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Sample records for promotes pulmonary fibrosis

  1. 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 ...

  2. Lysyl oxidase promotes epithelial-to-mesenchymal transition during paraquat-induced pulmonary fibrosis.

    PubMed

    Wang, Jinfeng; Zhu, Yong; Tan, Jiuting; Meng, Xiaoxiao; Xie, Hui; Wang, Ruilan

    2016-02-01

    Lysyl oxidase (LOX) is a copper-dependent amine oxidase that plays a critical role in pulmonary fibrosis. Our previous study demonstrated that epithelial-to-mesenchymal transition (EMT) was strongly associated with paraquat (PQ) induced pulmonary fibrosis. This present study was aimed to evaluate the potential involvement of LOX on EMT in the process of pulmonary fibrosis induced by PQ. We established an in vivo rat model and an in vitro cell model induced by PQ treatment and found that LOX protein expression was significantly up-regulated and collagen deposition was enhanced in rats. The EMT process was strongly found in A549 and RLE-6TN cells after PQ exposure. After inactivating LOX with an inhibitor, pulmonary fibrosis was significantly reduced and EMT was also suppressed. Additionally, small interfering RNA (siRNA) targeting LOX was used to silence LOX expression to observe EMT in A549 cells. As a result, LOX could promote the progress of EMT, and inactivating LOX alleviated the EMT process in PQ-induced pulmonary fibrosis and mesenchymal-to-epithelial transition (MET) occurred after inactivating LOX in vitro and in vivo. In conclusion, LOX could promote the progress of EMT and inactivating LOX alleviated EMT in PQ-induced pulmonary fibrosis. Therefore, LOX could potentially be a new candidate therapeutic target for pulmonary fibrosis induced by PQ by regulating the balance between EMT and MET. PMID:26670953

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

    PubMed Central

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

    2012-01-01

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

  4. 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' ...

  5. Bone Marrow CD11c+ Cell-Derived Amphiregulin Promotes Pulmonary Fibrosis.

    PubMed

    Ding, Lin; Liu, Tianju; Wu, Zhe; Hu, Biao; Nakashima, Taku; Ullenbruch, Matthew; Gonzalez De Los Santos, Francina; Phan, Sem H

    2016-07-01

    Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and fibrosis, but its cellular source and role in regeneration versus fibrosis remain unclear. In this study, we hypothesize that AREG induced in bone marrow-derived CD11c(+) cells is essential for pulmonary fibrosis. Thus, the objectives were to evaluate the importance and role of AREG in pulmonary fibrosis, identify the cellular source of AREG induction, and analyze its regulation of fibroblast function and activation. The results showed that lung AREG expression was significantly induced in bleomycin-induced pulmonary fibrosis. AREG deficiency in knockout mice significantly diminished pulmonary fibrosis. Analysis of AREG expression in major lung cell types revealed induction in fibrotic lungs predominantly occurred in CD11c(+) cells. Moreover, depletion of bone marrow-derived CD11c(+) cells suppressed both induction of lung AREG expression and pulmonary fibrosis. Conversely, adoptive transfer of bone marrow-derived CD11c(+) cells from bleomycin-treated donor mice exacerbated pulmonary fibrosis, but not if the donor cells were made AREG deficient prior to transfer. CD11c(+) cell-conditioned media or coculture stimulated fibroblast proliferation, activation, and myofibroblast differentiation in an AREG-dependent manner. Furthermore, recombinant AREG induced telomerase reverse transcriptase, which appeared to be essential for the proliferative effect. Finally, AREG significantly enhanced fibroblast motility, which was associated with increased expression of α6 integrin. These findings suggested that induced AREG specifically in recruited bone marrow-derived CD11c(+) cells promoted bleomycin-induced pulmonary fibrosis by activation of fibroblast telomerase reverse transcriptase-dependent proliferation, motility, and indirectly, myofibroblast differentiation. PMID:27206766

  6. Familial pulmonary fibrosis.

    PubMed

    Borie, R; Kannengiesser, C; Nathan, N; Tabèze, L; Pradère, P; Crestani, B

    2015-04-01

    The occurrence of pulmonary fibrosis in numerous individuals from the same family suggests a genetic cause for the disease. During the last 10 years, mutations involving proteins from the telomerase complex and from the surfactant system have been identified in association with pulmonary fibrosis. Mutations of TERT, the coding gene for the telomerase reverse transcriptase, are the most frequently identified mutations and are present in 15% of cases of familial pulmonary fibrosis. Other mutations (TERC, surfactant proteins genes) are only rarely evidenced in adults. Patients with mutations involving the telomerase complex may present with pulmonary fibrosis, hematologic, cutaneous or liver diseases. Other genetic variations associated with pulmonary fibrosis such as a polymorphism in the promoter of MUC5B or a polymorphism in TERT have been recently described, and could be considered to be part of a polygenic transmission. Evidence for mutations associated with the development of pulmonary fibrosis raises numerous clinical questions from establishing a diagnosis, providing counselling to deciding on therapy, and requires specific studies. From a pathophysiological point of view, the function of the genes highlights the central role of alveolar epithelium and aging in fibrogenesis. PMID:25596800

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

    PubMed Central

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

    2014-01-01

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

  8. 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. PMID:26779814

  9. 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

  10. Familial Pulmonary Fibrosis

    MedlinePlus

    ... are here: Health Information > Condition Information Familial Pulmonary Fibrosis: Overview When two or more members within the ... Associate Professor View full profile More Familial Pulmonary Fibrosis Information Forms Causes Genetic Counseling Print Page Email ...

  11. 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.

  12. MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis

    PubMed Central

    Gharib, Sina A.; Johnston, Laura K.; Huizar, Isham; Birkland, Timothy P.; Hanson, Josiah; Wang, Ying; Parks, William C.; Manicone, Anne M.

    2014-01-01

    Members of the MMP family function in various processes of innate immunity, particularly in controlling important steps in leukocyte trafficking and activation. MMP28 (epilysin) is a member of this family of proteinases, and we have found that MMP28 is expressed by macrophages and regulates their recruitment to the lung. We hypothesized that MMP28 regulates other key macrophage responses, such as macrophage polarization. Furthermore, we hypothesized that these MMP28-dependent changes in macrophage polarization would alter fibrotic responses in the lung. We examined the gene expression changes in WT and Mmp28−/− BMDMs, stimulated with LPS or IL-4/IL-13 to promote M1 and M2 cells, respectively. We also collected macrophages from the lungs of Pseudomonas aeruginosa-exposed WT and Mmp28−/− mice to evaluate changes in macrophage polarization. Lastly, we evaluated the macrophage polarization phenotypes during bleomycin-induced pulmonary fibrosis in WT and Mmp28−/− mice and assessed mice for differences in weight loss and total collagen levels. We found that MMP28 dampens proinflammatory macrophage function and promots M2 programming. In both in vivo models, we found deficits in M2 polarization in Mmp28−/− mice. In bleomycin-induced lung injury, these changes were associated with reduced fibrosis. MMP28 is an important regulator of macrophage polarization, promoting M2 function. Loss of MMP28 results in reduced M2 polarization and protection from bleomycin-induced fibrosis. These findings highlight a novel role for MMP28 in macrophage biology and pulmonary disease. PMID:23964118

  13. 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

  14. Idiopathic Pulmonary Fibrosis (IPF)

    MedlinePlus

    ... cough, shortness of breath, fatigue and low blood oxygen levels. Pulmonary fibrosis can be caused by an ... breath. Your health care provider may notice the oxygen levels in your blood drop when you walk. ...

  15. Upregulation of Steroidogenic Acute Regulatory Protein by Hypoxia Stimulates Aldosterone Synthesis in Pulmonary Artery Endothelial Cells to Promote Pulmonary Vascular Fibrosis

    PubMed Central

    Maron, Bradley A.; Oldham, William M.; Chan, Stephen Y.; Vargas, Sara O.; Arons, Elena; Zhang, Ying-Yi; Loscalzo, Joseph; Leopold, Jane A.

    2014-01-01

    Background The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension (PAH), suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in PAH. Methods and Results Patients with PAH, rats with Sugen/hypoxia-PAH, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia-StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldosterone levels selectively in HPAECs, which was confirmed by liquid chromatography-mass spectrometry. Increased aldosterone by hypoxia resulted from enhanced c-Fos/c-Jun binding to the proximal activator protein (AP-1) site of the StAR promoter in HPAECs, which increased StAR expression and activity. In HPAECs transfected with StAR-siRNA or treated with the AP-1 inhibitor, SR-11302, hypoxia failed to increase aldosterone, confirming that aldosterone biosynthesis required StAR activation by c-Fos/c-Jun. The functional consequences of aldosterone were confirmed by pharmacological inhibition of the mineralocorticoid receptor with spironolactone or eplerenone, which attenuated hypoxia-induced upregulation of the fibrogenic protein connective tissue growth factor and collagen III in vitro, and decreased pulmonary vascular fibrosis to improve pulmonary hypertension in Conclusions Our findings identify autonomous aldosterone synthesis in HPAECs due to hypoxia-mediated upregulation of StAR as a novel molecular mechanism that promotes pulmonary vascular

  16. Pulmonary Fibrosis Foundation

    MedlinePlus

    ... 844.825.5733) to speak with a representative today. LEARN MORE It's Global PF Awareness Month! Download the toolkit to learn ... 19 NEW SITES The Pulmonary Fibrosis Foundation (PFF) today announced the expansion of the PFF Care Center Network with the selection of 19 additional sites, bringing the total number to 40 in 27 states. More Announcements ... SEP 12 ...

  17. Reduced Ets Domain-containing Protein Elk1 Promotes Pulmonary Fibrosis via Increased Integrin αvβ6 Expression*

    PubMed Central

    Habgood, Anthony; Porte, Joanne; John, Alison E.; Stavrou, Anastasios; Hodge, Emily; Kerama-Likoko, Cheryl; Violette, Shelia M.; Weinreb, Paul H.; Knox, Alan J.; Laurent, Geoffrey; Parfrey, Helen; Wolters, Paul John; Wallace, William; Alberti, Siegfried; Nordheim, Alfred; Jenkins, Gisli

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with high mortality. Active TGFβ1 is considered central to the pathogenesis of IPF. A major mechanism of TGFβ1 activation in the lung involves the epithelially restricted αvβ6 integrin. Expression of the αvβ6 integrin is dramatically increased in IPF. How αvβ6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the β6 subunit gene (ITGB6) promoter acting to markedly repress basal gene transcription, which responds to both the Ets domain-containing protein Elk1 (Elk1) and the glucocorticoid receptor (GR). Both Elk1 and GR can regulate αvβ6 integrin expression in vitro. We demonstrate Elk1 binding to the ITGB6 promoter basally and that manipulation of Elk1 or Elk1 binding alters ITGB6 promoter activity, gene transcription, and αvβ6 integrin expression. Crucially, we find that loss of Elk1 causes enhanced Itgb6 expression and exaggerated lung fibrosis in an in vivo model of fibrosis, whereas the GR agonist dexamethasone inhibits Itgb6 expression. Moreover, Elk1 dysregulation is present in epithelium from patients with IPF. These data reveal a novel role for Elk1 regulating ITGB6 expression and highlight how dysregulation of Elk1 can contribute to human disease. PMID:26861876

  18. Reduced Ets Domain-containing Protein Elk1 Promotes Pulmonary Fibrosis via Increased Integrin αvβ6 Expression.

    PubMed

    Tatler, Amanda L; Habgood, Anthony; Porte, Joanne; John, Alison E; Stavrou, Anastasios; Hodge, Emily; Kerama-Likoko, Cheryl; Violette, Shelia M; Weinreb, Paul H; Knox, Alan J; Laurent, Geoffrey; Parfrey, Helen; Wolters, Paul John; Wallace, William; Alberti, Siegfried; Nordheim, Alfred; Jenkins, Gisli

    2016-04-29

    Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with high mortality. Active TGFβ1 is considered central to the pathogenesis of IPF. A major mechanism of TGFβ1 activation in the lung involves the epithelially restricted αvβ6 integrin. Expression of the αvβ6 integrin is dramatically increased in IPF. How αvβ6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the β6 subunit gene (ITGB6) promoter acting to markedly repress basal gene transcription, which responds to both the Ets domain-containing protein Elk1 (Elk1) and the glucocorticoid receptor (GR). Both Elk1 and GR can regulate αvβ6 integrin expression in vitro We demonstrate Elk1 binding to the ITGB6 promoter basally and that manipulation of Elk1 or Elk1 binding alters ITGB6 promoter activity, gene transcription, and αvβ6 integrin expression. Crucially, we find that loss of Elk1 causes enhanced Itgb6 expression and exaggerated lung fibrosis in an in vivo model of fibrosis, whereas the GR agonist dexamethasone inhibits Itgb6 expression. Moreover, Elk1 dysregulation is present in epithelium from patients with IPF. These data reveal a novel role for Elk1 regulating ITGB6 expression and highlight how dysregulation of Elk1 can contribute to human disease. PMID:26861876

  19. The von Hippel–Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice

    PubMed Central

    Hickey, Michele M.; Richardson, Theresa; Wang, Tao; Mosqueira, Matias; Arguiri, Evguenia; Yu, Hongwei; Yu, Qian-Chun; Solomides, Charalambos C.; Morrisey, Edward E.; Khurana, Tejvir S.; Christofidou-Solomidou, Melpo; Simon, M. Celeste

    2010-01-01

    Mutation of the von Hippel–Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (VhlR/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating VhlR/R mice as a model for Chuvash disease. Lungs from VhlR/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2α activity was increased in lungs from VhlR/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the VhlR/R mice. Furthermore, Hif2a heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in VhlR/R lungs, suggesting a selective role for HIF-2α in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2α and suggest potential treatments for Chuvash patients. PMID:20197624

  20. The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice.

    PubMed

    Hickey, Michele M; Richardson, Theresa; Wang, Tao; Mosqueira, Matias; Arguiri, Evguenia; Yu, Hongwei; Yu, Qian-Chun; Solomides, Charalambos C; Morrisey, Edward E; Khurana, Tejvir S; Christofidou-Solomidou, Melpo; Simon, M Celeste

    2010-03-01

    Mutation of the von Hippel-Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (VhlR/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating VhlR/R mice as a model for Chuvash disease. Lungs from VhlR/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2alpha activity was increased in lungs from VhlR/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the VhlR/R mice. Furthermore, Hif2a heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in VhlR/R lungs, suggesting a selective role for HIF-2alpha in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2alpha and suggest potential treatments for Chuvash patients. PMID:20197624

  1. [Idiopathic Pulmonary Fibrosis].

    PubMed

    Prasse, A

    2015-10-01

    Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and a disease of the elderly. Cigarette smoking and longterm exposure to substances harming alveolar epithelial cells are risk factors for the development of IPF. There is also evidence for a genetic susceptibility. IPF is defined as the idiopathic variant of Usual Interstitial Pneumonitis (UIP). Diagnosis of IPF is complex and based on the exclusion of other diseases associated with an UIP pattern. The only cure is lung transplantation. In the last years there was a breakthrough in the treatment of IPF. With pirfenidone and nintedanib there are now two compounds approved for the treatment of IPF. PMID:26444136

  2. Idiopathic Pulmonary Fibrosis.

    PubMed

    Martin, Maria D; Chung, Jonathan H; Kanne, Jeffrey P

    2016-05-01

    Idiopathic pulmonary fibrosis (IPF) is the most common fibrosing lung disease and is associated with a very poor prognosis. IPF manifests histopathologically as usual interstitial pneumonia (UIP) and as subpleural and basal predominant reticulation with honeycombing on high-resolution computed tomography (HRCT) of the chest. When a high-confidence radiologic diagnosis of UIP is made on HRCT, surgical biopsy is rarely required. Therefore, radiologists should recognize a UIP pattern on HRCT as well as recognize other patterns of fibrosing lung disease such as nonspecific interstitial pneumonia or chronic hypersensitivity pneumonitis, both of which can be mistaken for UIP. This article reviews the clinical, CT, and histopathologic features of IPF, discusses the impact of CT findings on prognosis, and describes complications associated with IPF. PMID:27043425

  3. How Is Idiopathic Pulmonary Fibrosis Treated?

    MedlinePlus

    ... the NHLBI on Twitter. How Is Idiopathic Pulmonary Fibrosis Treated? Doctors may prescribe medicines, oxygen therapy , pulmonary ... PR), and lung transplant to treat idiopathic pulmonary fibrosis (IPF). Medicines Currently, no medicines are proven to ...

  4. Pulmonary complications of cystic fibrosis.

    PubMed

    Ng, M Y; Flight, W; Smith, E

    2014-03-01

    The life expectancy of patients with cystic fibrosis (CF) has steadily increased over recent decades with a corresponding increase in the frequency of complications of the disease. Radiologists are increasingly involved with managing and identifying the pulmonary complications of CF. This article reviews the common manifestations of CF lung disease as well as updating radiologists with a number of less well-known complications of the condition. Early and accurate detection of the pulmonary effects of CF are increasingly important to prevent irreversible lung damage and give patients the greatest possibility of benefiting from the new therapies becoming available, which correct the underlying defect causing CF. PMID:24361142

  5. Novel therapeutic approaches for pulmonary fibrosis

    PubMed Central

    Datta, Arnab; Scotton, Chris J; Chambers, Rachel C

    2011-01-01

    Pulmonary fibrosis represents the end stage of a number of heterogeneous conditions and is, to a greater or lesser degree, the hallmark of the interstitial lung diseases. It is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium leading to the obliteration of functional alveolar units and in many cases, respiratory failure. While a small number of interstitial lung diseases have known aetiologies, most are idiopathic in nature, and of these, idiopathic pulmonary fibrosis is the most common and carries with it an appalling prognosis – median survival from the time of diagnosis is less than 3 years. This reflects the lack of any effective therapy to modify the course of the disease, which in turn is indicative of our incomplete understanding of the pathogenesis of this condition. Current prevailing hypotheses focus on dysregulated epithelial–mesenchymal interactions promoting a cycle of continued epithelial cell injury and fibroblast activation leading to progressive fibrosis. However, it is likely that multiple abnormalities in a myriad of biological pathways affecting inflammation and wound repair – including matrix regulation, epithelial reconstitution, the coagulation cascade, neovascularization and antioxidant pathways – modulate this defective crosstalk and promote fibrogenesis. This review aims to offer a pathogenetic rationale behind current therapies, briefly outlining previous and ongoing clinical trials, but will focus on recent and exciting advancements in our understanding of the pathogenesis of idiopathic pulmonary fibrosis, which may ultimately lead to the development of novel and effective therapeutic interventions for this devastating condition. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1 PMID:21265830

  6. Nintedanib in idiopathic pulmonary fibrosis.

    PubMed

    Woodcock, H V; Maher, T M

    2015-06-01

    Idiopathic pulmonary fibrosis (IPF) conveys a median survival of 3 years and until recently has lacked effective therapies. Nintedanib, an orally available, small-molecule tyrosine kinase inhibitor with selectivity for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptors has recently been shown, in two pivotal phase III studies, to effectively slow IPF disease progression. Consequently, nintedanib was given accelerated approval by the FDA in October 2014 for the treatment of IPF. This monograph explores the preclinical rationale for the antifibrotic role of nintedanib and provides an overview of the available data on pharmacokinetics, efficacy and safety. PMID:26261848

  7. Smoking-associated fibrosis and pulmonary asbestosis.

    PubMed

    Bledsoe, Jacob R; Christiani, David C; Kradin, Richard L

    2015-01-01

    The diagnosis of pulmonary asbestosis is most often established based on clinical criteria and has both clinical and legal implications. Unfortunately, one of the confounding features in the diagnosis may be a history of cigarette abuse, which can produce interstitial opacities on chest imaging as well as diffusion defects on pulmonary function testing, criteria that are used in the diagnosis of pulmonary asbestosis. The objective of the present study was to evaluate the correlation of radiographically detected pulmonary fibrosis with fibrosis established histopathologically as attributable to asbestos, in a cohort referred for diagnosis of an asbestos-related malignancy in the context of litigation. We examined the slides of 186 cases with reported asbestos exposure, referred in consultation for asbestos-related malignancy and the presence of pulmonary fibrosis. Sixty-five cases had what was judged to be adequate tissue sampling for histopathologic evaluation of asbestosis as well as an existing radiologic assessment of pulmonary fibrosis by B-reader report. Of 24 cases judged to have asbestosis radiographically, which had sufficient tissue for pathologic examination, six showed asbestosis histopathologically. The remaining 18 cases (mean smoking history of 53 pack-years) showed interstitial fibrosis that was judged to be most consistent with smoking-associated pulmonary fibrosis. We conclude that the clinical diagnosis of mild asbestosis cannot be reliably distinguished from interstitial fibrosis in heavy smokers. PMID:25565798

  8. Cough in idiopathic pulmonary fibrosis.

    PubMed

    van Manen, Mirjam J G; Birring, Surinder S; Vancheri, Carlo; Cottin, Vincent; Renzoni, Elisabetta A; Russell, Anne-Marie; Wijsenbeek, Marlies S

    2016-09-01

    Many patients with idiopathic pulmonary fibrosis (IPF) complain of chronic refractory cough. Chronic cough is a distressing and disabling symptom with a major impact on quality of life. During recent years, progress has been made in gaining insight into the pathogenesis of cough in IPF, which is most probably "multifactorial" and influenced by mechanical, biochemical and neurosensory changes, with an important role for comorbidities as well. Clinical trials of cough treatment in IPF are emerging, and cough is increasingly included as a secondary end-point in trials assessing new compounds for IPF. It is important that such studies include adequate end-points to assess cough both objectively and subjectively. This article summarises the latest insights into chronic cough in IPF. It describes the different theories regarding the pathophysiology of cough, reviews the different methods to assess cough and deals with recent and future developments in the treatment of cough in IPF. PMID:27581827

  9. 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

  10. Epigenomics of idiopathic pulmonary fibrosis

    PubMed Central

    Yang, Ivana V

    2012-01-01

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

  11. MUC5B and Idiopathic Pulmonary Fibrosis.

    PubMed

    Yang, Ivana V; Fingerlin, Tasha E; Evans, Christopher M; Schwarz, Marvin I; Schwartz, David A

    2015-11-01

    Idiopathic pulmonary fibrosis (IPF), a fatal disease that is a result of complex interactions between genetics and the environment, has limited treatment options. We have identified the MUC5B promoter polymorphism and other common genetic variants that in aggregate explain roughly one-third of disease risk. The MUC5B promoter polymorphism is the strongest and the most replicated genetic risk factor for IPF, appears to be protective and predictive in this disease, and is likely involved in disease pathogenesis through an increase in MUC5B expression in terminal bronchi and honeycombed cysts. Expression of MUC5B is also highly correlated with expression of cilium genes in IPF lung. Our work suggests that mucociliary dysfunction in the distal airway may play a role in the development of progressive fibroproliferative lung disease. In addition, our work has important implications for secondary prevention, early detection, and future early and personalized treatment based on genetic profiles. PMID:26595739

  12. Genetics Home Reference: idiopathic pulmonary fibrosis

    MedlinePlus

    ... However, the course of the disease is highly variable; some affected people become seriously ill within a ... idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med. 2014 Jul;2(7): ...

  13. Molecular and cellular mechanisms of pulmonary fibrosis

    PubMed Central

    2012-01-01

    Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease. PMID:22824096

  14. "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. PMID:19170216

  15. Alveolar epithelial disintegrity in pulmonary fibrosis.

    PubMed

    Kulkarni, Tejaswini; de Andrade, Joao; Zhou, Yong; Luckhardt, Tracy; Thannickal, Victor J

    2016-08-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive decline in lung function, resulting in significant morbidity and mortality. Current concepts of the pathogenesis of IPF primarily center on dysregulated epithelial cell repair and altered epithelial-mesenchymal communication and extracellular matrix deposition following chronic exposure to cigarette smoke or environmental toxins. In recent years, increasing attention has been directed toward the role of the intercellular junctional complex in determining the specific properties of epithelia in pulmonary diseases. Additionally, recent genomewide association studies suggest that specific genetic variants predictive of epithelial cell dysfunction may confer susceptibility to the development of sporadic idiopathic pulmonary fibrosis. A number of genetic disorders linked to pulmonary fibrosis and familial interstitial pneumonias are associated with loss of epithelial integrity. However, the potential links between extrapulmonary clinical syndromes associated with defects in epithelial cells and the development of pulmonary fibrosis are not well understood. Here, we report a case of hereditary mucoepithelial dysplasia that presented with pulmonary fibrosis and emphysema on high-resolution computed tomography. This case illustrates a more generalizable concept of epithelial disintegrity in the development of fibrotic lung diseases, which is explored in greater detail in this review article. PMID:27233996

  16. 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.

  17. Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFβ-1 signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis.

