scholarly journals Age-driven developmental drift in the pathogenesis of idiopathic pulmonary fibrosis

2016 ◽  
Vol 48 (2) ◽  
pp. 538-552 ◽  
Author(s):  
Moisés Selman ◽  
Carlos López-Otín ◽  
Annie Pardo
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Alveolar Epithelial Cells ◽  
Cell Behaviour ◽  
Alveolar Epithelial ◽  
Similar Expression Profile ◽  
Age Related ◽  
Developmental Signalling

Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal disease of unknown aetiology. A growing body of evidence supports that IPF represents an epithelial-driven process characterised by aberrant epithelial cell behaviour, fibroblast/myofibroblast activation and excessive accumulation of extracellular matrix with the subsequent destruction of the lung architecture. The mechanisms involved in the abnormal hyper-activation of the epithelium are unclear, but we propose that recapitulation of pathways and processes critical to embryological development associated with a tissue specific age-related stochastic epigenetic drift may be implicated. These pathways may also contribute to the distinctive behaviour of IPF fibroblasts. Genomic and epigenomic studies have revealed that wingless/Int, sonic hedgehog and other developmental signalling pathways are reactivated and deregulated in IPF. Moreover, some of these pathways cross-talk with transforming growth factor-β activating a profibrotic feedback loop. The expression pattern of microRNAs is also dysregulated in IPF and exhibits a similar expression profile to embryonic lungs. In addition, senescence, a process usually associated with ageing, which occurs early in alveolar epithelial cells of IPF lungs, likely represents a conserved programmed developmental mechanism. Here, we review the major developmental pathways that get twisted in IPF, and discuss the connection with ageing and potential therapeutic approaches.

Lung infection with γ-herpesvirus induces progressive pulmonary fibrosis in Th2-biased mice

2005 ◽  
Vol 289 (5) ◽  
pp. L711-L721 ◽  
Author(s):  
Ana L. Mora ◽  
Charles R. Woods ◽  
Anapatricia Garcia ◽  
Jianguo Xu ◽  
Mauricio Rojas ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Pulmonary Infection ◽  
Transforming Growth Factor ◽  
Light And Electron Microscopy ◽  
Transforming Growth Factor Β ◽  
Alveolar Epithelial Cells ◽  
Unknown Etiology ◽  
Type Ii ◽  
Alveolar Epithelial ◽  
Fibrotic Lung Disease

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease of unknown etiology. A viral pathogenesis in IPF has been suggested since >95% of IPF patients have evidence of chronic pulmonary infection with one or more herpesviruses. To determine whether pulmonary infection with herpesvirus can cause lung fibrosis, we infected mice with the murine γ-herpesvirus 68 (MHV68). Because IPF patients have a T helper type 2 (Th2) pulmonary phenotype, we used IFN-γR−/−, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-γR−/− mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in IPF, increased transforming growth factor-β expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7, were also present in chronically infected IFN-γR−/− mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial IPF. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus pulmonary infection in IFN-γR−/− mice causes progressive pulmonary fibrosis and many of the pathological features seen in IPF.

scholarly journals GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis

2019 ◽  
Vol 317 (4) ◽  
pp. L510-L521 ◽  
Author(s):  
Yingze Zhang ◽  
Mao Jiang ◽  
Mehdi Nouraie ◽  
Mark G. Roth ◽  
Tracy Tabib ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Primary Source ◽  
Transforming Growth Factor Β ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Secreted Protein ◽  
Telomere Dysfunction

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 ( Gdf15), as the most significantly upregulated secreted protein. Gdf15 expression is induced in response to telomere dysfunction and bleomycin challenge in mice. Gdf15 mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, GDF15 mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of GDF15, and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.

scholarly journals Epithelial–Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Medicina ◽  
2019 ◽  
Vol 55 (4) ◽  
pp. 83 ◽  
Author(s):  
Francesco Salton ◽  
Maria Volpe ◽  
Marco Confalonieri
Keyword(s):  
Epithelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Treatment Options ◽  
Alveolar Epithelium ◽  
Alveolar Epithelial Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Serious Disease

Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung, which leads to extensive parenchymal scarring and death from respiratory failure. The most accepted hypothesis for IPF pathogenesis relies on the inability of the alveolar epithelium to regenerate after injury. Alveolar epithelial cells become apoptotic and rare, fibroblasts/myofibroblasts accumulate and extracellular matrix (ECM) is deposited in response to the aberrant activation of several pathways that are physiologically implicated in alveologenesis and repair but also favor the creation of excessive fibrosis via different mechanisms, including epithelial–mesenchymal transition (EMT). EMT is a pathophysiological process in which epithelial cells lose part of their characteristics and markers, while gaining mesenchymal ones. A role for EMT in the pathogenesis of IPF has been widely hypothesized and indirectly demonstrated; however, precise definition of its mechanisms and relevance has been hindered by the lack of a reliable animal model and needs further studies. The overall available evidence conceptualizes EMT as an alternative cell and tissue normal regeneration, which could open the way to novel diagnostic and prognostic biomarkers, as well as to more effective treatment options.

