Plumbagin ameliorates LPS-induced acute lung injury by regulating PI3K/AKT/mTOR and Keap1-Nrf2/HO-1 signalling pathways.
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.
Liu Z
，Wei J
，Sun H
，Xu L
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The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1-mediated TLR4/NF-κB and PI3K/Akt/mTOR pathways.
The aim of present study was to evaluate the protective effects of dexmedetomidine (DEX) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and investigate its possible mechanisms mediated by HMGB1. In vivo, pulmonary pathology observation and myeloperoxidase (MPO) activity were also examined to evaluate the protective effect of DEX in the lungs. Tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF), serum and lung tissues LPS-induced rats were detected. The oxidative indices including superoxide dismutase (SOD), Malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in serum were also determined. Additionally, nitric oxide (NO), TNF-α, IL-6 and IL-1β, MDA, SOD and GSH-Px in the supernatants of LPS-induced BEAS-2B cells were measured. Furthermore, we detected the protein expression of high mobility group box-1 protein (HMGB1), Toll-like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), inhibitor of NF-κB (IκBα), p-IκBα, nuclear factor kappa-B (NF-κB), p-NF-κB, phosphatidylinositol 3'-kinase (PI3K), p-PI3K, protein kinase B (Akt), p-Akt, mammalian target of rapamycin (mTOR) and p-mTOR in LPS-induced ALI rats and LPS-induced BEAS-2B cells. Immunohistochemical and immunofluorescence analyses of HMGB1 in lung tissues or BEAS-2B cells were also conducted to evaluate the mechanisms of DEX. DEX effectively attenuated pulmonary pathology, and ameliorated the levels of MPO, SOD, MDA, GSH-Px, TNF-α, IL-6, IL-1β and NO in LPS-stimulated rats and BEAS-2B cells. Additionally, treatment with DEX inhibited the expression of HMGB1, TLR4, MyD88, p-IκB, p-NF-κB, p-PI3K, p-Akt and p-mTOR in vivo and in vitro. Immunohistochemical and immunofluorescence analyses also showed that DEX suppressed HMGB1 levels in lung sections and BEAS-2B cells. Treatment with glycyrrhizin, an inhibitor of HMGB1, confirmed that HMGB1 was involved in the mechanism of DEX on LPS-induced ALI. The transfection of HGMB1 siRNA also confirmed these findings in vitro. In conclusion, the present study showed that DEX exerted a protective effect on LPS-induced ALI rats likely through the HMGB1-mediated TLR4/NF-κB and PI3K/Akt/mTOR pathways.
Meng L
，Li L
，Lu S
，Li K
，Su Z
，Wang Y
，Fan X
，Li X
，Zhao G
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ResearchGate
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钛学术
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