The leading role of epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and devastating interstitial lung disease of unknown etiology, where the normal lung architecture is lost and replaced by fibrotic tissue leading to an irreversible and progressive respiratory insufficiency. Historically, IPF was considered a chronic inflammatory disorder, which gradually progressed to established fibrosis. However, strong clinical and experimental evidence indicates that the disease represents an epithelial-driven disorder which results from a complex interplay of genetic and environmental risk factors, aging-associated processes and a profibrotic epigenetic reprogramming. The convergence of these factors results in the aberrant activation of epithelial cells that initiate the development of the disease, producing virtually all the mediators that participate in the migration, proliferation and activation of fibroblasts, their differentiation to myofibroblasts and the excessive and chaotic secretion of extracellular matrix proteins. Although progress has been made in understanding the causes and consequences of this abnormal behavior of distal airways and alveolar epithelium, the mechanisms that initiate and perpetuate the vicious circle of multidirectional abnormal communications between the epithelium and fibroblasts and other resident cells have not been elucidated. In this review, we discuss the role of epithelial cells and the mechanisms underlying the fibrotic response in IPF, and highlight some promising therapeutic targets for these cells. • Idiopathic pulmonary fibrosis is a progressive and devastating epithelial-driven disease of unknow etiology. • Common and rare variants affecting lung epithelium integrity and regeneration underlie initiation and progression of IPF. • Exaggerated hallmarks of aging, contribute to the aberrant behavior of lung epithelial cells. • Abnormally re-programmed epithelial cells induce the activation of fibroblasts, and the chaotic production of ECM.