Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts, as well as continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, potentially novel flow cytometry strategies to quantify lung fibroblast subsets, and transcriptional profiling of lung fibroblasts by bulk and single cell RNA sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued profibrotic functions of lung fibroblasts. Our studies provide insights into the mechanisms that contribute to fibroblast survival, persistence, and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis impairs fibrosis resolution.
Highlights
Idiopathic pulmonary fibrosis (IPF), a progressive fibrotic lung disorder of high morbidity and mortality, develops in response to initial alveolar epithelial injury and results in an aberrant repair response in which resident lung interstitial and perivascular fibroblasts proliferate, differentiate into myofibroblasts, and persist within the collapsed alveoli and septal interstitium [1, 2]
To ensure that Fas was deleted, we isolated lung fibroblasts from WT and Dermo1-Cre;Fas–/– mice, and we assessed their level of cell surface Fas expression by flow cytometry and their ability to undergo apoptosis (a) following sensitization with TNF-α and IFN-α and Fas-ligation with agonistic antiFas antibody (Jo2), and (b) in response to staurosporine, an activator of the intrinsic apoptosis pathway
Substantial progress has been made in understanding the mechanisms of alveolar epithelial injury and its role in driving fibroblast recruitment, proliferation, and excessive extracellular matrix (ECM) deposition in the distal lung
Summary
Idiopathic pulmonary fibrosis (IPF), a progressive fibrotic lung disorder of high morbidity and mortality, develops in response to initial alveolar epithelial injury and results in an aberrant repair response in which resident lung interstitial and perivascular fibroblasts proliferate, differentiate into myofibroblasts, and persist within the collapsed alveoli and septal interstitium [1, 2]. Acute respiratory distress syndrome (ARDS) patients exhibit high morbidity and mortality resulting from initial alveolar epithelial injury [3] Likewise, they accumulate profibrotic fibroblasts that secrete collagen and ECM components within the injured alveoli early in their clinical course [4,5,6]. While ARDS patients experience high initial mortality, the early fibroproliferative response can resolve, and lung structure and function can return toward normality in some, though not all, survivors [3, 7, 8]
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