    PubMed

    Nan, Ling; Jacko, Anastasia M; Tan, Jiangning; Wang, Dan; Zhao, Jing; Kass, Daniel J; Ma, Haichun; Zhao, Yutong

    2016-01-01

    Transforming growth factor β-1 (TGFβ-1)-induced phosphorylation of transcription factors Smad2 and Smad3 plays a crucial role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the molecular regulation of Smad2/Smad3 proteins stability remains a mystery. Here, we show that ubiquitin carboxyl-terminal hydrolase-L5 (UCHL5 or UCH37) de-ubiquitinates both Smad2 and Smad3, up-regulates their stability, and promotes TGFβ-1-induced expression of profibrotic proteins, such as fibronectin (FN) and α-smooth muscle actin (α-SMA). Inhibition or down-regulation of UCHL5 reduced Smad2/Smad3 levels and TGFβ-1-induced the expression of FN and α-SMA in human lung fibroblast. We demonstrate that Smad2 and Smad3 ubiquitination was diminished by over-expression of UCHL5, while it was enhanced by inhibition or down-regulation of UCHL5. UCHL5 is highly expressed in IPF lungs. UCHL5, Smad2, and Smad3 levels were increased in bleomycin-injured lungs. Administration of UCHL5 inhibitor, b-AP15, reduced the expression of FN, type I collagen, Smad2/Smad3, and the deposition of collagen in lung tissues in a bleomycin-induced model of pulmonary fibrosis. Our studies provide a molecular mechanism by which UCHL5 mitigates TGFβ-1 signaling by stabilizing Smad2/Smad3. These data indicate that UCHL5 may contribute to the pathogenesis of IPF and may be a potential therapeutic target. PMID:27604640

  18. Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFβ-1 signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis

    PubMed Central

    Nan, Ling; Jacko, Anastasia M.; Tan, Jiangning; Wang, Dan; Zhao, Jing; Kass, Daniel J.; Ma, Haichun; Zhao, Yutong

    2016-01-01

    Transforming growth factor β-1 (TGFβ-1)-induced phosphorylation of transcription factors Smad2 and Smad3 plays a crucial role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the molecular regulation of Smad2/Smad3 proteins stability remains a mystery. Here, we show that ubiquitin carboxyl-terminal hydrolase-L5 (UCHL5 or UCH37) de-ubiquitinates both Smad2 and Smad3, up-regulates their stability, and promotes TGFβ-1-induced expression of profibrotic proteins, such as fibronectin (FN) and α-smooth muscle actin (α-SMA). Inhibition or down-regulation of UCHL5 reduced Smad2/Smad3 levels and TGFβ-1-induced the expression of FN and α-SMA in human lung fibroblast. We demonstrate that Smad2 and Smad3 ubiquitination was diminished by over-expression of UCHL5, while it was enhanced by inhibition or down-regulation of UCHL5. UCHL5 is highly expressed in IPF lungs. UCHL5, Smad2, and Smad3 levels were increased in bleomycin-injured lungs. Administration of UCHL5 inhibitor, b-AP15, reduced the expression of FN, type I collagen, Smad2/Smad3, and the deposition of collagen in lung tissues in a bleomycin-induced model of pulmonary fibrosis. Our studies provide a molecular mechanism by which UCHL5 mitigates TGFβ-1 signaling by stabilizing Smad2/Smad3. These data indicate that UCHL5 may contribute to the pathogenesis of IPF and may be a potential therapeutic target. PMID:27604640

  19. 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

  20. Managing comorbidities in idiopathic pulmonary fibrosis

    PubMed Central

    Fulton, Blair G; Ryerson, Christopher J

    2015-01-01

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

  1. Bosentan for pulmonary hypertension secondary to idiopathic pulmonary fibrosis

    PubMed Central

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

    2014-01-01

    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. PMID:26029570

  2. Idiopathic pulmonary fibrosis: an Australian perspective.

    PubMed

    Prasad, J; Holland, A E; Glaspole, I; Westall, G

    2016-06-01

    Idiopathic pulmonary fibrosis is a progressive interstitial lung disease of unknown aetiology with a dismal median survival of 3 years. Patients typically develop progressive dyspnoea and increasing exercise limitation. With a rising incidence and prevalence, an unpredictable disease course and limited treatment options, it is rapidly becoming an important public health concern. To date, lung transplantation has been the sole viable hope for treatment for those who qualify. However, the landscape of idiopathic pulmonary fibrosis management is changing, with the recent emergence of novel pharmacotherapy shown to have a favourable influence on the natural history of this disease. PMID:27257148

  3. Genetics and Early Detection in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Putman, Rachel K.; Rosas, Ivan O.

    2014-01-01

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

  4. 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. PMID:26741177

  5. MicroRNA mimicry blocks pulmonary fibrosis

    PubMed Central

    Montgomery, Rusty L; Yu, Guoying; Latimer, Paul A; Stack, Christianna; Robinson, Kathryn; Dalby, Christina M; Kaminski, Naftali; van Rooij, Eva

    2014-01-01

    Over the last decade, great enthusiasm has evolved for microRNA (miRNA) therapeutics. Part of the excitement stems from the fact that a miRNA often regulates numerous related mRNAs. As such, modulation of a single miRNA allows for parallel regulation of multiple genes involved in a particular disease. While many studies have shown therapeutic efficacy using miRNA inhibitors, efforts to restore or increase the function of a miRNA have been lagging behind. The miR-29 family has gained a lot of attention for its clear function in tissue fibrosis. This fibroblast-enriched miRNA family is downregulated in fibrotic diseases which induces a coordinate increase of many extracellular matrix genes. Here, we show that intravenous injection of synthetic RNA duplexes can increase miR-29 levels in vivo for several days. Moreover, therapeutic delivery of these miR-29 mimics during bleomycin-induced pulmonary fibrosis restores endogenous miR-29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis. Our data support the feasibility of using miRNA mimics to therapeutically increase miRNAs and indicate miR-29 to be a potent therapeutic miRNA for treating pulmonary fibrosis. PMID:25239947

  6. Mica-associated pulmonary interstitial fibrosis.

    PubMed

    Landas, S K; Schwartz, D A

    1991-09-01

    We present the clinical and biopsy findings of a 63-yr-old white male with interstitial pulmonary fibrosis and a long history of extensive exposure to mica while working in the rubber industry. The patient presented 30 yr after the initial exposure with complaints of progressive shortness of breath and a chronic nonproductive cough. Pulmonary function testing revealed restrictive lung function with a mild reduction in the total lung capacity (80% of predicted) and a moderate-to-severe reduction in the diffusing capacity of carbon monoxide (50% of predicted). The chest radiogram and high-resolution chest CT scan showed diffuse fibrosis and focal honeycombing involving the upper and lower lung zones bilaterally. Bronchoalveolar lavage revealed 20% neutrophils in the lavage fluid with abundant rectangular flaking crystals. Open-lung biopsy exhibited extensive fibrosis and architectural remodeling with abundant sheets and fragments of engulfed polarizable crystalline material. Energy-dispersive spectroscopy and electron diffraction studies confirmed the material to have the features of mica. Asbestos and other silicates were not identified. The documentation of prolonged exposure to mica, the clinical and radiographic features of severe interstitial fibrosis, and the histopathologic delineation of the interstitial lesion, including spectroscopic and crystallographic verification of crystalline mica, support the causal relationship between mica and interstitial fibrosis. PMID:1892315

  7. 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.

  8. The genetic and environmental causes of pulmonary fibrosis.

    PubMed

    Macneal, Ken; Schwartz, David A

    2012-07-01

    Although substantial progress has been made in understanding the clinical, radiological, and pathological manifestations of fibrosing interstitial lung diseases (ILD), it remains difficult for the clinician to predict the clinical course or the response to therapy for the subtypes of ILD, even from individual to individual with the same diagnosis. This article reviews the genetic and environmental causes of pulmonary fibrosis, specifically focusing on genetic and epigenetic variants of MUC5B and several types of ILD, to discuss why only some individuals with the MUC5B promoter polymorphism develop pulmonary fibrosis. Once we discover how these genetic and epigenetic risks lead to the development of ILD, we and others can apply these discoveries to: (1) identify individuals at risk of developing ILD, (2) diagnose the condition at an earlier stage, (3) identify novel mechanisms that cause ILD, and (4) eventually develop personalized therapeutic strategies for intervention. PMID:22802285

  9. Inositol-requiring protein 1 - X-box-binding protein 1 pathway promotes epithelial-mesenchymal transition via mediating snail expression in pulmonary fibrosis.

    PubMed

    Mo, Xiao-Ting; Zhou, Wen-Cheng; Cui, Wen-Hui; Li, De-Lin; Li, Liu-Cheng; Xu, Liang; Zhao, Ping; Gao, Jian

    2015-08-01

    Epithelial-mesenchymal transition (EMT) is a complex biological program during which cells loss epithelial phenotype and acquire mesenchymal features. EMT is thought to be involved in the pathogenesis of various fibrotic diseases including pulmonary fibrosis (PF). Recent studies suggest that endoplasmic reticulum (ER) stress is associated with EMT in the progression of PF. However, the exact mechanism is unclear. Here, we developed a PF model with bleomycin (BLM) administration in rats and conducted several simulation experiments in alveolar epithelial cell (AECs) RLE-6TN to unravel the role of inositol-requiring protein 1 (IRE1) - X-box-binding protein 1 (XBP1) signal pathway in ER stress-induced EMT in PF. First, we observed that ER stress was occurred in type II AECs accompanied by EMT in BLM-induced PF. Then we explored the role of IRE1-XBP1-snail pathway in transforming growth factor (TGF)-β1/tunicamycin (TM)-induced EMT. When TGF-β1/TM was treated on AECs, IRE1 and XBP1 were overexpressed, meanwhile, snail expression was upregulated accompanied with EMT. However, when IRE1 or XBP1 was knockdown, TGF-β1/TM-induced EMT were blocked while the expression of snail was inhibited. Then we silenced snail and found that TGF-β1/TM-induced EMT were also suppressed, but it had no effect on the up-regulated expression of IRE1 and XBP1. Thus, we concluded that IRE1-XBP1 pathway promotes EMT via mediating snail expression in PF. PMID:26065400

  10. Molecular mechanisms in progressive idiopathic pulmonary fibrosis.

    PubMed

    Steele, Mark P; Schwartz, David A

    2013-01-01

    There is clear evidence that environmental exposures and genetic predisposition contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cigarette smoking increases the risk of developing IPF several-fold, as do other exposures such as metal-fume and wood-dust exposure. Occupations that increase the risk of IPF are agricultural work, hairdressing, and stone polishing, supporting the role of environmental exposure in disease pathogenesis. Genetic predisposition to IPF is evident from its familial aggregation and the fact that pulmonary fibrosis develops in several rare genetic disorders. Mutations in surfactant proteins lead to pulmonary fibrosis and are associated with endoplasmic reticulum stress in alveolar type II epithelial cells. Mutations in telomerase have been found in several families with IPF, and shortened telomeres are found in sporadic cases of IPF. A common variant in mucin 5B predisposes to both familial and sporadic IPF and is present in the majority of cases, indicating sporadic IPF occurs in those with genetic predisposition. PMID:23020878

  11. Association Between the MUC5B Promoter Polymorphism rs35705950 and Idiopathic Pulmonary Fibrosis: A Meta-analysis and Trial Sequential Analysis in Caucasian and Asian Populations.

    PubMed

    Zhu, Qing-Qing; Zhang, Xin-Lin; Zhang, Si-Min; Tang, Shao-Wen; Min, Hai-Yan; Yi, Long; Xu, Biao; Song, Yong

    2015-10-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. A number of studies reported the association between MUC5B promoter polymorphism rs35705950 and IPF, but substantial inconsistent findings were observed and the strength of association remains unclear.The aim of the study was to investigate the association between rs35705950 and IPF in different ethnic populations.PubMed, EMBASE, Web of Science, and CENTRAL were searched from their inception to April 15, 2015. Allelic and phenotypic comparisons were conducted separately, as were comparisons in Caucasian and Asian populations. A meta-analysis with trial sequential analysis was conducted.Nine studies presented in 7 full-text articles were included, encompassing 2733 IPF patients and 5044 controls. Six studies were carried out in the Caucasian population, and 3 in the Asian population. Minor T allele was associated with an increased risk of IPF compared with G allele (odds ratio [OR] 4.85, 95% confidence interval [CI] 3.79-6.21, P = 5.88 × 10), as were TG and TT genotypes compared with GG genotype (TG vs GG: OR 6.20, 95% CI 5.14-7.48, P = 1.70 × 10; TT vs GG: OR 11.29, 95% CI 5.69-22.40, P = 4.22 × 10), in an allele dose-dependent manner. These observations were confirmed in trial sequential analysis in both populations. The strength of association was more remarkable in the Caucasian population than in the Asian population, and no homozygous TT genotype was detected in the Asian population in our study.Our study revealed strong association between the MUC5B promoter rs35705950 polymorphism and the risk of IPF. The strength of association between rs35705950 minor T allele and IPF susceptibility was particularly evident in the Caucasian population, and milder but still significant in the Asian population. PMID:26512610

  12. Pulmonary arteriole gene expression signature in idiopathic pulmonary fibrosis.

    PubMed

    Patel, Nina M; Kawut, Steven M; Jelic, Sanja; Arcasoy, Selim M; Lederer, David J; Borczuk, Alain C

    2013-06-01

    A third of patients with idiopathic pulmonary fibrosis (IPF) develop pulmonary hypertension (PH-IPF), which is associated with increased mortality. Whether an altered gene expression profile in the pulmonary vasculature precedes the clinical onset of PH-IPF is unknown. We compared gene expression in the pulmonary vasculature of IPF patients with and without PH with controls. Pulmonary arterioles were isolated using laser capture microdissection from 16 IPF patients: eight with PH (PH-IPF) and eight with no PH (NPH-IPF), and seven controls. Probe was prepared from extracted RNA, and hybridised to Affymetrix Hu133 2.0 Plus genechips. Biometric Research Branch array tools and Ingenuity Pathway Analysis software were used for analysis of the microarray data. Univariate analysis revealed 255 genes that distinguished IPF arterioles from controls (p<0.001). Mediators of vascular smooth muscle and endothelial cell proliferation, Wnt signalling and apoptosis were differentially expressed in IPF arterioles. Unsupervised and supervised clustering analyses revealed similar gene expression in PH-IPF and NPH-IPF arterioles. The pulmonary arteriolar gene expression profile is similar in IPF patients with and without coexistent PH. Pathways involved in vascular proliferation and aberrant apoptosis, which may contribute to pulmonary vascular remodelling, are activated in IPF patients. PMID:23728404

  13. Combined pulmonary fibrosis and emphysema (CPFE): an entity different from emphysema or pulmonary fibrosis alone

    PubMed Central

    Lin, Huijin

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) and idiopathic interstitial pneumonias (IIP), with different radiological, pathological, functional and prognostic characteristics, have been regarded as separate entities for a long time. However, there is an increasing recognition of the coexistence of emphysema and pulmonary fibrosis in individuals. The association was first described as a syndrome by Cottin in 2005, named “combined pulmonary fibrosis and emphysema (CPFE)”, which is characterized by exertional dyspnea, upper-lobe emphysema and lower-lobe fibrosis, preserved lung volume and severely diminished capacity of gas exchange. CPFE is frequently complicated by pulmonary hypertension, acute lung injury and lung cancer and prognosis of it is poor. Treatments for CPFE patients with severe pulmonary hypertension are less effective other than lung transplantation. However, CPFE has not yet attracted wide attention of clinicians and there is no research systematically contrasting the differences among CPFE, emphysema/COPD and IIP at the same time. The authors will review the existing knowledge of CPFE and compare them to either entity alone for the first time, with the purpose of improving the awareness of this syndrome and exploring novel effective therapeutic strategies in clinical practice. PMID:25973246

  14. Signaling pathways in the epithelial origins of pulmonary fibrosis.

    PubMed

    Hardie, William D; Hagood, James S; Dave, Vrushank; Perl, Anne-Karina T; Whitsett, Jeffrey A; Korfhagen, Thomas R; Glasser, Stephan

    2010-07-15

    Pulmonary fibrosis complicates a number of disease processes and leads to substantial morbidity and mortality. Idiopathic pulmonary fibrosis (IPF) is perhaps the most pernicious and enigmatic form of the greater problem of lung fibrogenesis with a median survival of three years from diagnosis in affected patients. In this review, we will focus on the pathology of IPF as a model of pulmonary fibrotic processes, review possible cellular mechanisms, review current treatment approaches and review two transgenic mouse models of lung fibrosis to provide insight into processes that cause lung fibrosis. We will also summarize the potential utility of signaling pathway inhibitors as a future treatment in pulmonary fibrosis. Finally, we will present data demonstrating a minimal contribution of epithelial-mesenchymal transition in the development of fibrotic lesions in the transforming growth factor-alpha transgenic model of lung fibrosis. PMID:20676040

  15. Cardiac manifestations of idiopathic pulmonary fibrosis

    PubMed Central

    Agrawal, Abhinav; Verma, Isha; Shah, Varun; Agarwal, Abhishek; Sikachi, Rutuja R

    2016-01-01

    Summary Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, parenchymal disease of the lung with an estimated prevalence of 14–43 per 100,000. Patient usually presents with coughing and exertional dyspnea, which can lead to acute respiratory failure. IPF has been associated with various co-morbidities such as lung cancer, emphysema, obstructive sleep apnea (OSA), GERD and multiple cardiovascular consequences. The cardiovascular manifestations of IPF include pulmonary hypertension, heart failure, coronary artery disease, cardiac arrhythmias & cardiac manifestations of drugs used to treat IPF. This review will outline evidence of the association between IPF and cardiovascular conditions and attempt to provide insights into the underlying pathophysiology. We also discuss the impact of these cardiovascular diseases on patients with IPF including increased morbidity and mortality. PMID:27195188

  16. Cardiac manifestations of idiopathic pulmonary fibrosis.

    PubMed

    Agrawal, Abhinav; Verma, Isha; Shah, Varun; Agarwal, Abhishek; Sikachi, Rutuja R

    2016-05-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, parenchymal disease of the lung with an estimated prevalence of 14-43 per 100,000. Patient usually presents with coughing and exertional dyspnea, which can lead to acute respiratory failure. IPF has been associated with various co-morbidities such as lung cancer, emphysema, obstructive sleep apnea (OSA), GERD and multiple cardiovascular consequences. The cardiovascular manifestations of IPF include pulmonary hypertension, heart failure, coronary artery disease, cardiac arrhythmias & cardiac manifestations of drugs used to treat IPF. This review will outline evidence of the association between IPF and cardiovascular conditions and attempt to provide insights into the underlying pathophysiology. We also discuss the impact of these cardiovascular diseases on patients with IPF including increased morbidity and mortality. PMID:27195188

  17. Pulmonary fibrosis and occupational exposure to aluminum.

    PubMed

    al-Masalkhi, A; Walton, S P

    1994-02-01

    Many reports of respiratory disease attributable to aluminum exposure have appeared in the European medical literature during the last 50 years. Great Britain and Germany are two major industrialized nations that acknowledge a causal relationship between occupational exposure to aluminum and respiratory impairment. For factory workers in these countries, pulmonary disease attributed to respirable aluminum particulates is compensated as a workplace disability. In North America, however, there is a lack of consensus regarding the pathogenicity of aluminum fumes and dust to the worker. This view may be based on a difference in the types of industrial usage, the updated methods of aluminum processing in this country, or the benefits of a modern workplace. It has also been proposed that the development of aluminum-induced pulmonary disease may depend on a particular host factor that has not yet been identified. We describe a patient whom we believe developed severe respiratory compromise and irreversible pulmonary fibrosis from a lifetime of industrial aluminum exposure. PMID:8163901

  18. The role of gastroesophageal reflux in idiopathic pulmonary fibrosis.

    PubMed

    Raghu, Ganesh

    2003-08-18

    Fibroblast foci are indicative of idiopathic pulmonary fibrosis and appear to be a cellular attempt to repair the damaged alveolus. Although this progressive, often fatal, clinical syndrome is thought to be dependent on alveolar injury of unknown origin, significant clinical and preclinical evidence points to gastric acid as a causative harmful agent. Graded instillation of various forms of acid in several animal models resulted in aspiration-induced lung injury, including pulmonary fibrosis in pigs. Moreover, compelling clinical data suggest that a high percentage of patients with idiopathic pulmonary fibrosis also experience abnormal esophageal acid exposure, without necessarily experiencing the typical symptoms of gastroesophageal reflux disease (GERD). Aggressive, long-term therapeutic trials of patients with GERD and evaluation of the therapeutic effects on pulmonary disease will allow determination of the real influences of abnormal esophageal acid exposure in the development of idiopathic pulmonary fibrosis. PMID:12928077

  19. Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents.

    PubMed

    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

  20. 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

  1. A Mathematical Model of Idiopathic Pulmonary Fibrosis

    PubMed Central

    Hao, Wenrui; Marsh, Clay; Friedman, Avner

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology, and life expectancy of 3-5 years after diagnosis. The incidence rate in the United States is estimated as high as 15 per 100,000 persons per year. The disease is characterized by repeated injury to the alveolar epithelium, resulting in inflammation and deregulated repair, leading to scarring of the lung tissue, resulting in progressive dyspnea and hypoxemia. The disease has no cure, although new drugs are in clinical trials and two agents have been approved for use by the FDA. In the present paper we develop a mathematical model based on the interactions among cells and proteins that are involved in the progression of the disease. The model simulations are shown to be in agreement with available lung tissue data of human patients. The model can be used to explore the efficacy of potential drugs. PMID:26348490

  2. [Idiopathic pulmonary fibrosis and lung cancer].

    PubMed

    Yoshimura, Akinobu; Kudoh, Syoji

    2003-02-01

    It is widely known that patients with idiopathic pulmonary fibrosis (IPF) are frequently associated with lung cancer. Although a complication with lung cancer is an important prognostic factor for IPF, standard treatments for lung cancer cannot be given because of IPF. Especially, the administration of many anticancer agents is limited by a complication with IPF, which is recognized as a risk factor for the development of fatal lung injury in cancer chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both IPF and lung cancer. It has been assumed that metaplasia in fibrous lesions is pathologically a precancerous lesion, but it is necessary to prove several genetic abnormalities in the process of carcinogenesis in order to clarify that. Currently, several genetic abnormalities in IPF, including in p53, K-ras, FHIT and transforming growth factor (TGF)-beta 1 type II receptor, have been reported. PMID:12610869

  3. A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis.

    PubMed

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

    2008-03-01

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

  4. 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

  5. Medical Therapy in Idiopathic Pulmonary Fibrosis.

    PubMed

    Antoniou, Katerina M; Wuyts, Wim; Wijsenbeek, Marlies; Wells, Athol U

    2016-06-01

    Medical therapy for idiopathic fibrosis remains controversial. Idiopathic pulmonary fibrosis (IPF) was uniformly a disease that progressed inexorably, typically leading to death within 3 to 5 years from onset of symptoms. Until recently, lung transplantation was the only effective transplant option. Within the past decade, several placebo-controlled trials failed to show benefit in patients with IPF. However, within the past 2 years, two novel antifibrotic agents (pirfenidone and nintedanib) were approved by the Food and Drug Administration (FDA) in the United States and European Medicines Agency (EMA) based upon pivotal studies that showed benefit (specifically slowing of the rate of disease progression) with both agents. Short-term outcomes (12 months) showed less deterioration of physiological parameters (e.g., change in forced vital capacity), although survival benefit has not convincingly been established with either agent. Nonetheless, these agents bring a glimmer of hope to patients with this deadly disease. The appropriate indications for initiating therapy, best candidates for therapy, and possible role for combination therapy remain controversial. Additional studies using agents that attenuate or abrogate profibrotic cytokines and chemokines may provide even further improvement in the future. PMID:27231861

  6. PROFILEing idiopathic pulmonary fibrosis: rethinking biomarker discovery.

    PubMed

    Maher, Toby M

    2013-06-01

    Despite major advances in the understanding of the pathogenesis of idiopathic pulmonary fibrosis (IPF), diagnosis and management of the condition continue to pose significant challenges. Clinical management of IPF remains unsatisfactory due to limited availability of effective drug therapies, a lack of accurate indicators of disease progression, and an absence of simple short-term measures of therapeutic response. The identification of more accurate predictors of prognosis and survival in IPF would facilitate counseling of patients and their families, aid communication among clinicians, and would guide optimal timing of referral for transplantation. Improvements in molecular techniques have led to the identification of new disease pathways and a more targeted approach to the development of novel anti-fibrotic agents. However, despite an increased interest in biomarkers of IPF disease progression there are a lack of measures that can be used in early phase clinical trials. Careful longitudinal phenotyping of individuals with IPF together with the application of novel omics-based technology should provide important insights into disease pathogenesis and should address some of the major issues holding back drug development in IPF. The PROFILE (Prospective Observation of Fibrosis in the Lung Clinical Endpoints) study is a currently enrolling, prospective cohort study designed to tackle these issues. PMID:23728868

  7. Update on diagnosis and treatment of idiopathic pulmonary fibrosis.

    PubMed

    Baddini-Martinez, José; Baldi, Bruno Guedes; Costa, Cláudia Henrique da; 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

  8. 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

  9. Objective cough frequency in Idiopathic Pulmonary Fibrosis

    PubMed Central

    2010-01-01

    Background Cough is a common presenting symptom in patients with Idiopathic Pulmonary Fibrosis (IPF). This study measured cough rates in IPF patients and investigated the association between cough and measures of health related quality of life and subjective cough assessments. In addition, IPF cough rates were related to measures of physiological disease severity and compared to cough rates in health and other respiratory conditions. Methods Nineteen IPF patients, mean age 70.8 years ± 8.6, five female (26.3%) were studied. Subjects performed full pulmonary function testing, 24 hour ambulatory cough recordings, completed a cough related quality of life questionnaire (Leicester Cough Questionnaire) and subjectively scored cough severity with a visual analogue scale. Ambulatory cough recordings were manually counted and reported as number of coughs per hour. Results The 24hr cough rates were high (median 9.4, range 1.5-39.4), with day time rates much higher than night time (median 14.6, range 1.9-56.6 compared to 1.9, range 0-19.2, p = 0.003). Strong correlations were found between objective cough frequency and both the VAS (day r = 0.80, p < 0.001, night r = 0.71, p = 0.001) and LCQ (r = -0.80, p < 0.001), but not with measures of pulmonary function. Cough rates in IPF were higher than healthy subjects (p < 0.001) and asthma patients (p < 0.001) but similar to patients with chronic cough (p = 0.33). Conclusions This study confirms objectively that cough is a major, very distressing and disabling symptom in IPF patients. The strong correlations between objective cough counts and cough related quality of life measures suggest that in IPF patient's, perception of cough frequency is very accurate. PMID:20565979

  10. 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

  11. Practical management of Idiopathic Pulmonary Fibrosis.

    PubMed

    Kishaba, Tomoo

    2015-01-01

    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. PMID:26278687

  12. 17(R)-resolvin D1 ameliorates bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Yatomi, Masakiyo; Hisada, Takeshi; Ishizuka, Tamotsu; Koga, Yasuhiko; Ono, Akihiro; Kamide, Yosuke; Seki, Kaori; Aoki-Saito, Haruka; Tsurumaki, Hiroaki; Sunaga, Noriaki; Kaira, Kyoichi; Dobashi, Kunio; Yamada, Masanobu; Okajima, Fumikazu

    2015-12-01

    Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. Inflammation plays an integral role in the development of pulmonary fibrosis. Unresolved inflammatory responses can lead to substantial tissue injury, chronic inflammation, and fibrosis. The resolvins are a family of endogenous ω-3 fatty acid derived-lipid mediators of inflammation resolution. Resolvin D1 (RvD1) displays potent anti-inflammatory, pro-resolving activity, without causing immunosuppression. Its epimer, 17(R)-resolvin D1 (17(R)-RvD1), exhibits equivalent functionality to RvD1. In addition, 17(R)-RvD1 is resistant to rapid inactivation by eicosanoid oxidoreductases. In the present study, we tested the hypothesis that 17(R)-RvD1 can provide a therapeutic benefit in IPF by reducing inflammation and pulmonary fibrosis, while leaving the normal immune response intact. Mice were exposed to bleomycin (BLM) via micro-osmotic pump to induce pulmonary fibrosis, and were then treated with 17(R)-RvD1 or vehicle by intraperitoneal injection. Administration of 17(R)-RvD1 from the start of BLM treatment attenuated neutrophil alveolar infiltration, lung collagen content, and Interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), and type I collagen mRNA expression, along with subsequent reduction in histologically detectable fibrosis. The 17(R)-RvD1-induced infiltration of inflammatory cells was inhibited by an antagonist of lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2). The administration of 17(R)-RvD1 at the later fibrotic stage also improved the lung failure. These results suggest that 17(R)-RvD1 attenuates pulmonary fibrosis by promoting the resolution of neutrophilic inflammation and also provides pulmonary restoration. These data highlight the therapeutic potential of 17(R)-RvD1 in the management of this intractable disease. PMID:26660549

  13. 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. PMID:26773067

  14. The treatment of idiopathic pulmonary fibrosis.

    PubMed

    Woodcock, Hannah V; Maher, Toby M

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive and invariably fatal disease with a median survival of less than three years from diagnosis. The last decade has seen an exponential increase in clinical trial activity in IPF and this in turn has led to important developments in the treatment of this terrible disease. Previous therapeutic approaches based around regimens including corticosteroids and azathioprine have, when tested in randomized clinical trials, been shown to be harmful in IPF. By contrast, compounds with anti-fibrotic actions have been shown to be beneficial. Subsequently, the novel anti-fibrotic agent pirfenidone has, in many parts of the world, become the first treatment ever to be licensed for use in IPF. This exciting development, coupled with ongoing clinical trials of a range of other novel compounds, is bringing hope to patients and their clinicians and raises the prospect that, in the future, it may become possible to successfully arrest the development of progressive scarring in IPF. PMID:24669297

  15. Mineralogical microanalysis of idiopathic pulmonary fibrosis

    SciTech Connect

    Monso, E.; Tura, J.M.; Marsal, M.; Morell, F.; Pujadas, J.; Morera, J. )

    1990-05-01

    A mineralogical analysis of lung tissue was conducted on 25 samples from patients who had been diagnosed as having idiopathic pulmonary fibrosis (IPF). Scanning electron microscopy (SEM) at low magnification and energy-dispersive x-ray analysis (EDXA) was used. In all samples, the surface silicon/sulfur (Si/S) ratio was calculated. The Si/S ratio for 25 samples of normal lung and 6 samples of pneumoconiotic lung was also determined (upper limit of normal Si/S ratio = 0.3). The difference between the Si/S ratio in the group with IPF and group with normal lung tissue was significantly significant (p less than .007, Wilcoxon test). Six of 12 patients with a previous diagnosis of IPF and a Si/S ratio greater than 0.3 had an exposure history that could imply inhalation of silica/silicates, and the correct diagnosis for these patients is most probably pneumoconiosis. The silica/silicate deposits detected in patients with IPF, and who had a ratio and no past exposure to dusts, could be either a cause or an effect of the disease.

