Atg5 deficiency alters myofibroblast accumulation and alveolar regeneration in lung fibrosis.

Abstract

Lung fibrosis progression is marked by impaired alveolar epithelial regeneration and uncontrolled myofibroblast differentiation, though the underlying mechanisms remain poorly understood. In this study, we discovered that Atg5 was upregulated in the mesenchymal cells of lungs from both patients with idiopathic pulmonary fibrosis (IPF) and mice with bleomycin (BLM)-induced fibrosis. Selective deletion of Atg5 in lung mesenchymal cells increased the susceptibility of mice to BLM-induced lung fibrosis. Mechanistically, the loss of Atg5 promoted transforming growth factor β 1 (TGF-β1)-induced oxidative stress and cellular senescence in fibroblasts, myofibroblast differentiation, and extracellular matrix deposition. Intriguingly, loss of Atg5 impaired the secretion of tissue repair-favoring factors in fibroblasts, causing defects in the proliferation and differentiation of alveolar type 2 cells. This study showed that Atg5 is essential for alveolar epithelial repair and myofibroblast control in lung fibrosis.