on bleomycin-induced pulmonary fibrosis in mice and its possible mechanism. Pulmonary fibrosis was induced in C57BL/6 male mice by intratracheal instillation of bleomycin (5 mg.kg(-1)), which were randomly divided into control, bleomycin, and ATRA groups. Five mice in each group were sacrificed on day 28 after intratracheal instillation. Hemotoxylin and eosin (H&E) and Masson staining were used for pathological examination, and hydroxyproline in lung tissue was measured. Interleukin (IL)-17A protein expression was observed in lung with immunohistochemistry. The expression of IL-17A, IL-10, IL-6, and transforming growth factor (TGF)-β mRNAs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Th17 and Treg expression in spleen lymphocytes were measured by flow cytometry. H&E and masson staining and expression of hydroxyproline showed that ATRA significantly alleviated lung fibrosis than in the bleomycin group. The expression of IL-17A, IL-10, IL-6, and TGF-β mRNAs were higher in the bleomycin group than in the normal group. ATRA can decrease these cytokines except for IL-10. CD4+CD25+ Treg cell ratio in the bleomycin group was significantly lower than normal, but CD4+IL-17+ T cells was higher; ARTA reversed this kind of expression. ATRA may ease the bleomycin-induced pulmonary fibrosis by inhibiting the expression of IL-6 and TGF-β, shifting the Treg/Th17 ratio and reducing the secretion of IL-17A.

  8. Right ventricular reverse remodelling in Idiopathic Pulmonary Arterial Hypertension diagnosed during pregnancy: Is it possible?

    PubMed

    Paciocco, Giuseppe; Lombi, Andrea; Vincenzi, Antonella; Pesci, Alberto; Achilli, Felice

    2017-01-01

    We present a case of a 36-year-old woman who developed a severe form of Idiopathic Pulmonary Arterial Hypertension (IPAH) during pregnancy and after emergency delivery. The management of IPAH during or after pregnancy is complex. Due to the severity of her IPAH, an upfront triple combination therapy, including i.v. epoprostenol, was started. The rapid institution of this treatment regimen allowed a complete right ventricular reverse remodelling after 1 year of therapy, leading to a down-titration until complete suspension of epoprostenol from the treatment regimen.

  9. Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM) Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4) Induced Hepatic Fibrosis in Mice

    PubMed Central

    Chow, Leola N.; Schreiner, Petra; Ng, Betina Y. Y.; Lo, Bernard; Hughes, Michael R.; Scott, R. Wilder; Gusti, Vionarica; Lecour, Samantha; Simonson, Eric; Manisali, Irina; Barta, Ingrid; McNagny, Kelly M.; Crawford, Jason; Webb, Murray; Underhill, T. Michael

    2016-01-01

    Modulation of chemokine CXCL12 and its receptor CXCR4 has been implicated in attenuation of bleomycin (BLM)-induced pulmonary fibrosis and carbon tetrachloride (CCl4)-induced hepatic injury. In pulmonary fibrosis, published reports suggest that collagen production in the injured lung is derived from fibrocytes recruited from the circulation in response to release of pulmonary CXCL12. Conversely, in hepatic fibrosis, resident hepatic stellate cells (HSC), the key cell type in progression of fibrosis, upregulate CXCR4 expression in response to activation. Further, CXCL12 induces HSC proliferation and subsequent production of collagen I. In the current study, we evaluated AMD070, an orally bioavailable inhibitor of CXCL12/CXCR4 in alleviating BLM-induced pulmonary and CCl4-induced hepatic fibrosis in mice. Similar to other CXCR4 antagonists, treatment with AMD070 significantly increased leukocyte mobilization. However, in these two models of fibrosis, AMD070 had a negligible impact on extracellular matrix deposition. Interestingly, our results indicated that CXCL12/CXCR4 signaling has a role in improving mortality associated with BLM induced pulmonary injury, likely through dampening an early inflammatory response and/or vascular leakage. Together, these findings indicate that the CXCL12-CXCR4 signaling axis is not an effective target for reducing fibrosis. PMID:26998906

  10. Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM) Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4) Induced Hepatic Fibrosis in Mice.

    PubMed

    Chow, Leola N; Schreiner, Petra; Ng, Betina Y Y; Lo, Bernard; Hughes, Michael R; Scott, R Wilder; Gusti, Vionarica; Lecour, Samantha; Simonson, Eric; Manisali, Irina; Barta, Ingrid; McNagny, Kelly M; Crawford, Jason; Webb, Murray; Underhill, T Michael

    2016-01-01

    Modulation of chemokine CXCL12 and its receptor CXCR4 has been implicated in attenuation of bleomycin (BLM)-induced pulmonary fibrosis and carbon tetrachloride (CCl4)-induced hepatic injury. In pulmonary fibrosis, published reports suggest that collagen production in the injured lung is derived from fibrocytes recruited from the circulation in response to release of pulmonary CXCL12. Conversely, in hepatic fibrosis, resident hepatic stellate cells (HSC), the key cell type in progression of fibrosis, upregulate CXCR4 expression in response to activation. Further, CXCL12 induces HSC proliferation and subsequent production of collagen I. In the current study, we evaluated AMD070, an orally bioavailable inhibitor of CXCL12/CXCR4 in alleviating BLM-induced pulmonary and CCl4-induced hepatic fibrosis in mice. Similar to other CXCR4 antagonists, treatment with AMD070 significantly increased leukocyte mobilization. However, in these two models of fibrosis, AMD070 had a negligible impact on extracellular matrix deposition. Interestingly, our results indicated that CXCL12/CXCR4 signaling has a role in improving mortality associated with BLM induced pulmonary injury, likely through dampening an early inflammatory response and/or vascular leakage. Together, these findings indicate that the CXCL12-CXCR4 signaling axis is not an effective target for reducing fibrosis.

  11. Immunophenotypic and Ultrastructural Analysis of Mast Cells in Hermansky-Pudlak Syndrome Type-1: A Possible Connection to Pulmonary Fibrosis

    PubMed Central

    Kirshenbaum, Arnold S.; Cruse, Glenn; Desai, Avanti; Bandara, Geethani; Leerkes, Maarten; Lee, Chyi-Chia R.; Fischer, Elizabeth R.; O’Brien, Kevin J.; Gochuico, Bernadette R.; Stone, Kelly; Gahl, William A.; Metcalfe, Dean D.

    2016-01-01

    Hermansky-Pudlak Syndrome type-1 (HPS-1) is an autosomal recessive disorder caused by mutations in HPS1 which result in reduced expression of the HPS-1 protein, defective lysosome-related organelle (LRO) transport and absence of platelet delta granules. Patients with HPS-1 exhibit oculocutaneous albinism, colitis, bleeding and pulmonary fibrosis postulated to result from a dysregulated immune response. The effect of the HPS1 mutation on human mast cells (HuMCs) is unknown. Since HuMC granules classify as LROs along with platelet granules and melanosomes, we set out to determine if HPS-1 cutaneous and CD34+ culture-derived HuMCs have distinct granular and cellular characteristics. Cutaneous and cultured CD34+-derived HuMCs from HPS-1 patients were compared with normal cutaneous and control HuMCs, respectively, for any morphological and functional differences. One cytokine-independent HPS-1 culture was expanded, cloned, designated the HP proMastocyte (HPM) cell line and characterized. HPS-1 and idiopathic pulmonary fibrosis (IPF) alveolar interstitium showed numerous HuMCs; HPS-1 dermal mast cells exhibited abnormal granules when compared to healthy controls. HPS-1 HuMCs showed increased CD63, CD203c and reduced mediator release following FcɛRI aggregation when compared with normal HuMCs. HPM cells also had the duplication defect, expressed FcɛRI and intracytoplasmic proteases and exhibited less mediator release following FcɛRI aggregation. HPM cells constitutively released IL-6, which was elevated in patients’ serum, in addition to IL-8, fibronectin-1 (FN-1) and galectin-3 (LGALS3). Transduction with HPS1 rescued the abnormal HPM morphology, cytokine and matrix secretion. Microarray analysis of HPS-1 HuMCs and non-transduced HPM cells confirmed upregulation of differentially expressed genes involved in fibrogenesis and degranulation. Cultured HPS-1 HuMCs appear activated as evidenced by surface activation marker expression, a decrease in mediator content and

  12. Idiopathic interstitial pneumonias: progress in classification, diagnosis, pathogenesis and management.

    PubMed Central

    King, Talmadge E.

    2004-01-01

    The idiopathic interstitial pneumonias are a heterogeneous group of poorly understood diseases with often devastating consequences for those afflicted. Subclassification of the idiopathic interstitial pneumonia based on clinical-radiological-pathological criteria has highlighted important pathogenic, therapeutic and prognostic implications. The most critical distinction is the presence of usual interstitial pneumonia, the histopathological pattern seen in idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis has a worse response to therapy and prognosis. New insight into the pathophysiology of usual interstitial pneumonia suggests a distinctly fibroproliferative process, and antifibrotic therapies show promise. While the clinical and radiographic diagnosis of idiopathic interstitial pneumonias can be made confidently in some cases, many patients require surgical lung biopsy to determine their underlying histopathology. A structured, clinical-radiological-pathological approach to the diagnosis of the idiopathic interstitial pneumonias, with particular attention to the identification of idiopathic pulmonary fibrosis, insures proper therapy, enhances prognostication, and allows for further investigation of therapies aimed at distinct pathophysiology. Images Fig. 2 Fig. 4 Fig. 5 Fig. 6 PMID:17060957

  13. Role of eukaryotic translation initiation factor 3a in bleomycin-induced pulmonary fibrosis.

    PubMed

    Li, Xian-Wei; Wu, Yue-Han; Li, Xiao-Hui; Li, Dai; Du, Jie; Hu, Chang-Ping; Li, Yuan-Jian

    2015-02-15

    Eukaryotic translation initiation factor 3a (eIF3a) is a multifunctional protein and plays an important role in regulation of cellular function including proliferation and differentiation. In the present study, we tested the function of eIF3a in pulmonary fibrosis. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5mg/kg) in rats. Primary pulmonary fibroblasts were cultured for proliferation investigation by BrdU incorporation method and flow cytometry. The expression/level of eIF3a, TGF-β1, ERK1/2 and α-SMA were analyzed by ELISA, real-time PCR or western blot. Results showed that the expression of eIF3a was obviously increased in lungs of pulmonary fibrosis rats accompanied by up-regulation of α-SMA and collagens. In cultured pulmonary fibroblasts, application of exogenous TGF-β1 induced cell proliferation and differentiation concomitantly with up-regulation of eIF3a expression and ERK1/2 phosphorylation. The effects of TGF-β1-induced proliferation of fibroblasts and up-regulation of α-SMA were abolished by eIF3a siRNA. TGF-β1-induced eIF3a expression was reversed in the presence of PD98059, an inhibitor of ERK1/2. These findings suggest that eIF3a plays an important role in bleomycin-induced pulmonary fibrosis by regulating pulmonary fibroblasts׳ function, and up-regulation of eIF3a induced by TGF-β1 is mediated via the ERK1/2 pathway.

  14. Pulmonary interstitial fibrosis with evidence of aflatoxin B1 in lung tissue

    SciTech Connect

    Dvorackova, I.; Pichova, V.

    1986-01-01

    Three cases of pulmonary interstitial fibrosis, two in agricultural workers and one in a textile worker, are reported. In lung samples of all three patients the presence of aflatoxin B1 was demonstrated by radioimmunoassay (RIA). A possible occupational risk of aflatoxin exposure via the respiratory tract is suggested.