  16. 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

  17. Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Dong, Yingying; Geng, Yan; Li, Lian; Li, Xiaohe; Yan, Xiaohua; Fang, Yinshan; Li, Xinxin; Dong, Siyuan; Liu, Xue; Li, Xue; Yang, Xiuhong; Zheng, Xiaohong; Xie, Ting; Liang, Jiurong; Dai, Huaping; Liu, Xinqi; Yin, Zhinan; Noble, Paul W; Jiang, Dianhua; Ning, Wen

    2015-02-01

    Progressive tissue fibrosis is a cause of major morbidity and mortality. Pulmonary fibrosis is an epithelial-mesenchymal disorder in which TGF-β1 plays a central role in pathogenesis. Here we show that follistatin-like 1 (FSTL1) differentially regulates TGF-β and bone morphogenetic protein signaling, leading to epithelial injury and fibroblast activation. Haplodeletion of Fstl1 in mice or blockage of FSTL1 with a neutralizing antibody in mice reduced bleomycin-induced fibrosis in vivo. Fstl1 is induced in response to lung injury and promotes the accumulation of myofibroblasts and subsequent fibrosis. These data suggest that Fstl1 may serve as a novel therapeutic target for treatment of progressive lung fibrosis. PMID:25584011

  18. Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice

    PubMed Central

    Dong, Yingying; Geng, Yan; Li, Lian; Li, Xiaohe; Yan, Xiaohua; Fang, Yinshan; Li, Xinxin; Dong, Siyuan; Liu, Xue; Li, Xue; Yang, Xiuhong; Zheng, Xiaohong; Xie, Ting; Liang, Jiurong; Dai, Huaping; Liu, Xinqi; Yin, Zhinan; Noble, Paul W.

    2015-01-01

    Progressive tissue fibrosis is a cause of major morbidity and mortality. Pulmonary fibrosis is an epithelial-mesenchymal disorder in which TGF-β1 plays a central role in pathogenesis. Here we show that follistatin-like 1 (FSTL1) differentially regulates TGF-β and bone morphogenetic protein signaling, leading to epithelial injury and fibroblast activation. Haplodeletion of Fstl1 in mice or blockage of FSTL1 with a neutralizing antibody in mice reduced bleomycin-induced fibrosis in vivo. Fstl1 is induced in response to lung injury and promotes the accumulation of myofibroblasts and subsequent fibrosis. These data suggest that Fstl1 may serve as a novel therapeutic target for treatment of progressive lung fibrosis. PMID:25584011

  19. 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.

  20. TINF2 Gene Mutation in a Patient with Pulmonary Fibrosis

    PubMed Central

    Hoffman, T. W.; van der Vis, J. J.; van Oosterhout, M. F. M.; van Es, H. W.; van Kessel, D. A.; Grutters, J. C.; van Moorsel, C. H. M.

    2016-01-01

    Pulmonary fibrosis is a frequent manifestation of telomere syndromes. Telomere gene mutations are found in up to 25% and 3% of patients with familial disease and sporadic disease, respectively. The telomere gene TINF2 encodes an eponymous protein that is part of the shelterin complex, a complex involved in telomere protection and maintenance. A TINF2 gene mutation was recently reported in a family with pulmonary fibrosis. We identified a heterozygous Ser245Tyr mutation in the TINF2 gene of previously healthy female patient that presented with progressive cough due to pulmonary fibrosis as well as panhypogammaglobulinemia at age 52. Retrospective multidisciplinary evaluation classified her as a case of possible idiopathic pulmonary fibrosis. Telomere length-measurement indicated normal telomere length in the peripheral blood compartment. This is the first report of a TINF2 mutation in a patient with sporadic pulmonary fibrosis, which represents another association between TINF2 mutations and this disease. Furthermore, this case underlines the importance of telomere dysfunction and not telomere length alone in telomere syndromes and draws attention to hypogammaglobulinemia as a manifestation of telomere syndromes. PMID:27088026

  1. Participation of miR-200 in Pulmonary Fibrosis

    PubMed Central

    Yang, Shanzhong; Banerjee, Sami; de Freitas, Andressa; Sanders, Yan Y.; Ding, Qiang; Matalon, Sadis; Thannickal, Victor J.; Abraham, Edward; Liu, Gang

    2012-01-01

    Excessive extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF). Epithelial-mesenchymal transition, involving transition of alveolar epithelial cells (AECs) to pulmonary fibroblasts, appears to be an important contributory process to lung fibrosis. Although aberrant expression of microRNAs (miRs) is involved in a variety of pathophysiologic processes, the role of miRs in fibrotic lung diseases is less well understood. In the present study, we found that miR-200a, miR-200b, and miR-200c are significantly down-regulated in the lungs of mice with experimental lung fibrosis. Levels of miR-200a and miR-200c were reduced in the lungs of patients with IPF. miR-200 had greater expression in AECs than in lung fibroblasts, and AECs from mice with experimental pulmonary fibrosis had diminished expression of miR-200. We found that the miR-200 family members inhibit transforming growth factor-β1–induced epithelial-mesenchymal transition of AECs. miR-200 family members can reverse the fibrogenic activity of pulmonary fibroblasts from mice with experimental pulmonary fibrosis and from patients with IPF. Indeed, the introduction of miR-200c diminishes experimental pulmonary fibrosis in mice. Thus, the miR-200 family members participate importantly in fibrotic lung diseases and suggest that restoring miR-200 expression in the lungs may represent a novel therapeutic approach in treating pulmonary fibrotic diseases. PMID:22189082

  2. [Drepanocytosis and diffuse interstitial pulmonary fibrosis (author's transl)].

    PubMed

    Raison, J; Krivitzky, A; Bentata-Pessayre, M; Volter, F; Delzant, G

    1981-01-01

    Respiratory disorders in homozygous drepanocytosis and double SC heterozygosis are mainly dependent on two factors : repeated infections with, more particularly, pneumococcus or mycoplasma, and epidoses of occlusion of the pulmonary circulation. Mutual reinforcement of these two factors occurs, in so far as the relative hypoxia of an infected lung increases the risk of falciform and thrombosis formation in the pulmonary arterioles. The particular physical and chemical properties of the drepanocyte red cell, and the anaemia, themselves lead to parallel disturbances in pulmonary circulation function and gas exchanges. Possible development of respiratory insufficiency is generally, therefore, the result of chronic pulmonary arterial hypertension. However, the results of respiratory function tests are often fairly analogous to those observed in moderate interstitial fibrosis : reduction in vital capacity, alveolo-capillary block, reduction in CO diffusion space, a shunt effect, and diminished pulmonary compliance. This problem is discussed in relation to findings of diffuse interstitial fibrosis in a 34-year-old man with double SC heterozygosis, who had numerous episodes of bone, abdominal, and pulmonary microinfarcts. The presence of a diffuse interstitial pulmonary fibrosis, evoked by radiological criteria and respiratory function tests and confirmed by transbronchial biopsy, no other aetiology being established, raises the question of the possible genesis of the fibrosis from repeated episodes of microvascular occlusion. Many factors may therefore be involved in the formation of fibrosis of this type, not only the pulmonary artery obstruction from the microthrombi but also the macrophagic perivascular inflammatory response related to the presence of foci of infarction and precipitation of pathological intravascular material. PMID:7337330

  3. A new model of progressive pulmonary fibrosis in rats

    SciTech Connect

    Last, J.A.; Gelzleichter, T.R.; Pinkerton, K.E.; Walker, R.M.; Witschi, H. )

    1993-08-01

    Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.

  4. Combined pulmonary fibrosis and emphysema in a welder.

    PubMed

    Roshan, R; Guptal, M; Kulshrestha, R; Menon, B; Chhabra, S K

    2012-03-01

    Combined pulmonary fibrosis and emphysema (CPFE) syndrome is an uncommon entity characterised by emphysema of the upper lobes and diffuse fibrosis of the lower lobes and carries a bad prognosis with the onset of pulmonary hypertension. Lung involvement due to exposures suffered by welders is generally considered benign though, rarely, a diffuse interstitial fibrotic disease has been reported. CPFE syndrome has however never been reported in welders. A 65-year-old man, welder by occupation and an ex-smoker, presented with progressive exertional dyspnoea associated with dry cough noticed for the last four months. On examination, there was mild tachypnea, clubbing and bilateral basal velcro crepitations on chest auscultation. Lung function test revealed mild mixed ventilatory impairment with severe diffusion defect. HRCT chest showed bilateral upper lobe emphysema and diffuse interstitial fibrosis in the lower lobes. Transbronchial lung biopsy revealed interstitial fibrosis, chronic inflammation and iron deposits. A diagnosis of combined pulmonary fibrosis with emphysema (CPFE) with interstitial pulmonary siderofibrosis (IPS) was established. A review of literature did not show any other report of a similar nature. PMID:22662643

  5. Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Wang, Xingqi; Ouyang, Zijun; You, Qian; He, Shuai; Meng, Qianqian; Hu, Chunhui; Wu, Xudong; Shen, Yan; Sun, Yang; Wu, Xuefeng; Xu, Qiang

    2016-07-15

    Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid. Moreover, obaculactone inhibited the expression of icam1, vcam1, inos and cox2, and attenuated oxidative stress in bleomycin-treated lungs. Importantly, the production of collagen I and α-SMA in lung tissues as well as the levels of TGF-β1, ALK5, p-Smad2 and p-Smad3 in lung homogenates was also reduced after obaculactone treatment. Finally, the TGF-β1-induced epithelial-mesenchymal transition via Smad-dependent and Smad-independent pathways was reversed by obaculactone. Collectively, these data suggest that obaculactone may be a promising drug candidate for the treatment of idiopathic pulmonary fibrosis. PMID:27180239

  6. Combined pulmonary fibrosis and emphysema in a tyre industry worker.

    PubMed

    Karkhanis, Vinaya S; Joshi, J M

    2012-07-01

    We report a case of combined pulmonary fibrosis and emphysema (CPFE) with severe pulmonary hypertension in a 46-year-old man, nonsmoker, tyre industry worker. CPFE is commonly reported to be associated with tobacco smoking. This case highlights the possible role of environmental dust exposure (talc) in the pathogenesis of the disease and confirms the clinical characteristics of CPFE described in previous studies. PMID:22919169

  7. Altered Expression of Bone Morphogenetic Protein Accessory Proteins in Murine and Human Pulmonary Fibrosis.

    PubMed

    Murphy, Noelle; Gaynor, Katherine U; Rowan, Simon C; Walsh, Sinead M; Fabre, Aurelie; Boylan, John; Keane, Michael P; McLoughlin, Paul

    2016-03-01

    Idiopathic pulmonary fibrosis is a chronic, progressive fibrotic disease with a poor prognosis. The balance between transforming growth factor β1 and bone morphogenetic protein (BMP) signaling plays an important role in tissue homeostasis, and alterations can result in pulmonary fibrosis. We hypothesized that multiple BMP accessory proteins may be responsible for maintaining this balance in the lung. Using the bleomycin mouse model for fibrosis, we examined an array of BMP accessory proteins for changes in mRNA expression. We report significant increases in mRNA expression of gremlin 1, noggin, follistatin, and follistatin-like 1 (Fstl1), and significant decreases in mRNA expression of chordin, kielin/chordin-like protein, nephroblastoma overexpressed gene, and BMP and activin membrane-bound inhibitor (BAMBI). Protein expression studies demonstrated increased levels of noggin, BAMBI, and FSTL1 in the lungs of bleomycin-treated mice and in the lungs of idiopathic pulmonary fibrosis patients. Furthermore, we demonstrated that transforming growth factor β stimulation resulted in increased expression of noggin, BAMBI, and FSTL1 in human small airway epithelial cells. These results provide the first evidence that multiple BMP accessory proteins are altered in fibrosis and may play a role in promoting fibrotic injury. PMID:26765958

  8. A Novel Telomerase Activator Suppresses Lung Damage in a Murine Model of Idiopathic Pulmonary Fibrosis

    PubMed Central

    Le Saux, Claude Jourdan; Davy, Philip; Brampton, Christopher; Ahuja, Seema S.; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B.; Allsopp, Richard

    2013-01-01

    The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2–4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis. PMID:23516479

  9. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

    PubMed

    Le Saux, Claude Jourdan; Davy, Philip; Brampton, Christopher; Ahuja, Seema S; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B; Allsopp, Richard

    2013-01-01

    The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis. PMID:23516479

  10. Unified baseline and longitudinal mortality prediction in idiopathic pulmonary fibrosis.

    PubMed

    Ley, Brett; Bradford, Williamson Z; Weycker, Derek; Vittinghoff, Eric; du Bois, Roland M; Collard, Harold R

    2015-05-01

    The Gender-Age-Physiology (GAP) model is a validated, baseline-risk prediction model for mortality in idiopathic pulmonary fibrosis. Longitudinal variables have been shown to contribute to risk prediction in idiopathic pulmonary fibrosis and may improve the predictive performance of the baseline GAP model. Our aims were to further validate the GAP model and evaluate whether the addition of longitudinal variables improves its predictive performance. The study population was derived from a large clinical trials cohort of patients with idiopathic pulmonary fibrosis (n=1109). Model performance was determined by improvement in the C-statistic, net reclassification improvement, clinical net reclassification improvement, and a goodness-of-fit test. The GAP model had good discriminative performance with a C-statistic of 0.757 (95% CI 0.750-0.764). However, the original GAP model tended to overestimate risk in this cohort. A novel, easy to use model, consisting of the original GAP predictors plus history of respiratory hospitalisation and 24-week change in forced vital capacity (the longitudinal GAP model) improved model performance with a C-statistic of 0.785 (95% CI 0.780-0.790), net reclassification improvement of 8.5%, clinical net reclassification improvement of 25%, and a goodness-of-fit test of 0.929. The Longitudinal GAP model, along with the original GAP model, may unify baseline and longitudinal mortality risk prediction in idiopathic pulmonary fibrosis. PMID:25614172

  11. Treatment of pulmonary exacerbations in cystic fibrosis - could do better?

    PubMed

    Smyth, Alan

    2016-08-01

    This article describes the nature and significance of pulmonary exacerbations in cystic fibrosis (CF). The effectiveness and safety of current exacerbation treatment are explored. The article concludes with a summary of clinical trials (completed and ongoing) which aim to improve the efficacy and safety of exacerbation treatment. PMID:27349725

  12. 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

  13. Pulmonary Artery Aneurysm Thrombosis with Combined Pulmonary Fibrosis and Emphysema: A Case Report

    PubMed Central

    Awad, Nilkant Tukaram

    2016-01-01

    We report a rare case of Pulmonary Artery Aneurysm (PAA) thrombosis with Combined Pulmonary Fibrosis and Emphysema (CPFE) with pulmonary hypertension. A 75-year-old male presented with haemoptysis, dyspnoea, clubbing and bilateral fine end inspiratory rales on examination. He was diagnosed to have PAA thrombosis with CPFE on the basis of computed tomographical angiography and high resolution computed tomography. He was then managed conservatively with pirfenidone for the interstitial lung disease. PMID:27437277

  14. Role of granulocyte‐macrophage colony‐stimulating factor in pulmonary fibrosis following pulmonary alveolar proteinosis

    PubMed Central

    Sha, Joy

    2016-01-01

    Abstract Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by accumulation of lipoproteinacious material in alveoli, with distinct features on high resolution computed tomography and biopsy. Its association with pulmonary fibrosis is infrequently encountered, and a clear understanding of the underlying pathogenesis is yet to be established. We report the case of a 48‐year‐old woman with known autoimmune PAP (aPAP) first diagnosed 20 years ago, who presented with worsening hypoxemia and radiological features consistent with pulmonary fibrosis, after many years of stable disease. We present a review of previously considered mechanisms of causation behind such changes, and in particular, postulate the role of granulocyte‐macrophage colony‐stimulating factor deficiency in pulmonary fibrosis seen in aPAP. PMID:27512562

  15. [Treatment of pulmonary fibrosis. New substances and new interventions].

    PubMed

    Costabel, U; Bonella, F

    2011-12-01

    Idiopathic pulmonary fibrosis is a chronic progressive lung disease with poor prognosis. The IFIGENIA trial showed that antioxidative therapy with N-acetylcysteine versus placebo for patients under treatment with prednisone plus azathioprine significantly slowed the deterioration of pulmonary function after 12 months. A number of other drugs have recently been evaluated in large multicenter placebo-controlled trials. Etanercept, interferon-γ, bosentan, ambrisentan, imatinib, and sildenafil did not show efficacy. The antifibrotic active ingredient pirfenidone is the first drug approved for the treatment of adult patients with mild to moderate idiopathic pulmonary fibrosis in the European Union. Approval was based on the results of 4 randomized, placebo-controlled clinical trials including more than 1,100 patients. Pirfenidone slowed the decline in lung function and reduced the risk of disease progression. Side effects include gastrointestinal discomfort, skin reactions, including photosensitivity, and rarely increased liver enzymes. PMID:22095049

  16. 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. PMID:25188360

  17. Lung-Specific Loss of α3 Laminin Worsens Bleomycin-Induced Pulmonary Fibrosis

    PubMed Central

    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.

    2015-01-01

    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 (Lama3fl/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. PMID:25188360

  18. Expression of mutant bone morphogenetic protein receptor II worsens pulmonary hypertension secondary to pulmonary fibrosis

    PubMed Central

    Robinson, Linda J.; Moore, Christy S.; Blackwell, Thomas R.; Gladson, Santhi; Penner, Niki L.; Burman, Ankita; McClellan, Lucas J.; Polosukhin, Vasiliy V.; Tanjore, Harikrishna; McConaha, Melinda E.; Gleaves, Linda A.; Talati, Megha A.; Hemnes, Anna R.; Fessel, Joshua P.; Lawson, William E.; Blackwell, Timothy S.; West, James D.

    2015-01-01

    Abstract Pulmonary fibrosis is often complicated by pulmonary hypertension (PH), and previous studies have shown a potential link between bone morphogenetic protein receptor II (BMPR2) and PH secondary to pulmonary fibrosis. We exposed transgenic mice expressing mutant BMPR2 and control mice to repetitive intraperitoneal injections of bleomycin for 4 weeks. The duration of transgene activation was too short for mutant BMPR2 mice to develop spontaneous PH. Mutant BMPR2 mice had increased right ventricular systolic pressure compared to control mice, without differences in pulmonary fibrosis. We found increased hypoxia-inducible factor (HIF)1-α stabilization in lungs of mutant-BMPR2-expressing mice compared to controls following bleomycin treatment. In addition, expression of the hypoxia response element protein connective tissue growth factor was increased in transgenic mice as well as in a human pulmonary microvascular endothelial cell line expressing mutant BMPR2. In mouse pulmonary vascular endothelial cells, mutant BMPR2 expression resulted in increased HIF1-α and reactive oxygen species production following exposure to hypoxia, both of which were attenuated with the antioxidant TEMPOL. These data suggest that expression of mutant BMPR2 worsens secondary PH through increased HIF activity in vascular endothelium. This pathway could be therapeutically targeted in patients with PH secondary to pulmonary fibrosis. PMID:26697175

  19. Increased alveolar soluble annexin V promotes lung inflammation and fibrosis.

    PubMed

    Buckley, Susan; Shi, Wei; Xu, Wei; Frey, Mark R; Moats, Rex; Pardo, Annie; Selman, Moises; Warburton, David

    2015-11-01

    The causes underlying the self-perpetuating nature of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal disease, remain unknown. We hypothesised that alveolar soluble annexin V contributes to lung fibrosis, based on the observation that human IPF bronchoalveolar lavage fluid (BALF) containing high annexin V levels promoted fibroblast involvement in alveolar epithelial wound healing that was reduced when annexin V was depleted from the BALF. Conditioned medium from annexin V-treated alveolar epithelial type 2 cells (AEC2), but not annexin V per se, induced proliferation of human fibroblasts and contained pro-fibrotic, IPF-associated proteins, as well as pro-inflammatory cytokines that were found to correlate tightly (r>0.95) with annexin V levels in human BALF. ErbB2 receptor tyrosine kinase in AECs was activated by annexin V, and blockade reduced the fibrotic potential of annexin V-treated AEC-conditioned medium. In vivo, aerosol delivery of annexin V to mouse lung induced inflammation, fibrosis and increased hydroxyproline, with activation of Wnt, transforming growth factor-β, mitogen-activated protein kinase and nuclear factor-κB signalling pathways, as seen in IPF. Chronically increased alveolar annexin V levels, as reflected in increased IPF BALF levels, may contribute to the progression of IPF by inducing the release of pro-fibrotic mediators. PMID:26160872

  20. 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

  1. MicroRNAs as potential targets for progressive pulmonary fibrosis

    PubMed Central

    Rajasekaran, Subbiah; Rajaguru, P.; Sudhakar Gandhi, P. S.

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and devastating disorder. It is characterized by alveolar epithelial cell injury and activation, infiltration of inflammatory cells, initiation of epithelial mesenchymal transition (EMT), aberrant proliferation and activation of fibroblasts, exaggerated deposition of extracellular matrix (ECM) proteins, and finally leading to the destruction of lung parenchyma. MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that post-transcriptionally regulate gene expression in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis and metastasis. As a result, miRNAs have emerged as a major area of biomedical research with relevance to pulmonary fibrosis. In this context, the present review discusses specific patterns of dysregulated miRNAs in patients with IPF. Further, we discuss the current understanding of miRNAs involvement in regulating lung inflammation, TGF-β1-mediated EMT and fibroblast differentiation processes, ECM genes expression, and in the progression of lung fibrosis. The possible future directions that might lead to novel therapeutic strategies for the treatment of pulmonary fibrosis are also reviewed. PMID:26594173

  2. 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.

  3. 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.

