Adiponectin Mediates FGF21 to Alleviate Sepsis-induced Acute Lung Injury by Ameliorating Fibrosis and Inhibiting...

Acute lung injury (ALI) is the initial complication in the pathogenesis of sepsis and a leading cause of mortality in patients with sepsis. Adiponectin (APN), an important downstream effector of fibroblast growth factor 21 (FGF21), exerts metabolic regulatory effects; however, the specific role of FGF21 in alleviating sepsis-induced ALI through APN remains to be fully elucidated.

The present study established a sepsis-induced ALI model in C57BL/6J mice via intraperitoneal injection of lipopolysaccharide (LPS, 15.0 mg/kg). Three FGF21 treatment groups were set up (intraperitoneal injection of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg FGF21 6 hours after LPS administration) to explore the optimal usage concentration of FGF21 in this study. Additionally, adeno-associated virus (AAV)-mediated APN overexpression and knockdown were performed to verify the mediating role of APN.

LPS-induced sepsis significantly increased FGF21 levels in mouse serum (p < 0.05) and lung tissues (p < 0.01), while reducing APN expression (p < 0.01), increasing percent weight loss (%WL ≈ 15%), elevating lung wet-to-dry (W/D) ratio by ~125%, upregulating mRNA levels of inflammatory factors (IL-1β, IL-6, TNF-α; p < 0.001), and promoting pulmonary fibrosis (increased α-SMA and TGF-β1 expression; p < 0.05 or p < 0.01). Among the FGF21 treatment groups, the medium dose (1.0 mg/kg) exhibited the most potent therapeutic effects: it reduced %WL by approximately 40%, decreased lung W/D ratio by approximately 30%, significantly downregulated the expression of inflammatory factors, and attenuated pulmonary fibrosis. APN overexpression mimicked the protective effects of FGF21, whereas APN knockdown partially abolished FGF21's therapeutic benefits. Mechanistically, FGF21 administration significantly reversed the sepsis-induced decrease in APN expression, inhibited pulmonary collagen deposition, and reversed the dysregulated Nrf2-Keap1-HO-1 pathway (upregulating Nrf2 and HO-1, downregulating Keap1; p < 0.05 or p < 0.01), which in turn restored redox homeostasis by increasing serum levels of catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) (p < 0.05 or p < 0.001).

The present study revealed that APN mediates FGF21 to alleviate sepsis-induced ALI in mice, and its mechanism of action may be related to the alleviation of pulmonary fibrosis, the improvement of redox imbalance, and the down-regulation of inflammatory factor expression. This discovery provides a new strategy for the treatment of ALI.

APN mediates FGF21's protective effects against sepsis-induced ALI in mice. The underlying mechanism involves reversing the sepsis-induced decrease in APN expression, inhibiting pulmonary fibrosis, downregulating inflammatory factor expression, and restoring redox homeostasis via the Nrf2-Keap1-HO-1 pathway. This discovery provides a novel therapeutic strategy for the treatment of sepsis-induced ALI.