The pathomechanistic role of autophagy in lung fibrosis

Abstract

Autophagy is a fundamental biological process of every cell that aims to maintain cellular homeostasis by degrading unnecessary macromolecules and non-functional organelles. Dysfunctional autophagy was reported in idiopathic pulmonary fibrosis (IPF), a disease with a remarkable age-related onset which may be triggered by chronic lung alveolar epithelial cell type II (AECII) injury and apoptosis. The principle role of autophagy in cellular homeostasis has been well defined, but remains to be studied in the evolution of several forms of lung fibrosis. Amiodarone (AD) and bleomycin are two lung fibrosis inducing agents which trigger disturbed autophagy within the AECII. In this study, we aimed to identify the role of the autophagy marker protein, LC3B in the development of these two forms of lung fibrosis. First, we performed knock down of LC3B in mouse lung epithelial cells and treated them with AD or bleomycin. LC3B knockdown rescued AD induced apoptosis but on the contrary, increased susceptibility to bleomycin induced injury and apoptosis. A systematic analysis of the LC3B-/- mice lungs revealed that aged LC3B-/- mice showed lung collagen deposition, increased cellularity, decreased alveolar spaces, increased apoptosis of AECII paralleled with surfactant alterations, increased lysosomal and endoplasmic reticulum stress providing clues on the importance of this distal autophagy protein in lung fibrosis development. Further, we were able to identify novel LC3B interaction partners within the AECII by mass spectrometric analysis which are being further confirmed. In conclusion, our studies reveal that autophagy has a pathomechanistic but context-specific role in the development of lung fibrosis.