  4. Idiopathic pulmonary fibrosis: Recent advances on pharmacological therapy.

    PubMed

    Spagnolo, P; Maher, T M; Richeldi, L

    2015-08-01

    Idiopathic pulmonary fibrosis (IPF) is the most common and lethal of the idiopathic interstitial pneumonias with an estimated 5-year survival of approximately 20%. In the last two decades our understanding of disease pathogenesis has substantially evolved and novel compounds have been developed consequent to the increasing knowledge of the mechanisms underlying disease pathobiology. The disease appears to be driven - following chronic injury - by abnormal/dysfunctional alveolar epithelial cells that promote fibroblast recruitment and proliferation, resulting in scarring of the lung and irreversible loss of function. With very few exceptions, clinical trials evaluating novel potential therapies have provided disappointing results. More recently, pirfenidone and nintedanib, two compounds with pleiotropic mechanisms of action, have proven effective in slowing functional decline and disease progression in IPF patients with mild to moderate functional impairment, highlighting the importance of timely diagnosis and administration of treatment in early stages of disease. However, due to the complexity and uncertainties intrinsic to IPF, it is essential that each therapeutic strategy be tailored to the individual patient, after evaluation of potential benefits and risks. This article provides an overview of the most recent clinical trials in IPF and discusses how their results are going to change the clinical and clinical research landscape in IPF. A number of agents with high potential are currently being tested and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF. PMID:25946646

  5. Chop Deficiency Protects Mice Against Bleomycin-induced Pulmonary Fibrosis by Attenuating M2 Macrophage Production.

    PubMed

    Yao, Yingying; Wang, Yi; Zhang, Zhijun; He, Long; Zhu, Jianghui; Zhang, Meng; He, Xiaoyu; Cheng, Zhenshun; Ao, Qilin; Cao, Yong; Yang, Ping; Su, Yunchao; Zhao, Jianping; Zhang, Shu; Yu, Qilin; Ning, Qin; Xiang, Xudong; Xiong, Weining; Wang, Cong-Yi; Xu, Yongjian

    2016-05-01

    C/EBP homologous protein (Chop) has been shown to have altered expression in patients with idiopathic pulmonary fibrosis (IPF), but its exact role in IPF pathoaetiology has not been fully addressed. Studies conducted in patients with IPF and Chop(-/-) mice have dissected the role of Chop and endoplasmic reticulum (ER) stress in pulmonary fibrosis pathogenesis. The effect of Chop deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis were affected by the altered Chop expression and ER stress. In particular, Chop deficiency protected mice against BLM-induced lung injury and fibrosis. Loss of Chop significantly attenuated transforming growth factor β (TGF-β) production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that Chop deficiency repressed the M2 program in macrophages, which then attenuated TGF-β secretion. Specifically, loss of Chop promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which Chop deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that Chop and ER stress are implicated in IPF pathoaetiology, involving at least the induction and differentiation of M2 macrophages. PMID:26883801

  6. 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

  7. Pulmonary nocardiosis in an immunocompetent patient with cystic fibrosis.

    PubMed

    Schoen, Lucy; Santoro, Jonathan D; Milla, Carlos; Bhargava, Sumit

    2015-01-01

    Nocardia spp. are bacteria of low virulence that cause infection classically in immunocompromised hosts with the lungs as the primary site of infection in the majority of cases. Patients with cystic fibrosis have pulmonary disease characterized by frequent and progressive bacterial infections. Reports of Nocardia spp. isolation in CF are rare in the literature and may represent colonization or active infection, the significance and optimal treatment of which are unknown. We report the second case to date of Nocardia transvalensis pulmonary infection in an immunocompetent patient with CF and the first in a child under the age of eighteen. PMID:25960909

  8. Dihydroartemisinin supresses inflammation and fibrosis in bleomycine-induced pulmonary fibrosis in rats

    PubMed Central

    Yang, Dongxia; Yuan, Wendan; Lv, Changjun; Li, Naie; Liu, Tongshen; Wang, Liang; Sun, Yufei; Qiu, Xueshan; Fu, Qiang

    2015-01-01

    Pulmonary fibrosis is a respiratory disease with a high mortality rate and its pathogenesis involves multiple mechanisms including epithelial cell injury, fibroblast proliferation, inflammation, and collagen coagulation. The treatment regimens still fail to recover this disease. We have previously found that dihydroartemisinin inhibits the development of pulmonary fibrosis in rats. This study aimed to determine the mechanisms of dihydroartemisinin in bleomycin-induced pulmonary fibrosis. The experimental rats were divided into six groups as normal saline control group (NS group), bleomycin group (BLM group), dihydroartemisinin-1, -2, or -3 group (DHA-1, DHA-2 and DHA-3 group) and dexamethasone group (DXM group). In BLM group, rats were treated with intratracheal instillation of bleomycin. NS group received the same volume of saline instead of bleomycin. In DHA-1, DHA-2 and DHA-3 group, in addition to intratracheal instillation of bleomycin, respectively, dihydroartemisinin (25 mg/kg, 50 mg/kg, 100 mg/kg daily) was administrated by intraperitoneal instillation. In DXM group, rats were treated with intraperitoneal instillation of dexamethasone as control. Immunocytochemical assay, reverse transcription PCR and western blot were used for detecting the expression of TGF-β1, TNF-α, α-SMA and NF-κB in lung tissues. What’s more, morphological change and collagen deposition were analyzed by hematoxylin-eosin staining and Masson staining. Collagen synthesis was detected by hydroxyproline chromatometry. Results showed that dihydroartemisinin significantly decreased the amount of inflammatory cytokines and collagen synthesis, and inhibited fibroblast proliferation in bleomycin-induced pulmonary fibrosis (P < 0.001). This study provides experimental evidence that dihydroartemisinin could decrease cytokines, alveolar inflammation and attenuates lung injury and fibrosis. PMID:25973011

  9. 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. PMID:26991475

  10. Pulmonary fibrosis following household exposure to asbestos dust?

    PubMed

    Schneider, Joachim; Brückel, Bernd; Fink, Ludger; Woitowitz, Hans-Joachim

    2014-01-01

    An 81-year-old woman was dying from histologically confirmed pulmonary fibrosis without having had any asbestos exposure in the workplace. The lung dust fibre analysis showed significantly increased "asbestos bodies" (AB) (2,640 AB per gram of wet lung tissue) and asbestos fibre concentrations (8,600,000 amphibole fibres of all lengths and 540,000 amphibole fibres with a length ≥5 μm per gram of dry lung tissue). Asbestos exposure was revealed to have occurred during household contact after 27 years of washing her husband's industrial clothing that had been contaminated by asbestos at his workplace in an asbestos textile factory. Household asbestos dust exposure as a risk or co-factor in the aetiology of the fatal pulmonary fibrosis is discussed. PMID:25419224

  11. Paraquat induced pulmonary fibrosis in three survivors.

    PubMed Central

    Hudson, M; Patel, S B; Ewen, S W; Smith, C C; Friend, J A

    1991-01-01

    Pulmonary lesions following paraquat poisoning are believed to be almost invariably fatal. The three patients reports here survived despite persistent radiological change. One of the patients died after taking a larger dose of paraquat one year later, and at necropsy histological changes attributable to the two episodes of paraquat poisoning were apparent. Images PMID:2028434

  12. Idiopathic pulmonary fibrosis. A rare cause of scintigraphic ventilation-perfusion mismatch

    SciTech Connect

    Pochis, W.T.; Krasnow, A.Z.; Collier, B.D.; Mewissen, M.W.; Almagro, U.A.; Hellman, R.S.; Isitman, A.T. )

    1990-05-01

    A case of idiopathic pulmonary fibrosis with multiple areas of mismatch on ventilation-perfusion lung imaging in the absence of pulmonary embolism is presented. Idiopathic pulmonary fibrosis is one of the few nonembolic diseases producing a pulmonary ventilation-perfusion mismatch. In this condition, chest radiographs may not detect the full extent of disease, and xenon-133 ventilation imaging may be relatively insensitive to morbid changes in small airways. Thus, when examining patients with idiopathic pulmonary fibrosis, one should be aware that abnormal perfusion imaging patterns without matching ventilation abnormalities are not always due to embolism. In this setting, contrast pulmonary angiography is often needed for accurate differential diagnosis.

  13. Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis.

    PubMed

    Kannengiesser, Caroline; Borie, Raphael; Ménard, Christelle; Réocreux, Marion; Nitschké, Patrick; Gazal, Steven; Mal, Hervé; Taillé, Camille; Cadranel, Jacques; Nunes, Hilario; Valeyre, Dominique; Cordier, Jean François; Callebaut, Isabelle; Boileau, Catherine; Cottin, Vincent; Grandchamp, Bernard; Revy, Patrick; Crestani, Bruno

    2015-08-01

    Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomere-associated genes implicated in FPF. PMID:26022962

  14. 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

  15. 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. PMID:26527068

  16. Under-recognised co-morbidities in idiopathic pulmonary fibrosis: A review.

    PubMed

    de Boer, Kaïssa; Lee, Joyce S

    2016-08-01

    Co-morbidities in idiopathic pulmonary fibrosis are common. These co-morbidities include obstructive sleep apnoea, gastro-oesophageal reflux disease, pulmonary hypertension and depression. The presence of co-morbidities among patients with idiopathic pulmonary fibrosis contributes to worse quality of life, morbidity and mortality. Despite the high prevalence of certain co-morbidities in idiopathic pulmonary fibrosis, the optimal screening and management of many of these conditions remains unclear. The impact of co-morbidities on this patient population is becoming more apparent. Their relevance will only increase as significant effort is being made to develop novel therapeutics that will alter the disease trajectory of patients with idiopathic pulmonary fibrosis. The purpose of this review is to focus on the epidemiology, pathophysiology, diagnosis and management of select co-morbidities, including obstructive sleep apnoea, gastro-oesophageal reflux disease, pulmonary hypertension and depression, in idiopathic pulmonary fibrosis. PMID:26365251

  17. Combined pulmonary fibrosis and emphysema: effect of pulmonary rehabilitation in comparison with chronic obstructive pulmonary disease

    PubMed Central

    Tomioka, Hiromi; Mamesaya, Nobuaki; Yamashita, Shyuji; Kida, Yoko; Kaneko, Masahiro; Sakai, Hideki

    2016-01-01

    Objective To evaluate the effectiveness of short-term comprehensive inpatient pulmonary rehabilitation for patients with combined pulmonary fibrosis and emphysema (CPFE), and to compare responses with those of patients with chronic obstructive pulmonary disease (COPD) who underwent an identical programme. Design Retrospective analysis of several outcome measures. Setting Pulmonary ward at a 358-bed community teaching hospital. Methods 3-week inpatient pulmonary rehabilitation programme assessed by pulmonary function tests, 6 min walk test and health-related quality of life (HRQL) using the Short Form-36 (SF-36). Results 17 patients with CPFE and 49 patients with COPD were referred to and completed the programme between March 2007 and February 2015. Age, sex, smoking status, body mass index and the Medical Research Council dyspnoea grade were comparable between groups. In the CPFE group, improvement from the start of the programme to the programme end was observed in forced expiratory volume in 1 s (FEV1) (from 1.7±0.4 to 1.8±0.4, p=0.034); however, there was no significant improvement in the 6 min walk test (distance, SpO2 nadir and Borg scale on exercise). With regard to HRQL, improvement was observed in physical function (p=0.015) whereas deterioration was observed in social functioning (p=0.044). In the COPD group, significant improvement was observed after the programme in the FEV1, 6 min walk test and 4 of the 8 SF-36 subscales. There was a significant difference in changes in the 6 min walk distance: −16.6±58.4 in CPFE versus 30.2±55.6 in COPD (p=0.009). In 2 domains, there was a significant difference in SF-36 scores between groups: Δvitality, −6.3±22.4 in CPFE versus 11.3±21.1 in COPD, p=0.009; and Δsocial functioning, −18.8±34.2 in CPFE versus 5.3±35.9 in COPD, p=0.027. Conclusion Patients with COPD derived greater benefits than those with CPFE, from the relatively short periods of inpatient pulmonary rehabilitation. PMID:26933506

  18. Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

    PubMed Central

    Guzy, Robert D.; Stoilov, Ivan; Elton, Timothy J.; Mecham, Robert P.

    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. PMID:24988442

  19. Viruses in Idiopathic Pulmonary Fibrosis. Etiology and Exacerbation.

    PubMed

    Moore, Bethany B; Moore, Thomas A

    2015-11-01

    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

  20. 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. PMID:26892068

  1. Establishment of a mouse model for pulmonary inflammation and fibrosis by intratracheal instillation of polyhexamethyleneguanidine phosphate

    PubMed Central

    Lee, Sang Jin; Park, Jong-Hwan; Lee, Jun-Young; Jeong, Yu-Jin; Song, Jeong Ah; Lee, Kyuhong; Kim, Dong-Jae

    2016-01-01

    Although several animal models have been developed to study human pulmonary fibrosis, lack of a perfect model has raised the need for various animal models of pulmonary fibrosis. In this study, we evaluated the pulmonary effect of polyhexamethyleneguanidine phosphate instillation into the lungs of mice to determine the potential of these mice as a murine model of pulmonary fibrosis. Intratracheal instillation of polyhexamethyleneguanidine phosphate induced severe lung inflammation manifested by the infiltration of mononuclear cells and neutrophils and increased production of IL-6, TNF-α, CCL2 and CXCL1. The lung inflammation gradually increased until 28 days after polyhexamethyleneguanidine phosphate exposure, and increases of collagen deposition and TGF-β production, which are indicators of pulmonary fibrosis, were seen. Our study showed that intratracheal instillation of polyhexamethyleneguanidine phosphate induces pulmonary inflammation and fibrosis in mice. PMID:27182113

  2. Aluminum-induced pulmonary fibrosis: do fibers play a role?

    PubMed

    Gilks, B; Churg, A

    1987-07-01

    A 50-yr-old man with a history of 19 yr of work in the aluminum smelting industry, including 14 years in the potrooms, was found to have diffuse interstitial fibrosis, slightly more severe in the upper zones. He died of respiratory insufficiency 5 yr after initial presentation. Analysis of lung by electron optical techniques revealed 15,000,000,000 nonfibrous particles and 1,300,000,000 fibrous particles of aluminum oxide/g dry lung, values representing approximately a 1,000-fold increase over background exposure. The nonfibrous particles had a geometric mean diameter of 0.4 mu, and the fibers had a geometric mean length of 1.0 mu, a width of 0.06 mu, and an aspect ratio of 16. X-ray diffraction demonstrated alpha but not gamma aluminum oxide. These studies indicate that previous suggestions relating aluminum-induced fibrosis to the presence of gamma aluminum oxide are not correct. Although pulmonary fibrosis in this case may be a response to a very high total aluminum particle burden, the presence of large numbers of fibers raises the possibility that fibers play a role in aluminum fibrosis. PMID:3605831

  3. Echocardiographic and Hemodynamic Predictors of Mortality in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Rivera-Lebron, Belinda N.; Forfia, Paul R.; Kreider, Maryl; Lee, James C.; Holmes, John H.

    2013-01-01

    Background: Idiopathic pulmonary fibrosis (IPF) can lead to the development of pulmonary hypertension, which is associated with an increased risk of death. In pulmonary arterial hypertension, survival is directly related to the capacity of the right ventricle to adapt to elevated pulmonary vascular load. The relative importance of right ventricular function in IPF is not well understood. Our objective was to evaluate right ventricular echocardiographic and hemodynamic predictors of mortality in a cohort of patients with IPF referred for lung transplant evaluation. Methods: We performed a retrospective cohort study of 135 patients who met 2011 American Thoracic Society/European Respiratory Society criteria for IPF and who were evaluated for lung transplantation at the Hospital of the University of Pennsylvania. Results: Right ventricle:left ventricle diameter ratio (hazard ratio [HR], 4.5; 95% CI, 1.7-11.9), moderate to severe right atrial and right ventricular dilation (HR, 2.9; 95% CI, 1.4-5.9; and HR, 2.7; 95% CI, 1.4-5.4, respectively) and right ventricular dysfunction (HR, 5.5; 95% CI, 2.6-11.5) were associated with an increased risk of death. Higher pulmonary vascular resistance was also associated with increased mortality (HR per 1 Wood unit, 1.3; 95% CI, 1.1-1.5). These risk factors were independent of age, sex, race, height, weight, FVC, and lung transplantation status. Other hemodynamic indices, such as mean pulmonary artery pressure and cardiac index, were not associated with outcome. Conclusions: Right-sided heart size and right ventricular dysfunction measured by echocardiography and higher pulmonary vascular resistance by invasive hemodynamic assessment predict mortality in patients with IPF evaluated for lung transplantation. PMID:23450321

  4. 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

  5. Gastroesophageal reflux and idiopathic pulmonary fibrosis: A long term relationship

    PubMed Central

    Gnanapandithan, Karthik; Popkin, Joel H.; Devadoss, Ramprakash; Martin, Kevin

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a dreaded disease of uncertain etiology and no available cure. It is still unclear if a causal relationship exists between gastro-esophageal reflux (GER) and IPF, but studies have shown an increased prevalence of acid reflux in patients with IPF. We describe a patient with achalasia and GER who went on to develop IPF. She underwent a rapidly worsening course punctuated by acute exacerbations of IPF, despite best efforts to manage the acid GER. We also reviewed the literature on the role of GER in the etiology and progression of IPF and the impact of antireflux measures on its course. PMID:27222783

  6. 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. PMID:26780485

  7. Elevated expression of NEU1 sialidase in idiopathic pulmonary fibrosis provokes pulmonary collagen deposition, lymphocytosis, and fibrosis.

    PubMed

    Luzina, Irina G; Lockatell, Virginia; Hyun, Sang W; Kopach, Pavel; Kang, Phillip H; Noor, Zahid; Liu, Anguo; Lillehoj, Erik P; Lee, Chunsik; Miranda-Ribera, Alba; Todd, Nevins W; Goldblum, Simeon E; Atamas, Sergei P

    2016-05-15

    Idiopathic pulmonary fibrosis (IPF) poses challenges to understanding its underlying cellular and molecular mechanisms and the development of better therapies. Previous studies suggest a pathophysiological role for neuraminidase 1 (NEU1), an enzyme that removes terminal sialic acid from glycoproteins. We observed increased NEU1 expression in epithelial and endothelial cells, as well as fibroblasts, in the lungs of patients with IPF compared with healthy control lungs. Recombinant adenovirus-mediated gene delivery of NEU1 to cultured primary human cells elicited profound changes in cellular phenotypes. Small airway epithelial cell migration was impaired in wounding assays, whereas, in pulmonary microvascular endothelial cells, NEU1 overexpression strongly impacted global gene expression, increased T cell adhesion to endothelial monolayers, and disrupted endothelial capillary-like tube formation. NEU1 overexpression in fibroblasts provoked increased levels of collagen types I and III, substantial changes in global gene expression, and accelerated degradation of matrix metalloproteinase-14. Intratracheal instillation of NEU1 encoding, but not control adenovirus, induced lymphocyte accumulation in bronchoalveolar lavage samples and lung tissues and elevations of pulmonary transforming growth factor-β and collagen. The lymphocytes were predominantly T cells, with CD8(+) cells exceeding CD4(+) cells by nearly twofold. These combined data indicate that elevated NEU1 expression alters functional activities of distinct lung cell types in vitro and recapitulates lymphocytic infiltration and collagen accumulation in vivo, consistent with mechanisms implicated in lung fibrosis. PMID:26993524

  8. 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

    2016-01-01

    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. PMID:26891294

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

    PubMed Central

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

    2016-01-01

    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. PMID:26891294

  10. 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. PMID:27299520

  11. A retired shipyard worker with rapidly progressive pulmonary interstitial fibrosis.

    PubMed Central

    Moy, E V; Hu, H; Christiani, D C

    1999-01-01

    We present a case of progressive interstitial fibrosis in a retired shipyard worker who was exposed to asbestos during the postwar era of the late 1940s and 1950s, when asbestos exposures in the workplace were not regulated. Forty years later, at 63 years of age, the patient presented with restrictive lung disease. The patient was diagnosed with asbestos-related pleural disease and parenchymal asbestosis. He remained stable for the next 7 years, but then he began to manifest rapid clinical progression, which raised the possibility of an unusual variant of asbestosis, a concomitant interstitial process, or an unrelated disease. Lung biopsy was not undertaken because of the patient's low pulmonary reserve and limited treatment options. An empiric trial of oral steroids was initiated, but his pulmonary status continued to deteriorate and he died of pulmonary failure at 72 years of age. Many diseases result in pulmonary interstitial fibrosis. Ideally, open lung biopsy should be performed, but this procedure inevitably causes complications in many patients with end-stage restrictive lung disease. Furthermore, while the presence of asbestos bodies in tissue sections is a sensitive and specific marker of asbestos exposure, neither this finding nor any other charge is a marker indicative of asbestosis or the severity of asbestosis. With the enactment of the Asbestos Standard in the United States, asbestos exposures have been decreasing in this country. However, industries that produce asbestos products and wastes continue to expand in developing countries. Prevention of asbestos-related lung disease should be a global endeavor, and asbestos exposures should be regulated in both developed and developing countries. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:10090713

  12. Cystic Fibrosis Transmembrane Conductance Regulator. Implications in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

    PubMed

    Cantin, André M

    2016-04-01

    Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) have traditionally been viewed as two distinct entities of unrelated origins. However, molecular, cellular, and clinical studies have revealed that cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction is common to both conditions, one (CF) being defined genetically and the other (COPD) as an acquired CFTR deficiency. Multiple molecular mechanisms of cigarette smoke-induced CFTR dysfunction have been reported. More importantly, considerable evidence of cigarette smoke-induced CFTR dysfunction in several respiratory and nonrespiratory tissues have been confirmed, making CFTR a target that cannot be overlooked in our quest to understand COPD and improve therapies for individuals affected by this disease. This review summarizes the molecular, cellular, and clinical evidence that CFTR dysfunction is induced by cigarette smoke exposure both in vitro and in vivo, and explores how this may contribute to the development of COPD. PMID:27115950

  13. Serum Amyloid P Therapeutically Attenuates Murine Bleomycin-Induced Pulmonary Fibrosis via Its Effects on Macrophages

    PubMed Central

    Murray, Lynne A.; Rosada, Rogerio; Moreira, Ana Paula; Joshi, Amrita; Kramer, Michael S.; Hesson, David P.; Argentieri, Rochelle L.; Mathai, Susan; Gulati, Mridu; Herzog, Erica L.; Hogaboam, Cory M.

    2010-01-01

    Macrophages promote tissue remodeling but few mechanisms exist to modulate their activity during tissue fibrosis. Serum amyloid P (SAP), a member of the pentraxin family of proteins, signals through Fcγ receptors which are known to affect macrophage activation. We determined that IPF/UIP patients have increased protein levels of several alternatively activated pro-fibrotic (M2) macrophage-associated proteins in the lung and monocytes from these patients show skewing towards an M2 macrophage phenotype. SAP therapeutically inhibits established bleomycin-induced pulmonary fibrosis, when administered systemically or locally to the lungs. The reduction in aberrant collagen deposition was associated with a reduction in M2 macrophages in the lung and increased IP10/CXCL10. These data highlight the role of macrophages in fibrotic lung disease, and demonstrate a therapeutic action of SAP on macrophages which may extend to many fibrotic indications caused by over-exuberant pro-fibrotic macrophage responses. PMID:20300636

  14. Idiopathic pulmonary fibrosis: Diagnosis, epidemiology and natural history.

    PubMed

    Sgalla, Giacomo; Biffi, Alice; Richeldi, Luca

    2016-04-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing lung disorder of unknown aetiology whose diagnosis involves the careful exclusion of secondary causes for pulmonary fibrosis and the presence of a pattern of usual interstitial pneumonia (UIP) at either high-resolution computed tomography (HRCT) scan or surgical lung biopsy. Despite great efforts made in establishing precise, universally acknowledged diagnostic criteria for IPF, its ascertainment remains a challenge, especially in those individuals presenting with atypical HRCT patterns. With new drugs emerging, establishing a precise diagnosis is becoming a clinically relevant issue. Although regarded as a rare disease, IPF epidemiology is controversial due to studies relying on old data and adopting mixed, incomparable methodologies for cases definition. Overall, the prevalence and incidence appear to be increasing over the last decades, suggesting that in earlier studies they might have been underestimated because of diagnostic uncertainty. IPF is invariably progressive, although its clinical course might greatly vary on an individual basis, with episodes of severe acute respiratory deterioration (acute exacerbations) being unpredictable. A deeper understanding of the mechanisms responsible for an accelerated course of the disease and the identification of biomarkers of progression would lead to a better stratification of the disease, essential for delivering individualized therapeutic strategies. PMID:26595062

  15. Acute exacerbation of idiopathic pulmonary fibrosis: shifting the paradigm.

    PubMed

    Ryerson, Christopher J; Cottin, Vincent; Brown, Kevin K; Collard, Harold R

    2015-08-01

    The goal of this review is to summarise the clinical features, management, and prognosis of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). AE-IPF has previously been defined based on clinical and radiological features that include the subacute onset of dyspnoea, bilateral ground glass changes on chest high-resolution computed tomography, and the absence of an identifiable aetiology. The annual incidence of AE-IPF is typically reported at 5-15%, but is less common in mild disease. Features of diffuse alveolar damage are present when a biopsy is performed. Idiopathic pulmonary fibrosis (IPF) patients with acute respiratory worsening are often initially treated with high dose corticosteroids and antimicrobials; however, there are no clear data to support these therapies, and the short-term mortality of AE-IPF is ~50%. Recent studies have shown that the features and prognosis of AE-IPF are similar to other causes of acute respiratory worsening, including infection, aspiration, air pollution and mechanical injury to the alveolar epithelium. Based on this emerging evidence, we propose a novel approach to the classification of acute respiratory worsening events in patients with IPF that focuses on clinical and radiological findings consistent with an underlying pathobiology of diffuse alveolar damage. PMID:26232481

  16. 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. PMID:27510385

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

    PubMed Central

    Collins, Samuel L.; Chan-Li, Yee; Oh, MinHee; Vigeland, Christine L.; Limjunyawong, Nathachit; 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

  18. Association between MUC5B polymorphism and susceptibility and severity of idiopathic pulmonary fibrosis

    PubMed Central

    Jiang, Haiming; Hu, Yejia; Shang, Li; Li, Yuzhu; Yang, Lihua; Chen, Yuguo

    2015-01-01

    Objectives: Idiopathic pulmonary fibrosis (IPF) is a group of lung diseases that cause irreversible architectural distortion and impair gas, and finally progressive pulmonary functional decline and death, in which the common variant in the promoter region of the mucin 5B (MUC5B) gene may be involved. The present study aims to investigate whether variants within the MUC5B gene rs35705950 contributed to IPF susceptibility and severity in Chinese Han Population. Methods: A total of 187 patients diagnosed with IPF and 250 healthy controls were enrolled in this study. All subjects were genotyped for MUV5B SNP rs35705950. The demographic, comorbidity, clinical and functional data were recorded. Results: The rs35705950 of MUC5B were found significantly associated with increased risk of IPF susceptibility. One way ANOVA analysis found that there was a significant decreased FVC (P < 0.0001) and DLco (P < 0.0001) in correction with the minor allele of the SNP rs35705950. In the 5 years’ follow-up, the carriers of the minor allele T increased mortality (P = 0.0294). Conclusion: This study demonstrated that the MUC5B polymorphism rs35705950 is associated with increased risk of idiopathic pulmonary fibrosis susceptibility, severity, and the decreased overall survival. PMID:26823827

  19. New perspectives on management of idiopathic pulmonary fibrosis

    PubMed Central

    Puglisi, Silvia; Torrisi, Sebastiano Emanuele; Vindigni, Virginia; Giuliano, Riccardo; Palmucci, Stefano; Mulè, Massimiliano; Vancheri, Carlo

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive parenchymal lung disease characterized by a median survival of 3–5 years following diagnosis. The diagnosis is based on clinical, radiological and histopathological evaluation. Therefore, a multidisciplinary team is needed to reach the correct diagnosis. For a long time, supportive care and lung transplantation in selected cases, have been considered the only possible treatments for IPF. In the last decade many studies have investigated IPF pathogenesis, leading to an improved knowledge of the mechanisms underlying the disease and to the approval of two new drugs for IPF treatment (pirfenidone and nintedanib). The therapeutic approach of IPF cannot be limited to the administration of antifibrotic drugs, but it is necessary for improving the quality of life of patients and for facilitating, as far as possible, the performance of normal daily activities and relationships. IPF patients are also afflicted by disease-related complications such as gastroesophageal reflux, pulmonary hypertension, acute exacerbations and an increased risk of developing lung cancer. The clinician who treats IPF patients, should also treat these possible complications to slow disease progression, thus maintaining the possibility of a pulmonary transplantation. PMID:26977280

  20. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review.

