A dual role of fibroblast–epithelial crosstalk in acute and chronic lung injury

Dysfunctional interactions between fibroblasts and epithelial cells contribute to the progression of chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). In this study, we developed an air-liquid interface coculture model of human-derived small airway epithelial cells and lung fibroblasts to investigate intercellular dynamics during disease progression. Our findings showed that chronic epithelial damage initiates a bidirectional fibrotic cascade between the epithelium and the lung fibroblasts, exacerbating epithelial injury and the release of pro-fibrotic mediators. Conversely, our transcriptomic and proteomic analyses revealed that, in the context of acute epithelial injury, a protective signaling environment emerges that mitigates further damage. By delineating secreted regulators involved in these beneficial responses, we identified pentraxin 3 (PTX3) as a leading antifibrotic candidate. Supplementation with PTX3 in chronically injured epithelial cells alleviated the pro-fibrotic phenotype and preserved epithelial barrier integrity through modulation of the AKT/claudin-2 axis. These insights highlight key differences between acute and chronic lung injuries and underscore the importance of the complex interplay between epithelial cells and fibroblasts in lung injury and repair.