  15. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis

    PubMed Central

    Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis. PMID:27992456

  16. Anti-profibrotic effects of artesunate on bleomycin-induced pulmonary fibrosis in Sprague Dawley rats.

    PubMed

    Wang, Changming; Xuan, Xiuping; Yao, Wenmin; Huang, Guojin; Jin, Junfei

    2015-07-01

    The present study aimed to determine whether artesunate has beneficial effects on bleomycin-induced pulmonary fibrosis in rats and to examine the possible mechanisms underlying these effects. All experiments were performed with male Sprague Dawley rats weighing 180-250 g. Animals were randomly divided into four experimental groups that were administered either saline alone, artesunate alone, bleomycin alone or bleomycin + artesunate. Lung histopathology was investigated by hematoxylin and eosin staining and Masson staining. Lung profibrotic molecules were analyzed by reverse transcription polymerase chain reaction, immunoblotting and immunohistochemistry. In rats treated with artesunate, pulmonary fibrosis induced by bleomycin was significantly reduced. Administration of artesunate significantly improved bleomycin-induced morphological alterations. Profibrotic molecules, including transforming growth factor-β1, Smad3, heat shock protein 47, α-smooth muscle actin and collagen type I were also reduced by artesunate. These findings suggest that artesunate improves bleomycin-induced pulmonary fibrosis pathology in rats possibly by inhibiting profibrotic molecules associated with pulmonary fibrosis.

  17. Effects of sildenafil on pulmonary hypertension and exercise tolerance in severe cystic fibrosis-related lung disease.

    PubMed

    Montgomery, Gregory S; Sagel, Scott D; Taylor, Amy L; Abman, Steven H

    2006-04-01

    Cystic fibrosis (CF) patients with advanced lung disease are at risk for developing pulmonary vascular disease and pulmonary hypertension, characterized by progressive exercise intolerance beyond the exercise-limiting effects of airways disease in CF. We report on a patient with severe CF lung disease who experienced clinically significant improvements in exercise tolerance and pulmonary hypertension without changing lung function during sildenafil therapy.

  18. Severity of lung fibrosis affects early surgical outcomes of lung cancer among patients with combined pulmonary fibrosis and emphysema.

    PubMed

    Mimae, Takahiro; Suzuki, Kenji; Tsuboi, Masahiro; Ikeda, Norihiko; Takamochi, Kazuya; Aokage, Keiju; Shimada, Yoshihisa; Miyata, Yoshihiro; Okada, Morihito

    2016-07-01

    Combined pulmonary fibrosis and emphysema (CPFE) is defined as upper lobe emphysema and lower lobe fibrosis, which are representative lung disorders that increase the prevalence of lung cancer. This unique disorder may affect the morbidity and mortality during the early period after surgery. The present study aimed to identify which clinicopathological features significantly affect early surgical outcomes after lung resection in nonsmall cell lung cancer (NSCLC) patients and in those with CPFE.We retrospectively assessed 2295 patients with NSCLC and found that 151 (6.6%) had CPFE. All were surgically treated between January 2008 and December 2010 at 4 institutions.The postoperative complication rates for patients with and without CPFE were 39% and 17%, respectively. The 90-day mortality rates were higher among patients with than without CPFE (7.9% vs 1%). Acute exacerbation of interstitial pneumonia was the main cause of death among 12 patients with CPFE who died within 90 days after surgery. Multivariate logistic regression analysis selected CPFE, gender, age, and clinical stage as independent predictive factors for postoperative complications, and CPFE, clinical stage, and sex for 90-day mortality. The severity of lung fibrosis on preoperative CT images was an independent predictive factor for 90-day mortality among patients with CPFE.The key predictive factor for postoperative mortality and complications of lung resection for NSCLC was CPFE. The severity of lung fibrosis was the principal predictor of early outcomes after lung surgery among patients with CPFE and NSCLC.

  19. Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis.

    PubMed

    Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L; Hamill, Kevin J; Soberanes, Saul; Nigdelioglu, Recep; Chi, Monica; Cho, Takugo; Radigan, Kathryn A; Ridge, Karen M; Misharin, Alexander V; Woychek, Alex; Hopkinson, Susan; Perlman, Harris; Mutlu, Gokhan M; Pardo, Annie; Selman, Moises; Jones, Jonathan C R; Budinger, G R Scott

    2015-04-01

    Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the α3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the α3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant protein C promoter (SPC-Cre) with mice expressing floxed alleles encoding the α3 laminin gene (Lama3(fl/fl)). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-β was worse in mice deficient in α3 laminin in the lung. Taken together, our results suggest that the loss of α3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-β. Thus, we speculate that the loss of the normal basement membrane organization of α3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression.

  20. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis

    PubMed Central

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y.; Fong, Guo-Hua; Sakmar, Thomas P.; Rafii, Shahin; Ding, Bi-Sen

    2016-01-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin–dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladaptbed hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis. PMID:26779814

  1. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

    PubMed

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y; Fong, Guo-Hua; Sakmar, Thomas P; Rafii, Shahin; Ding, Bi-Sen

    2016-02-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

  2. Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-β signaling pathway.

    PubMed

    Li, Li; Huang, Wenting; Li, Kunlin; Zhang, Kejun; Lin, Caiyu; Han, Rui; Lu, Conghua; Wang, Yubo; Chen, Hengyi; Sun, Fenfen; He, Yong

    2015-12-22

    Interstitial lung disease (ILD) is a serious side-effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Therefore, it is necessary to study underlying mechanisms for the development of pulmonary fibrosis induced by EGFR-TKI and potential approaches to attenuate it. Metformin is a well-established and widely prescribed oral hypoglycemic drug, and has gained attention for its potential anticancer effects. Recent reports have also demonstrated its role in inhibiting epithelial-mesenchymal transition and fibrosis. However, it is unknown whether metformin attenuates EGFR-TKI-induced pulmonary fibrosis. The effect of metformin on EGFR-TKI-induced exacerbation of pulmonary fibrosis was examined in vitro and in vivo using MTT, Ki67 incorporation assay, flow cytometry, immunostaining, Western blot analysis, and a bleomycin-induced pulmonary fibrosis rat model. We found that in lung HFL-1 fibroblast cells, TGF-β or conditioned medium from TKI-treated lung cancer PC-9 cells or conditioned medium from TKI-resistant PC-9GR cells, induced significant fibrosis, as shown by increased expression of Collegen1a1 and α-actin, while metformin inhibited expression of fibrosis markers. Moreover, metformin decreased activation of TGF-β signaling as shown by decreased expression of pSMAD2 and pSMAD3. In vivo, oral administration of gefitinib exacerbated bleomycin-induced pulmonary fibrosis in rats, as demonstrated by HE staining and Masson staining. Significantly, oral co-administration of metformin suppressed exacerbation of bleomycin-induced pulmonary fibrosis by gefitinib. We have shown that metformin attenuates gefitinib-induced exacerbation of TGF-β or bleomycin-induced pulmonary fibrosis. These observations indicate metformin may be combined with EGFR-TKI to treat NSCLC patients.

  3. Mycobacterium chimaera pulmonary infection complicating cystic fibrosis: a case report

    PubMed Central

    2011-01-01

    Background Mycobacterium chimaera is a recently described species within the Mycobacterium avium complex. Its pathogenicity in respiratory tract infection remains disputed. It has never been isolated during cystic fibrosis respiratory tract infection. Case presentation An 11-year-old boy of Asian ethnicity who was born on Réunion Island presented to our hospital with cystic fibrosis after a decline in his respiratory function over the course of seven years. We found that the decline in his respiratory function was correlated with the persistent presence of a Mycobacterium avium complex organism further identified as M. chimaera. Conclusion Using sequencing-based methods of identification, we observed that M. chimaera organisms contributed equally to respiratory tract infections in patients with cystic fibrosis when compared with M. avium subsp. hominissuis isolates. We believe that M. chimaera should be regarded as an emerging opportunistic respiratory pathogen in patients with cystic fibrosis, including young children, and that its detection warrants long-lasting appropriate anti-mycobacterial treatment to eradicate it. PMID:21939536

  4. Pathophysiology of Pulmonary Hypertension in Chronic Parenchymal Lung Disease.

    PubMed

    Singh, Inderjit; Ma, Kevin Cong; Berlin, David Adam

    2016-04-01

    Pulmonary hypertension commonly complicates chronic obstructive pulmonary disease and interstitial lung disease. The association of chronic lung disease and pulmonary hypertension portends a worse prognosis. The pathophysiology of pulmonary hypertension differs in the presence or absence of lung disease. We describe the physiological determinants of the normal pulmonary circulation to better understand the pathophysiological factors implicated in chronic parenchymal lung disease-associated pulmonary hypertension. This review will focus on the pathophysiology of 3 forms of chronic lung disease-associated pulmonary hypertension: idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and sarcoidosis.

  5. Superantigen staphylococcal enterotoxin C1 mutant can reduce paraquat pulmonary fibrosis.

    PubMed

    Li, Tiegang; Xu, Mingkai; Wang, Nana; Zhao, Min

    2015-01-01

    A network of inflammation factors is related to pulmonary fibrosis induced by paraquat (PQ) poisoning. At high doses, the superantigen staphylococcal enterotoxin C1 (SEC1) can induce immunological unresponsiveness and inhibit release of inflammation factors. In this study, site-directed mutagenesis was performed at the H118 and H122 amino acid residues of SEC1 to reduce SEC1 toxicity. The SEC1 mutant showed significantly decreased pyrogenic toxicity, but retained clonal anergy at high dosages in vitro. Pretreatment with the SEC1 mutant prior to PQ poisoning in mice reduced symptom duration and severity, prolonged survival time, and decreased the splenocyte response to ConA induction. The SEC1 mutant also down-regulated several important cytokines related to fibrosis in the plasma after PQ poisoning. SEC1 decreased the expression of genes related to pulmonary fibrosis, including α-SMA, COL1a1, COL3 and TGF-β1, in PQ poisoned mice. Histomorphological observation indicated alleviation of pathological changes in the lungs after SEC1 pretreatment compared to mice in the PQ group. In conclusion, the SEC1 mutant reduced pulmonary interstitial fibrosis induced by PQ poisoning.

  6. Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis.