    PubMed

    Raghu, Ganesh; Amatto, Valeria C; Behr, Jürgen; Stowasser, Susanne

    2015-10-01

    Idiopathic pulmonary fibrosis (IPF) is associated with a fatal prognosis and manifests in patients over 60 years old who may have comorbidities. The prevalence and impact of comorbidities on the clinical course of IPF is unclear.This systematic literature review examined the prevalence of comorbidities and mortality associated with comorbidities in IPF patients. Relevant observational studies published in English from January 1990 to January 2015 identified via MEDLINE and EMBASE were included; bibliographies of articles were also searched.Among the 126 studies included, prevalence of pulmonary hypertension (PH) was 3-86%, 6-91% for obstructive sleep apnoea, 3-48% for lung cancer and 6-67% for chronic obstructive pulmonary disease (COPD). Nonrespiratory comorbidities included ischaemic heart disease (IHD) (3-68%) and gastro-oesophageal reflux (GER) (0-94%). Mortality was highest among patients with IPF and lung cancer. Most studies assessed relatively small samples of patients with IPF.PH, COPD, lung cancer, GER and IHD are significant comorbidities; differences in IPF severity, case definitions and patient characteristics limited the comparability of findings. The identification and prompt treatment of comorbidities may have a clinically significant impact on overall outcome that is meaningful for patients with IPF. PMID:26424523

  1. New perspectives on management of idiopathic pulmonary fibrosis.

    PubMed

    Puglisi, Silvia; Torrisi, Sebastiano Emanuele; Vindigni, Virginia; Giuliano, Riccardo; Palmucci, Stefano; Mulè, Massimiliano; Vancheri, Carlo

    2016-03-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive parenchymal lung disease characterized by a median survival of 3-5 years following diagnosis. The diagnosis is based on clinical, radiological and histopathological evaluation. Therefore, a multidisciplinary team is needed to reach the correct diagnosis. For a long time, supportive care and lung transplantation in selected cases, have been considered the only possible treatments for IPF. In the last decade many studies have investigated IPF pathogenesis, leading to an improved knowledge of the mechanisms underlying the disease and to the approval of two new drugs for IPF treatment (pirfenidone and nintedanib). The therapeutic approach of IPF cannot be limited to the administration of antifibrotic drugs, but it is necessary for improving the quality of life of patients and for facilitating, as far as possible, the performance of normal daily activities and relationships. IPF patients are also afflicted by disease-related complications such as gastroesophageal reflux, pulmonary hypertension, acute exacerbations and an increased risk of developing lung cancer. The clinician who treats IPF patients, should also treat these possible complications to slow disease progression, thus maintaining the possibility of a pulmonary transplantation. PMID:26977280

  2. 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.

  3. Protection from Radiation-Induced Pulmonary Fibrosis by Peripheral Targeting of Cannabinoid Receptor-1.

    PubMed

    Bronova, Irina; Smith, Brett; Aydogan, Bulent; Weichselbaum, Ralph R; Vemuri, Kiran; Erdelyi, Katalin; Makriyannis, Alex; Pacher, Pal; Berdyshev, Evgeny V

    2015-10-01

    Radiation-induced pulmonary fibrosis (RIF) is a severe complication of thoracic radiotherapy that limits its dose, intensity, and duration. The contribution of the endocannabinoid signaling system in pulmonary fibrogenesis is not known. Using a well-established mouse model of RIF, we assessed the involvement of cannabinoid receptor-1 (CB1) in the onset and progression of pulmonary fibrosis. Female C57BL/6 mice and CB1 knockout mice generated on C57BL/6 background received 20 Gy (2 Gy/min) single-dose thoracic irradiation that resulted in pulmonary fibrosis and animal death within 15 to 18 weeks. Some C57BL/6 animals received the CB1 peripherally restricted antagonist AM6545 at 1 mg/kg intraperitoneally three times per week. Animal survival and parameters of pulmonary inflammation and fibrosis were evaluated. Thoracic irradiation (20 Gy) was associated with marked pulmonary inflammation and fibrosis in mice and high mortality within 15 to 18 weeks after exposure. Genetic deletion or pharmacological inhibition of CB1 receptors with a peripheral CB1 antagonist AM6545 markedly attenuated or delayed the lung inflammation and fibrosis and increased animal survival. Our results show that CB1 signaling plays a key pathological role in the development of radiation-induced pulmonary inflammation and fibrosis, and peripherally restricted CB1 antagonists may represent a novel therapeutic approach against this devastating complication of radiotherapy/irradiation. PMID:26426981

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

    PubMed Central

    2014-01-01

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

  5. A retrospective study of microscopic polyangiitis patients presenting with pulmonary fibrosis in China

    PubMed Central

    2014-01-01

    Background Pulmonary involvement is a common feature of MPA. Although alveolar hemorrhage is the most common pulmonary manifestation of MPA, a few recent studies have described instances of MPA patients with pulmonary fibrosis. Pulmonary fibrosis was seen to predate, be concomitant with, or occur after the diagnosis of MPA. The goal of this study was to describe the clinical features and prognosis of microscopic polyangiitis (MPA) patients whose initial respiratory presentation was pulmonary fibrosis. Methods We conducted a retrospective analysis of 19 MPA patients who presented with pulmonary fibrosis at Peking Union Medical College Hospital between 1990 and 2012. Results Of 67 total MPA cases, 19 patients presented with pulmonary fibrosis. There were 8 males and 11 females, with a median age of 63.6 years. Common clinical manifestations included fever (89.5%), cough (84.2%), dyspnea (78.9%) and velcro rales (84.2%). Eleven patients experienced weight loss, several had kidney involvement, and most had an increased erythrocyte sedimentation rate and C-reactive protein. All were positive for myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA), with 6 patients being positive at the time of their initial diagnosis of pulmonary fibrosis. Every patient had typical features of usual interstitial pneumonia on High-resolution CT. All were treated with corticosteroids and cyclophosphamide, which lead to an improvement in twelve cases. One of the remaining patients progressed slowly, whereas six died. Conclusions Patients with MPA, who also presented with pulmonary fibrosis in our cohort, were more likely to be older, female, and have extrapulmonic involvement. Most patients had a delayed positive ANCA. Corticosteroids plus cyclophosphamide was the remission-induction treatment scheme for all cases. The current prognosis for MPA patients with pulmonary fibrosis appears to be poor, suggesting that they may be candidates for new therapies. PMID:24468083

  6. Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice.

    PubMed

    Shivshankar, Pooja; Brampton, Christopher; Miyasato, Shelley; Kasper, Michael; Thannickal, Victor J; Le Saux, Claude Jourdan

    2012-07-01

    Idiopathic pulmonary fibrosis is associated with a decreased expression of caveolin-1 (cav-1), yet its role remains unclear. To investigate the role of cav-1, we induced pulmonary fibrosis in wild-type (WT) and cav-1-deficient (cav-1(-/-)) mice using intratracheal instillation of bleomycin. Contrary to expectations, significantly less collagen deposition was measured in tissue from cav-1(-/-) mice than in their WT counterparts, consistent with reduced mRNA expression of procollagen1a2 and procollagen3a1. Moreover, cav-1(-/-) mice demonstrated 77% less α-smooth muscle actin staining, suggesting reduced mesenchymal cell activation. Levels of pulmonary injury, assessed by tenascin-C mRNA expression and CD44v10 detection, were significantly increased at Day 21 after injury in WT mice, an effect significantly attenuated in cav-1(-/-) mice. The apparent protective effect against bleomycin-induced fibrosis in cav-1(-/-) mice was attributed to reduce cellular senescence and apoptosis in cav-1(-/-) epithelial cells during the early phase of lung injury. Reduced matrix metalloproteinase (MMP)-2 and MMP-9 expressions indicated a low profile of senescence-associated secretory phenotype (SASP) in the bleomycin-injured cav-1(-/-) mice. However, IL-6 and macrophage inflammatory protein 2 were increased in WT and cav-1(-/-) mice after bleomycin challenge, suggesting that bleomycin-induced inflammatory response substantiated the SASP pool. Thus, loss of cav-1 attenuates early injury response to bleomycin by limiting stress-induced cellular senescence/apoptosis in epithelial cells. In contrast, decreased cav-1 expression promotes fibroblast activation and collagen deposition, effects that may be relevant in later stages of reparative response. Hence, therapeutic strategies to modulate the expression of cav-1 should take into account cell-specific effects in the regenerative responses of the lung epithelium to injury. PMID:22362388

  7. 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

  8. Idiopathic Pulmonary Fibrosis and Myasthenia Gravis: An Unusual Association.

    PubMed

    Chogtu, Bharti; Malik, Daliparty Vasudev; Magazine, Rahul

    2016-04-01

    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

  9. 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. PMID:27041165

  10. 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

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

    PubMed

    Parfrey, H; Babar, J; Fiddler, C A; Chilvers, E R

    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

  12. A Controlled Trial of Sildenafil in Advanced Idiopathic Pulmonary Fibrosis

    PubMed Central

    2013-01-01

    BACKGROUND Sildenafil, a phosphodiesterase-5 inhibitor, may preferentially improve blood flow to well-ventilated regions of the lung in patients with advanced idiopathic pulmonary fibrosis, which could result in improvements in gas exchange. We tested the hypothesis that treatment with sildenafil would improve walk distance, dyspnea, and quality of life in patients with advanced idiopathic pulmonary fibrosis, defined as a carbon monoxide diffusion capacity of less than 35% of the predicted value. METHODS We conducted a double-blind, randomized, placebo-controlled trial of sildenafil in two periods. The first period consisted of 12 weeks of a double-blind comparison between sildenafil and a placebo control. The primary outcome was the proportion of patients with an increase in the 6-minute walk distance of 20% or more. Key secondary outcomes included changes in oxygenation, degree of dyspnea, and quality of life. The second period was a 12-week open-label evaluation involving all patients receiving sildenafil. RESULTS A total of 180 patients were enrolled in the study. The difference in the primary outcome was not significant, with 9 of 89 patients (10%) in the sildenafil group and 6 of 91 (7%) in the placebo group having an improvement of 20% or more in the 6-minute walk distance (P = 0.39). There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group. Serious adverse events were similar in the two study groups. CONCLUSIONS This study did not show a benefit for sildenafil for the primary outcome. The presence of some positive secondary outcomes creates clinical equipoise for further research. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00517933.) PMID:20484178

  13. Stem Cell-Based Therapy in Idiopathic Pulmonary Fibrosis.

    PubMed

    Barczyk, Marek; Schmidt, Matthias; Mattoli, Sabrina

    2015-08-01

    Idiopathic pulmonary fibrosis is a progressive fibrosing disorder for which there is no cure and no pharmacological treatment capable of increasing in a meaningful way the survival rate. Lung transplantation remains the only possible treatment for patients with advanced disease, although the increase in 5-year survival is only 45 %. Some preclinical studies have generated promising results about the therapeutic potential of exogenous stem cells. However, two initial clinical trials involving the endobronchial or systemic delivery of autologous adipose tissue-derived or unrelated-donor, placenta-derived mesenchymal stem cells have not convincingly demonstrated that these treatments are acceptably safe. The results of other ongoing clinical trials may help to identify the best source and delivery route of mesenchymal stem cells and to estimate the risk of unwanted effects related to the mesenchymal nature of the transplanted cells. Considering that most of the therapeutic potential of these cells has been ascribed to paracrine signaling, the use of mesenchymal stem cell-derived secretome as an alternative to the transplantation of single cell suspension may circumvent many regulatory and clinical problems. Technical and safety concerns still limit the possibility of clinical applications of other promising interventions that are based on the use of human amnion stem cells, embryonic stem cells or induced pluripotent stem cells to replace or regenerate the dysfunctional alveolar epithelium. We summarize the current status of the field and identify major challenges and opportunities for the possible future integration of stem cell-based treatments into the currently recommended clinical management strategy for idiopathic pulmonary fibrosis. PMID:25896401

  14. Metabolic Profiling Regarding Pathogenesis of Idiopathic Pulmonary Fibrosis.

    PubMed

    Kang, Yun Pyo; Lee, Sae Bom; Lee, Ji-Min; Kim, Hyung Min; Hong, Ji Yeon; Lee, Won Jun; Choi, Chang Woo; Shin, Hwa Kyun; Kim, Do-Jin; Koh, Eun Suk; Park, Choon-Sik; Kwon, Sung Won; Park, Sung-Woo

    2016-05-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive, eventually fatal disease characterized by fibrosis of the lung parenchyma and loss of lung function. IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair process including uncontrolled proliferation of lung (myo) fibroblasts and excessive deposition of extracellular matrix proteins in the interstitial space; however, the pathogenic pathways involved in IPF have not been fully elucidated. In this study, we attempted to characterize metabolic changes of lung tissues involved in the pathogenesis of IPF using gas chromatography-mass spectrometry-based metabolic profiling. Partial least-squares discriminant analysis (PLS-DA) model generated from metabolite data was able to discriminate between the control subjects and IPF patients (R(2)X = 0.37, R(2)Y = 0.613 and Q(2) (cumulative) = 0.54, receiver operator characteristic AUC > 0.9). We discovered 25 metabolite signatures of IPF using both univariate and multivariate statistical analyses (FDR < 0.05 and VIP score of PLS-DA > 1). These metabolite signatures indicated alteration in metabolic pathways: adenosine triphosphate degradation pathway, glycolysis pathway, glutathione biosynthesis pathway, and ornithine aminotransferase pathway. The results could provide additional insight into understanding the disease and potential for developing biomarkers. PMID:27052453

  15. Idiopathic Pulmonary Fibrosis: Epidemiology, Clinical Features, Prognosis, and Management.

    PubMed

    Lynch, Joseph P; Huynh, Richard H; Fishbein, Michael C; Saggar, Rajan; Belperio, John A; Weigt, S Sam

    2016-06-01

    Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic interstitial lung pneumonia associated with the histologic pattern of usual interstitial pneumonia (UIP). Although UIP is a distinct histologic lesion, this histologic pattern is not specific for IPF and can also be found in other diseases (e.g., connective tissue disease and asbestosis). Clinical features of IPF include progressive cough, dyspnea, restrictive ventilatory defect, and progressive fibrosis and destruction of the lung parenchyma. IPF is rare (13-42 cases/100,000), and primarily affects older adults (>50 years of age). The diagnosis of IPF often requires surgical lung biopsy, but the diagnosis can be affirmed with confidence in some patients provided the results of computed tomographic (CT) scans and clinical features are consistent. The clinical course is variable, but inexorable progression (typically over months to years) is typical. Mean survival from the onset of symptoms approximates 3 to 5 years. Medical treatment is only modestly effective, primarily by slowing the rate of disease progression. Lung transplantation is the best therapeutic option. PMID:27231859

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

    PubMed Central

    Heppleston, A. G.

    1986-01-01

    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. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:3026427

  17. Familial idiopathic pulmonary fibrosis. Evidence of lung inflammation in unaffected family members

    SciTech Connect

    Bitterman, P.B.; Rennard, S.I.; Keogh, B.A.; Wewers, M.D.; Adelberg, S.; Crystal, R.G.

    1986-05-22

    We evaluated 17 clinically unaffected members of three families with an autosomal dominant form of idiopathic pulmonary fibrosis for evidence of alveolar inflammation. Each person in the study was examined by gallium-67 scanning for a general estimate of pulmonary inflammation, and by bronchoalveolar lavage for characterization of the types of recovered cells and their state of activation. Eight of the 17 subjects had evidence of alveolar inflammation on the lavage studies. Supporting data included increased numbers of neutrophils and activated macrophages that released one or more neutrophil chemoattractants, and growth factors for lung fibroblasts--findings similar to those observed in patients with overt idiopathic pulmonary fibrosis. Four of these eight also had a positive gallium scan; in all the other clinically unaffected subjects the scan was normal. During a follow-up of two to four years in seven of the eight subjects who had evidence of inflammation, no clinical evidence of pulmonary fibrosis has appeared. These results indicate that alveolar inflammation occurs in approximately half the clinically unaffected family members at risk of inheriting autosomal dominant idiopathic pulmonary fibrosis. Whether these persons with evidence of pulmonary inflammation but no fibrosis will proceed to have clinically evident pulmonary fibrosis is not yet known.

  18. Pulmonary Physiology of Chronic Obstructive Pulmonary Disease, Cystic Fibrosis, and Alpha-1 Antitrypsin Deficiency.

    PubMed

    Stockley, James A; Stockley, Robert A

    2016-04-01

    Cystic fibrosis is predominantly an airway disease with marked bronchiectatic changes associated with inflammation, chronic colonization, and progressive airflow obstruction. The condition can be identified in childhood and monitored with detectable airway changes early in life while conventional spirometry remains in the normal range. Alpha-1 antitrypsin deficiency can also be detected early in life through blood spot and genetic testing and leads (in some) to the development of airflow obstruction and a predominant emphysema phenotype with bronchiectatic changes in about 30%. Early detection also allows the natural history of the pulmonary physiological changes to be determined. Chronic obstructive pulmonary disease is usually detected late in the disease process when significant damage has occurred. The condition consists of varying combinations of airway disease, bronchiectasis, colonization, and emphysema. Lessons learned from the physiological evolution of airway disease in cystic fibrosis and the emphysema of alpha-1 antitrypsin deficiency provide strategies to enable early detection of chronic obstructive pulmonary disease in general and its phenotypes. PMID:27115945

  19. 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

  20. [Idiopatic pulmonary fibrosis - news in multidisciplinary diagnostic and therapeutic approaches].

    PubMed

    Vašáková, Martina; Matěj, Radoslav

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a primary fibrosing pulmonary process. Due to the ineffectiveness of current therapeutic strategies and unfavorable prognosis, IPF is the most serious example of idiopathic interstitial lung diseases (ILD). Etiology and pathogenesis of this disorder have not been fully clarified yet; but it is anticipated, that the fibroproliferation is caused by the imbalance of reparative and immunologic processes in the genetically predisposed patients. Radiologically and histopathologically, IPF is characterized by specific pattern called usual interstitial pneumonia (UIP), however, this pattern is not fully typical in all cases, and, moreover, it could be seen in other ILD´s, e.g. chronic hypersensitivity pneumonitis, asbestosis, autoimmune connective tissue diseases and many others as well. The final diagnosis of IPF is a consensual result of multidisciplinary team composed of pulmologist, pathologist and radiologist. IPF was an incurable disease with prognosis worse than cancer till the year 2011, when antifibrotic drugs decelerating a progression of this disease have been introduced. Earlier and correct diagnosis of IPF is the most important issue for the patients because they could be effectively treated and thus, prolonging their survival as much as possible. PMID:27223586

  1. 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

  2. Pulmonary function impairment in patients with combined pulmonary fibrosis and emphysema with and without airflow obstruction

    PubMed Central

    Kitaguchi, Yoshiaki; Fujimoto, Keisaku; Hanaoka, Masayuki; Honda, Takayuki; Hotta, Junichi; Hirayama, Jiro

    2014-01-01

    Background The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is a recently described entity associating upper-lobe emphysema and lower-lobe fibrosis. We sought to evaluate differences in pulmonary function between CPFE patients with and without airflow obstruction. Subjects and methods Thirty-one CPFE patients were divided into two groups according to the presence or absence of irreversible airflow obstruction based on spirometry (forced expiratory volume in 1 second/forced vital capacity <70% following inhalation of a β2-agonist) as follows: CPFE patients with airflow obstruction (CPFE OB+ group, n=11), and CPFE patients without airflow obstruction (CPFE OB− group, n=20). Pulmonary function, including respiratory impedance evaluated using impulse oscillometry and dynamic hyperinflation following metronome-paced incremental hyperventilation, was retrospectively analyzed in comparison with that observed in 49 chronic obstructive pulmonary disease (COPD) patients (n=49). Results In imaging findings, low-attenuation-area scores on chest high-resolution computed tomography, representing the degree of emphysema, were significantly lower in the CPFE OB− group than in the CPFE OB+ and COPD groups. In contrast, the severity of pulmonary fibrosis was greater in the CPFE OB− group than in the CPFE OB+ group. In pulmonary function, lung hyperinflation was not apparent in the CPFE OB− group. Impairment of diffusion capacity was severe in both the CPFE OB− and CPFE OB+ groups. Impulse oscillometry showed that respiratory resistance was not apparent in the CPFE OB− group compared with the COPD group, and that easy collapsibility of small airways during expiration of tidal breath was not apparent in the CPFE OB+ group compared with the COPD group. Dynamic hyperinflation following metronome-paced incremental hyperventilation was significantly greater in the COPD group than in the CPFE OB− group, and also tended to be greater in the CPFE OB+ group than

  3. The inter-connection between fibrosis and microvascular remodeling in idiopathic pulmonary fibrosis: Reality or just a phenomenon

    PubMed Central

    Mlika, Mona; Bacha, Saoussen; Braham, Emna; El Mezni, Faouzi

    2015-01-01

    Background Idiopathic pulmonary fibrosis is the most frequent interstitial disease with the worst prognosis. It is characterized by an uncontrolled fibrosis which is difficult to manage. The pathogenesis of this disease remains unclear with many theories resulting in multiple target therapies. The relation between fibrosis and vascular remodeling has been debated in the literature with different results that may seem contradictory. Aim We target to evaluate the connection between fibrosis and vascular remodeling in usual interstitial pneumonia. Material and methods 26 cases of idiopathic pulmonary fibrosis were reviewed by 2 pathologists and the diagnosis of UIP was retained according to the American Thoracic Society's criteria. Fibrotic changes and vascular remodeling were evaluated blindly. The fibrotic changes were classified as severe, intermediate and mild. Vascular occlusion was graded in 4 grades extending from medial hypertrophy (grade 1) to plexiform lesions of the vascular wall (grade 4). Results We noticed that severe degrees of fibrosis were correlated with severe grades of vascular obstruction. In fact, our 26 cases were classified as severe fibrosis in 11 cases with grade IV vascular lesions in 6 cases, intermediate fibrosis in 12 cases with grade II vascular lesions in 8 cases and mild fibrosis in 3 cases with grade I vascular lesions in all cases. Conclusion Many theories have been reported concerning the UIP's pathogenesis. Recently, many authors reported that the primum movens of these lesions was an epithelial/endothelial injury which induces uncontrolled fibrosis and microvascular remodeling using different pathways. This puts emphasis on the necessity of multi-target therapies in order to improve the management of this fatal disease. PMID:27222781

  4. Pulmonary fibrosis in response to environmental cues and molecular targets involved in its pathogenesis.

    PubMed

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

    2011-03-01

    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

  5. 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

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

    PubMed

    Porteous, Mary K; Rivera-Lebron, Belinda N; Kreider, Maryl; Lee, James; Kawut, Steven M

    2016-03-01

    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 ([Formula: see text]). For each 200-mL reduction in forced vital capacity, the walk distance decreased by 15.0 m (95% CI, 9.0-21.1; [Formula: see text]). 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; [Formula: see text]). 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

  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. Paradoxical function for the receptor for advanced glycation end products in mouse models of pulmonary fibrosis

    PubMed Central

    Englert, Judson M; Kliment, Corrine R; Ramsgaard, Lasse; Milutinovic, Pavle S; Crum, Lauren; Tobolewski, Jacob M; Oury, Tim D

    2011-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor survival. The identification of therapeutic targets is essential to improving outcomes. Previous studies found that expression of the receptor for advanced glycation end products (RAGE) in the lung is significantly decreased in human IPF lungs and in two animal models of pulmonary fibrosis. In addition, RAGE-null mice spontaneously develop pulmonary fibrosis with age and more severe fibrosis when challenged with asbestos. In contrast to the findings that the lack of RAGE enhanced pulmonary fibrosis, He et al. found that RAGE null mice were protected from bleomycin-induced fibrosis and suggested the effect was due to a lack of HMGB1 induced RAGE signaling. The current study further tests this hypothesis by blocking RAGE signaling via administration of soluble RAGE, a decoy receptor, to determine if this will also protect against pulmonary fibrosis. Wild-type, RAGE+/-, and RAGE-/- mice were treated with bleomycin and assessed for fibrosis. Wild-type mice were also treated with exogenous soluble RAGE or vehicle control. In addition, in vitro studies with primary alveolar epithelial cells from wild-type and RAGE null mice were used to investigate the effect of RAGE on cell viability and migration in response to injury. A lack of RAGE was found to be protective against bleomycin injury in both in vivo and in vitro studies. However, soluble RAGE administration was unable to ameliorate fibrosis. This study confirms paradoxical responses to two different models of pulmonary fibrosis and suggests a further role for RAGE in cellular migration. PMID:21487520

  9. SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis.

    PubMed

    Elkouris, Maximilianos; Kontaki, Haroula; Stavropoulos, Athanasios; Antonoglou, Anastasia; Nikolaou, Kostas C; Samiotaki, Martina; Szantai, Eszter; Saviolaki, Dimitra; Brown, Peter J; Sideras, Paschalis; Panayotou, George; Talianidis, Iannis

    2016-06-21

    TGF-β signaling regulates a variety of cellular processes, including proliferation, apoptosis, differentiation, immune responses, and fibrogenesis. Here, we describe a lysine methylation-mediated mechanism that controls the pro-fibrogenic activity of TGF-β. We find that the methyltransferase Set9 potentiates TGF-β signaling by targeting Smad7, an inhibitory downstream effector. Smad7 methylation promotes interaction with the E3 ligase Arkadia and, thus, ubiquitination-dependent degradation. Depletion or pharmacological inhibition of Set9 results in elevated Smad7 protein levels and inhibits TGF-β-dependent expression of genes encoding extracellular matrix components. The inhibitory effect of Set9 on TGF-β-mediated extracellular matrix production is further demonstrated in mouse models of pulmonary fibrosis. Lung fibrosis induced by bleomycin or Ad-TGF-β treatment was highly compromised in Set9-deficient mice. These results uncover a complex regulatory interplay among multiple Smad7 modifications and highlight the possibility that protein methyltransferases may represent promising therapeutic targets for treating lung fibrosis. PMID:27292644

  10. miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Xiao, Jun; Meng, Xiao-Ming; Huang, Xiao R; Chung, Arthur Ck; Feng, Yu-Lin; Hui, David Sc; Yu, Cheuk-Man; Sung, Joseph Jy; Lan, Hui Y

    2012-06-01

    Loss of microRNA-29 (miR-29) is known to be a mechanism of transforming growth factor-β (TGF-β)-mediated pulmonary fibrosis, but the therapeutic implication of miR-29 for pulmonary fibrosis remains unexplored. The present study investigated whether miR-29 had therapeutic potential for lung disease induced by bleomycin in mice. In addition, the signaling mechanisms that regulated miR-29 expression were investigated in vivo and in vitro. We found that miR-29 was a downstream target gene of Smad3 and negatively regulated by TGF-β/Smad signaling in fibrosis. This was evidenced by the findings that mice or pulmonary fibroblasts null for Smad3 were protected against bleomycin or TGF-β1-induced loss of miR-29 along with fibrosis in vivo and in vitro. Interestingly, overexpression of miR-29 could in turn negatively regulated TGF-β and connective tissue growth factor (CTGF) expression and Smad3 signaling. Therefore, Sleeping Beauty (SB)-mediated miR-29 gene transfer into normal and diseased lung tissues was capable of preventing and treating pulmonary fibrosis including inflammatory macrophage infiltration induced by bleomycin in mice. In conclusion, miR-29 is negatively regulated by TGF-β/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis. PMID:22395530

  11. Pulmonary fibrosis following pneumonia due to acute Legionnaires' disease. Clinical, ultrastructural, and immunofluorescent study.

