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

LING Lin, TONG Jing, ZENG Liang

Abstract

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: Paeoniflorin, Sepsis, Acute lung injury, Nrf2/Keap1 signaling pathway

 

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