    PubMed Central

    Miyazaki, Y; Araki, K; Vesin, C; Garcia, I; Kapanci, Y; Whitsett, J A; Piguet, P F; Vassalli, P

    1995-01-01

    The murine TNF-alpha gene was expressed under the control of the human surfactant protein SP-C promoter in transgenic mice. A number of the SP-C TNF-alpha mice died at birth or after a few weeks with very severe lung lesions. Surviving mice transmitted a pulmonary disease to their offspring, the severity and evolution of which was related to the level of TNF-alpha mRNA in the lung; TNF-alpha RNA was detected in alveolar epithelium, presumably in type II epithelial cells. In a longitudinal study of two independent mouse lines, pulmonary pathology, at 1-2 mo of age, consisted of a leukocytic alveolitis with a predominance of T lymphocytes. Leukocyte infiltration was associated with endothelial changes and increased levels of mRNA for the endothelial adhesion molecule VCAM-1. In the following months, alveolar spaces enlarged in association with thickening of the alveolar walls due to an accumulation of desmin-containing fibroblasts, collagen fibers, and lymphocytes. Alveolar surfaces were lined by regenerating type II epithelial cells, and alveolar spaces contained desquamating epithelial cells in places. Platelet trapping in the damaged alveolar capillaries was observed. Pulmonary pathology in the SP-C TNF-alpha mice bears a striking resemblance to human idiopathic pulmonary fibrosis, in which increased expression of TNF-alpha in type II epithelial cells has also been noted. These mice provide a valuable animal model for understanding the pathogenesis of pulmonary fibrosis and exploring possible therapeutic approaches. Images PMID:7542280

  7. Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis

    PubMed Central

    Gilhodes, Jean-Claude; Kreuz, Sebastian; Stierstorfer, Birgit; Stiller, Detlef; Wollin, Lutz

    2017-01-01

    Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. One of the major limits of histological scoring concerns the fact that it is observer-dependent and consequently subject to variability, which may preclude comparative studies between different laboratories. To achieve a reliable and observer-independent quantification of lung fibrosis we developed an automated software histological image analysis performed from digital image of entire lung sections. This automated analysis was compared to standard evaluation methods with regard to its validation as an end-point measure of fibrosis. Lung fibrosis was induced in mice by intratracheal administration of bleomycin (BLM) at 0.25, 0.5, 0.75 and 1 mg/kg. A detailed characterization of BLM-induced fibrosis was performed 14 days after BLM administration using lung function testing, micro-computed tomography and Ashcroft scoring analysis. Quantification of fibrosis by automated analysis was assessed based on pulmonary tissue density measured from thousands of micro-tiles processed from digital images of entire lung sections. Prior to analysis, large bronchi and vessels were manually excluded from the original images. Measurement of fibrosis has been expressed by two indexes: the mean pulmonary tissue density and the high pulmonary tissue density frequency. We showed that tissue density indexes gave access to a very accurate and reliable quantification of morphological changes induced by BLM even for the lowest concentration used (0.25 mg/kg). A reconstructed 2D-image of the entire lung section at high resolution (3.6 μm/pixel) has been performed from tissue density values allowing the visualization of their distribution throughout fibrotic and non-fibrotic regions. A significant correlation (p<0.0001) was found between automated analysis and the above standard evaluation methods. This correlation establishes

  8. Adipokines: A Possible Contribution to Vascular and Bone Remodeling in Idiopathic Pulmonary Arterial Hypertension.

    PubMed

    Kochetkova, Evgenia A; Ugai, Ludmila G; Maistrovskaia, Yuliya V; Nevzorova, Vera A

    2017-04-01

    Osteoporosis is a major comorbidity of cardio-respiratory diseases, but the mechanistic links between pulmonary arterial hypertension and bone remain elusive. The purpose of the stud was to evaluate serum adipokines and endothelin-1 (ET-1) levels in the patients with idiopathic pulmonary arterial hypertension (IPAH) NYHA class III-IV and to determine its associations with bone mineral density (BMD). Pulmonary and hemodynamic parameters, BMD Z-scores at the lumbar spine (LS) and femoral neck (FN), serum leptin, adiponectin, visfatin and endothelin-1 (ET-1), were evaluated in 32 patients with IPAH NYHA class III-IV and 30 healthy volunteers. Leptin, adiponectin and ET-1 were higher in the patients with IPAH than in healthy subjects. Visfatin level showed a tendency to increase compared to that of healthy subjects (p = 0.076). The univariate analysis revealed a positive correlation between BMD Z-scores at both sites and 6-min walk test, and inverse relation with pulmonary vascular resistance (PVR) and mean pulmonary arterial pressure (mPAP). Adiponectin and visfatin showed positive correlations with PVR (p = 0.009 and p = 0.006). Serum adiponectin, visfatin and leptin were inversely associated with Z-scores. After adjusting for BMI and FMI, such associations persisted between visfatin and adiponectin levels and Z-scores at both sites. ET-1 related to mPAP, cardiac index and PVR. Negative correlation was observed between ET-1 and FN BMD (p = 0.01). Positive correlations have revealed between ET-1 and adiponectin (p = 0.02), visfatin (p = 0.004) in IPAH patients. These results provide further evidence that adipokine and endothelial dysregulation may cause not only a decrease in BMD, but also an increase in hemodynamic disorders of IPAH.

  9. CD44 expression in plexiform lesions of idiopathic pulmonary arterial hypertension.

    PubMed

    Ohta-Ogo, Keiko; Hao, Hiroyuki; Ishibashi-Ueda, Hatsue; Hirota, Seiichi; Nakamura, Kazufumi; Ohe, Tohru; Ito, Hiroshi

    2012-04-01

    Plexiform lesions in pulmonary arteries are a characteristic histological feature for idiopathic pulmonary arterial hypertension (IPAH). The pathogenesis of the plexiform lesion is not fully understood, although it may be related to endothelial cell dysfunction and local inflammation. CD44 is a cell adhesion molecule and it is also involved in angiogenesis, endothelial cell proliferation and migration. The expression of CD44 was examined in lung plexiform lesions obtained from patients with IPAH (IPAH group, n= 7) and pulmonary arterial hypertension associated with atrial septal defect (ASD-PAH group, n= 4). Expression of CD44 was detected in 49 out of 52 plexiform lesions (93%) from all patients in the IPAH group, whereas 31 plexiform lesions obtained from the ASD-PAH group lacked CD44 positivity by immunohistochemistry. In the IPAH group, CD44 was localized in the endothelial cells of microvessels within plexiform lesions and activated T cells in and around the lesions. Furthermore, T cell infiltration and endothelial cell proliferation activity were prominent in the plexiform lesions of the IPAH group, compared to those of the ASD-PAH group. These findings suggest that CD44 and activated T cell infiltration play an important role in the development of plexiform lesions particularly in IPAH.

  10. Evaluation of the Effects of Caffeic Acid Phenethyl Ester on Prostaglandin E2 and Two Key Cytokines Involved in Bleomycin-induced Pulmonary Fibrosis

    PubMed Central

    Larki-Harchegani, Amir; Hemmati, Ali Asghar; Arzi, Ardeshir; Ghafurian-Boroojerdnia, Mehri; Shabib, Somayeh; Zadkarami, Mohammad Reza; Esmaeilzadeh, Saleh

    2013-01-01

    Objective(s): Pulmonary fibrosis (PF) is the most common outcome of a collection of diverse lung disorders known as interstitial lung diseases. It is proposed that alterations in the levels of fibrogenic mediators and the profibrotic/antifibrotic imbalance play a substantial role in the progression of PF in animal models and possibly in humans. Caffeic acid phenethyl ester (CAPE), an active component of propolis, has numerous biological effects. In the present study, the main objective was to investigate the effects of CAPE on some key mediators including TGF-β1, TNF-α and prostaglandin E2 (PGE2) involved in profibrotic/antifibrotic balance and pathogenesis of idiopathic pulmonary fibrosis (IPF). Materials and Methods: In this study, forty male Sprague–Dawley rats were divided into 5 groups (n=8). (1) “Bleomycin (BLM)-treated (Model) group”: BLM (5 mg/kg, single intratracheal dose), (2) “Saline-treated group”: the rats were given only saline, (3) “Treatment-1 group”: BLM + CAPE (5 μmol/kg/day, 28 days, IP), (4) “Treatment-2 group”: BLM + CAPE (10 μmol/kg/day, 28 days, IP) and (5) “Vehicle + CAPE group”: CAPE (10 μmol/kg/day, 28 days, IP). Results: BLM could significantly increase the levels of TNF-α and TGF-β1 and decrease the PGE2 concentration compared to the saline control group. CAPE could considerably improve these values almost close to normal levels. Conclusion: Briefly, CAPE can be suggested as a novel, attractive and effective agent for prevention and treatment of pulmonary fibrosis. PMID:23997916

  11. Nuclear Factor κ-B Is Activated in the Pulmonary Vessels of Patients with End-Stage Idiopathic Pulmonary Arterial Hypertension

    PubMed Central

    Price, Laura C.; Caramori, Gaetano; Perros, Frederic; Meng, Chao; Gambaryan, Natalia; Dorfmuller, Peter; Montani, David; Casolari, Paolo; Zhu, Jie; Dimopoulos, Konstantinos; Shao, Dongmin; Girerd, Barbara; Mumby, Sharon; Proudfoot, Alastair; Griffiths, Mark; Papi, Alberto; Humbert, Marc; Adcock, Ian M.; Wort, S. John

    2013-01-01

    Objectives To assess activation of the inflammatory transcription factor NF-kappa B (NF-κB) in human idiopathic pulmonary arterial hypertension (PAH). Background Idiopathic PAH is a severe progressive disease characterized by pulmonary vascular remodeling and excessive proliferation of vascular cells. Increasing evidence indicates that inflammation is important in disease pathophysiology. Methods NF-κB-p65 and CD68, CD20 and CD45 were measured by immunohistochemistry and confocal microscopy on lung specimens from patients with idiopathic PAH (n = 12) and controls undergoing lung surgery (n = 14). Clinical data were recorded for all patients including invasive pulmonary hemodynamics for the PAH patients. Immunohistochemical images were analyzed by blinded observers to include standard pulmonary vascular morphometry; absolute macrophage counts/mm2 and p65-positivity (p65+) using composite images and image-analysis software; and cytoplasmic:nuclear p65+ of individual pulmonary arterial endothelial and smooth muscle cells (PASMC) in 10–20 pulmonary arteries or arterioles per subject. The expression of ET-1 and CCL5 (RANTES) in whole lung was determined by RT-qPCR. Results Macrophage numbers were increased in idiopathic PAH versus controls (49.0±4.5 vs. 7.95±1.9 macrophages/100 mm2, p<0.0001): these macrophages demonstrated more nuclear p65+ than in macrophages from controls (16.9±2.49 vs. 3.5±1.25%, p<0.001). An increase in p65+ was also seen in perivascular lymphocytes in patients with PAH. Furthermore, NF-κB activation was increased in pulmonary arterial endothelial cells (62.3±2.9 vs. 14.4±3.8, p<0.0001) and PASMC (22.6±2.3 vs. 11.2±2.0, p<0.001) in patients with PAH versus controls, with similar findings in arterioles. Gene expression of both ET-1 mRNA ((0.213±0.069 vs. 1.06±0.23, p<0.01) and CCL5 (RANTES) (0.16±0.045 vs. 0.26±0.039, p<0.05) was increased in whole lung homogenates from patients with PAH. Conclusions NF-κB is activated in

  12. Green tea extract inhibits paraquat-induced pulmonary fibrosis by suppression of oxidative stress and endothelin-l expression.

