[Paeoniflorin Improves Acute Lung Injury in Sepsis by Activating Nrf2/Keap1 Signaling Pathway]

Objective: To investigate the effect of paeoniflorin (PF) on sepsis-induced acute lung injury and its relationship with nuclear factor erythyroid 2-related factor 2 (Nrf2)/Kelch-like ECH2 associated protein 1 (Keap1) signaling pathway.

Methods: Cecal ligation and puncture (CLP) was used to induce the sepsis rat model. Rats were randomly divided into 5 groups (n=10): sham group (Sham), model group (Model), low dose PF group (L-PF group, 50 mg/kg PF), high dose PF group (H-PF group, 150 mg/kg PF) and high dose PF+Nrf2 inhibitor group (H-PF+ML385 group, 150 mg/kg PF+30 mg/kg ML385). The severity of sepsis in rats was scored according to the improved severity scale of sepsis; the pathological changes of lung tissue were observed by HE staining; the activity of superoxide dismutase (SOD) in lung tissue was determined by xanthine oxidase method; the content of malondialdehyde (MDA) in lung tissue was measured by thiobarbituric acid method; and the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in lung tissues were detected by ELISA. Western blot was used to detect the expression of Nrf2, Keap1 and HO-1 proteins in lung tissues.

Results: Compared with Sham group, the sepsis symptoms in Model group were more serious, severe inflammatory infiltration in lung tissue, macrophages and interstitial enlargement, and the contents of pro-inflammatory factors IL-1β, TNF-α, IL-6 and oxidative index MDA in lung tissues were significantly increased (P<0.05), while the activity of antioxidant index SOD were significantly decreased (P<0.05). The protein and mRNA expression levels of Nrf2 and HO-1 were significantly decreased (P<0.05), while the protein and mRNA expression levels of Keap1 were markedly increased (P<0.05). Compared with the Model group, the severity of sepsis in PF groups was decreased, the lung tissue injury was improved, the contents of IL-1β, TNF-α, IL-6 and MDA in lung tissue were significantly decreased (P<0.05), the activity of SOD was markedly increased (P<0.05), the protein and mRNA expression levels of Nrf2 and HO-1 were significantly increased (P<0.05), and the expression levels of Keap1 protein and mRNA were significantly decreased (P<0.05). Compared with the H-PF group, Nrf2 inhibitor ML385 significantly inhibited the improvement of PF on lung injury in sepsis rats.

Conclusion: PF can reduce oxidative stress and inflammation by activating Nrf2/Keap1 signaling pathway, and improve sepsis-induced acute lung injury.

Keywords: Acute lung injury; Nrf2/Keap1 signaling pathway; Paeoniflorin; Sepsis.