Lung Fibrosis and Fibrosis in the Lungs: Is It All about Myofibroblasts? (original) (raw)
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A Refined Approach to Target the Molecular and Cellular Mechanisms in Pulmonary Fibrosis
Targeting Cellular Signalling Pathways in Lung Diseases
The COVID-19 scenario has heated up the entire scientific community including those dealing with pulmonary fibrosis. The fibrotic sequelae of SARS-CoV-2 have given value to the anti-fibrotic therapies that are being evaluated to prevent the severity of the pandemic. However, our understanding of the precise mechanism that drives fibrosis and knowledge about effective management of pulmonary fibrosis are still in the state of darkness. A landscape of pulmonary fibrosis (PF) and dismal prognosis continues to mar the progression of society over the past decades. It was in 2014 that two "umbrella" therapies were approved by the FDA for IPF management, nintedanib and pirfenidone, post which there are no significant additions in this field. An interplay between genetic and environmental factors leads to cause microinjuries to the alveolar epithelium. The maladaptive repair process over time contributes to the fibroblast proliferation and epitheliummesenchymal crosstalk leading to the pathogenesis of PF. Although there are several hurdles to combat this deadly disease, our next step is to develop efficacious treatment regimens that can ameliorate survivability and functional quality of life. This chapter presents recent updates in PF pathogenesis and possible novel therapeutic strategies. The authors declare no competing financial interests. Sabita Singh, Joytri Dutta and Archita Ray contributed equally with all other contributors.
Epithelial Cell Apoptosis by Fas Ligand–Positive Myofibroblasts in Lung Fibrosis
American Journal of Respiratory Cell and Molecular Biology, 2007
The Fas/Fas ligand (FasL) apoptotic pathway has been shown to be involved in bleomycin-induced lung fibrosis. We examined the hypothesis that myofibroblasts from fibrotic lungs possess a cytotoxic phenotype that causes apoptosis of epithelial cells via the Fas/FasL pathway. We show in vivo epithelial cell apoptosis and associated upregulation of Fas and apoptotic Fas pathway genes in epithelial cells of lungs with bleomycin-induced fibrosis. In addition, we show that FasL surface molecules are overexpressed on ␣-SMA-positive cells in mice with bleomycin-induced fibrosis, and in humans with idiopathic pulmonary fibrosis. This enables the molecules to kill Fas-positive epithelial cells. In contrast, FasL-deficient myofibroblasts lose this myofibroblast cytotoxic phenotype, both in vivo and in vitro. In vivo, there was no bleomycin-induced epithelial cell apoptosis, as assessed by specific M30 staining in chimeric FasLdeficient mice that lacked FasL-positive myofibroblasts. In vitro, FasLpositive, but not FasL-negative myofibroblasts, induce mouse lung epithelial cell apoptosis. Thus myofibroblast cytotoxicity may underlie the absence of re-epithelialization, resulting in persistent lung fibrosis.
Idiopathic pulmonary fibrosis: new insights in its pathogenesis
The International Journal of Biochemistry & Cell Biology, 2002
Idiopathic pulmonary fibrosis (IPF) is a unique type of chronic fibrosing lung disease of unknown etiology. The sequence of the pathogenic mechanisms is unknown, but the disease is characterized by epithelial injury and activation, the formation of distinctive subepithelial fibroblast/myofibroblast foci, and excessive extracellular matrix accumulation. These pathological processes usually lead to progressive and irreversible changes in the lung architecture resulting in progressive respiratory insufficiency and an almost universally terminal outcome in a relatively short period of time. While research has largely focused on inflammatory mechanisms for initiating the fibrotic response, recent evidence strongly suggests that disruption of the alveolar epithelium is an underlying pathogenic event. Although treatment to date has proved largely ineffective, this new approach has opened up several promising therapeutic avenues.
