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
... -
《-》
Dexmedetomidine Attenuates Myocardial Injury Induced by Renal Ischemia/Reperfusion by Inhibiting the HMGB1-TLR4-MyD88-NF-κB Signaling Pathway.
To investigate the effect of dexmedetomidine (DEX) on myocardial injury induced by renal ischemia/reperfusion (I/R) and to explore the role of the HMGB1-TLR4-MyD88-NF-κB signaling pathway.
Adult male Wistar rats were randomly allocated into the control group, renal I/R group, renal I/R group pretreated with a low dose of DEX (L-Dex+I/R), renal I/R group pretreated with a medium dose of DEX (M-Dex+I/R), and renal I/R group pretreated with a high dose of DEX (H-Dex+I/R). Outcome measures included the plasma concentrations of HMGB1, IL-6, IL-10, IL-17, and TnI, the expression levels of HMGB1, TLR4, MyD88, NF-κBp65, and P-NF-κBp65, the pathological change, and the cell apoptosis.
Renal I/R led to severe myocardial histological injury and cell apoptosis. DEX reduced the plasma concentration of IL-17 and TnI in a dose-dependent manner in the renal I/R model rats and inhibited the protein expression of TLR4 and NF-κBp65 in a dose-dependent manner in the myocardial tissue. Additionally, mRNA expression of MyD88 was elevated in the I/R group compared with the control group, and DEX significantly reduced mRNA expression of MyD88 in the renal I/R model rats. DEX inhibited myocardial cell apoptosis in the renal I/R model rats.
DEX could attenuate myocardial injury induced by renal I/R in a dose-dependent manner. The potential mechanisms are associated with inhibition of the HMGB1-TLR4-NF-κB signaling pathway and myocardial cell apoptosis.
Zhang B
，Zhang J
，Ainiwaer Y
，He B
，Geng Q
，Lin L
，Li X
... -
《-》
Dexmedetomidine protects against lung injury induced by limb ischemia-reperfusion via the TLR4/MyD88/NF-κB pathway.
Dexmedetomidine (DEX) can protect the lung from ischemia-reperfusion (I/R) injury, but the underlying mechanisms are not fully understood. The aims of this study were to determine whether DEX attenuates lung injury following lower extremity I/R and to investigate the related toll-like receptor 4 (TLR4) signaling pathway. Twenty-eight SD rats were divided into four groups (n = 7): Sham, I/R, I/R + DEX (25 μg/kg prior to ischemia), and I/R + DEX + Atip (250 μg/kg atipamezole before DEX treatment). Lower extremity I/R was induced by left femoral artery clamping for 3 hours and followed by 2 hours reperfusion. Quantitative alveolar damage and the wet/dry (W/D) ratio were calculated. Interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α in the bronchoalveolar lavage fluid (BALF) and serum and myeloperoxidase (MPO) in the lung were measured. The TLR4 and MyD88 mRNA expression levels were measured by RT-PCR, nuclear factor (NF)-κB, and phosphorylated NF-κB by western blot, respectively. Quantitative alveolar damage, W/D ratio, MPO, BALF and serum IL-1, IL-6, and TNF-α, and TLR4, MyD88, NF-κB, and p-NF-κB expression significantly increased in the I/R group relative to the Sham group. DEX preconditioning significantly reduced lung edema, and histological injury relative to the I/R group. Serum and BALF IL-1, IL-6, and TNF-α levels, MPO activity and TLR4, MyD88, NF-κB, and p-NF-κB expression were also significantly reduced in the I/R + DEX group compared with the I/R group. Atipamezole partially reversed all the aforementioned effects. DEX preconditioning protects the lungs against lower extremity I/R injury via α2-adrenoceptor-dependent and α2-adrenoceptor-independent mechanisms. It also suppresses the TLR4 pathway and reduces inflammation.
Xue BB
，Chen BH
，Tang YN
，Weng CW
，Lin LN
... -
《-》
ResearchGate
(全网免费下载)
钛学术
(全网免费下载)