    PubMed

    Kim, Hak-Ryul; Park, Byung-Kyu; Oh, Yeon-Mok; Lee, Yun-Song; Lee, Dong-Soon; Kim, Hyun-Kuk; Kim, Joo-Young; Shim, Tae-Sun; Lee, Sang-Do

    2006-01-01

    Paraquat-induced pulmonary fibrosis involves two factors, direct injury by oxygen free radicals and indirect injury by inflammatory cells and fibroblasts. Endothelin-1 (ET-1) has been shown to act as a mediator of pulmonary fibrosis, and its formation increases during oxidative stress. We investigated whether green tea extract (GTE), which has antioxidant properties, inhibits paraquat-induced pulmonary fibrosis and whether ET-1 is involved in this process. Paraquat (0.3 mg/kg) was instilled into the right lungs of rats, following which the rats were either not further treated (Group P, n = 7), or they were administered 1% GTE mixed with feed (Group PG; n = 7) or the ET(A) receptor antagonist ZD2574 (10 mg/kg through gavage; Group PZ; n = 7) for two weeks. As control, we used rats instilled with saline (Group N; n = 6). Two weeks after paraquat instillation, we assayed the degree of pulmonary fibrosis by light microscopic morphometry and hydroxyproline content; lipid peroxidation as a marker of oxidative stresses by measurement of malondialdehyde (MDA); ET-1 by immunohistochemistry; and prepro-ET-1 mRNA expression by reverse transcription-polymerase chain reaction. Compared with Group N, significant pulmonary fibrosis was observed in Group P, accompanied by increases in MDA, ET-1, and prepro-ET-1 mRNA expression. Compared with Group P, Group PG showed significant decreases in pulmonary fibrosis, along with decreases in MDA, ET-1, and prepro-ET-1 mRNA expression. We also observed significant decreases in pulmonary fibrosis in Group PZ compared with Group P. These findings suggest that GTE inhibits paraquat-induced pulmonary fibrosis by suppression of oxidative stress and ET-1 expression.

  13. Interaction of asbestos, age, and cigarette smoking in producing radiographic evidence of diffuse pulmonary fibrosis

    SciTech Connect

    Kilburn, K.H.; Lilis, R.; Anderson, H.A.; Miller, A.; Warshaw, R.H.

    1986-03-01

    The study of 3,472 chest x-rays from four populations with different levels of exposure to asbestos and with different cigarette smoking histories shows that smoking in the general population does not produce pulmonary fibrosis recognizable on chest radiography. In the general population of Michigan, the prevalence of a radiographic pattern of fibrosis was 0.5 percent in men and 0.0 percent in women. In a Long Beach, California census tract population, the prevalences were 3.7 percent for men and 0.6 percent for women. Similarly, cigarette smoking does not enhance fibrosis when the exposure to asbestos has been as light as that in households of shipyard workers. Asbestosis was recognized in 6.6 percent of 137 shipyard workers' wives who have never smoked and 7.6 percent of 132 who had ever smoked. Cigarette smoking and asbestos appear to be synergistic in those occupationally exposed to asbestos (as insulators), since 7.2 percent of 97 nonsmokers and 20.5 percent of 316 ever-smokers showed fibrosis. This apparent synergy was also found in shipyard workers up to age 70 with 31 percent of nonsmokers and 43.3 percent of ever-smokers having fibrosis. There were increases of approximately 10 percent in the prevalence of fibrosis in cigarette smokers and nonsmokers for each decade after age 40.

  14. Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

    PubMed

    Howard, Luke S G E; Watson, Geoffrey M J; Wharton, John; Rhodes, Christopher J; Chan, Kakit; Khengar, Rajeshree; Robbins, Peter A; Kiely, David G; Condliffe, Robin; Elliott, Charlie A; Pepke-Zaba, Joanna; Sheares, Karen; Morrell, Nicholas W; Davies, Rachel; Ashby, Deborah; Gibbs, J Simon R; Wilkins, Martin R

    2013-01-01

    Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.

  15. [Effects of erdosteine on inflammation and fibrosis in rats with pulmonary fibrosis induced by bleomycin].

    PubMed

    Erden, Ersin Sükrü; Kirkil, Gamze; Deveci, Figen; Ilhan, Nevin; Cobanoğlu, Bengü; Turgut, Teyfik; Muz, Mehmet Hamdi

    2008-01-01

    We aimed to investigate the levels of some chemokines, inflammatory cell counts in bronchoalveolar lavage (BAL) fluid, histopathological changes in lung tissue, to determine the effect of erdosteine on acute inflammatory changes and fibrosis in a rat fibrosis model induced by bleomycine (BLM). Forty-five Wistar male rats were taken into the study. On day 0, intratracheal saline to control group (group 1, n= 15), intratracheal BLM 7.5 U/kg to BLM (group 2, n= 15) and erdosteine group (group 3, n= 15) was administered. In group 3, oral erdosteine (10 mg/kg/day) was applied two days before BLM. On day 0, 14, and 29th five rats in each groups were sacrificed, BAL fluid was performed. Malonyldialdehyde (MDA), macrophage inflammatory protein (MIP)-1alpha, MIP-2 levels in BAL fluid, hydroxyproline levels in lung tissue were measured. Histopathological examination was performed. When BLM group compared to erdosteine group, the levels of MDA, MIP-1alpha, MIP-2, and neutrophil counts, the hydroxyproline (OH-P) level of lung tissue were decreased in erdosteine group on acute inflammatory phase (day 14) (p< 0.001, p= 0.017, p= 0.009, p< 0.001, p= 0.009, respectively), and late fibrosis phase (day 29) except BAL MIP-2 (p= 0.022, p= 0.025, p= 0.01, p< 0.001, respectively). Fibrosis level was significantly lower in erdosteine group than BLM group on day 29 (p= 0.01). We conclude that erdosteine may prevent the acute lung inflammation and fibrosis by suppressing the accumulation of neutrophils, inhibition of lipid peroxydation, chemokine production, and release.

  16. Association of Celiac Disease With Idiopathic Pulmonary Hemosiderosis; Lane Hamilton Syndrome

    PubMed Central

    Nacaroglu, Hikmet Tekin; Sandal, Ozlem Sarac; Bag, Ozlem; Erdem, Semiha Bahceci; Bekem Soylu, Ozlem; Diniz, Gulden; Ozturk, Aysel; Can, Demet

    2015-01-01

    Introduction: Idiopathic Pulmonary Hemosiderosis (IPH) is a rare cause of alveolar hemorrhage, which is seen primarily in childhood. Celiac disease is defined as a chronic, immune-mediated enteropathy of the small intestine, caused by exposure to dietary gluten in genetically pre-disposed individuals. Association of IPH and celiac disease is known as Lane Hamilton syndrome. There are limited number of case reports of this syndrome in literature. Case Presentation: Although there were no growth and developmental delay and gastrointestinal symptoms like chronic diarrhea, chronic constipation, vomiting, abdominal bloating and pain in the two patients with IPH, they were diagnosed with Lane Hamilton Syndrome. After initiation of gluten-free diet, their IPH symptoms disappeared and hemoglobin levels were observed to return to normal. Conclusions: Even if there were no gastrointestinal symptoms in a patient with IPH, celiac disease should be investigated. These patients may benefit from gluten free diet and IPH symptoms may disappear. PMID:26495097

  17. Idiopathic pulmonary hemosiderosis presenting in an adult: A case report and review of the literature

    PubMed Central

    Sherani, Khalid M.; Upadhyay, Hinesh N.; Sherani, Farha K.; Vakil, Abhay P.; Sarkar, Samir S.

    2015-01-01

    Diffuse alveolar hemorrhage (DAH) is characterized by the presence of hemoptysis, anemia, and the presence of diffuse parenchymal infiltrates on imaging studies. Idiopathic pulmonary hemosiderosis (IPH) is an uncommon cause of diffuse alveolar hemorrhage (DAH) and is classically known to present in childhood. Adult-onset IPH is extremely rare. We report the case of a 48-year-old female patient who presented with hemoptysis and acute hypoxic respiratory failure, requiring intubation and mechanical ventilation. Imaging studies showed diffuse bilateral patchy infiltrates. Bronchoalveolar lavage (BAL) confirmed the diagnosis of DAH. Extensive workup including video-assisted thoracoscopic surgical lung biopsy (VATS) failed to reveal any vasculitis, infectious, immunological or connective tissue disorder, as the underlying cause for DAH. The patient was successfully treated with high-dose steroid therapy. PMID:26180395

  18. [Pulmonary metabolism of nitric oxide (NO) in patients with cystic fibrosis].

    PubMed

    Grasemann, H; Ratjen, F

    2002-06-01

    Airway nitric oxide (NO) and its metabolites are involved in a number of physiological and pathophysiological processes. For instance, NO relaxes airway smooth muscle, improves airway ciliary motility, has antimicrobial effects, and increases expression of the CFTR (cystic fibrosis transmembrane regulator) protein in airway epithelial cells. Of interest, concentrations of NO and of bioactive S-nitrosothiols (SNOs) are decreased in the airways of patients with cystic fibrosis (CF). When compared to patients with relatively normal pulmonary NO formation, CF patients with low NO-concentrations have a significantly reduced pulmonary function and a higher frequency of bacterial colonisation of the airways with pathogens such as P. aeruginosa. As a consequence of these observations clinical trails have now been initiated to study possible effects of an augmented bronchial NO-concentration in CF-patients.

  19. Inhibition of Excessive Cell Proliferation by Calcilytics in Idiopathic Pulmonary Arterial Hypertension

    PubMed Central

    Yamamura, Aya; Ohara, Naoki; Tsukamoto, Kikuo

    2015-01-01

    Idiopathic pulmonary arterial hypertension (IPAH) is a rare and progressive disease of unknown pathogenesis. Vascular remodeling due to excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is a critical pathogenic event that leads to early morbidity and mortality. The excessive cell proliferation is closely linked to the augmented Ca2+ signaling in PASMCs. More recently, we have shown by an siRNA knockdown method that the Ca2+-sensing receptor (CaSR) is upregulated in PASMCs from IPAH patients, involved in the enhanced Ca2+ response and subsequent excessive cell proliferation. In this study, we examined whether pharmacological blockade of CaSR attenuated the excessive proliferation of PASMCs from IPAH patients by MTT assay. The proliferation rate of PASMCs from IPAH patients was much higher (~1.5-fold) than that of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). Treatment with NPS2143, an antagonist of CaSR or calcilytic, clearly suppressed the cell proliferation in a concentration-dependent manner (IC50 = 2.64 μM) in IPAH-PASMCs, but not in normal and CTEPH PASMCs. Another calcilytic, Calhex 231, which is structurally unrelated to NPS2143, also concentration-dependently inhibited the excessive proliferation of IPAH-PASMCs (IC50 = 1.89 μM). In contrast, R568, an activator of CaSR or calcimimetic, significantly facilitated the proliferation of IPAH-PASMCs (EC50 = 0.33 μM). Similar results were obtained by BrdU incorporation assay. These results reveal that the excessive PASMC proliferation was modulated by pharmacological tools of CaSR, showing us that calcilytics are useful for a novel therapeutic approach for pulmonary arterial hypertension. PMID:26375676

  20. Common and distinct mechanisms of induced pulmonary fibrosis by particulate and soluble chemical fibrogenic agents

    PubMed Central

    Dong, Jie; Yu, Xiaoqing; Porter, Dale W.; Battelli, Lori A.; Kashon, Michael L.

