FGF8 alleviates LPS-induced acute lung injury via the PPARγ/ERK1/2 signalling pathway in mice

Acute lung injury (ALI) and progressive acute respiratory distress syndrome (ARDS) have high mortality and limited effective therapies. Fibroblast growth factor 8 (FGF8) participates in lung development, inflammation and cell regulation, yet its function in ALI remains unclear.

We constructed an LPS-induced mouse ALI model to detect FGF8 expression. FGF8 haploinsufficiency and overexpression systems were used to explore its biological function. RNA-seq combined with GO and KEGG enrichment analyses screened target pathways, which were further verified via experiments. The PPARγ antagonist GW9662 was applied to confirm the regulatory role of PPARγ.

Lung FGF8 expression was significantly upregulated in LPS-challenged mice. FGF8 haploinsufficiency exacerbated weight loss, pulmonary edema, lung histological injury, pro-inflammatory cytokine (IL-1β, IL-6, TNF-α) release, and apoptosis imbalance. It also accelerated collagen accumulation and elevated profibrotic markers including α-SMA, TGF-β1 and COL1A1. Conversely, FGF8 overexpression relieved all these pathological phenotypes. Mechanistically, FGF8 haploinsufficiency inhibited PPARγ and activated ERK1/2 phosphorylation, while FGF8 overexpression reversed this change. Blocking PPARγ with GW9662 further boosted ERK1/2 activation and abolished the protective effects of FGF8 against ALI.

FGF8 alleviates inflammation, apoptosis and early pulmonary fibrosis in LPS-induced ALI mice via the PPARγ/ERK1/2 signaling pathway.