Epithelial Injury and Dysfunction in the Pathogenesis of Idiopathic PulmonaryFibrosis

Abstract

Idiopathic pulmonary fibrosis is a disease of older adults leading to progressive dyspnea and reduced exercise capacity, typically resulting in death within 3-5years of diagnosis. Underlying genetic susceptibility combined with environmental insults is proposed to trigger a chronic wound repair response, leading to activation of the fibrotic cascade. Perturbations in several molecular pathways mediate vulnerability of the alveolar epithelium to injurious agents, including the unfolded protein response, autophagy, mitophagy, and cellular senescence. These cellular responses are intricately intertwined and link genetic susceptibility to the progressive fibrotic phenotype. Ongoing studies investigating these pathways in type II alveolar epithelial cells show promise for identifying new targeted interventions that could prevent or halt the progression of IPF.

Keywords: Autophagy; Endoplasmic reticulum stress; Idiopathic pulmonary fibrosis; Mitophagy; Senescence.

Figure 1.. Molecular pathways influencing pro-fibrotic phenotypes of type II alveolar epithelial (AT2) cells in IPF.

Genetic and environmental factors converge to regulate pathways that affect the ability of AT2 cells to respond to injury, including ER stress, mitophagy, autophagy, and DNA damage response. Pathological interactions and imbalances between these pathways result in pro-fibrotic phenotypes in AT2 cells, including senescence and apoptosis, which contribute to IPF pathogenesis.