    2016-01-01

    Pulmonary fibrosis results from the excessive deposition of collagen fibers and scarring in the lungs with or without an identifiable cause. The mechanism(s) underlying lung fibrosis development is poorly understood, and effective treatment is lacking. Here we compared mouse lung fibrosis induced by pulmonary exposure to prototypical particulate (crystalline silica) or soluble chemical (bleomycin or paraquat) fibrogenic agents to identify the underlying mechanisms. Young male C57BL/6J mice were given silica (2 mg), bleomycin (0.07 mg), or paraquat (0.02 mg) by pharyngeal aspiration. All treatments induced significant inflammatory infiltration and collagen deposition, manifesting fibrotic foci in silica-exposed lungs or diffuse fibrosis in bleomycin or paraquat-exposed lungs on day 7 post-exposure, at which time the lesions reached their peaks and represented a junction of transition from an acute response to chronic fibrosis. Lung genomewide gene expression was analyzed, and differential gene expression was confirmed by quantitative RT-PCR, immunohistochemistry, and immunoblotting for representative genes to demonstrate their induced expression and localization in fibrotic lungs. Canonical signaling pathways, gene ontology, and upstream transcription networks modified by each agent were identified. In particular, these inducers elicited marked proliferative responses; at the same time, silica preferentially activated innate immune functions and the defense against foreign bodies, whereas bleomycin and paraquat boosted responses related to cell adhesion, platelet activation, extracellular matrix remodeling, and wound healing. This study identified, for the first time, the shared and unique genes, signaling pathways, and biological functions regulated by particulate and soluble chemical fibrogenic agents during lung fibrosis, providing insights into the mechanisms underlying human lung fibrotic diseases. PMID:26345256

  1. Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice

    PubMed Central

    Latoche, Joseph D.; Ufelle, Alexander Chukwuma; Fazzi, Fabrizio; Ganguly, Koustav; Leikauf, George D.; Fattman, Cheryl L.

    2016-01-01

    Background: Fibrotic lung diseases occur predominantly in males, and reports describe better survival in affected females. Male mice are more sensitive to silica-induced lung fibrosis than silica-treated female mice. Secreted phosphoprotein 1 (SPP1, also known as osteopontin) increases in pulmonary fibrosis, and Spp1 transcription may be regulated by estrogen or estrogen receptor–related receptors. Objective: We determined whether differences in silica-induced SPP1 levels contribute to sex differences in lung fibrosis. Methods: Male and female mice were treated with 0.2 g/kg intratracheal silica, and lung injury was assessed 1, 3, or 14 days post-exposure. Gene-targeted (Spp1–/–) mice, control Spp1+/+ (C57BL/6J) mice, ovariectomized (OVX) female mice, and estrogen-treated male mice were treated with silica, and lung injury was assessed. Results: Silica-induced SPP1 in lung tissue, bronchoalveolar lavage, and serum increased more in male than in female mice. Following silica treatment, bronchoalveolar lavage cell infiltrates decreased in female Spp1–/– mice compared with female Spp1+/+ mice, and lung hydroxyproline decreased in male Spp1–/– mice compared with male Spp1+/+ mice. OVX female mice had increased lung SPP1 expression in response to silica compared with silica-treated sham female mice. Silica-induced lung collagen and hydroxyproline (markers of fibrosis), and SPP1 levels decreased in estrogen-treated males compared with untreated males. Conclusion: These findings suggest that sex-specific differences in SPP1 levels contribute to the differential sensitivity of male and female mice to the development of silica-induced fibrosis. Citation: Latoche JD, Ufelle AC, Fazzi F, Ganguly K, Leikauf GD, Fattman CL. 2016. Secreted phosphoprotein 1 and sex-specific differences in silica-induced pulmonary fibrosis in mice. Environ Health Perspect 124:1199–1207; http://dx.doi.org/10.1289/ehp.1510335 PMID:26955063

  2. Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

    PubMed Central

    Young, Lisa R.; Gulleman, Peter M.; Short, Chelsi W.; Tanjore, Harikrishna; Sherrill, Taylor; Qi, Aidong; McBride, Andrew P.; Zaynagetdinov, Rinat; Benjamin, John T.; Lawson, William E.; Novitskiy, Sergey V.; Blackwell, Timothy S.

    2016-01-01

    Alveolar epithelial cell (AEC) dysfunction underlies the pathogenesis of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS) and other genetic syndromes associated with interstitial lung disease; however, mechanisms linking AEC dysfunction and fibrotic remodeling are incompletely understood. Since increased macrophage recruitment precedes pulmonary fibrosis in HPS, we investigated whether crosstalk between AECs and macrophages determines fibrotic susceptibility. We found that AECs from HPS mice produce excessive MCP-1, which was associated with increased macrophages in the lungs of unchallenged HPS mice. Blocking MCP-1/CCR2 signaling in HPS mice with genetic deficiency of CCR2 or targeted deletion of MCP-1 in AECs normalized macrophage recruitment, decreased AEC apoptosis, and reduced lung fibrosis in these mice following treatment with low-dose bleomycin. We observed increased TGF-β production by HPS macrophages, which was eliminated by CCR2 deletion. Selective deletion of TGF-β in myeloid cells or of TGF-β signaling in AECs through deletion of TGFBR2 protected HPS mice from AEC apoptosis and bleomycin-induced fibrosis. Together, these data reveal a feedback loop in which increased MCP-1 production by dysfunctional AECs results in recruitment and activation of lung macrophages that produce TGF-β, thus amplifying the fibrotic cascade through AEC apoptosis and stimulation of fibrotic remodeling. PMID:27777976

  3. IL-21 Promotes Pulmonary Fibrosis through the Induction of Pro-fibrotic CD8+ T Cells

    PubMed Central

    Brodeur, Tia Y.; Robidoux, Tara E.; Weinstein, Jason S.; Craft, Joseph; Swain, Susan L.; Marshak-Rothstein, Ann

    2015-01-01

    Type 2 effector production of IL-13, a demonstrated requirement in models of fibrosis, is routinely ascribed to CD4+ Th2 cells. We now demonstrate a major role for CD8+ T cells in a murine model of sterile lung injury. These pulmonary CD8+ T cells differentiate into IL-13-producing Tc2 and play a major role in a bleomycin-induced model of fibrosis. Differentiation of these Tc2 cells in the lung requires IL-21, and bleomycin treated IL-21- and IL-21R-deficient mice develop inflammation but not fibrosis. Moreover, IL-21R-expressing CD8+ cells are sufficient to reconstitute the fibrotic response in the IL-21R-deficient mice. We further show that the combination of IL-4 and IL-21 skews naïve CD8+ T cells to produce IL-21, which in turn acts in an autocrine manner to support robust IL-13 production. Our data reveal a novel pathway involved in the onset and regulation of pulmonary fibrosis, and identify Tc2 cells as key mediators of fibrogenesis. PMID:26519529

  4. Presentation of idiopathic retroperitoneal fibrosis at a young age: A rare case report

    PubMed Central

    Minocha, Priyanka; Setia, Ankur

    2016-01-01

    Summary Abdominal pain is a very common symptom in all age groups but retroperitoneal fibrosis is a rare differential diagnosis suspected in young patients presenting with nonspecific abdominal pain and symptoms of obstructive uropathy. Presented here is a case of a 16-year-old boy who presented with symptoms of persistent abdominal pain and a previous history of swelling in the left leg. A computed tomography (CT) scan suggested retroperitoneal fibrosis and an exploratory laparotomy and histopathological examination were performed for definitive diagnosis. This case report is intended to promote awareness of retroperitoneal fibrosis in young patients among health care providers. PMID:27904827

  5. Effects of NOX1 on fibroblastic changes of endothelial cells in radiation-induced pulmonary fibrosis

    PubMed Central

    CHOI, SEO-HYUN; KIM, MISEON; LEE, HAE-JUNE; KIM, EUN-HO; KIM, CHUN-HO; LEE, YOON-JIN

    2016-01-01

    Lung fibrosis is a major complication in radiation-induced lung damage following thoracic radiotherapy, while the underlying mechanism has remained to be elucidated. The present study performed immunofluorescence and immunoblot assays on irradiated human pulmonary artery endothelial cells (HPAECs) with or without pre-treatment with VAS2870, a novel NADPH oxidase (NOX) inhibitor, or small hairpin (sh)RNA against NOX1, -2 or -4. VAS2870 reduced the cellular reactive oxygen species content induced by 5 Gy radiation in HPAECs and inhibited phenotypic changes in fibrotic cells, including increased alpha smooth muscle actin and vimentin, and decreased CD31 and vascular endothelial cadherin expression. These fibrotic changes were significantly inhibited by treatment with NOX1 shRNA, but not by NOX2 or NOX4 shRNA. Next, the role of NOX1 in pulmonary fibrosis development was assessed in the lung tissues of C57BL/6J mice following thoracic irradiation using trichrome staining. Administration of an NOX1-specific inhibitor suppressed radiation-induced collagen deposition and fibroblastic changes in the endothelial cells (ECs) of these mice. The results suggested that radiation-induced pulmonary fibrosis may be efficiently reduced by specific inhibition of NOX1, an effect mediated by reduction of fibrotic changes of ECs. PMID:27053172

  6. Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Makino, Hideki; Aono, Yoshinori; Azuma, Momoyo; Kishi, Masami; Yokota, Yuki; Kinoshita, Katsuhiro; Takezaki, Akio; Kishi, Jun; Kawano, Hiroshi; Ogawa, Hirohisa; Uehara, Hisanori; Izumi, Keisuke; Sone, Saburo; Nishioka, Yasuhiko

    2013-01-01

    Circulating fibrocytes had been reported to migrate into the injured lungs, and contribute to fibrogenesis via chemokine-chemokine receptor systems including CXCL12-CXCR4 axis. Here we hypothesized that blockade of CXCR4 might inhibit the migration of fibrocytes to the injured lungs and the subsequent pulmonary fibrosis. To explore the antifibrotic effects of blockade of CXCR4, we used a specific antagonist for CXCR4, AMD3100, in bleomycin-induced pulmonary fibrosis model in mice. Administration of AMD3100 significantly improved the loss of body weight of mice treated with bleomycin, and inhibited the fibrotic lesion in subpleural areas of the lungs. The quantitative analysis demonstrated that treatment with AMD3100 reduced the collagen content and fibrotic score (Aschcroft score) in the lungs. Although AMD3100 did not affect cell classification in bronchoalveolar lavage fluid on day 7, the percentage of lymphocytes was reduced by AMD3100 on day 14. AMD3100 directly inhibited the migration of human fibrocytes in response to CXCL12 in vitro, and reduced the trafficking of fibrocytes into the lungs treated with bleocmycin in vivo. These results suggest that the blockade of CXCR4 might be useful strategy for therapy of patients with pulmonary fibrosis via inhibiting the migration of circulating fibrocytes.

  7. Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis.

    PubMed

    Song, Jeong Sup; Kang, Chun Mi; Kang, Hyeon Hui; Yoon, Hyung Kyu; Kim, Young Kyoon; Kim, Kwan Hyung; Moon, Hwa Sik; Park, Sung Hak

    2010-06-30

    CXC chemokine receptor 4 (CXCR4), which binds the stromal cell-derived factor-1 (SDF-1), has been shown to play a critical role in mobilizing the bone marrow (BM)-derived stem cells and inflammatory cells. We studied the effects of AMD3100, CXCR4 antagonist, on a murine bleomycin-induced pulmonary fibrosis model. Treatment of mice with AMD3100 in bleomycin-treated mice resulted in the decrease of SDF-1 in bronchoalveolar lavage (BAL) fluids at an early stage and was followed by the decrease of fibrocytes in the lung. AMD3100 treatment decreased the SDF-1 mRNA expression, fibrocyte numbers in the lung at an early stage (day 3) and CXCR4 expression at the later stage (day 7 and 21) after bleomycin injury. The collagen content and pulmonary fibrosis were significantly attenuated by AMD3100 treatment in later stage of bleomycin injury. AMD3100 treatment also decreased the murine mesenchymal and hematopoietic stem cell chemotaxis when either in the stimulation with bleomycin treated lung lysates or SDF-1 in vitro. In BM stem cell experiments, the phosphorylation of p38 MAPK which was induced by SDF-1 was significantly blocked by addition of AMD3100. Our data suggest that AMD3100 might be effective in preventing the pulmonary fibrosis by inhibiting the fibrocyte mobilization to the injured lung via blocking the SDF-1/CXCR4 axis.