    PubMed

    Chastre, J; Raghu, G; Soler, P; Brun, P; Basset, F; Gibert, C

    1987-01-01

    During a recent nosocomial outbreak, 20 critically ill patients with acute Legionnaires' disease were admitted to the intensive care unit of Hopital Bichat, Paris. Pulmonary specimens were obtained at surgery or immediately after death in 12 patients and were examined by light, immunofluorescent, and electron microscopy. Five of these 12 patients showed evidence of pulmonary fibrosis. In all of these five patients, infection with Legionella pneumophila was evidenced by bacteriologic methods, and other diseases known to cause fibrosis were excluded. The condition of four patients deteriorated rapidly with respiratory failure, and they died with pulmonary fibrosis. Only one patient finally recovered but was left with pulmonary sequelae. Two distinctive morphologic patterns were observed, one in which interstitial fibrosis was predominant and one in which intra-alveolar organization and fibrosis were also present. The alveolar epithelial lining and the basement membranes were disrupted in all patients, as evidenced by ultrastructural observations and by immunofluorescent studies showing gaps in the distribution of type 4 collagen and laminin. Types 1 and 3 collagen accumulated in areas corresponding to thickened interstitium and intra-alveolar fibrosis. Thus, some patients who survive the acute pneumonia of Legionnaires' disease may develop pulmonary fibrosis, and this process may lead to functional impairment or death despite prompt and appropriate treatment. PMID:3539546

  12. Pathological and radiological correlation in an autopsy case of combined pulmonary fibrosis and emphysema

    PubMed Central

    Karata, Hiroki; Tanaka, Tomonori; Egashira, Ryoko; Tabata, Kazuhiro; Otani, Kyoko; Hayashi, Ryuji; Hori, Takashi; Fukuoka, Junya

    2015-01-01

    We report an educational autopsy case of combined pulmonary fibrosis and emphysema. Radiological patterns of the upper lung were considered as mostly emphysema, but pathological observation revealed significant interstitial fibrosis of usual interstitial pneumonia as a major pathology. The patient eventually developed acute exacerbation of background interstitial pneumonia. Careful radiological and pathological correlation of the current case indicates that regions with distal acinar emphysema on computed tomography image may possess histologically marked dense fibrosis of lethal interstitial pneumonia. PMID:26185436

  13. 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…

  14. Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

    PubMed Central

    Henderson, William R.; Chi, Emil Y.; Ye, Xin; Nguyen, Cu; Tien, Ying-tzang; Zhou, Beiyun; Borok, Zea; Knight, Darryl A.; Kahn, Michael

    2010-01-01

    Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a ravaging condition of progressive lung scarring and destruction. Anti-inflammatory therapies including corticosteroids have limited efficacy in this ultimately fatal disorder. An important unmet need is to identify new agents that interact with key molecular pathways involved in the pathogenesis of pulmonary fibrosis to prevent progression or reverse fibrosis in these patients. Because aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs of patients with IPF, we have targeted this pathway for intervention in pulmonary fibrosis using ICG-001, a small molecule that specifically inhibits T-cell factor/β-catenin transcription in a cyclic AMP response-element binding protein binding protein (CBP)-dependent fashion. ICG-001 selectively blocks the β-catenin/CBP interaction without interfering with the β-catenin/p300 interaction. We report here that ICG-001 (5 mg/kg per day) significantly inhibits β-catenin signaling and attenuates bleomycin-induced lung fibrosis in mice, while concurrently preserving the epithelium. Administration of ICG-001 concurrent with bleomycin prevents fibrosis, and late administration is able to reverse established fibrosis and significantly improve survival. Because no effective treatment for IPF exists, selective inhibition of Wnt/β-catenin-dependent transcription suggests a potential unique therapeutic approach for pulmonary fibrosis. PMID:20660310

  15. 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. PMID:25919965

  16. 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. PMID:24011020

  17. Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis.

    PubMed

    Sisson, Thomas H; Ajayi, Iyabode O; Subbotina, Natalya; Dodi, Amos E; Rodansky, Eva S; Chibucos, Lauren N; Kim, Kevin K; Keshamouni, Venkateshwar G; White, Eric S; Zhou, Yong; Higgins, Peter D R; Larsen, Scott D; Neubig, Richard R; Horowitz, Jeffrey C

    2015-04-01

    Myofibroblasts are crucial to the pathogenesis of tissue fibrosis. Their formation of stress fibers results in the release of myocardin-related transcription factor (MRTF), a transcriptional coactivator of serum response factor (SRF). MRTF-A (Mkl1)-deficient mice are protected from lung fibrosis. We hypothesized that the SRF/MRTF pathway inhibitor CCG-203971 would modulate myofibroblast function in vitro and limit lung fibrosis in vivo. Normal and idiopathic pulmonary fibrosis lung fibroblasts were treated with/without CCG-203971 (N-[4-chlorophenyl]-1-[3-(2-furanyl)benzoyl]-3-piperidine carboxamide) and/or Fas-activating antibody in the presence/absence of transforming growth factor (TGF)-β1, and apoptosis was assessed. In vivo studies examined the effect of therapeutically administered CCG-203971 on lung fibrosis in two distinct murine models of fibrosis induced by bleomycin or targeted type II alveolar epithelial injury. In vitro, CCG-203971 prevented nuclear localization of MRTF-A; increased the apoptotic susceptibility of normal and idiopathic pulmonary fibrosis fibroblasts; blocked TGF-β1-induced myofibroblast differentiation; and inhibited TGF-β1-induced expression of fibronectin, X-linked inhibitor of apoptosis, and plasminogen activator inhibitor-1. TGF-β1 did not protect fibroblasts or myofibroblasts from apoptosis in the presence of CCG-203971. In vivo, CCG-203971 significantly reduced lung collagen content in both murine models while decreasing alveolar plasminogen activator inhibitor-1 and promoting myofibroblast apoptosis. These data support a central role of the SRF/MRTF pathway in the pathobiology of lung fibrosis and suggest that its inhibition can help resolve lung fibrosis by promoting fibroblast apoptosis. PMID:25681733

  18. Inhibition of Myocardin-Related Transcription Factor/Serum Response Factor Signaling Decreases Lung Fibrosis and Promotes Mesenchymal Cell Apoptosis

    PubMed Central

    Sisson, Thomas H.; Ajayi, Iyabode O.; Subbotina, Natalya; Dodi, Amos E.; Rodansky, Eva S.; Chibucos, Lauren N.; Kim, Kevin K.; Keshamouni, Venkateshwar G.; White, Eric S.; Zhou, Yong; Higgins, Peter D.R.; Larsen, Scott D.; Neubig, Richard R.; Horowitz, Jeffrey C.

    2016-01-01

    Myofibroblasts are crucial to the pathogenesis of tissue fibrosis. Their formation of stress fibers results in the release of myocardin-related transcription factor (MRTF), a transcriptional coactivator of serum response factor (SRF). MRTF-A (Mkl1)-deficient mice are protected from lung fibrosis. We hypothesized that the SRF/MRTF pathway inhibitor CCG-203971 would modulate myofibroblast function in vitro and limit lung fibrosis in vivo. Normal and idiopathic pulmonary fibrosis lung fibroblasts were treated with/without CCG-203971 (N-[4-chlorophenyl]-1-[3-(2-furanyl)benzoyl]-3-piperidine carboxamide) and/or Fas-activating antibody in the presence/absence of transforming growth factor (TGF)-β1, and apoptosis was assessed. In vivo studies examined the effect of therapeutically administered CCG-203971 on lung fibrosis in two distinct murine models of fibrosis induced by bleomycin or targeted type II alveolar epithelial injury. In vitro, CCG-203971 prevented nuclear localization of MRTF-A; increased the apoptotic susceptibility of normal and idiopathic pulmonary fibrosis fibroblasts; blocked TGF-β1–induced myofibroblast differentiation; and inhibited TGF-β1–induced expression of fibronectin, X-linked inhibitor of apoptosis, and plasminogen activator inhibitor-1. TGF-β1 did not protect fibroblasts or myofibroblasts from apoptosis in the presence of CCG-203971. In vivo, CCG-203971 significantly reduced lung collagen content in both murine models while decreasing alveolar plasminogen activator inhibitor-1 and promoting myofibroblast apoptosis. These data support a central role of the SRF/MRTF pathway in the pathobiology of lung fibrosis and suggest that its inhibition can help resolve lung fibrosis by promoting fibroblast apoptosis. PMID:25681733

  19. Unplugging Mucus in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

    PubMed

    Mall, Marcus A

    2016-04-01

    Airway mucus obstruction is a key feature of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The thin layer of mucus that covers healthy airway surfaces has important protective functions in lung defense. However, excess mucus produces airflow obstruction and provides a nidus for bacterial infection and inflammation. Despite its importance in pathogenesis, understanding of the mechanisms underlying airway mucus obstruction, as well as therapeutic options, remain limited. Studies in the rare genetic disease CF identified airway surface dehydration due to cystic fibrosis transmembrane conductance regulator (CFTR) gene dysfunction as an important disease mechanism that may explain mucus stasis and plugging in a spectrum of muco-obstructive lung diseases, including COPD. This concept is supported by the phenotype of the β-epithelial Na(+) channel-transgenic mouse that exhibits airway surface dehydration and develops a spontaneous lung disease that shares key features with CF and COPD, such as airway mucus plugging, chronic neutrophilic inflammation, and structural lung damage. Furthermore, preclinical testing demonstrated that hydration strategies, including osmotically active hypertonic saline and preventive inhibition of the amiloride-sensitive epithelial Na(+) channel are effective in unplugging airways in this mouse model of chronic obstructive lung disease. On the other hand, genetic deletion of neutrophil elastase, a potent stimulus for mucus hypersecretion, reduced goblet cell metaplasia and mucin expression but had no effect on mucus obstruction in vivo. Collectively, these studies demonstrate that airway surface dehydration is sufficient to produce mucus obstruction even in the absence of mucus hypersecretion and support further clinical testing of hydrating agents as a promising therapeutic strategy to unplug mucus in CF and COPD. PMID:27115954

  20. Update on therapeutic management of idiopathic pulmonary fibrosis

    PubMed Central

    Tzouvelekis, Argyris; Bonella, Francesco; Spagnolo, Paolo

    2015-01-01

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

  1. Mechanical induction of cough in Idiopathic Pulmonary Fibrosis

    PubMed Central

    2011-01-01

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

  2. P311 promotes renal fibrosis via TGFβ1/Smad signaling

    PubMed Central

    Yao, Zhihui; Yang, Sisi; He, Weifeng; Li, Lian; Xu, Rui; Zhang, Xiaorong; Li, Haisheng; Zhan, Rixing; Sun, Wei; Tan, Jianglin; Zhou, Junyi; Luo, Gaoxing; Wu, Jun

    2015-01-01

    P311, a gene that was identified in 1993, has been found to have diverse biological functions in processes such as cell proliferation, migration and differentiation. However, its role in fibrosis is unknown. We previously observed that P311 is highly expressed in skin hypertrophic scars. In this study, P311 over-expression was detected in a subset of tubular epithelial cells in clinical biopsy specimens of renal fibrosis; this over-expression, was found concurrent with α-smooth muscle actin (α-SMA) and transforming growth factor beta1 (TGFβ1) expression. Subsequently, these results were verified in a mouse experimental renal fibrosis model induced by unilateral ureteral obstruction. The interstitial deposition of collagen, α-SMA and TGF-β1 expression, and macrophage infiltration were dramatically decreased when P311 was knocked out. Moreover, TGFβ/Smad signaling had a critical effect on the promotion of renal fibrosis by P311. In conclusion, this study demonstrate that P311 plays a key role in renal fibrosis via TGFβ1/Smad signaling, which could be a novel target for the management of renal fibrosis. PMID:26616407

  3. Idiopathic pulmonary fibrosis: New insights to functional characteristics at diagnosis

    PubMed Central

    Cortes-Telles, Arturo; Forkert, Lutz; O’Donnell, Denis E; Morán-Mendoza, Onofre

    2014-01-01

    BACKGROUND: The lung function of patients with idiopathic pulmonary fibrosis (IPF) has not been characterized in detail. OBJECTIVE: To characterize the heterogeneous physiological abnormalities that exist in patients with IPF during their initial clinical evaluation. METHODS: Lung function tests from 93 patients, performed within six months of the initial diagnosis of IPF, were obtained from a referral pulmonary function laboratory at a tertiary care hospital in Canada. A restrictive pattern was defined as total lung capacity (TLC) <95th percentile of predicted value. Patients with obstructive lung disease, lung cancer, emphysema and other restrictive lung diseases were excluded. RESULTS: On diagnosis, 73% of patients with IPF had a restrictive pattern, with a mean TLC of 72% of predicted. Mean forced vital capacity (FVC) was 71% and 44% of patients had an FVC <95th percentile. Mean diffusing capacity for carbon monoxide (DLco) was 60% and DLco/alveolar volume (VA) 92% of predicted. Increased severity of restriction – based on TLC – was associated with lower DLco (74% of predicted in mild restriction and 39% of predicted in severe restriction) and higher forced expiratory volume in 1 s (FEV1)/FVC ratio (82% of predicted in mild restriction and 90% of predicted in severe restriction) but not with age (76 years in mild restriction and 69 years in severe restriction). Regardless of severity of restriction, the average DLco/VA (≥86% of predicted) remained within normal limits. CONCLUSIONS: One in four patients with IPF had normal TLC and more than one-half had a normal FVC during initial evaluation. As the severity of the restriction increased, FEV1/FVC increased, DLco decreased but DLco/VA remained normal. PMID:24712014

  4. Induction of pulmonary fibrosis by cerium oxide nanoparticles

    PubMed Central

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

    2015-01-01

    Cerium compounds have been used as a diesel engine catalyst to lower the mass of diesel exhaust particles, but are emitted as cerium oxide (CeO2) nanoparticles in the diesel exhaust. In a previous study, we have demonstrated a wide range of CeO2-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 CeO2 in a rat model at various time points up to 84 days post-exposure. Male Sprague Dawley rats were exposed to CeO2 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 CeO2 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. CeO2 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 CeO2 and euthanized at 28 days post-exposure. Collectively, our studies show that CeO2 induced fibrotic lung injury in rats, suggesting it may cause potential health effects. PMID:22613087

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

    PubMed

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

    2016-08-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. The development of pulmonary hypertension (PH) is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced BMPR2 expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3, demonstrating reduced BMPR2 signaling and elevated TGF-β activity in IPF. In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 expression compared with control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2. We also demonstrate that isolated bone marrow-derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with immunohistochemistry showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of BMPR2 mediated by a collection of miRs induced by IL6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF. PMID:27317687

  6. Latent cytomegalovirus infection exacerbates experimental pulmonary fibrosis by activating TGF-β1.

    PubMed

    Li, Yonghuai; Gao, Jian; Wang, Guoliang; Fei, Guanghe

    2016-08-01

    The aim of the present study was to investigate the hypotheses that cytomegalovirus (CMV) may trigger idiopathic pulmonary fibrosis (IPF) in a susceptible host and/or that the presence of CMV may alter IPF in response to a well-defined trigger of pulmonary fibrosis. A mouse model of murine CMV (MCMV) infection was established, and the mice were divided into a control group, bleomycin group and an MCMV+bleomycin group. Changes in the weights of the mice were determined in the three groups. Pulmonary fibrosis was detected using a histopathological method. The activity of transforming growth factor (TGF)‑β1 was measured, and the levels of E‑cadherin, Vimentin and phosphorylated (phospho)‑small mothers against decapentaplegic (SMAD)2 were determined using western blot analysis. MCMV was found to invade the lungs, however, it did not cause pulmonary fibrosis. The progression of fibrosis in the mice treated with MCMV+bleomycin was more rapid, compared with that in the control mice. The protein levels of Vimentin and phospho-SMAD2 were upregulated, whereas the level of E‑cadherin was downregulated in the MCMV+bleomycin group,. The results suggested that latent MCMV infection aggravated pulmonary fibrosis in the mouse model, possibly through the activation of TGF-β1. PMID:27279470

  7. Chronic pulmonary interstitial fibrosis in a blue-fronted Amazon parrot (Amazona aestiva aestiva).

    PubMed

    Amann, Olga; Kik, Marja J L; Passon-Vastenburg, Maartje H A C; Westerhof, Ineke; Lumeij, Johannes T; Schoemaker, Nico J

    2007-03-01

    A 30-yr-old blue-fronted Amazon parrot (Amazon aestiva aestiva) was presented to the clinic with a history of sneezing more often during the last 2 mo. Physical examination revealed only a mild nasal discharge. Complete hematologic and plasma biochemical examination showed no abnormalities. Computerized tomography (CT) of the complete bird showed generalized lung alterations consistent with lung fibrosis. Two lung biopsies were taken. The results of the histologic examination of the biopsies confirmed the tentative CT diagnosis of pulmonary interstitial fibrosis. To our knowledge this is the first reported case of chronic pulmonary interstitial fibrosis diagnosed by means of a lung biopsy in an avian species. The histologic characteristics are discussed and compared with those of human idiopathic pulmonary fibrosis. PMID:17461284

  8. 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

  9. Pharmacologic Therapies for Idiopathic Pulmonary Fibrosis, Past and Future

    PubMed Central

    Staitieh, Bashar S; Renzoni, Elisabetta A; Veeraraghavan, Srihari

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a severe, progressive fibrotic disease of the lung of unknown etiology that affects approximately 150,000 patients in the United States. It carries a median survival of two to three years, but clinical course can vary markedly from patient to patient. There has been no established treatment for IPF, but recent advances in coordinated clinical trials through groups such as IPFnet and academia-industry partnerships have allowed this relatively rare disease to be studied in much greater depth. Historically, the default therapy for IPF was a combination of prednisone, N-acetylcysteine, and azathioprine, but recent trials have shown that this regimen actually increases mortality. An enormous body of work in recent years, spanning the bench to the bedside, has radically altered our understanding of the molecular mechanisms underlying IPF. Newer modalities, particularly those involving monoclonal antibodies targeted at specific pathways known to contribute to the fibrotic process, have generated a great deal of excitement in the field, and recent clinical trials on therapies such as pirfenidone and nintedanib herald a new era in targeted IPF therapies. PMID:25613169

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

    PubMed

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

    2016-05-01

    The disease course in idiopathic pulmonary fibrosis (IPF) is variable, but patients experience a progressive decline in lung function and increased symptom burden leading to death. Little is known about the patients' experience and their needs during the disease course or about the burden on family caregivers. Both patients and family caregivers face an altered life as the disease progresses. The aim of our study was to increase knowledge of life with IPF for patients and family caregivers.This study had a qualitative descriptive design using in-depth dyadic interviews with IPF patients (n=25) and family caregivers (n=24). We used the five-step analysis from the framework method and analysed the data on three levels: the patient, the family caregivers and couple level.The following six themes emerged as the main results: information and disclosure, reactional dyssynchrony, perpetual vigilance, emotional ambivalence, gradual and tacit role shift, and adapted coping strategies.Our findings suggest that IPF patients need information at the time of diagnosis, but some issues should be paced as the disease progresses. A palliation plan was demanded by patients and their caregivers. Further efforts are required to provide palliative care to IPF patients starting at the time of diagnosis. PMID:26846831

  11. UK asbestos imports and mortality due to idiopathic pulmonary fibrosis

    PubMed Central

    Wiggans, R. E.; Young, C.; Fishwick, D.

    2016-01-01

    Background Previous studies have demonstrated that the rising mortality due to mesothelioma and asbestosis can be predicted from historic asbestos usage. Mortality due to idiopathic pulmonary fibrosis (IPF) is also rising, without any apparent explanation. Aims To compare mortality due to these conditions and examine the relationship between mortality and national asbestos imports. Methods Mortality data for IPF and asbestosis in England and Wales were available from the Office for National Statistics. Data for mesothelioma deaths in England and Wales and historic UK asbestos import data were available from the Health & Safety Executive. The numbers of annual deaths due to each condition were plotted separately by gender, against UK asbestos imports 48 years earlier. Linear regression models were constructed. Results For mesothelioma and IPF, there was a significant linear relationship between the number of male and female deaths each year and historic UK asbestos imports. For asbestosis mortality, a similar relationship was found for male but not female deaths. The annual numbers of deaths due to asbestosis in both sexes were lower than for IPF and mesothelioma. Conclusions The strength of the association between IPF mortality and historic asbestos imports was similar to that seen in an established asbestos-related disease, i.e. mesothelioma. This finding could in part be explained by diagnostic difficulties in separating asbestosis from IPF and highlights the need for a more accurate method of assessing lifetime occupational asbestos exposure. PMID:26511746

  12. 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

  13. Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis

    PubMed Central

    Calfee, Carolyn S.; Wolters, Paul J.; Song, Jin Woo; Hong, Sang-Bum; Brady, Sandra; Ishizaka, Akitoshi; Jones, Kirk D.; King, Talmadge E.; Matthay, Michael A.; Kim, Dong Soon

    2010-01-01

    Little is known about the pathobiology of acute exacerbation of idiopathic pulmonary fibrosis (IPF), a condition that shares clinical and histopathological features with acute lung injury. Plasma biomarkers have been well studied in acute lung injury and have provided insight into the underlying disease mechanism. The objective of this study was to determine the plasma biomarker profile of acute exacerbation of IPF and compare this profile with that of stable IPF and acute lung injury. Plasma was collected from patients with stable IPF, acute exacerbation of IPF, and acute lung injury for measurement of biomarkers of cellular activity/injury (receptor for advanced glycation endproducts, surfactant protein D, KL-6, von Willebrand factor), systemic inflammation (IL-6), and coagulation/fibrinolysis (protein C, thrombomodulin, plasminogen activator inhibitor-1). Plasma from patients with acute exacerbation of IPF showed significant elevations in markers of type II alveolar epithelial cell injury and/or proliferation, endothelial cell injury, and coagulation. This profile differed from the biomarker profile in patients with acute lung injury. These findings support the hypothesis that type II alveolar epithelial cells are centrally involved in the pathobiology of acute exacerbation of IPF. Furthermore, they suggest that acute exacerbation of IPF has a distinct plasma biomarker profile from that of acute lung injury. PMID:20418386

  14. Idiopathic pulmonary fibrosis: can cell mediated immunity markers predict clinical outcome?

    PubMed Central

    Meliconi, R; Lalli, E; Borzì, R M; Sturani, C; Galavotti, V; Gunella, G; Miniero, R; Facchini, A; Gasbarrini, G

    1990-01-01

    Most of the cells found in lung parenchyma in patients with idiopathic pulmonary fibrosis are activated T lymphocytes and macrophages. The serum levels of three markers of cell mediated immunity were measured in 20 patients with idiopathic pulmonary fibrosis, in 20 normal subjects and in 12 patients with sarcoidosis to evaluate their clinical and prognostic significance in idiopathic pulmonary fibrosis. The three markers were: soluble CD8 (from activated suppressor-cytotoxic lymphocytes), soluble interleukin (IL)-2 receptors (from activated T cells and macrophages), and neopterin (from activated macrophages). Patients with idiopathic pulmonary fibrosis had higher levels of all three markers than the control subjects. Soluble IL-2 receptor and neopterin tended to be lower (though not significantly) in patients with idiopathic pulmonary fibrosis than in those with sarcoidosis, whereas soluble CD8 was similar in the two groups of patients. No correlation was found between soluble IL-2 receptors or soluble CD8 and the clinical, radiological, and physiological measures of disease activity or with clinical outcome (after a mean follow up of 23 months). Tumour necrosis factor levels were also determined. Only 30% of patients with idiopathic pulmonary fibrosis or sarcoidosis had detectable circulating tumour necrosis factor; these patients had a lower percentage of bronchoalveolar lavage fluid neutrophils in their lavage fluid. Tumour necrosis factor levels did not correlate with clinical measures of severity or outcome. Thus our data support the hypothesis that cell mediated alveolitis occurs in idiopathic pulmonary fibrosis. They do not, however, provide evidence to support the use of these markers of cell mediated immunity to monitor the clinical course in these patients. PMID:2118691

  15. Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis

    PubMed Central

    Weng, Tingting; Poth, Jens M.; Karmouty-Quintana, Harry; Garcia-Morales, Luis J.; Melicoff, Ernestina; Luo, Fayong; Chen, Ning-yuan; Evans, Christopher M.; Bunge, Raquel R.; Bruckner, Brian A.; Loebe, Matthias; Volcik, Kelly A.; Eltzschig, Holger K.

    2014-01-01

    Rationale: Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease with few therapeutic options. Apoptosis of alveolar epithelial cells, followed by abnormal tissue repair characterized by hyperplastic epithelial cell formation, is a pathogenic process that contributes to the progression of pulmonary fibrosis. However, the signaling pathways responsible for increased proliferation of epithelial cells remain poorly understood. Objectives: To investigate the role of deoxycytidine kinase (DCK), an important enzyme for the salvage of deoxynucleotides, in the progression of pulmonary fibrosis. Methods: DCK expression was examined in the lungs of patients with IPF and mice exposed to bleomycin. The regulation of DCK expression by hypoxia was studied in vitro and the importance of DCK in experimental pulmonary fibrosis was examined using a DCK inhibitor and alveolar epithelial cell-specific knockout mice. Measurements and Main Results: DCK was elevated in hyperplastic alveolar epithelial cells of patients with IPF and in mice exposed to bleomycin. Increased DCK was localized to cells associated with hypoxia, and hypoxia directly induced DCK in alveolar epithelial cells in vitro. Hypoxia-induced DCK expression was abolished by silencing hypoxia-inducible factor 1α and treatment of bleomycin-exposed mice with a DCK inhibitor attenuated pulmonary fibrosis in association with decreased epithelial cell proliferation. Furthermore, DCK expression, and proliferation of epithelial cells and pulmonary fibrosis was attenuated in mice with conditional deletion of hypoxia-inducible factor 1α in the alveolar epithelium. Conclusions: Our findings suggest that the induction of DCK after hypoxia plays a role in the progression of pulmonary fibrosis by contributing to alveolar epithelial cell proliferation. PMID:25358054

  16. Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis

    PubMed Central

    Warsinske, Hayley C.; Wheaton, Amanda K.; Kim, Kevin K.; Linderman, Jennifer J.; Moore, Bethany B.; Kirschner, Denise E.

    2016-01-01

    Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited with enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGF-β1 receptor ligand signaling in fibroblasts. PGE2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. Thus, a two-hit therapeutic intervention strategy

  17. Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis

    DOE PAGESBeta

    Warsinske, Hayley C.; Wheaton, Amanda K.; Kim, Kevin K.; Linderman, Jennifer J.; Moore, Bethany B.; Kirschner, Denise E.

    2016-06-23

    Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited withmore » enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGFβ1 receptor ligand signaling in fibroblasts. PGE2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. In conclusion, a two-hit therapeutic

  18. Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis.

    PubMed

    Warsinske, Hayley C; Wheaton, Amanda K; Kim, Kevin K; Linderman, Jennifer J; Moore, Bethany B; Kirschner, Denise E

    2016-01-01

    Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited with enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGF-β1 receptor ligand signaling in fibroblasts. PGE2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. Thus, a two-hit therapeutic intervention strategy

  19. Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis.

