Epithelial⁻Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung, which leads to extensive parenchymal scarring and death from respiratory failure. The most accepted hypothesis for IPF pathogenesis relies on the inability of the alveolar epithelium to regenerate after injury. Alveolar epithelial cells become apoptotic and rare, fibroblasts/myofibroblasts accumulate and extracellular matrix (ECM) is deposited in response to the aberrant activation of several pathways that are physiologically implicated in alveologenesis and repair but also favor the creation of excessive fibrosis via different mechanisms, including epithelial⁻mesenchymal transition (EMT). EMT is a pathophysiological process in which epithelial cells lose part of their characteristics and markers, while gaining mesenchymal ones. A role for EMT in the pathogenesis of IPF has been widely hypothesized and indirectly demonstrated; however, precise definition of its mechanisms and relevance has been hindered by the lack of a reliable animal model and needs further studies. The overall available evidence conceptualizes EMT as an alternative cell and tissue normal regeneration, which could open the way to novel diagnostic and prognostic biomarkers, as well as to more effective treatment options.

Keywords: UIP; epithelial mesenchymal transition; idiopathic pulmonary fibrosis; lung repair; myofibroblasts.

Figure 1

Key pathways regulating lung fibrosis. Repetitive injuries of lung lead to an aberrant activation of developmental/EMT (epithelial–mesenchymal transition) pathways (e.g., Wnt, Sonic Hedgehog and transforming growth factor-beta (TGF-β)) due to the inability of the alveolar epithelium to regenerate. This creates a pro-fibrotic environment in which loss of epithelial phenotype, acquisition of mesenchymal phenotype, fibroblasts activation and collagen production take place. The combination of these events leads to lung fibrosis.