  8. Enhancement of antioxidant defense system by epigallocatechin-3-gallate during bleomycin induced experimental pulmonary fibrosis.

    PubMed

    Sriram, Narayanan; Kalayarasan, Srinivasan; Sudhandiran, Ganapasam

    2008-07-01

    Oxidative stress resulting from an imbalance between radical-generating and radical scavenging systems plays an important role in the pathogenesis of pulmonary fibrosis. Epigallocatechin-3-gallate (EGCG), a polyphenol and a major component of green tea, possess a potent antioxidant property. This study was designed to evaluate the potential antioxidative activity of EGCG in the plasma and lungs during bleomycin induced experimental pulmonary fibrosis. Intratracheal administration of bleomycin (6.5 U/kg body weight) to rats resulted in significant reduction of body weight, enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) and non-enzymic antioxidants (reduced glutathione, vitamin C, vitamin E and vitamin A). Elevations in lung W/D (wet weight/dry weight) ratio, hydroxyproline content was observed with a synchronized increase in lipid peroxidation markers (thiobarbituric acid reactive substances and hydroperoxides). Intraperitoneal administration of EGCG at a dose of 20 mg/kg body weight significantly improved the body weight, enzymic and non enzymic antioxidants and considerably decreased the W/D ratio, hydroxyproline and lipid peroxidation marker levels. Histological observations also correlated with the biochemical parameters. Thus, this study confirms the beneficial use of EGCG in alleviating the oxidative stress induced during pulmonary fibrosis.

  9. Regulation of macroautophagy in amiodarone-induced pulmonary fibrosis.

    PubMed

    Mahavadi, Poornima; Knudsen, Lars; Venkatesan, Shalini; Henneke, Ingrid; Hegermann, Jan; Wrede, Christoph; Ochs, Matthias; Ahuja, Saket; Chillappagari, Shashi; Ruppert, Clemens; Seeger, Werner; Korfei, Martina; Guenther, Andreas

    2015-10-01

    Amiodarone (AD) is an iodinated benzofuran derivative, especially known for its antiarrhythmic properties. It exerts serious side-effects even in patients receiving low doses. AD is well-known to induce apoptosis of type II alveolar epithelial cells (AECII), a mechanism that has been suggested to play an important role in AD-induced lung fibrosis. The precise molecular mechanisms underlying this disease are, however, still unclear. Because of its amphiphilic nature, AD becomes enriched in the lysosomal compartments, affecting the general functions of these organelles. Hence, in this study, we aimed to assess the role of autophagy, a lysosome-dependent homeostasis mechanism, in driving AECII apoptosis in response to AD. In vitro, AD-treated MLE12 and primary AECII cells showed increased proSP-C and LC3B positive vacuolar structures and underwent LC3B-dependent apoptosis. In addition, AD-induced autophagosome-lysosome fusion and increased autophagy flux were observed. In vivo, in C57BL/6 mice, LC3B was localised at the limiting membrane of lamellar bodies, which were closely connected to the autophagosomal structures in AECIIs. Our data suggest that AD causes activation of macroautophagy in AECIIs and extensive autophagy-dependent apoptosis of alveolar epithelial cells. Targeting the autophagy pathway may therefore represent an attractive treatment modality in AD-induced lung fibrosis.

  10. Regulation of macroautophagy in amiodarone‐induced pulmonary fibrosis

    PubMed Central

    Mahavadi, Poornima; Knudsen, Lars; Venkatesan, Shalini; Henneke, Ingrid; Hegermann, Jan; Wrede, Christoph; Ochs, Matthias; Ahuja, Saket; Chillappagari, Shashi; Ruppert, Clemens; Seeger, Werner; Korfei, Martina

    2015-01-01

    Abstract Amiodarone (AD) is an iodinated benzofuran derivative, especially known for its antiarrhythmic properties. It exerts serious side‐effects even in patients receiving low doses. AD is well‐known to induce apoptosis of type II alveolar epithelial cells (AECII), a mechanism that has been suggested to play an important role in AD‐induced lung fibrosis. The precise molecular mechanisms underlying this disease are, however, still unclear. Because of its amphiphilic nature, AD becomes enriched in the lysosomal compartments, affecting the general functions of these organelles. Hence, in this study, we aimed to assess the role of autophagy, a lysosome‐dependent homeostasis mechanism, in driving AECII apoptosis in response to AD. In vitro, AD‐treated MLE12 and primary AECII cells showed increased proSP‐C and LC3B positive vacuolar structures and underwent LC3B‐dependent apoptosis. In addition, AD‐induced autophagosome‐lysosome fusion and increased autophagy flux were observed. In vivo, in C57BL/6 mice, LC3B was localised at the limiting membrane of lamellar bodies, which were closely connected to the autophagosomal structures in AECIIs. Our data suggest that AD causes activation of macroautophagy in AECIIs and extensive autophagy‐dependent apoptosis of alveolar epithelial cells. Targeting the autophagy pathway may therefore represent an attractive treatment modality in AD‐induced lung fibrosis. PMID:27499909

  11. Idiopathic pulmonary haemosiderosis: spectrum of thoracic imaging findings in the adult patient.

    PubMed

    Khorashadi, L; Wu, C C; Betancourt, S L; Carter, B W

    2015-05-01

    Idiopathic pulmonary haemosiderosis (IPH) is a rare disease characterized by alveolar capillary haemorrhage resulting in deposition and accumulation of haemosiderin in the lungs. Although its precise pathophysiology remains unclear, several hypotheses have been proposed to explain the aetiology of the disorder, including autoimmune, environmental, allergic, and genetic theories. IPH is typically diagnosed in childhood, usually before the age of 10 years; however, this entity may be encountered in older patients given the greater awareness of the diagnosis, availability and utilization of advanced imaging techniques, and improved treatment and survival. The classic presentation of IPH consists of the triad of haemoptysis, iron-deficiency anaemia, and pulmonary opacities on chest radiography. The diagnosis is usually confirmed via bronchoscopy with bronchoalveolar lavage (BAL), at which time haemosiderin-laden macrophages referred to as siderophages, considered pathognomonic for IPH, may be identified. However, lung biopsy may ultimately be necessary to exclude other disease processes. For children with IPH, the disease course is severe and the prognosis is poor. However, adults generally have a longer disease course with milder symptoms and the prognosis is more favourable. Specific imaging features, although non-specific in isolation, may be identified on thoracic imaging studies, principally chest radiography and CT, depending on the phase of disease (acute or chronic). Recognition of these findings is important to guide appropriate clinical management.

  12. In Vivo Assessment of Pulmonary Arterial Wall Fibrosis by Intravascular Optical Coherence Tomography in Pulmonary Arterial Hypertension: A New Prognostic Marker of Adverse Clinical Follow-Up§

    PubMed Central

    Domingo, Enric; Grignola, Juan C; Aguilar, Rio; Montero, María Angeles; Arredondo, Christian; Vázquez, Manuel; López-Messeguer, Manuel; Bravo, Carlos; Bouteldja, Nadia; Hidalgo, Cristina; Roman, Antonio

    2013-01-01

    Background: The aim is to correlate pulmonary arterial (PA) remodeling estimated by PA fibrosis in PA hypertension (PAH) with clinical follow-up. Histology of PA specimens is also performed. Methods: 19 patients, aged 54±16 (4 men), functional class II-III were studied with right heart catheterization, PA Intravascular Ultrasound and optical coherence tomography (OCT) in inferior lobe segment. PA wall fibrosis was obtained by OCT ( area of fibrosis/PA cross sectional area × 100). Patients follow-up was blind to OCT. Events were defined as mortality, lung transplantation, need of intravenous prostaglandins or onset of right ventricular failure. Results: OCT measurements showed high intra- and interobserver agreement. There was a good correlation between OCT and histology in PA fibrosis from explanted lungs. Area of fibrosis was 1.4±0.8 mm2, % fibrosis was 22.3±8. Follow-up was 3.5 years (2.5-4.5). OCT %Fib was significantly correlated with PA capacitance (r=-0.536) and with pulmonary vascular rsistance (r=0.55). Patients were divided according to the median value of PA fibrosis. There were 10 patients with a high (≥ 22%) and 9 with a low fibrosis (<22%). Events occurred in 6 (1 death, 1 lung transplantation, 2 intravenous prostaglandins, 2 right heart failure) out of 10 patients with high and in 0 out of 9 patients with low fibrosis (p<0.01). Conclusions: In PAH, the severity of PA remodeling assessed by OCT wall fibrosis was significantly predictive of severely unfavorable clinical outcome. In vivo assessment of pulmonary arterial wall fibrosis by intravascular OCT in PAH is a promising new prognostic marker of adverse clinical outcome. PMID:23730366

  13. Computed tomography imaging of a leopard tortoise (Geochelone pardalis pardalis) with confirmed pulmonary fibrosis: a case report

    PubMed Central

    2013-01-01

    An approximately 20-year-old, female Leopard tortoise (Geochelone pardalis pardalis) was presented with dypsnea, wheezing, anorexia and depression. Whole body radiographs revealed generalized diffuse unstructured ‘interstitial lung pattern’ with thickened pulmonary septae while computed tomography (CT) showed emphysematous lung parenchyma and thickened pulmonary septae bordered by irregular ground-glass opacity with smaller areas of ‘honeycombing’. These imaging findings together with histopathologic findings were compatible with chronic, extensive ‘interstitial’ pulmonary fibrosis. PMID:23618386

  14. Computed tomography imaging of a leopard tortoise (Geochelone pardalis pardalis) with confirmed pulmonary fibrosis: a case report.

    PubMed

    Lim, Chee Kin; Kirberger, Robert M; Lane, Emily P; Elliott, Dorianne L

    2013-04-23

    An approximately 20-year-old, female Leopard tortoise (Geochelone pardalis pardalis) was presented with dypsnea, wheezing, anorexia and depression. Whole body radiographs revealed generalized diffuse unstructured 'interstitial lung pattern' with thickened pulmonary septae while computed tomography (CT) showed emphysematous lung parenchyma and thickened pulmonary septae bordered by irregular ground-glass opacity with smaller areas of 'honeycombing'. These imaging findings together with histopathologic findings were compatible with chronic, extensive 'interstitial' pulmonary fibrosis.

  15. Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

    SciTech Connect

    Xiong, Shanshan; Pan, Xiujie; Xu, Long; Yang, Zhihua; Guo, Renfeng; Gu, Yongqing; Li, Ruoxi; Wang, Qianjun; Xiao, Fengjun; Du, Li; Zhou, Pingkun; Zhu, Maoxiang

    2015-10-01

    Purpose: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4{sup +}CD25{sup +}FoxP3{sup +} regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Methods and Materials: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Results: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Conclusions: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis.

  16. Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis.

