Local Lung Fibroblast Autophagy in the Context of Lung Fibrosis Pathogenesis

Abstract

Abstract: The current molecular advances in lung fibrosis pathogenesis distend beyond the cellular to involve subcellular and molecular levels. Lung fibrogenesis and autophagy impairment are tight-ly associated. Autophagy is involved in cell cycle control and regulation of the intracellular micro-environment. Degradation of impaired intracellular organelles and biproducts is crucial to maintain-ing a healthy cell and preventing its metaplasia / transdifferentiation to a pathological cell. Autoph-agy modifies the metabolism of alveolar epithelial cells, endothelial cells, and lung fibroblasts. Au-tophagy upregulation induces local lung fibroblast hyperactivity and fibrosis. Several molecular triggers were found to induce lung fibroblast autophagy including TGFβ by inhibition of the PI3K/AKT/mTOR. However, physiologically, a balance is retained between autophagy inducers and inhibitors. Each type of autophagy plays its role in the initiation and progression of lung fibro-sis. The pathogenesis of pulmonary fibrosis is multifactorial and involves dysfunction / dysregula-tion of alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells. The deposition of extracellular matrix proteins, the remodeling of the lung architecture and the mo-lecular changes include impaired glycolysis, mitochondrial oxidation, gene expression modification, altered phospholipid and sphingolipid metabolism, and dysregulated protein folding lead to repro-gramming of lung fibroblast into myofibroblast and their activation. The paper thoroughly addresses the molecular triggers and inhibitors of lung fibroblast autophagy in lung fibrosis.