PMC:7565665 / 38538-41679 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7565665","sourcedb":"PMC","sourceid":"7565665","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7565665","text":"4.6. Autophagy Defects in IPF\nIPF is a chronic, progressive, and frequently fatal disease associated with aging and dysfunctional autophagy. It is accepted that accelerated epithelial cell senescence plays a vital role in IPF pathogenesis by virtue of atypical epithelial–mesenchymal interactions, and insufficient autophagy is attributed as a mechanism of accelerated epithelial cell senescence and myofibroblast differentiation in IPF [155]. Bleomycin is widely used as a model of drug-induced lung fibrosis. The first study to describe the protective role of autophagy in bleomycin-induced lung fibrosis used the Atg4b-deficient mice model [156]. After 7 days of bleomycin treatment, these mice demonstrated a significantly higher neutrophilic infiltration and inflammatory cytokine production as compared to untreated mice [156]. Additionally, after 28 days of bleomycin treatment, mice developed extensive lung fibrosis, which was accompanied by an elevated collagen deposition and deregulated expression of extracellular matrix genes [156]. Similarly, in mice deficient in LC3B (LC3B−/−), bleomycin-mediated lung injury and fibrotic changes were more pronounced, suggesting the protective role of autophagy in bleomycin-induced lung injury and the resulting development of fibrotic lung disease in mice [157]. Another recent study describes the protective role of the anti-inflammatory cytokine IL-37 in the IPF murine model [158]. A further mechanistic delve into the mechanism of IL-37-mediated protection showed that it induces Beclin-1-dependent autophagy while downregulating TGFβ1-mediated lung fibroblast proliferation [158]. Moreover, IL-37 also decreased inflammation and collagen deposition in bleomycin-treated murine lungs while the protective effect was reversed by treatment with 3-methyladinine (3MA), an autophagy inhibitor [158]. Thus, it is plausible that a decrease in IL-37-mediated autophagy might be involved in the progression of IPF. Moreover, the protective effects of autophagy are apparent from this and the other mechanistic studies mentioned above.\nAdditional mechanistic evidence comes from a study that showed bleomycin directly binds to annexin A2 (ANXA2) in lung epithelial cells, thereby preventing the nuclear translocation of TFEB; thus, there is an inhibition of the autophagy flux resulting in fibrotic lung disease pathogenesis [159]. Moreover, torin1-mediated TFEB activation restores autophagy flux and ameliorates bleomycin-induced pulmonary fibrosis [159]. Autophagy dysfunction is also reported in human lung fibroblasts from IPF patients, and it is believed that defective autophagy is required to maintain a cell death-resistant phenotype in IPF fibroblasts, suggesting that autophagy dysfunction is a profibrotic mechanism and promotes IPF pathogenesis [64]. Hence, in age-related IPF pathogenesis, autophagy declines with age and the resulting imbalance of inflammatory-oxidative responses is anticipated to mediate the initiation of fibrotic pathophysiology. However, further clinical evaluation is needed to evaluate the therapeutic potential of autophagy augmentation in IPF 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