Molecular mechanisms of pulmonary fibrosis
Frontiers in Bioscience, 2002
Introduction 3. Lessons from the inflammatory pathway 3.1. The paradigm of type 1 or type 2 cytokine network commitment 3.2. Chemokines 3.2.1. Chemokines in inflammatory/fibrotic lung disorders 3.2.2. Chemokines and Th1/Th2 cytokines circuit 3.2.3. Chemokines and angiogenesis 4. The epithelial pathway. Tying loose ends 4.1. Idiopathic pulmonary fibrosis and the alveolar epithelium 4.2. Epithelial cell apoptosis and alveolar re-epithelialization. 4.3. Epithelial cells: The source of profibrotic cytokines/growth factors in IPF 4.4. Alveolar epithelial cells and intra-alveolar coagulation 4.5. Are epithelial cells directly participating in fibrilar collagens accumulation? 5. Fibroblasts/myofibroblasts: the common route for the inflammatory and epithelial pathways to pulmonary fibrosis 5.1. Fibroblast heterogeneity 5.2. First call: Fibroblast migration to the site of lesion 5.3. Second call: Fibroblast proliferation in the site of lesion 5.4. Third and last call: Fibroblasts differentiate into myofibroblasts 5.5. Myofibroblast persistence in the active fibrotic site 5.6. Myofibroblasts and lung fibrogenesis 6. Matrix remodeling: a crucial role for matrix metalloproteinase family 6.1. MMPs/TIMPs relationships in pulmonary fibrosis 7. Genetic susceptibility and pulmonary fibrosis 7.1. Genetic polymorphisms and pulmonary fibrosis 7.2. Gene-gene and gene-gene-environment interactions 7.3. Functional genomics and gene-expression profile 8. Perspective 9. References
Pathogenetic pathways and novel pharmacotherapeutic targets in idiopathic pulmonary fibrosis
Pulmonary Pharmacology & Therapeutics, 2007
Idiopathic pulmonary fibrosis (IPF) is a poorly understood disease that usually leads to death within 5 years of diagnosis. Despite our better understanding of IPF pathogenesis, the etiology and the precise cellular and molecular mechanisms involved are not well known. Current therapies are of unproven benefit. The aim of this review is to identify possible candidate pathways that might offer novel therapeutic targets changing the natural course of this disease.
Scientific Reports, 2018
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. KCa3.1 ion channels play a critical role in TGFβ1-dependent pro-fibrotic responses in human lung myofibroblasts. We aimed to develop a human lung parenchymal model of fibrogenesis and test the efficacy of the selective KCa3.1 blocker senicapoc. 2 mm3 pieces of human lung parenchyma were cultured for 7 days in DMEM ± TGFβ1 (10 ng/ml) and pro-fibrotic pathways examined by RT-PCR, immunohistochemistry and collagen secretion. Following 7 days of culture with TGFβ1, 41 IPF- and fibrosis-associated genes were significantly upregulated. Immunohistochemical staining demonstrated increased expression of ECM proteins and fibroblast-specific protein after TGFβ1-stimulation. Collagen secretion was significantly increased following TGFβ1-stimulation. These pro-fibrotic responses were attenuated by senicapoc, but not by dexamethasone. This 7 day ex vivo model of human lung fibrogenesis...
Molecular biology of the cell, 2017
The contribution of epithelial-to-mesenchymal transition (EMT) to the pro-fibrotic stiff microenvironment and myofibroblast accumulation in pulmonary fibrosis remains unclear. We examined EMT-competent lung epithelial cells and lung fibroblasts from control (fibrosis-free) donors or patients with idiopathic pulmonary fibrosis (IPF), which is a very aggressive fibrotic disorder. Cells were cultured on pro-fibrotic conditions including stiff substrata and TGF-β1, and analyzed in terms of morphology, stiffness and expression of EMT/myofibroblast markers and fibrillar collagens. All fibroblasts acquired a robust myofibroblast phenotype upon TGF-β1 stimulation. Yet, IPF-myofibroblasts exhibited higher stiffness and expression of fibrillar collagens than control fibroblasts, concomitantly with enhanced FAK(Y397) activity. FAK inhibition was sufficient to decrease fibroblast stiffness and collagen expression, supporting that FAK(Y397) hyperactivation may underlie the aberrant mechanobiolog...
Idiopathic Pulmonary Fibrosis: Molecular Mechanisms and Possible Therapeutic Strategies
Inflammation, 2001
A © bstract. Idiopathic pulmonary fibrosis (IPF) is a devastating disease with an almost universally t erminal outc ome. In recent years much insight has been gained into the pathogenesis of IPF from both a bleo mycin mice-model as well as e x vivo human tissue studies. Alveolar damage and inflammation of unknown etiology, e ventually leading to interstitial fibrosis, characterize IPF. Apoptosis has emerged as an i mportant factor in the p athogenesis of IPF. This review will outline the current understanding of the immunologica l and molecular m echanisms underlying IPF and discuss new therapeutic strategies.