Abstract Rationale Epithelial injury and impaired repair are key initiating events in pulmonary fibrosis. Hepatocyte Growth Factor (HGF) promotes proliferation and repair across multiple cell types and exhibits anti-fibrotic effects in several organs. Because type II alveolar epithelial cells (AT2) , which are essential for alveolar repair, express Met—the receptor for HGF—we investigated whether HGF suppresses pulmonary fibrosis by acting on AT2. Methods We used a mouse model of pulmonary fibrosis induced by intratracheal administration of bleomycin. Mice received daily intraperitoneal injections of recombinant HGF or vehicle from day 7. The severity of fibrosis was evaluated on day 21 by chest computed tomography (CT), lung hydroxyproline content and histological score. AT2 cell dynamics were analyzed by genetic fate mapping, multicolor flow cytometry, and immunofluorescence imaging. Results In the BLM model, mice treated with HGF showed faster recovery from weight loss and improved survival compared with vehicle-treated mice. On day 21 after BLM administration, the HGF group exhibited smaller lesion areas on chest CT, lower hydroxyproline content, and reduced pathological fibrosis scores. The number of inflammatory cells in the lungs did not differ significantly between the two groups. Immunostaining revealed Met expression in AT2. In lineage-tracing experiments using Sftpc-CreER;RCL-ZsGreen mice, AT2 decreased and KRT8+ transitional epithelial cells increased on day 10 after BLM treatment. HGF administration significantly enhanced AT2 proliferation (Sftpc+Ki-67+) compared with vehicle treatment. Conclusions HGF promotes alveolar epithelial repair by stimulating AT2 proliferation and thereby suppresses pulmonary fibrosis. Targeting the HGF/Met pathway may offer a promising therapeutic strategy for fibrotic lung disease. This abstract is funded by: Kringle Pharma
Muto et al. (Fri,) studied this question.