    PubMed

    Mehrad, Borna; Burdick, Marie D; Strieter, Robert M

    2009-01-01

    Fibrotic interstitial lung diseases are characterized by progressive decline in lung function and premature death from respiratory failure. Fibrocytes are circulating bone marrow-derived progenitor cells that traffic to the lungs and contribute to fibrosis and may represent novel therapeutic targets in these diseases. We have previously found the recruitment of fibrocytes to the lung to be dependent on the chemokine ligand CXCL12. Given that the expression of the CXCL12 receptor, CXCR4, can be modulated pharmacologically in other cell types, we tested the hypotheses that the regulation of CXCR4 expression on fibrocytes mediates their influx to the lung in the context of pulmonary fibrosis and that pharmacologic inhibition of this process results in attenuated disease severity. CXCR4 was the predominant chemokine receptor on human fibrocytes, and its expression on fibrocytes was enhanced by hypoxia and by growth factors including platelet-derived growth factor. Both hypoxia-induced and growth factor-induced CXCR4 expressions were attenuated by specific inhibition of PI3-kinase and mTOR. Finally, in the mouse model of bleomycin-induced pulmonary fibrosis, treatment with the mTOR inhibitor rapamycin resulted in reduced numbers of CXCR4-expressing fibrocytes in the peripheral blood and lung as well as reduced lung collagen deposition. Taken together, these experiments support the notion that pharmacologic inhibition of the CXCR4/CXCL12 biological axis is achievable in human fibrocytes and reduces the magnitude of pulmonary fibrosis in an animal model. This approach may hold promise in human fibrotic lung diseases.

  17. Evaluating the Ameliorative Potential of Quercetin against the Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats

    PubMed Central

    Kushwah, Lokendra; Gohel, Darpesh; Patel, Manish; Marvania, Tulsi; Balakrishnan, Suresh

    2013-01-01

    The current study deals with the effect of a dietary flavanoid quercetin on fibrotic lung tissue in rats. Bleomycin was administered by single intratracheal instillation to Wistar rats to induce lung fibrosis. The pathologies associated with this included significantly reduced antioxidant capacity, ultimately leading to protracted inflammation of the lung tissue. The hallmark of this induced fibrosis condition was an excessive collagen deposition in peribronchial and perialveolar regions of the lung. Oral quercetin treatment over a period of twenty days resulted in significant reversal of the pathologies. The antioxidant defense in lung tissue was revived. Moreover, activity of the collagenase MMP-7, which was high in fibrotic tissue, was seen restored after quercetin administration. Trichome staining of lung tissue sections showed high collagen deposition in fibrotic rats, which may be a direct result of increased mobilization of collagen by MMP-7. This was appreciably reduced in quercetin treated animals. These results point towards an important protective role of quercetin against idiopathic lung fibrosis, which remains a widely prevalent yet incurable condition in the present times. PMID:24396596

  18. Lung volume quantified by MRI reflects extracellular-matrix deposition and altered pulmonary function in bleomycin models of fibrosis: effects of SOM230.

    PubMed

    Egger, Christine; Gérard, Christelle; Vidotto, Nella; Accart, Nathalie; Cannet, Catherine; Dunbar, Andrew; Tigani, Bruno; Piaia, Alessandro; Jarai, Gabor; Jarman, Elizabeth; Schmid, Herbert A; Beckmann, Nicolau

    2014-06-15

    Idiopathic pulmonary fibrosis is a progressive and lethal disease, characterized by loss of lung elasticity and alveolar surface area, secondary to alveolar epithelial cell injury, reactive inflammation, proliferation of fibroblasts, and deposition of extracellular matrix. The effects of oropharyngeal aspiration of bleomycin in Sprague-Dawley rats and C57BL/6 mice, as well as of intratracheal administration of ovalbumin to actively sensitized Brown Norway rats on total lung volume as assessed noninvasively by magnetic resonance imaging (MRI) were investigated here. Lung injury and volume were quantified by using nongated or respiratory-gated MRI acquisitions [ultrashort echo time (UTE) or gradient-echo techniques]. Lung function of bleomycin-challenged rats was examined additionally using a flexiVent system. Postmortem analyses included histology of collagen and hydroxyproline assays. Bleomycin induced an increase of MRI-assessed total lung volume, lung dry and wet weights, and hydroxyproline content as well as collagen amount. In bleomycin-treated rats, gated MRI showed an increased volume of the lung in the inspiratory and expiratory phases of the respiratory cycle and a temporary decrease of tidal volume. Decreased dynamic lung compliance was found in bleomycin-challenged rats. Bleomycin-induced increase of MRI-detected lung volume was consistent with tissue deposition during fibrotic processes resulting in decreased lung elasticity, whereas influences by edema or emphysema could be excluded. In ovalbumin-challenged rats, total lung volume quantified by MRI remained unchanged. The somatostatin analog, SOM230, was shown to have therapeutic effects on established bleomycin-induced fibrosis in rats. This work suggests MRI-detected total lung volume as readout for tissue-deposition in small rodent bleomycin models of pulmonary fibrosis.

  19. Adrenomedullin in inflammatory process associated with experimental pulmonary fibrosis

    PubMed Central

    2011-01-01

    Background Adrenomedullin (AM), a 52-amino acid ringed-structure peptide with C-terminal amidation, was originally isolated from human pheochromocytoma. AM are widely distributed in various tissues and acts as a local vasoactive hormone in various conditions. Methods In the present study, we investigated the efficacy of AM on the animal model of bleomycin (BLM)-induced lung injury. Mice were subjected to intratracheal administration of BLM and were assigned to receive AM daily by an intraperitoneal injection of 200 ngr/kg. Results and Discussion Myeloperoxidase activity, lung histology, immunohistochemical analyses for cytokines and adhesion molecules expression, inducible nitric oxide synthase (iNOS), nitrotyrosine, and poly (ADP-ribose) polymerase (PARP) were performed one week after fibrosis induction. Lung histology and transforming growth factor beta (TGF-β) were performed 14 and 21 days after treatments. After bleomycin administration, AM-treated mice exhibited a reduced degree of lung damage and inflammation compared with BLM-treated mice, as shown by the reduction of (1) myeloperoxidase activity (MPO), (2) cytokines and adhesion molecules expression, (3) nitric oxide synthase expression, (4) the nitration of tyrosine residues, (5) poly (ADP-ribose) (PAR) formation, a product of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) (6) transforming growth factor beta (TGF-β) (7)and the degree of lung injury. Conclusions Our results indicate that AM administration is able to prevent bleomycin induced lung injury through the down regulation of proinflammatory factors. PMID:21477302

  20. The exacerbating roles of CCAAT/enhancer-binding protein homologous protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis and the preventive effects of tauroursodeoxycholic acid (TUDCA) against pulmonary fibrosis in mice.

    PubMed

    Tanaka, Yuta; Ishitsuka, Yoichi; Hayasaka, Marina; Yamada, Yusei; Miyata, Keishi; Endo, Motoyoshi; Kondo, Yuki; Moriuchi, Hiroshi; Irikura, Mitsuru; Tanaka, Ken-ichiro; Mizushima, Tohru; Oike, Yuichi; Irie, Tetsumi

    2015-09-01

    The purpose of this study was to evaluate the role of CCAAT/enhancer-binding protein homologous protein (CHOP), an important transcription factor that regulates the inflammatory reaction during the endoplasmic reticulum (ER) stress response, in the development of pulmonary fibrosis induced by bleomycin (BLM) in mice. An intratracheal injection of BLM transiently increased the expression of CHOP mRNA and protein in an early phase (days 1 and 3) in mice lungs. BLM-induced pulmonary fibrosis was significantly attenuated in Chop gene deficient (Chop KO) mice, compared with wild-type (WT) mice. Furthermore, the inflammatory reactions evaluated by protein concentration, the total number of leucocytes and neutrophils in the bronchoalveolar lavage fluid (BALF), the mRNA expression of interleukin 1b and caspase 11, and the apoptotic cell death were suppressed in Chop KO mice compared with those in WT mice. In addition, administration of tauroursodeoxycholic acid (TUDCA), a pharmacological agent that can inhibit CHOP expression, inhibited the BLM-induced pulmonary fibrosis and inflammation, and the increase in Chop mRNA expression in WT mice in a dose-dependent manner. These results suggest that the ER stress-induced transcription factor, CHOP, at least in part, plays an important role in the development of BLM-induced pulmonary fibrosis in mice, and that the inhibition of CHOP expression by a pharmacological agent, such as TUDCA, may be a promising strategy for the prevention of pulmonary fibrosis.

  1. Idiopathic non-specific interstitial pneumonia.

    PubMed

    Belloli, Elizabeth A; Beckford, Rosemarie; Hadley, Ryan; Flaherty, Kevin R

    2016-02-01

    Non-specific interstitial pneumonia (NSIP) is an interstitial lung disease that may be idiopathic or secondary to connective tissue disease, toxins or numerous other causes. Idiopathic NSIP is a rare diagnosis and requires exclusion of these other possible causes. Patients typically present in mid-adulthood with dyspnoea, cough and often constitutional symptoms including fever and fatigue. The disease has a female predominance, and more than 50% of patients have never smoked. Physical exam features mild hypoxaemia and inspiratory rales. Pulmonary function tests demonstrate restriction and a low diffusing capacity for carbon monoxide. High-resolution computed tomography abnormalities include predominantly lower lobe subpleural reticular changes, traction bronchiectasis and ground-glass opacities; honeycombing is rarely seen. An evaluation of the underlying pathology is necessary for a firm diagnosis. Histologically, alveolar and interstitial mononuclear cell inflammation and fibrosis are seen in a temporally uniform pattern with preserved underlying alveolar architecture. NSIP must be differentiated from other parenchymal lung diseases including idiopathic pulmonary fibrosis and hypersensitivity pneumonitis. A thorough exposure history and assessment for underlying connective tissue diseases are highly important, as positive findings in these categories would likely denote a case of secondary NSIP. A multi-disciplinary discussion that includes pulmonologist(s), radiologist(s) and pathologist(s) assists in reaching a consensus diagnosis and improves diagnostic accuracy. Treatment of idiopathic NSIP, although not well proven, is generally instituted in the form of immunosuppression. Prognosis is favourable compared with idiopathic pulmonary fibrosis, although the diagnosis still carries an attributable mortality. Herein we will summarize the clinical characteristics and management of idiopathic NSIP.

  2. Differential expression of extracellular matrix remodeling genes in a murine model of bleomycin-induced pulmonary fibrosis.

    PubMed Central

    Swiderski, R. E.; Dencoff, J. E.; Floerchinger, C. S.; Shapiro, S. D.; Hunninghake, G. W.

    1998-01-01

    Exposure to the chemotherapeutic drug bleomycin leads to pulmonary fibrosis in humans and has been widely used in animal models of the disease. Using C57BL/6 bleomycin-sensitive mice, pulmonary fibrosis was induced by multiple intraperitoneal injections of the drug. An increase in the relative amounts of steady-state alpha1(I) procollagen, alpha1(III) procollagen, and fibronectin mRNA as well as histopathological evidence of fibrosis was observed. The effect of bleomycin on the expression of the enzymes responsible for extracellular matrix degradation, the matrix metalloproteinases (MMPs), and their inhibitors (TIMPs), was selective and showed temporal differences during the development of fibrosis. Of the MMPs tested, bleomycin treatment resulted in the up-regulation of gelatinase A and macrophage metalloelastase gene expression in whole-lung homogenates, whereas gelatinase B, stromelysin-1, and interstitial collagenase gene expression was not significantly changed. Timp2 and Timp3, the murine homologues of the respective TIMP genes, were constitutively expressed, whereas Timp1 was markedly up-regulated during fibrosis. The strong correlation between enhanced extracellular matrix gene expression, differential MMP and TIMP gene expression, and histopathological evidence of fibrosis suggest that dysregulated matrix remodeling is likely to contribute to the pathology of bleomycin-induced pulmonary fibrosis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:9502424

  3. What patients with pulmonary fibrosis and their partners think: a live, educative survey in the Netherlands and Germany.