    PubMed

    Booth, Adam J; Wood, Sherri C; Cornett, Ashley M; Dreffs, Alyssa A; Lu, Guanyi; Muro, Andrés F; White, Eric S; Bishop, D Keith

    2012-03-01

    Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA(-/-)) and wild-type (WT) mice. While EDA(-/-) mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA(-/-) mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which enhance

  20. CD4(+)CD25(hi)Foxp3(+) Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis.

    PubMed

    Birjandi, Shirin Z; Palchevskiy, Vyacheslav; Xue, Ying Ying; Nunez, Stefanie; Kern, Rita; Weigt, S Sam; Lynch, Joseph P; Chatila, Talal A; Belperio, John A

    2016-08-01

    Idiopathic pulmonary fibrosis is a fatal lung disease with a median survival of 2 to 5 years. A decade of studies has downplayed inflammation contributing to its pathogenesis. However, these studies preceded the discovery of regulatory T cells (Tregs) and all of their functions. On the basis of human studies demonstrating Tregs can decrease graft-versus-host disease and vasculitides, there is consideration of their use to treat idiopathic pulmonary fibrosis. We hypothesized that Treg therapy would attenuate the fibroplasia involved in a preclinical murine model of pulmonary fibrosis. IL-2 complex was used in vivo to expand CD4(+)CD25(hi)Foxp3(+) cells in the lung during intratracheal bleomycin challenge; however, this unexpectedly led to an increase in lung fibrosis. More important, this increase in fibrosis was a lymphocyte-dependent process. We corroborated these results using a CD4(+)CD25(hi)Foxp3(+) cellular-based therapy. Mechanistically, we demonstrated that CD4(+)CD25(hi)Foxp3(+) cells undergo alterations during bleomycin challenge and the IL-2 complex had no effect on profibrotic (eg, transforming growth factor-β) or type 17 immune response cytokines; however, there was a marked down-regulation of the type 1 and augmentation of the type 2 immune response cytokines from the lungs. Collectively, our animal studies show that a specific lung injury can induce Treg alterations, which can augment pulmonary fibrosis. PMID:27317904

  1. PGD2-CRTH2 pathway promotes tubulointerstitial fibrosis.

    PubMed

    Ito, Hideyuki; Yan, Xiaoxiang; Nagata, Nanae; Aritake, Kosuke; Katsumata, Yoshinori; Matsuhashi, Tomohiro; Nakamura, Masataka; Hirai, Hiroyuki; Urade, Yoshihiro; Asano, Koichiro; Kubo, Masato; Utsunomiya, Yasunori; Hosoya, Tatsuo; Fukuda, Keiichi; Sano, Motoaki

    2012-11-01

    Urinary excretion of lipocalin-type PGD(2) synthase (L-PGDS), which converts PG H(2) to PGD(2), increases in early diabetic nephropathy. In addition, L-PGDS expression in the tubular epithelium increases in adriamycin-induced nephropathy, suggesting that locally produced L-PGDS may promote the development of CKD. In this study, we found that L-PGDS-derived PGD(2) contributes to the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes. In a mouse model, the tubular epithelium synthesized L-PGDS de novo after unilateral ureteral obstruction (UUO). L-PGDS-knockout mice and CRTH2-knockout mice both exhibited less renal fibrosis, reduced infiltration of Th2 lymphocytes into the cortex, and decreased production of the Th2 cytokines IL-4 and IL-13. Furthermore, oral administration of a CRTH2 antagonist, beginning 3 days after UUO, suppressed the progression of renal fibrosis. Ablation of IL-4 and IL-13 also ameliorated renal fibrosis in the UUO kidney. Taken together, these data suggest that blocking the activation of CRTH2 by PGD(2) might be a strategy to slow the progression of renal fibrosis in CKD. PMID:22997255

  2. Transcription factor ets-2 plays an important role in the pathogenesis of pulmonary fibrosis.

    PubMed

    Baran, Christopher P; Fischer, Sara N; Nuovo, Gerard J; Kabbout, Mohamed N; Hitchcock, Charles L; Bringardner, Benjamin D; McMaken, Sara; Newland, Christie A; Cantemir-Stone, Carmen Z; Phillips, Gary S; Ostrowski, Michael C; Marsh, Clay B

    2011-11-01

    Ets-2 is a ubiquitous transcription factor activated after phosphorylation at threonine-72. Previous studies highlighted the importance of phosphorylated ets-2 in lung inflammation and extracellular matrix remodeling, two pathways involved in pulmonary fibrosis. We hypothesized that phosphorylated ets-2 played an important role in pulmonary fibrosis, and we sought to determine the role of ets-2 in its pathogenesis. We challenged ets-2 (A72/A72) transgenic mice (harboring a mutated form of ets-2 at phosphorylation site threonine-72) and ets-2 (wild-type/wild-type [WT/WT]) control mice with sequential intraperitoneal injections of bleomycin, followed by quantitative measurements of lung fibrosis and inflammation and primary cell in vitro assays. Concentrations of phosphorylated ets-2 were detected via the single and dual immunohistochemical staining of murine lungs and lung sections from patients with idiopathic pulmonary fibrosis. Ets-2 (A72/A72) mice were protected from bleomycin-induced pulmonary fibrosis, compared with ets-2 (WT/WT) mice. This protection was characterized by decreased lung pathological abnormalities and the fibrotic gene expression of Type I collagen, Type III collagen, α-smooth muscle actin, and connective tissue growth factor. Immunohistochemical staining of lung sections from bleomycin-treated ets-2 (WT/WT) mice and from patients with idiopathic pulmonary fibrosis demonstrated increased staining of phosphorylated ets-2 that colocalized with Type I collagen expression and to fibroblastic foci. Lastly, primary lung fibroblasts from ets-2 (A72/A72) mice exhibited decreased expression of Type I collagen in response to stimulation with TGF-β, compared with fibroblasts from ets-2 (WT/WT) mice. These data indicate the importance of phosphorylated ets-2 in the pathogenesis of pulmonary fibrosis through the expression of Type I collagen and (myo)fibroblast activation. PMID:21562315

  3. 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

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

    PubMed

    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. Transcription Factor ets-2 Plays an Important Role in the Pathogenesis of Pulmonary Fibrosis

    PubMed Central

    Baran, Christopher P.; Fischer, Sara N.; Nuovo, Gerard J.; Kabbout, Mohamed N.; Hitchcock, Charles L.; Bringardner, Benjamin D.; McMaken, Sara; Newland, Christie A.; Cantemir-Stone, Carmen Z.; Phillips, Gary S.; Ostrowski, Michael C.

    2011-01-01

    Ets-2 is a ubiquitous transcription factor activated after phosphorylation at threonine-72. Previous studies highlighted the importance of phosphorylated ets-2 in lung inflammation and extracellular matrix remodeling, two pathways involved in pulmonary fibrosis. We hypothesized that phosphorylated ets-2 played an important role in pulmonary fibrosis, and we sought to determine the role of ets-2 in its pathogenesis. We challenged ets-2 (A72/A72) transgenic mice (harboring a mutated form of ets-2 at phosphorylation site threonine-72) and ets-2 (wild-type/wild-type [WT/WT]) control mice with sequential intraperitoneal injections of bleomycin, followed by quantitative measurements of lung fibrosis and inflammation and primary cell in vitro assays. Concentrations of phosphorylated ets-2 were detected via the single and dual immunohistochemical staining of murine lungs and lung sections from patients with idiopathic pulmonary fibrosis. Ets-2 (A72/A72) mice were protected from bleomycin-induced pulmonary fibrosis, compared with ets-2 (WT/WT) mice. This protection was characterized by decreased lung pathological abnormalities and the fibrotic gene expression of Type I collagen, Type III collagen, α–smooth muscle actin, and connective tissue growth factor. Immunohistochemical staining of lung sections from bleomycin-treated ets-2 (WT/WT) mice and from patients with idiopathic pulmonary fibrosis demonstrated increased staining of phosphorylated ets-2 that colocalized with Type I collagen expression and to fibroblastic foci. Lastly, primary lung fibroblasts from ets-2 (A72/A72) mice exhibited decreased expression of Type I collagen in response to stimulation with TGF-β, compared with fibroblasts from ets-2 (WT/WT) mice. These data indicate the importance of phosphorylated ets-2 in the pathogenesis of pulmonary fibrosis through the expression of Type I collagen and (myo)fibroblast activation. PMID:21562315

  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

    2016-01-01

    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

  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. Vascular effects of sildenafil in patients with pulmonary fibrosis and pulmonary hypertension: an ex vivo/in vitro study.

    PubMed

    Milara, Javier; Escrivá, Juan; Ortiz, José Luis; Juan, Gustavo; Artigues, Enrique; Morcillo, Esteban; Cortijo, Julio

    2016-06-01

    Sildenafil improves the 6-min walking distance in patients with idiopathic pulmonary fibrosis (IPF) and right-sided ventricular systolic dysfunction.We analysed the previously unexplored role of sildenafil on vasoconstriction and remodelling of pulmonary arteries from patients with IPF and pulmonary hypertension (PH) ex vivo Pulmonary arteries from 18 donors without lung disease, nine IPF, eight PH+IPF and four PH patients were isolated to measure vasodilator and anti-contractile effects of sildenafil in isometric organ bath. Ventilation/perfusion was explored in an animal model of bleomycin lung fibrosis.Sildenafil relaxed serotonin (5-HT) pre-contracted pulmonary arteries in healthy donors and IPF patients and, to a lesser extent, in PH+IPF and PH. Sildenafil inhibited 5-HT dose-response contraction curve mainly in PH+IPF and PH, but not in healthy donors. Sildenafil did not impair the ventilation/perfusion mismatching induced by bleomycin. Pulmonary arteries from PH+IPF patients showed a marked expression of phosphodiesterse-5 and extracellular matrix components. Sildenafil inhibited pulmonary artery endothelial and smooth muscle cell to mesenchymal transition by inhibition of extracellular regulated kinases 1 and 2 (ERK1/2) and SMAD3 phosphorylation.These results suggest an absence of direct relaxant effect and a prominent anti-contractile and anti-remodelling role of sildenafil in PH+IPF pulmonary arteries that could explain the beneficial effects of sildenafil in IPF with PH phenotype. PMID:27009174

  9. Therapeutic Benefits of Young, But Not Old, Adipose-Derived Mesenchymal Stem Cells in a Chronic Mouse Model of Bleomycin-Induced Pulmonary Fibrosis

    PubMed Central

    Tashiro, Jun; Elliot, Sharon J.; Gerth, David J.; Xia, Xiaomei; Pereira-Simon, Simone; Choi, Rhea; Catanuto, Paola; Shahzeidi, Shahriar; Toonkel, Rebecca L.; Shah, Rahil H.; El Salem, Fadi; Glassberg, Marilyn K.

    2016-01-01

    The observation that pulmonary inflammatory lesions and bleomycin (BLM)-induced pulmonary fibrosis spontaneously resolve in young mice, while remaining irreversible in aged mice, suggests that impairment of pulmonary regeneration and repair is associated with aging. Since mesenchymal stem cells (MSCs) may promote repair following injury, we postulated that differences in MSCs from aged mice may underlie post-injury fibrosis in aging. The potential for young-donor MSCs to inhibit BLM-induced pulmonary fibrosis in aged male mice (>22 months) has not been studied. Adipose-derived MSCs (ASCs) from young (4-month) and old (22-month) male mice were infused 1-day following intratracheal BLM administration. At 21-day sacrifice, aged BLM mice demonstrated lung fibrosis by Ashcroft score, collagen content, and αv-integrin mRNA expression. Lung tissue from aged BLM mice receiving young ASCs exhibited decreased fibrosis, matrix metalloproteinase (MMP)-2 activity, oxidative stress, and markers of apoptosis vs. BLM controls. Lung mRNA expression of TNFα was also decreased in aged BLM mice receiving young-donor ASCs vs. BLM controls. In contrast, old-donor ASC treatment in aged BLM mice did not reduce fibrosis and related markers. On examination of the cells, young-donor ASCs had decreased mRNA expression of MMP-2, insulin-like growth factor receptor, and AKT activation compared to old-donor ASCs. These results show that the BLM-induced pulmonary fibrosis in aged mice could be blocked by young-donor ASCs and that the mechanisms involve changes in collagen turnover and markers of inflammation. PMID:26432923

  10. Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis.

    PubMed

    Tashiro, Jun; Elliot, Sharon J; Gerth, David J; Xia, Xiaomei; Pereira-Simon, Simone; Choi, Rhea; Catanuto, Paola; Shahzeidi, Shahriar; Toonkel, Rebecca L; Shah, Rahil H; El Salem, Fadi; Glassberg, Marilyn K

    2015-12-01

    The observation that pulmonary inflammatory lesions and bleomycin (BLM)-induced pulmonary fibrosis spontaneously resolve in young mice, whereas remaining irreversible in aged mice suggests that impairment of pulmonary regeneration and repair is associated with aging. Because mesenchymal stem cells (MSCs) may promote repair after injury, we postulated that differences in MSCs from aged mice may underlie postinjury fibrosis in aging. The potential for young-donor MSCs to inhibit BLM-induced pulmonary fibrosis in aged male mice (>22 months) has not been studied. Adipose-derived MSCs (ASCs) from young (4 months) and old (22 months) male mice were infused 1 day after intratracheal BLM administration. At 21-day sacrifice, aged BLM mice demonstrated lung fibrosis by Ashcroft score, collagen content, and α(v)-integrin messenger RNA (mRNA) expression. Lung tissue from aged BLM mice receiving young ASCs exhibited decreased fibrosis, matrix metalloproteinase (MMP)-2 activity, oxidative stress, and markers of apoptosis vs BLM controls. Lung mRNA expression of tumor necrosis factor-alpha was also decreased in aged BLM mice receiving young-donor ASCs vs BLM controls. In contrast, old-donor ASC treatment in aged BLM mice did not reduce fibrosis and related markers. On examination of the cells, young-donor ASCs had decreased mRNA expression of MMP-2, insulin-like growth factor (IGF) receptor, and protein kinase B (AKT) activation compared with old-donor ASCs. These results show that the BLM-induced pulmonary fibrosis in aged mice could be blocked by young-donor ASCs and that the mechanisms involve changes in collagen turnover and markers of inflammation. PMID:26432923

  11. 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

  12. Inflammatory response mechanisms exacerbating hypoxemia in coexistent pulmonary fibrosis and sleep apnea.

    PubMed

    Adegunsoye, Ayodeji; Balachandran, Jay

    2015-01-01

    Mediators of inflammation, oxidative stress, and chemoattractants drive the hypoxemic mechanisms that accompany pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis commonly have obstructive sleep apnea, which potentiates the hypoxic stimuli for oxidative stress, culminating in systemic inflammation and generalized vascular endothelial damage. Comorbidities like pulmonary hypertension, obesity, gastroesophageal reflux disease, and hypoxic pulmonary vasoconstriction contribute to chronic hypoxemia leading to the release of proinflammatory cytokines that may propagate clinical deterioration and alter the pulmonary fibrotic pathway. Tissue inhibitor of metalloproteinase (TIMP-1), interleukin- (IL-) 1α, cytokine-induced neutrophil chemoattractant (CINC-1, CINC-2α/β), lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG-1), macrophage inflammatory protein- (MIP-) 1α, MIP-3α, and nuclear factor- (NF-) κB appear to mediate disease progression. Adipocytes may induce hypoxia inducible factor (HIF) 1α production; GERD is associated with increased levels of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and tumor necrosis factor alpha (TNF-α); pulmonary artery myocytes often exhibit increased cytosolic free Ca2+. Protein kinase C (PKC) mediated upregulation of TNF-α and IL-1β also occurs in the pulmonary arteries. Increased understanding of the inflammatory mechanisms driving hypoxemia in pulmonary fibrosis and obstructive sleep apnea may potentiate the identification of appropriate therapeutic targets for developing effective therapies. PMID:25944985

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

    PubMed

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

    2016-05-01

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

  14. HIF-1α regulates EMT via the Snail and β-catenin pathways in paraquat poisoning-induced early pulmonary fibrosis.

    PubMed

    Zhu, Yong; Tan, Jiuting; Xie, Hui; Wang, Jinfeng; Meng, Xiaoxiao; Wang, Ruilan

    2016-04-01

    Paraquat (PQ) poisoning-induced pulmonary fibrosis is one of the primary causes of death in patients with PQ poisoning. Hypoxia-inducible factor-1α (HIF-1α) and epithelial-mesenchymal transition (EMT) are involved in the progression of pulmonary fibrosis. Snail and β-catenin are two other factors involved in promoting EMT. However, the relationship among HIF-1α, Snail and β-catenin in PQ poisoning-induced pulmonary fibrosis is not clear. Our research aimed to determine whether the regulation of HIF-1α in EMT occurs via the Snail and β-catenin pathways in PQ poisoning-induced pulmonary fibrosis. Sixty-six Sprague-Dawley rats were randomly and evenly divided into a control group and a PQ group. The PQ group was treated with an intragastric infusion of a 20% PQ solution (50 mg/kg) for 2, 6, 12, 24, 48 and 72 hrs. A549 and RLE-6TN cell lines were transfected with HIF-1α siRNA for 48 hrs before being exposed to PQ. Western blotting, real-time quantitative PCR, immunofluorescence, immunohistochemistry and other assays were used in our research. In vivo, the protein levels of HIF-1α and α-SMA were increased at 2 hrs and the level of ZO-1 (Zonula Occluden-1) was reduced at 12 hrs. In vitro, the transient transfection of HIF-1α siRNA resulted in a decrease in the degree of EMT. The expression levels of Snail and β-catenin were significantly reduced when HIF-α was silenced. These data demonstrate that EMT may be involved in PQ poisoning-induced pulmonary fibrosis and regulated by HIF-1α via the Snail and β-catenin pathways. Hypoxia-inducible factor-1α may be a therapeutic target for the treatment of PQ poisoning-induced pulmonary fibrosis. PMID:26781174

  15. Data on CUX1 isoforms in idiopathic pulmonary fibrosis lung and systemic sclerosis skin tissue sections.

    PubMed

    Ikeda, Tetsurou; Fragiadaki, Maria; Shi-Wen, Xu; Ponticos, Markella; Khan, Korsa; Denton, Christopher; Garcia, Patricia; Bou-Gharios, George; Yamakawa, Akio; Morimoto, Chikao; Abraham, David

    2016-09-01

    This data article contains complementary figures related to the research article entitled, "Transforming growth factor-β-induced CUX1 isoforms are associated with fibrosis in systemic sclerosis lung fibroblasts" (Ikeda et al. (2016) [2], http://dx.doi.org/10.1016/j.bbrep.2016.06.022), which presents that TGF-β increased CUX1 binding in the proximal promoter and enhancer of the COL1A2 and regulated COL1. Further, in the scleroderma (SSc) lung and diffuse alveolar damage lung sections, CUX1 localized within the α- smooth muscle actin (α-SMA) positive cells (Fragiadaki et al., 2011) [1], "High doses of TGF-beta potently suppress type I collagen via the transcription factor CUX1" (Ikeda et al., 2016) [2]. Here we show that CUX1 isoforms are localized within α-smooth muscle actin-positive cells in SSc skin and idiopathic pulmonary fibrosis (IPF) lung tissue sections. In particular, at the granular and prickle cell layers in the SSc skin sections, CUX1 and α-SMA are co-localized. In addition, at the fibrotic loci in the IPF lung tissue sections, CUX1 localized within the α-smooth muscle actin (α-SMA) positive cells. PMID:27583344

  16. Cartilage Oligomeric Matrix Protein in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Pandit, Kusum; Ben-Yehudah, Ahmi; Chu, Yanxia; Richards, Thomas; Sciurba, Joshua; Myerburg, Michael; Zhang, Yingze; Parwani, Anil V.; Gibson, Kevin F.; Kaminski, Naftali

    2013-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive and life threatening disease with median survival of 2.5–3 years. The IPF lung is characterized by abnormal lung remodeling, epithelial cell hyperplasia, myofibroblast foci formation, and extracellular matrix deposition. Analysis of gene expression microarray data revealed that cartilage oligomeric matrix protein (COMP), a non-collagenous extracellular matrix protein is among the most significantly up-regulated genes (Fold change 13, p-value <0.05) in IPF lungs. This finding was confirmed at the mRNA level by nCounter® expression analysis in additional 115 IPF lungs and 154 control lungs as well as at the protein level by western blot analysis. Immunohistochemical analysis revealed that COMP was expressed in dense fibrotic regions of IPF lungs and co-localized with vimentin and around pSMAD3 expressing cells. Stimulation of normal human lung fibroblasts with TGF-β1 induced an increase in COMP mRNA and protein expression. Silencing COMP in normal human lung fibroblasts significantly inhibited cell proliferation and negatively impacted the effects of TGF-β1 on COL1A1 and PAI1. COMP protein concentration measured by ELISA assay was significantly increased in serum of IPF patients compared to controls. Analysis of serum COMP concentrations in 23 patients who had prospective blood draws revealed that COMP levels increased in a time dependent fashion and correlated with declines in force vital capacity (FVC). Taken together, our results should encourage more research into the potential use of COMP as a biomarker for disease activity and TGF-β1 activity in patients with IPF. Hence, studies that explore modalities that affect COMP expression, alleviate extracellular matrix rigidity and lung restriction in IPF and interfere with the amplification of TGF-β1 signaling should be persuaded. PMID:24376648

  17. What We Know About the Pathogenesis of Idiopathic Pulmonary Fibrosis.

    PubMed

    Puglisi, S; Torrisi, S E; Giuliano, R; Vindigni, V; Vancheri, C

    2016-06-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause, occurring in adults, limited to the lungs and associated with the pathologic and radiologic pattern of usual interstitial pneumonia. Prognosis is poor, and most patients die of respiratory failure within 3 to 6 years from the onset of symptoms. Although our understanding of the pathogenesis of IPF has improved over the past two decades, the mechanisms responsible for this disorder have not been clearly defined. Aging is the single most important risk factor, but genetic, environmental, and diverse exogenous factors such as smoking, viral infections, chronic tissue injury (i.e., gastroesophageal reflux disease, traction injury) play contributory roles. In this review, we focus on pathogenetic mechanisms that we think are crucial for the initiation of the fibrotic process and for its progressive evolution. In the early stage of the disease, in the context of the permissive genetic background combined with the presence of specific risk factors, alveolar epithelial cells play a leading role. Subsequent evolution of the fibrotic process and its lethal progression is likely due to the abnormal tissue repair process that takes place in the lung and to the inability to counteract this process. In this phase of the disease, fibroblasts assume a crucial role. Current pharmacological treatment strategies for IPF have only modest value, principally by slowing the course of disease progression. Unfortunately, improvement or cure has not yet been achieved with pharmacological agents. The challenge for the future is to improve the comprehension of the mechanisms involved in the inception and evolution of IPF and their articulated interactions. This is fundamental not only to conceive and develop new drugs against this dreadful disease but also to apply different therapeutic approaches such as drug repositioning and personalized therapies in the management of IPF. PMID:27231860

  18. Promoting regular physical activity in pulmonary rehabilitation.

    PubMed

    Garcia-Aymerich, Judith; Pitta, Fabio

    2014-06-01

    Patients with chronic respiratory diseases are usually physically inactive, which is an important negative prognostic factor. Therefore, promoting regular physical activity is of key importance in reducing morbidity and mortality and improving the quality of life in this population. A current challenge to pulmonary rehabilitation is the need to develop strategies that induce or facilitate the enhancement of daily levels of physical activity. Because exercise training alone, despite improving exercise capacity, does not consistently generate similar improvements in physical activity in daily life, there is also a need to develop behavioral interventions that help to promote activity. PMID:24874131

  19. Regenerative medicine in the treatment of idiopathic pulmonary fibrosis: current position

    PubMed Central

    Álvarez, Diana; Levine, Melanie; Rojas, Mauricio

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible disease of the lung that has no lasting option for therapy other than transplantation. It is characterized by replacement of the normal lung tissue by fibrotic scarring, honeycombing, and increased levels of myofibroblasts. The underlying causes of IPF are still largely unknown. The focus of the current review is the possible use of stem cell therapy, specifically mesenchymal stem cells (MSCs), a multipotent stromal cell population, which have demonstrated promising data in multiple animal models of pulmonary fibrosis (PF). The most studied source of MSCs is the bone marrow, although they can be found also in the adipose tissue and umbilical cord, as well as in the placenta. MSCs have immunomodulatory and tissue-protective properties that allow them to manipulate the local environment of the injured tissue, ameliorating the inflammation and promoting repair. Because IPF primarily affects older patients, the issue of aging is intrinsically linked to many aspects of the disease, including the age of the stem cells. Animal models have shown the success of MSC therapy in mitigating the fibrotic effects of bleomycin-induced PF. However, bleomycin, the most commonly used model for PF, is imperfect in mimicking IPF as it presents in humans, as the duration of the illness is not parallel or reversible, and honeycombing is not produced. Furthermore, the time of MSC dosage has proven to be critical in determining whether the cells will ultimately have a positive or negative effect on disease progression, since it has been demonstrated that the maximal beneficial effect of MSCs occurs during the early inflammatory phase of the disease and that there is no or negative effect during the late fibrotic phase. Therefore, all the current clinical trials of MSCs and IPF, though promising, should proceed with caution as we move toward true stem cell therapy for this disease. PMID:25926746

  20. 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.

  1. Experimental Induction of Pulmonary Fibrosis in Horses with the Gammaherpesvirus Equine Herpesvirus 5

    PubMed Central

    Williams, Kurt J.; Robinson, N. Edward; Lim, Ailam; Brandenberger, Christina; Maes, Roger; Behan, Ashley; Bolin, Steven R.

