Pathomechanistic Role of Autophagy in Lung Fibrosis

Autophagy represents a fundamental biological process of a cell aiming to maintain cellular homeostasis by degrading unnecessary macromolecules and non-functional organelles. It is now known that autophagy plays an effective role in development and differentiation, type II programmed cell death, elimination of protein aggregates and protection against tumors and pathogen invasion. Autophagy was initially known as a “bulk” degradation pathway but more recently, selectivity has been ascribed to this pathway either due to binding of specific autophagy receptors or adaptors to the target organelle or specific proteins. Dysregulation of this pathway has been implicated in several pathologies including several lung diseases. In idiopathic pulmonary fibrosis (IPF) and in animal models of lung fibrosis, defective autophagy has been identified and in this study, we aimed to identify the pathomechanistic role of autophagy in the development of lung fibrosis. We summarize our analysis from the lungs and primary interstitial fibroblasts of IPF and healthy donors, mouse model and in vitro model of amiodarone induced lung fibrosis and Hermansky-Pudlak syndrome (HPS) associated lung fibrosis. We identified that autophagy is differently regulated in animal models of lung fibrosis, but lysosomal stress resulting in increased apoptosis of alveolar epithelial cells stands as a common mechanism in all the studied models and provide evidence on how in vitro studies corroborated with our in vivo observations. In addition, we aim to show how specific co-chaperones namely Bcl2 athanogenes influence the autophagy pathway and hint towards cell-type specific functions of autophagy which might essentially contribute towards the development of lung fibrosis.