scholarly journals Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Alison E. John ◽  
Rebecca H. Graves ◽  
K. Tao Pun ◽  
Giovanni Vitulli ◽  
Ellen J. Forty ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Small Molecule ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lung Epithelial Cells ◽  
Tgfβ Signaling ◽  
Lung Epithelial ◽  
Translational Pharmacology ◽  
Αvβ6 Integrin

Abstract The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

scholarly journals LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis

2018 ◽  
Vol 132 (14) ◽  
pp. 1565-1580 ◽  
Author(s):  
Yasunori Enomoto ◽  
Sayomi Matsushima ◽  
Kiyoshi Shibata ◽  
Yoichiro Aoshima ◽  
Haruna Yagi ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Bootstrap Method ◽  
Transforming Growth Factor Β ◽  
Lung Fibroblasts ◽  
Potential Biomarker ◽  
Fibrotic Process ◽  
Mouse Lungs

Although differentiation of lung fibroblasts into α-smooth muscle actin (αSMA)-positive myofibroblasts is important in the progression of idiopathic pulmonary fibrosis (IPF), few biomarkers reflecting the fibrotic process have been discovered. We performed microarray analyses between FACS-sorted steady-state fibroblasts (lineage (CD45, TER-119, CD324, CD31, LYVE-1, and CD146)-negative and PDGFRα-positive cells) from untreated mouse lungs and myofibroblasts (lineage-negative, Sca-1-negative, and CD49e-positive cells) from bleomycin-treated mouse lungs. Amongst several genes up-regulated in the FACS-sorted myofibroblasts, we focussed on Ltbp2, the gene encoding latent transforming growth factor-β (TGF-β) binding protein-2 (LTBP2), because of the signal similarity to Acta2, which encodes αSMA, in the clustering analysis. The up-regulation was reproduced at the mRNA and protein levels in human lung myofibroblasts induced by TGF-β1. LTBP2 staining in IPF lungs was broadly positive in the fibrotic interstitium, mainly as an extracellular matrix (ECM) protein; however, some of the αSMA-positive myofibroblasts were also stained. Serum LTBP2 concentrations, evaluated using ELISA, in IPF patients were significantly higher than those in healthy volunteers (mean: 21.4 compared with 12.4 ng/ml) and showed a negative correlation with % predicted forced vital capacity (r = −0.369). The Cox hazard model demonstrated that serum LTBP2 could predict the prognosis of IPF patients (hazard ratio for death by respiratory events: 1.040, 95% confidence interval: 1.026–1.054), which was validated using the bootstrap method with 1000-fold replication. LTBP2 is a potential prognostic blood biomarker that may reflect the level of differentiation of lung fibroblasts into myofibroblasts in IPF.

Release of biologically active TGF-β1 by alveolar epithelial cells results in pulmonary fibrosis

2003 ◽  
Vol 285 (3) ◽  
pp. L527-L539 ◽  
Author(s):  
Ying Dong Xu ◽  
Jiesong Hua ◽  
Alice Mui ◽  
Robert O'Connor ◽  
Gary Grotendorst ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Inflammatory Cells ◽  
Alveolar Epithelial Cells ◽  
Biologically Active ◽  
Aberrant Expression ◽  
Alveolar Epithelial ◽  
Fibrotic Lung Disease ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal fibrotic lung disease. Transforming growth factor (TGF)-β1 is present in a biologically active conformation in the epithelial cells lining lesions with advanced IPF. To determine the role of aberrant expression of biologically active TGF-β1 by alveolar epithelial cells (AECs), the AECs of explanted normal rat lungs were transfected with the TGF-β1 gene using the retrovirus pMX-L-s223,225-TGF-β1. In situ hybridization using a digoxigenin-labeled cDNA of the puromycin resistance gene contained in the pMX demonstrated that pMX-L-s233,225-TGF-β1 was selectively transfected into AECs of the explants. Conditioned media overlying explants obtained 7 days after being treated with pMX-L-s223,225-TGF-β1 contained 14.5 ± 3.15 pg/ml of active TGF-β1. With the use of Masson's trichrome staining of explant sections obtained 14 days after transfection, there were lesions similar to those in IPF, characterized by type II AEC hyperplasia, interstitial thickening, extensive increase in interstitial and subepithelial collagen, an increase in the number of fibroblasts, and areas resembling fibroblast buds. Collagens I, III, IV, and V and fibronectin were increased in explants treated with pMX-L-s223,225-TGF-β1. The findings in the current study suggest that IPF may be a disorder of epithelial cells and not inflammatory cells.

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