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

• Published in: Biochimica et biophysica acta 2013-07, Vol.1832 (7), p.911-921
• Main Authors: Sakai, Norihiko, Tager, Andrew M.
• Format: Article
• Language: English
• Subjects: Apoptosis; Epithelial cells; Epithelial Cells - metabolism; Extracellular matrix; Fibroblasts; Fibroblasts - metabolism; Humans; Idiopathic Pulmonary Fibrosis; Lung - metabolism; Myofibroblasts; Pulmonary Alveoli - metabolism; Pulmonary Fibrosis
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2013.03.001

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. •Interactions between alveolar epithelial cells and fibroblasts are central to IPF.•Injured epithelial cells regulate fibroblasts through TGF-β, CTGF, Shh and PGE2.•Activated fibroblasts injure epithelial cells by producing angiotensin II and ROS.•Epithelial cell-fibroblast interaction may be a common theme in organ fibrosis.