Abstract
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.
Keywords:
AKT; PTX3; acute and chronic injuries; epithelial-fibroblast crosstalk; pulmonary fibrosis.