    PubMed

    van Manen, Mirjam J G; Kreuter, Michael; van den Blink, Bernt; Oltmanns, Ute; Palmowski, Karin; Brunnemer, Eva; Hummler, Simone; Tak, Nelleke C; van den Toorn, Leon; Miedema, Jelle; Hoogsteden, Henk C; Wijsenbeek, Marlies S

    2017-01-01

    Pulmonary fibrosis greatly impacts patients and their partners. Unmet needs of patients are increasingly acknowledged; the needs of partners often remain unnoticed. Little is known about the best way to educate patients and partners. We investigated pulmonary fibrosis patients' and partners' perspectives and preferences in care, and the differences in these between the Netherlands and Germany. Additionally, we evaluated whether interactive interviewing could be a novel education method in this population. Patients and partners were interviewed during pulmonary fibrosis patient information meetings. In the Netherlands, voting boxes were used and results were projected directly. In Germany, questionnaires were used. In the Netherlands, 278 patients and partners participated; in Germany, 51. Many participants experienced anxiety. Almost all experienced misunderstanding, because people do not know what pulmonary fibrosis is. All expressed a need for information, psychological support and care for partners. Use of the interactive voting system was found to be pleasant (70%) and informative (94%). This study improves the knowledge of care needs of patients with pulmonary fibrosis and their partners. There were no major differences between the Netherlands and Germany. Interactive interviewing could be an attractive method to acquire insights into the needs and preferences of patients and partners, while providing them with information at the same time.

  4. What patients with pulmonary fibrosis and their partners think: a live, educative survey in the Netherlands and Germany

    PubMed Central

    van Manen, Mirjam J.G.; Kreuter, Michael; van den Blink, Bernt; Oltmanns, Ute; Palmowski, Karin; Brunnemer, Eva; Hummler, Simone; Tak, Nelleke C.; van den Toorn, Leon; Miedema, Jelle; Hoogsteden, Henk C.

    2017-01-01

    Pulmonary fibrosis greatly impacts patients and their partners. Unmet needs of patients are increasingly acknowledged; the needs of partners often remain unnoticed. Little is known about the best way to educate patients and partners. We investigated pulmonary fibrosis patients' and partners' perspectives and preferences in care, and the differences in these between the Netherlands and Germany. Additionally, we evaluated whether interactive interviewing could be a novel education method in this population. Patients and partners were interviewed during pulmonary fibrosis patient information meetings. In the Netherlands, voting boxes were used and results were projected directly. In Germany, questionnaires were used. In the Netherlands, 278 patients and partners participated; in Germany, 51. Many participants experienced anxiety. Almost all experienced misunderstanding, because people do not know what pulmonary fibrosis is. All expressed a need for information, psychological support and care for partners. Use of the interactive voting system was found to be pleasant (70%) and informative (94%). This study improves the knowledge of care needs of patients with pulmonary fibrosis and their partners. There were no major differences between the Netherlands and Germany. Interactive interviewing could be an attractive method to acquire insights into the needs and preferences of patients and partners, while providing them with information at the same time. PMID:28229083

  5. Fibroblast growth factor 2 is required for epithelial recovery, but not for pulmonary fibrosis, in response to bleomycin.

    PubMed

    Guzy, Robert D; Stoilov, Ivan; Elton, Timothy J; Mecham, Robert P; Ornitz, David M

    2015-01-01

    The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-β1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2(-/-)) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2(-/-) mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2(-/-) mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2(-/-) mice similarly have deficient recovery of club cell secretory protein(+) bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo.

  6. Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis

    PubMed Central

    Evans, Iona C.; Barnes, Josephine L.; Garner, Ian M.; Pearce, David R.; Maher, Toby M.; Shiwen, Xu; Renzoni, Elisabetta A.; Wells, Athol U.; Denton, Christopher P.; Laurent, Geoffrey J.; Abraham, David J.

    2016-01-01

    Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E2, due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5-aza-2′-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE2 production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4 in control fibroblasts down-regulated COX-2 and PGE2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE2 synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4. PMID:26744410

  7. Rat alveolar myofibroblasts acquire alpha-smooth muscle actin expression during bleomycin-induced pulmonary fibrosis.

    PubMed Central

    Vyalov, S. L.; Gabbiani, G.; Kapanci, Y.

    1993-01-01

    The majority of fibroblasts in alveolar septa are characterized by the presence of cytoplasmic bundles of microfilaments that contain cytoplasmic actin isoforms; these cells have been named contractile interstitial cells or V-type myofibroblasts. In the rat, they express desmin as intermediate filament protein. In this study, we explored the possibility that modulation and replication of such septal fibroblasts result in the appearance of alpha-smooth muscle (alpha-SM) actin-positive myofibroblasts, typical of lung fibrosis. Experimental pulmonary fibrosis was produced by a unique intratracheal instillation of bleomycin to 28 rats. Eight additional rats used as controls received the equivalent volume of saline. Paraffin and frozen sections of lungs were examined at days 1, 3, 5 and 7 after treatment. Microfilaments and intermediate filaments were stained using antibodies against total actin, alpha-SM actin, desmin, vimentin, keratin, and SM myosin. Electron microscopic labeling of desmin and alpha-SM actin using immunogold technique was done on Lowicryl K4M resin-embedded specimens. alpha-SM actin appeared in desmin-positive alveolar fibroblasts as early as 24 hours after intratracheal bleomycin instillation; the modulation of alpha-SM actin in these cells was preceded by a lymphomonocytic infiltration of alveolar septa. Twenty-four hours to 3 days after bleomycin administration, a proliferation of alveolar myofibroblasts occurred. Fibrosis with laying down of collagen fibers took place after the above mentioned cellular modifications. Our results support the view that septal fibroblastic cells can modulate into typical alpha-SM actin-containing myofibroblasts during experimental bleomycin-induced pulmonary fibrosis. In such a modulation a possible role of cytokines, particularly of transforming growth factor-beta, is considered. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14

  8. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis.

    PubMed Central

    Zhang, K.; Flanders, K. C.; Phan, S. H.

    1995-01-01

    Bleomycin-induced pulmonary fibrosis is associated with increased lung transforming growth factor-beta (TGF-beta) gene expression, but cellular localization of the source of this expression has not been unequivocally established. In this study, lung fibrosis was induced in rats by endotracheal bleomycin injection on day 0 and, on selected days afterwards, lungs were harvested for in situ hybridization, immunohistochemical and histochemical analyses for TGF-beta 1 mRNA and protein expression, and cell identification. The results show that control lungs express essentially no detectable TGF-beta 1 mRNA or protein in the parenchyma. Before day 3 after bleomycin treatment, scattered bronchiolar epithelial cells, mononuclear cells, and eosinophils expressed elevated levels of TGF-beta 1. Between days 3 and 14, there was a major increase in the number of eosinophils, myofibroblasts, and fibroblasts strongly expressing TGF-beta 1 mRNA and protein. TGF-beta 1-producing cells were predominantly localized within areas of injury and active fibrosis. After day 14, the intensity and number of TGF-beta 1-expressing cells significantly declined and were predominantly found in fibroblasts in fibrotic areas. The expression of TGF-beta 1 protein was generally coincident with that for mRNA with the exception of bronchiolar epithelial cells in which strong protein expression was unaccompanied by a commensurate increase in mRNA. The study demonstrates that myofibroblasts, fibroblasts, and eosinophils represent the major sources of increased lung TGF-beta 1 expression in this model of pulmonary fibrosis. Images Figure 2 Figure 3 Figure 4 PMID:7543734

  9. Fatal Pulmonary Infection Due to Multidrug-Resistant Mycobacterium abscessus in a Patient with Cystic Fibrosis

    PubMed Central

    Sanguinetti, Maurizio; Ardito, Fausta; Fiscarelli, Ersilia; La Sorda, Marilena; D'Argenio, Patrizia; Ricciotti, Gabriella; Fadda, Giovanni

    2001-01-01

    We report a case of fatal pulmonary infection caused by Mycobacterium abscessus in a young patient with cystic fibrosis, who underwent bipulmonary transplantation after a 1-year history of severe lung disease. Fifteen days after surgery he developed septic fever with progressive deterioration in lung function. M. abscessus, initially isolated from a pleural fluid specimen, was then recovered from repeated blood samples, suggesting a disseminated nature of the mycobacterial disease. Drug susceptibility testing assay, performed on two sequential isolates of the microorganism, showed a pattern of multidrug resistance. Despite aggressive therapy with several antimycobacterial drugs, including clarithromycin, the infection persisted, and the patient died. PMID:11158161

  10. Prevention of Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice by Paeonol

    PubMed Central

    Liu, Meng-Han; Lin, An-Hsuan; Ko, Hsin-Kuo; Perng, Diahn-Warng; Lee, Tzong-Shyuan; Kou, Yu Ru

    2017-01-01

    Pulmonary fibrosis is a severe and progressive disease that is characterized by an abnormal deposition of extracellular matrix, such as collagens. The pathogenesis of this disease may be initiated by oxidative damage of lung epithelial cells by fibrogenic stimuli, leading to lung inflammation, which in turn promotes various lung fibrotic responses. The profibrogenic effect of transforming growth factor-β1 (TGF-β1) on lung fibroblasts is crucial for the pathogenesis of this disease. Paeonol, the main phenolic compound present in the Chinese herb Paeonia suffruticosa, has antioxidant and anti-inflammatory properties. However, whether paeonol has therapeutic effects against pulmonary fibrosis remains unclear. Using a murine model, we showed that 21 days after the insult, intratracheal bleomycin caused pulmonary inflammation and fibrosis, as evidenced by lung histopathological manifestations and increase in various indices. The inflammatory indices included an increase in total cell count, differential cell count, and total protein concentration in bronchoalveolar lavage fluid. The fibrotic indices included an increase in lung levels of TGF-β1, total collagen, type 1α1 collagen (COL1A1), and α-smooth muscle actin (α-SMA; a marker of myofibroblasts). Bleomycin also was found to cause an increase in oxidative stress as reflected by increased levels of malondialdehyde and 4-hydroxynonenal in the lungs. Importantly, all these pathophysiological events were suppressed by daily treatment with paeonol. Using human lung fibroblasts, we further demonstrated that exposure of human lung fibroblasts to TGF-β1 increased productions of α-SMA and COL1A1, both of which were inhibited by inhibitors of Jun N-terminal kinase (JNK), p38, and Smad3. JNK and p38 are two subfamily members of mitogen-activated protein kinases (MAPKs), whereas Smad3 is a transcription factor. TGF-β1 exposure also increased the phosphorylation of JNK, p38, and Smad3 prior to the induction of α-SMA and

  11. Rac2 is involved in bleomycin-induced lung inflammation leading to pulmonary fibrosis

    PubMed Central

    2014-01-01

    Background Pulmonary fibrotic diseases induce significant morbidity and mortality, for which there are limited therapeutic options available. Rac2, a ras-related guanosine triphosphatase expressed mainly in hematopoietic cells, is a crucial molecule regulating a diversity of mast cell, macrophage, and neutrophil functions. All these cell types have been implicated in the development of pulmonary fibrosis in a variety of animal models. For the studies described here we hypothesized that Rac2 deficiency protects mice from bleomycin-induced pulmonary fibrosis. Methods To determine the role of Rac2 in