    2013-01-01

    Gammaherpesviruses (γHV) are implicated in the pathogenesis of pulmonary fibrosis in humans and murine models of lung fibrosis, however there is little direct experimental evidence that such viruses induce lung fibrosis in the natural host. The equine γHV EHV 5 is associated with equine multinodular pulmonary fibrosis (EMPF), a progressive fibrosing lung disease in its natural host, the horse. Experimental reproduction of EMPF has not been attempted to date. We hypothesized that inoculation of EHV 5 isolated from cases of EMPF into the lungs of clinically normal horses would induce lung fibrosis similar to EMPF. Neutralizing antibody titers were measured in the horses before and after inoculation with EHV 5. PCR and virus isolation was used to detect EHV 5 in antemortem blood and BAL samples, and in tissues collected postmortem. Nodular pulmonary fibrosis and induction of myofibroblasts occurred in EHV 5 inoculated horses. Mean lung collagen in EHV 5 inoculated horses (80 µg/mg) was significantly increased compared to control horses (26 µg/mg) (p < 0.5), as was interstitial collagen (32.6% ± 1.2% vs 23% ± 1.4%) (mean ± SEM; p < 0.001). Virus was difficult to detect in infected horses throughout the experiment, although EHV 5 antigen was detected in the lung by immunohistochemistry. We conclude that the γHV EHV 5 can induce lung fibrosis in the horse, and hypothesize that induction of fibrosis occurs while the virus is latent within the lung. This is the first example of a γHV inducing lung fibrosis in the natural host. PMID:24147074

  2. Wnt Coreceptor Lrp5 Is a Driver of Idiopathic Pulmonary Fibrosis

    PubMed Central

    Lam, Anna P.; Herazo-Maya, Jose D.; Sennello, Joseph A.; Flozak, Annette S.; Russell, Susan; Mutlu, Gökhan M.; Budinger, G. R. Scott; DasGupta, Ramanuj; Varga, John; Kaminski, Naftali

    2014-01-01

    Rationale: Wnt/β-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. Objectives: To determine whether the Wnt coreceptor Lrp5 drives pulmonary fibrosis in mice and is predictive of disease severity in humans. Methods: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor Lrp5 in models of lung fibrosis induced by bleomycin or an adenovirus encoding an active form of transforming growth factor (TGF)-β. We also analyzed gene expression in peripheral blood mononuclear cells (PBMC) from patients with idiopathic pulmonary fibrosis (IPF). Measurements and Main Results: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, Lrp5 and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. Lrp5 null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of β-catenin signaling by the small molecular inhibitor of β-catenin responsive transcription. Transplantation of Lrp5 null bone marrow cells into wild-type mice did not limit fibrosis. Instead, Lrp5 loss was associated with reduced TGF-β production by alveolar type 2 cells and leukocytes. Consistent with a role of Lrp5 in the activation of TGF-β, Lrp5 null mice were not protected against lung fibrosis induced by TGF-β. Conclusions: We show that the Wnt coreceptor, Lrp5, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-β signaling can override a loss in Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis. PMID:24921217

  3. 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

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

    PubMed

    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

  5. 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. PMID:26121126

  6. Conditional Knockout of Telomerase Reverse Transcriptase in Mesenchymal Cells Impairs Mouse Pulmonary Fibrosis

    PubMed Central

    Liu, Tianju; Yu, Hongfeng; Ding, Lin; Wu, Zhe; Gonzalez De Los Santos, Francina; Liu, Jianhua; Ullenbruch, Matthew; Hu, Biao; Martins, Vanessa; Phan, Sem H.

    2015-01-01

    Telomerase is typically expressed in cellular populations capable of extended replication, such as germ cells, tumor cells, and stem cells, but is also induced in tissue injury, repair and fibrosis. Its catalytic component, telomerase reverse transcriptase (TERT) is induced in lung fibroblasts from patients with fibrotic interstitial lung disease and in rodents with bleomycin-induced pulmonary fibrosis. To evaluate the fibroblast specific role of TERT in pulmonary fibrosis, transgenic mice bearing a floxed TERT allele were generated, and then crossed with an inducible collagen α2(I)-Cre mouse line to generate fibroblast specific TERT conditional knockout mice. TERT-specific deficiency in mesenchymal cells caused attenuation of pulmonary fibrosis as manifested by reduced lung hydroxyproline content, type I collagen and α-smooth muscle actin mRNA levels. The TERT-deficient mouse lung fibroblasts displayed decreased cell proliferative capacity and higher susceptibility to induced apoptosis compared with control cells. Additionally TERT deficiency was associated with heightened α-smooth muscle actin expression indicative of myofibroblast differentiation. However the impairment of cell proliferation and increased susceptibility to apoptosis would cause a reduction in the myofibroblast progenitor population necessary to mount a successful myofibroblast-dependent fibrotic response. These findings identified a key role for TERT in fibroblast proliferation and survival essential for pulmonary fibrosis. PMID:26555817

  7. Effects of buthionine sulfoximine on the development of ozone-induced pulmonary fibrosis.

    PubMed

    Sun, J D; Pickrell, J A; Harkema, J R; McLaughlin, S I; Hahn, F F; Henderson, R F

    1988-10-01

    The capacity of reduced glutathione (GSH) to protect lung tissue against ozone-induced pulmonary fibrosis was investigated. Male B6C3F1 mice were exposed to 0, 0.2, 0.5, and 1.0 ppm ozone for 23 hr/day for 14 days. During exposures and/or for a period of 90 days after exposures, subgroups of mice at each exposure level were given drinking water containing 30 mM L-buthionine-S,R-sulfoximine (BSO) to lower in vivo levels of GSH. These BSO treatments reduced blood glutamylcysteine synthetase (GCS) activity (regulatory enzyme for GSH biosynthesis) and lung nonprotein sulfhydryl (NPSH) levels in nonexposed animals by approximately half. In contrast, ozone exposures increased blood GCS activity and lung NPSH levels in a concentration-dependent manner, with smaller increases in the BSO-treated mice. Immediately after exposures, an ozone-related inflammatory response was seen in lungs, but no histopathological signs of developing fibrosis were evident. Ninety days later, mice exposed to 1 ppm ozone and not treated with BSO had modest evidence of pulmonary fibrosis. Mice exposed to 1 ppm ozone and treated with BSO during this post-exposure period (regardless of BSO treatment during exposures) showed histopathological evidence of exacerbated pulmonary fibrosis, compared to similarly exposed mice not treated with BSO postexposure. These results indicated that interference with the body's normal defense mechanisms against oxidant damage, including suppression of GSH biosynthesis, exacerbates the subsequent development of pulmonary fibrosis. PMID:2901982

  8. Mesenchymal-Specific Deletion of C/EBPβ Suppresses Pulmonary Fibrosis

    PubMed Central

    Hu, Biao; Wu, Zhe; Nakashima, Taku; Phan, Sem H.

    2012-01-01

    The CCAAT/enhancer-binding protein β (C/EBPβ) regulates a variety of factors and cellular responses associated with pulmonary fibrosis. To distinguish its role in the mesenchyme from that in other compartments, the effects of mesenchymal-specific deletion of C/EBPβ on pulmonary fibrosis was examined. Crossing of mice with the floxed C/EBPβ gene with α2(I) collagen enhancer-CreER(T)-bearing mice successfully generated progeny with a conditional knockout (CKO) of C/EBPβ in collagen I-expressing (“mesenchymal”) cells only on treatment with tamoxifen (C/EBPβ CKO). When treated with an endotracheal bleomycin injection, C/EBPβ CKO mice showed significant attenuation of pulmonary fibrosis relative to control C/EBPβ-intact mice. C/EBPβ CKO mice also had reduced myofibroblasts in the lung. However, no significant differences in inflammatory/immune cell influx were noted in the mutant mice relative to the control mice. DNA microarray and real-time PCR analyses identified a series of myofibroblast differentiation regulators as novel target genes of C/EBPβ. Interestingly, C/EBPβ deficiency caused a marked induction of matrix metalloproteinase 12 expression, suggesting its potential role as a repressor, which could account for the noted reduction in fibrosis in the C/EBPβ-deficient mice. Thus, these findings indicate an essential role for C/EBPβ in the mesenchymal compartment in pulmonary fibrosis that is independent of its effects on inflammation or immune cell infiltration. PMID:22503555

  9. Atomized paclitaxel liposome inhalation treatment of bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Zhou, Y; Zhu, W P; Cai, X J; Chen, M

    2016-01-01

    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. PMID:27173212

  10. Inhibition and Role of let-7d in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Pandit, Kusum V.; Corcoran, David; Yousef, Hanadie; Yarlagadda, Manohar; Tzouvelekis, Argyris; Gibson, Kevin F.; Konishi, Kazuhisa; Yousem, Samuel A.; Singh, Mandal; Handley, Daniel; Richards, Thomas; Selman, Moises; Watkins, Simon C.; Pardo, Annie; Ben-Yehudah, Ahmi; Bouros, Demosthenes; Eickelberg, Oliver; Ray, Prabir; Benos, Panayiotis V.; Kaminski, Naftali

    2010-01-01

    Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal fibrotic lung disease characterized by profound changes in epithelial cell phenotype and fibroblast proliferation. Objectives: To determine changes in expression and role of microRNAs in IPF. Methods: RNA from 10 control and 10 IPF tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the let-7d promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of let-7d in response to transforming growth factor-β. HMGA2, a let-7d target, was localized by immunohistochemistry. In mice, let-7d was inhibited by intratracheal administration of a let-7d antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry. Measurements and Main Results: Eighteen microRNAs including let-7d were significantly decreased in IPF. Transforming growth factor-β down-regulated let-7d expression, and SMAD3 binding to the let-7d promoter was demonstrated. Inhibition of let-7d caused increases in mesenchymal markers N-cadherin-2, vimentin, and α-smooth muscle actin (ACTA2) as well as HMGA2 in multiple epithelial cell lines. let-7d was significantly reduced in IPF lungs and the number of epithelial cells expressing let-7d correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of IPF lungs. let-7d inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2, and S100A4 expression in SFTPC (pulmonary-associated surfactant protein C) expressing alveolar epithelial cells. Conclusions: Our results indicate a role for microRNAs in IPF. The down-regulation of let-7d in IPF and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key

  11. Endothelial injury and repair in radiation-induced pulmonary fibrosis

    SciTech Connect

    Adamson, I.Y.; Bowden, D.H.

    1983-08-01

    Cytokinetic relationships between endothelial cells and fibroblasts during lung injury and repair in mice have been studied in a morphologic, autoradiographic, and biochemical study following whole body irradiation. After 650 rads, endothelial injury accompanied by interstitial edema was seen between weeks 1 and 2. The cell labeling curve had two components: predominant endothelial labeling to 3 weeks, then a smaller rise in DNA synthesis in interstitial cells. There was focal fibrosis but little change in total hydroxyproline to 20 weeks. After 1000 rads, cell injury, still confined to the endothelium, was more severe and lasted up to 6 weeks. Increased DNA synthesis occurred in the endothelium between Weeks 2 and 8 and in interstitial cells from Week 3 to 16, when total hydroxyproline was significantly elevated and many fibrotic areas were seen in the lung. The results indicate that acute endothelial injury may be rapidly repaired with little fibroblastic stimulation, whereas severe or prolonged injury with delayed regeneration disturbs endothelial-mesenchymal relationships. This may be a key factor in promoting fibroblast proliferation and the deposition of collagen.

  12. Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis

    PubMed Central

    Gregory, Alyssa D.; Kliment, Corrine R.; Metz, Heather E.; Kim, Kyoung-Hee; Kargl, Julia; Agostini, Brittani A.; Crum, Lauren T.; Oczypok, Elizabeth A.; Oury, Tim A.; Houghton, A. McGarry

    2015-01-01

    IPF is a progressive lung disorder characterized by fibroblast proliferation and myofibroblast differentiation. Although neutrophil accumulation within IPF lungs has been negatively correlated with outcomes, the role played by neutrophils in lung fibrosis remains poorly understood. We have demonstrated previously that NE promotes lung cancer cell proliferation and hypothesized that it may have a similar effect on fibroblasts. In the current study, we show that NE−/− mice are protected from asbestos-induced lung fibrosis. NE−/− mice displayed reduced fibroblast and myofibroblast content when compared with controls. NE directly both lung fibroblast proliferation and myofibroblast differentiation in vitro, as evidenced by proliferation assays, collagen gel contractility assays, and αSMA induction. Furthermore, αSMA induction occurs in a TGF-β-independent fashion. Treatment of asbestos-recipient mice with ONO-5046, a synthetic NE antagonist, reduced hydroxyproline content. Thus, the current study points to a key role for neutrophils and NE in the progression of lung fibrosis. Lastly, the study lends rationale to use of NE-inhibitory approaches as a novel therapeutic strategy for patients with lung fibrosis. PMID:25743626

  13. Prevention of bleomycin-induced pulmonary fibrosis after adenovirus-mediated transfer of the bacterial bleomycin resistance gene.

    PubMed Central

    Tran, P L; Weinbach, J; Opolon, P; Linares-Cruz, G; Reynes, J P; Grégoire, A; Kremer, E; Durand, H; Perricaudet, M

    1997-01-01

    A serious limitation in the use of the DNA-cleaving, antitumoral-antibiotic, bleomycin during chemotherapy is pulmonary toxicity. Lung injury induced by bleomycin is characterized by an increased deposition of interstitial extracellular matrix proteins in the alveolar wall that compromises respiratory function. Several drugs have been tested in animal models to prevent the pulmonary toxicity of bleomycin, but have not led to a useful clinical treatment because of their adverse effects on other tissues. We have shown that transgenic mice expressing Streptoalloteichus hindustanus (Sh) ble bleomycin resistance protein in pulmonary epithelial cells in the lungs are protected against bleomycin-induced toxicity in lungs. In the present study, we used intranasal administration by adenovirus-mediated gene transfer of the bleomycin resistance Sh ble gene to mouse lung for prevention of bleomycin-induced pulmonary fibrosis. We constructed recombinant adenoviruses Ad.CMVble and Ad.RSVble harboring the bleomycin resistance Sh ble gene under the control of the cytomegalovirus early promoter and the Rous sarcoma virus early promoter, respectively. Transgene expression was detected in epithelia of conducting airways and alveolar septa by immunostaining with a rabbit polyclonal antibody directed against the bleomycin resistance protein and persisted for the duration of drug treatment; i.e., up to 17 d. No toxic effect was seen in adenovirus-treated mice. Pretreatment of mice with Ad.CMVble or Ad.RSVble completely prevented collagen deposition 42-133 d after bleomycin treatment, as measured by lung OH-proline content. Histologic studies indicated that there was little or no lung injury in the adenovirus/bleomycin-treated mice compared with the bleomycin-treated mice. These observations may lead to new approaches for the prevention of bleomycin-induced pulmonary fibrosis. PMID:9045862

  14. Differentiation of radiation fibrosis from recurrent pulmonary neoplasm by magnetic resonance imaging

    SciTech Connect

    Glazer, H.S.; Levitt, R.G.; Lee, J.K.T.; Emami, B.; Gronemeyer, S.; Murphy, W.A.

    1984-10-01

    Recent reports have shown the value of magnetic resonance imaging (MRI) in demonstrating normal and abnormal mediastinal and hilar anatomy. The potential role of MRI in evaluating patients who have undergone prior chest irradiation for pulmonary neoplasm has not been emphasized. The MRI appearance of mediastinal fibrosis after treatment of a patient with Hodgkin disease has been illustrated. Although plain chest radiographs and CT can demonstrate radiation-induced changes within the thorax, it is often difficult to distinguish radiation fibrosis from residual tumor. The authors report a case in which MRI differentiated fibrosis from recurrent tumor, thus confirming both the conventional radiographic and CT suspicions of recurrent neoplasm.

  15. 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

  16. Biomarker expression in lung of rabbit with pulmonary fibrosis induced by ammonium perchlorate.

    PubMed

    Wu, Feng-hong; Guo, Hui-xia; Lin, Ming-fang; Chen, Zhi-ze; Zhou, Xuan; Peng, Kai-liang

    2011-04-01

    Ammonium perchlorate (AP), an oxidizer, has been used in solid propellants. Although AP exposure has been suspected as a risk factor for the development of pulmonary fibrosis, data are still inconclusive. To evaluate the pulmonary toxicity and the potential pulmonary fibrosis caused by occupational exposure to this compound, 25 male rabbits were randomly allocated into five groups to receive AP or bleomycin or saline by intratracheal injection. All rabbits were sacrificed and total RNA from the lungs was extracted. Expressions of types I and III collagens, transforming growth factor-β(1) (TGF-β(1)) and tumour necrosis factor-α (TNF-α) messenger RNA (mRNA) were measured by reverse transcription-polymerase chain reaction (RT-PCR). The expressions of type I and III collagen mRNA in low, moderate and high dose AP groups were significantly higher (p < 0.01 or p < 0.05) than that in the saline group. There was also a significant increased level of TGF-β(1) and TNF-α mRNA in the three AP groups compared with saline control group (p < 0.01 or p < 0.05). These results reveal that AP can increase gene expressions of types I, III collagens, TGF-β(1) and TNF-α in lung of rabbits exposed to AP. The overexpression of these biomarkers were considered as effective indicator linking to the development of pulmonary fibrosis and finally demonstrated that AP has potential to induce pulmonary fibrosis. PMID:20937628

  17. MEK-ERK Pathway Modulation Ameliorates Pulmonary Fibrosis Associated with Epidermal Growth Factor Receptor Activation

    PubMed Central

    Madala, Satish K.; Schmidt, Stephanie; Davidson, Cynthia; Ikegami, Machiko; Wert, Susan

    2012-01-01

    Pulmonary fibrosis remains a significant public health burden with no proven therapies. The mitogen-activated protein kinase (MAPK)/MAPK kinase (MEK)/extracellular signal–regulated kinase (ERK) signaling cascade is a major pathway controlling cellular processes associated with fibrogenesis, including growth, proliferation, and survival. Activation of the MAPK/ERK pathway is detected in the lungs of human fibrosis samples; however, the effect of modulating the pathway in vivo is unknown. Overexpression of transforming growth factor (TGF)-α in the lung epithelium of transgenic mice causes a progressive pulmonary fibrosis associated with increased MEK/ERK activation localized primarily in mesenchymal cells. To determine the role of the MEK pathway in the induction of TGF-α–induced lung fibrosis, TGF-α was overexpressed for 4 weeks while mice were simultaneously treated with the specific MEK inhibitor, ARRY-142886 (ARRY). Treatment with ARRY prevented increases in lung cell proliferation and total lung collagen, attenuated production of extracellular matrix genes, and protected mice from changes in lung function. ARRY administered as a rescue treatment after fibrosis was already established inhibited fibrosis progression, as assessed by lung histology, changes in body weights, extracellular matrix gene expression, and lung mechanics. These findings demonstrate that MEK inhibition prevents progression of established fibrosis in the TGF-α model, and provides proof of concept of targeting the MEK pathway in fibrotic lung disease. PMID:22021337

  18. Pulmonary Fibrosis in Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis

    PubMed Central

    Comarmond, Cloé; Crestani, Bruno; Tazi, Abdellatif; Hervier, Baptiste; Adam-Marchand, Sylvain; Nunes, Hilario; Cohen-Aubart, Fleur; Wislez, Marie; Cadranel, Jacques; Housset, Bruno; Lloret-Linares, Célia; Sève, Pascal; Pagnoux, Christian; Abad, Sébastien; Camuset, Juliette; Bienvenu, Boris; Duruisseaux, Michaël; Hachulla, Eric; Arlet, Jean-Benoît; Hamidou, Mohammed; Mahr, Alfred; Resche-Rigon, Matthieu; Brun, Anne-Laure; Grenier, Philippe; Cacoub, Patrice; Saadoun, David

    2014-01-01

    Abstract Pulmonary fibrosis (PF) is an uncommon manifestation observed in patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA). While patients with PF associated with AAV seem to have a worse prognosis, these patients have been described only in case reports or small retrospective case series. In this retrospective multicenter study, we report the main features and long-term outcomes of patients with PF associated with AAV, fulfilling the American College of Rheumatology criteria and/or Chapel Hill definitions. Forty-nine patients (30 men [61%]; median age at diagnosis of AAV, 68 [interquartile range, 58–73] years) with PF associated with AAV were identified. Forty (81.6%) patients had MPA and 9 (18.4%) had granulomatosis with polyangiitis. The diagnosis of PF preceded the onset of vasculitis in 22 (45%) patients. Usual interstitial pneumonia was the main radiologic pattern (n = 18, 43%). ANCA were mostly of antimyeloperoxidase specificity (88%). All patients were treated with glucocorticoids as induction therapy, combined with cyclophosphamide (CYC) (n = 36, 73.5%) or rituximab (RTX) (n = 1, 2%). Factors associated with mortality included occurrence of chronic respiratory insufficiency (hazard ratio [HR], 7.44; 95% confidence interval [CI], 1.6–34.5; p = 0.003), induction therapy with glucocorticoids alone (HR, 2.94; CI, 1.05–8.33; p = 0.04), and initial weigh loss (HR, 2.83; CI, 1.05–7.65; p = 0.041). The 3-year survival rate in patients treated with glucocorticoids alone or combined with an immunosuppressant (CYC or RTX) as induction therapy was 64% (95% CI, 41–99) and 94% (95% CI, 86–100), respectively (p = 0.03). After a median follow-up of 48 months [interquartile range, 14–88 mo], 18 (37%) patients died, including 11 related to respiratory insufficiency. PF is a rare manifestation of AAV with a very poor prognosis. Induction therapy with

  19. 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. PMID:26852294

  20. Functional Wnt Signaling Is Increased in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Königshoff, Melanie; Balsara, Nisha; Pfaff, Eva-Maria; Kramer, Monika; Chrobak, Izabella; Seeger, Werner; Eickelberg, Oliver

    2008-01-01

    Background Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, characterized by distorted lung architecture and loss of respiratory function. Alveolar epithelial cell injury and hyperplasia, enhanced extracellular matrix deposition, and (myo)fibroblast activation are features of IPF. Wnt/β-catenin signaling has been shown to determine epithelial cell fate during development. As aberrant reactivation of developmental signaling pathways has been suggested to contribute to IPF pathogenesis, we hypothesized that Wnt/β-catenin signaling is activated in epithelial cells in IPF. Thus, we quantified and localized the expression and activity of the Wnt/β-catenin pathway in IPF. Methodology/Principal Findings The expression of Wnt1, 3a, 7b, and 10b, the Wnt receptors Fzd1-4, Lrp5-6, as well as the intracellular signal transducers Gsk-3β, β-catenin, Tcf1, 3, 4, and Lef1 was analyzed in IPF and transplant donor lungs by quantitative real-time (q)RT-PCR. Wnt1, 7b and 10b, Fzd2 and 3, β-catenin, and Lef1 expression was significantly increased in IPF. Immunohistochemical analysis localized Wnt1, Wnt3a, β-catenin, and Gsk-3β expression largely to alveolar and bronchial epithelium. This was confirmed by qRT-PCR of primary alveolar epithelial type II (ATII) cells, demonstrating a significant increase of Wnt signaling in ATII cells derived from IPF patients. In addition, Western blot analysis of phospho-Gsk-3β, phospho-Lrp6, and β-catenin, and qRT-PCR of the Wnt target genes cyclin D1, Mmp 7, or Fibronectin 1 demonstrated increased functional Wnt/β-catenin signaling in IPF compared with controls. Functional in vitro studies further revealed that Wnt ligands induced lung epithelial cell proliferation and (myo)fibroblast activation and collagen synthesis. Conclusions/Significance Our study demonstrates that the Wnt/β-catenin pathway is expressed and operative in adult lung epithelium. Increased Wnt/β-catenin signaling may be involved in epithelial cell injury and

  1. 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

  2. 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. PMID:26998906

  3. Protective Role of Andrographolide in Bleomycin-Induced Pulmonary Fibrosis in Mice

    PubMed Central

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

    2013-01-01

    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. PMID:24300094

  4. Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis

    PubMed Central

    2013-01-01

    Introduction Recent advances suggest that the cellular redox state may play a significant role in the progression of fibrosis in systemic sclerosis (SSc). Another, and as yet poorly accounted for, feature of SSc is its overlap with thyroid abnormalities. Previous reports demonstrate that hypothyroidism reduces oxidant stress. The aim of this study was therefore to evaluate the effect of propylthiouracil (PTU), and of the hypothyroidism induced by it, on the development of cutaneous and pulmonary fibrosis in the oxidant stress murine model of SSc. Methods Chronic oxidant stress SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) for 6 weeks. Mice (n = 25) were randomized into three arms: HOCl (n = 10), HOCl plus PTU (n = 10) or vehicle alone (n = 5). PTU administration was initiated 30 minutes after HOCl subcutaneous injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histologic methods. Immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of vascular endothelial growth factor (VEGF), extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homolog gene family (Rho), and transforming growth factor (TGF) β were analyzed by Western blot. Results Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. PTU treatment prevented both dermal and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by PTU in the skin and lung. The increase in cutaneous and pulmonary expression of VEGF, ERK, Ras, and Rho in mice treated with HOCl was significantly prevented in mice co-administered ////with PTU. Conclusions PTU, probably through its direct effect on reactive oxygen species or indirectly through thyroid function inhibition, prevents the development of cutaneous and pulmonary fibrosis by blocking the activation of the Ras

  5. Recipient–derived EDA fibronectin promotes cardiac allograft fibrosis

    PubMed Central

    Booth, Adam J; Wood, Sherri C; Cornett, Ashley M; Dreffs, Alyssa A; Lu, Guanyi; Muro, Andrés F; White, Eric S; Bishop, D Keith

    2014-01-01

    Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA−/−) and wild-type (WT) mice. While EDA−/− mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA−/− mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which

  6. 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

  7. 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 ...

  8. Rapid and Progressive Pulmonary Fibrosis in 2 Families with DNA Repair Deficiencies of Undetermined Etiology

    PubMed Central

    Vece, Timothy J.; Schecter, Marc G.; Gatti, Richard A.; Tunuguntla, Rashmi; Garcia, Christine Kim; Langston, Claire; Dishop, Megan K.; Moore, Robert H.; Fan, Leland L.

    2016-01-01

    Known genetic causes of pediatric interstitial lung disease include disorders of surfactant metabolism, telomerase, and DNA repair. We report 4 children from 2 families with rapidly progressive and fatal pulmonary fibrosis. A novel DNA repair defect unrelated to the ataxia-telangiectasia mutated gene was found in 1 child from each family. PMID:22240110

  9. Improving care for patients with idiopathic pulmonary fibrosis (IPF) in the UK: a round table discussion.

    PubMed

    Thickett, David R; Kendall, Clare; Spencer, Lisa G; Screaton, Nick; Wallace, William A; Pinnock, Hilary; Bott, Julia; Pigram, Lucy; Watson, Sarah; Millar, Ann B

    2014-12-01

    This article is the result of a round table discussion held at BMA House. Its purpose is to outline the challenges facing both patients and doctors in managing idiopathic pulmonary fibrosis. A number of recommendations for service development and research have been identified. PMID:25335486

  10. Ponatinib ameliorates pulmonary fibrosis by suppressing TGF-β1/Smad3 pathway.

    PubMed

    Qu, Yubei; Zhang, Liang; Kang, Zechun; Jiang, Wanglin; Lv, Changjun

    2015-10-01

    TGF-β1/Smad3 pathway plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, including lung fibroblasts proliferation and epithelial cell aberrant activation. Ponatinib is a multi-targeted tyrosine-kinase inhibitor. However, whether Ponatinib has anti-fibrotic functions is unknown. In this study, the effects of Ponatinib on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1), on the apoptosis of human type I alveolar epithelial cells (AT I) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis was investigated in vivo. Treatment with Ponatinib resulted in a reduction of EMT in A549 cells with a decrease in vimentin and p-Smad3, whereas an increase in E-cadherin. Apoptosis of AT I was attenuated with an increase in the Bcl-2/Bax ratio. HLF-1 proliferation was reduced with a decrease in PDGF-BB and FGF-2 expressions. Treatment with Ponatinib resulted in an amelioration of the BLM-induced pulmonary fibrosis in rats with reductions of the pathological score, collagen deposition, p-Smad3, α-SMA, PDGF-BB and FGF-2 expression. In summary, Ponatinib reversed the EMT, inhibited the apoptosis of AT I, as well as HLF-1 proliferation and prevented pulmonary fibrosis by suppressing the TGF-β1/Smad3 pathway. PMID:26254990