Fibrosis of two: Epithelial cell-fibroblast interactions in pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. IPF is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological fibrosis due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger IPF remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell death provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and death, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the "pas de deux" (steps of two), or perhaps more appropriate to IPF pathogenesis, the "folie à deux" (madness of two) of epithelial cells and fibroblasts that drives the progression of pulmonary fibrosis. We describe the signaling molecules that mediate the interactions of these cell types in their "fibrosis of two", including transforming growth factor-β, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.

Figure 1. Epithelial-fibroblast interactions drive the progression of idiopathic pulmonary fibrosis

Environmental stimuli initially injure alveolar epithelial cells (AECs), inducing their apoptosis and their production and/or activation of pro-fibrotic mediators, including TGF-β, CTGF and Shh. These AEC-derived mediators direct fibroblast migration, proliferation, activation and myofibroblast differentiation, resulting in the accumulation myofibroblasts and extracellular matrix in the lung. Myofibroblasts in turn secrete mediators that amplify AEC injury and apoptosis, creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions that drives the progression of IPF. PGE₂ normally mediates anti-fibrotic interactions between epithelial cells and fibroblasts, but its production by AECs is reduced in IPF, as is fibroblast PGE₂-responsiveness. Green arrows indicate pro-fibrotic epithelial cell-fibroblast interactions; red arrows indicate anti-fibrotic interactions. TGF-β, transforming growth factor-β; CTGF, connective tissue growth factor; Shh, sonic hedgehog; ANG II, angiotensin II; H₂O₂, hydrogen peroxide; PGE₂, prostaglandin E₂.