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Abstract：
Acute lung injury (ALI) is a major pathophysiological problem characterized by severe inflammation, resulting in high morbidity and mortality. Plumbagin (PL), a major bioactive constituent extracted from the traditional Chinese herb Plumbago zeylanica, has been shown to possess anti-inflammatory and antioxidant pharmacological activities. However, its protective effect on ALI has not been extensively studied. The objective of this study was to investigate the protective effect of PL against ALI induced by LPS and to elucidate its possible mechanisms both in vivo and in vitro. PL treatment significantly inhibited pathological injury, MPO activity, and the wet/dry ratio in lung tissues, and decreased the levels of inflammatory cells and inflammatory cytokines TNF-α, IL-1β, IL-6 in BALF induced by LPS. In addition, PL inhibited the activation of the PI3K/AKT/mTOR signalling pathway, increased the activity of antioxidant enzymes CAT, SOD, GSH and activated the Keap1/Nrf2/HO-1 signalling pathway during ALI induced by LPS. To further assess the association between the inhibitory effects of PL on ALI and the PI3K/AKT/mTOR and Keap1/Nrf2/HO-1 signalling, we pretreated RAW264.7 cells with 740Y-P and ML385. The results showed that the activation of PI3K/AKT/mTOR signalling reversed the protective effect of PL on inflammatory response induced by LPS. Moreover, the inhibitory effects of PL on the production of inflammatory cytokines induced by LPS also inhibited by downregulating Keap1/Nrf2/HO-1 signalling. In conclusion, the results indicate that the PL ameliorate LPS-induced ALI by regulating the PI3K/AKT/mTOR and Keap1-Nrf2/HO-1 signalling, which may provide a novel therapeutic perspective for PL in inhibiting ALI.
摘要：
急性肺损伤(ALI)是以严重炎症为特征的主要病理生理问题,导致高发病率和死亡率。铅球（PL），一种从传统中草药白头翁中提取的主要生物活性成分，已被证明具有抗炎和抗氧化的药理活性。然而,其对ALI的保护作用尚未得到广泛研究。本研究的目的是研究PL对LPS诱导的ALI的保护作用，并阐明其在体内和体外的可能机制。PL治疗显著抑制病理损伤，MPO活动,和肺组织的湿/干比率，并降低炎症细胞和炎症细胞因子TNF-α的水平，IL-1β,LPS诱导的BALF中的IL-6。此外,PL抑制PI3K/AKT/mTOR信号通路的激活,增加了抗氧化酶CAT的活性，SOD,在LPS诱导的ALI过程中，GSH和激活Keap1/Nrf2/HO-1信号通路。为了进一步评估PL对ALI的抑制作用与PI3K/AKT/mTOR和Keap1/Nrf2/HO-1信号之间的关联，我们用740Y-P和ML385预处理RAW264.7细胞。结果表明，PI3K/AKT/mTOR信号的激活逆转了PL对LPS诱导的炎症反应的保护作用。此外，PL对LPS诱导的炎性细胞因子产生的抑制作用也通过下调Keap1/Nrf2/HO-1信号传导来抑制。总之,结果表明，PL通过调节PI3K/AKT/mTOR和Keap1-Nrf2/HO-1信号来改善LPS诱导的ALI，这可能为PL抑制ALI提供新的治疗视角。
