Objective To investigate the mechanism of dexmedetomidine regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1(Nrf2/HO-1) signaling pathway on oxidative stress and inflammatory response in lipopolysaccharide-induced acute lung injury (ALI). Methods Mice were randomly divided into a blank control group (Control group), ALI mouse model group (ALI group), dexmedetomidine intervention group (DEX group), and dexmedetomidine combined with Nrf2 inhibitor ML385 group (DEX+ML385 group). Calculate the wet/dry weight ratio of lung tissue, detect pathological changes in lung tissue using HE staining, detect oxidative stress indicators in lung tissue and levels of inflammatory factors in alveolar lavage fluid, and detect the expression of Nrf2 and HO-1 proteins in lung tissue using Western blotting. Results Compared with the control group, mice in the ALI group showed significantly higher lung tissue wet/dry weight ratio (W/D), lung injury pathological score, counts of total cells, neutrophils and macrophages in bronchoalveolar lavage fluid (BALF), levels of tumor necrosis factor-α (TNF-α), interleukin (IL) -6, IL-1β and IL-18, as well as malondialdehyde (MDA) content and myeloperoxidase (MPO) activity in lung tissue. In contrast, glutathione peroxidase (GSH-Px) content, superoxide dismutase (SOD) activity, and protein expressions of nuclear factor erythroid 2-related factor 2(Nrf2) and heme oxygenase-1(HO-1) in lung tissue were markedly lower in the ALI group. Compared with the ALI group, the DEX group showed significantly decreased lung tissue W/D value, lung injury histopathological score, total cell count, neutrophil count, macrophage count, TNF-α, IL-6, IL-1β, IL-18 levels in BALF, lung tissue MDA content and MPO activity. Moreover, the DEX group exhibited significantly increased lung tissue GSH-Px content, SOD activity, Nrf2, and HO-1 protein expression. However, compared with the DEX group, the DEX AL385 group showed significantly increased lung tissue W/D value, lung injury histopathological score, total cell count, neutrophil count, macrophage count, TNF-α, IL-6, IL-1β, IL-18 levels in BALF, lung tissue MDA content and MPO activity. Additionally, the DEX AL385 group exhibited significantly decreased lung tissue GSH-Px content, SOD activity, Nrf2, and HO-1 protein expression (P<0.05). Conclusion Dexmetomidine can improve the antioxidant capacity and inhibit inflammatory response in lipopolysaccharide-induced acute lung injury mice, thereby exerting a protective effect on lung tissue. Its mechanism of action may be related to the activation of the Nrf2/HO-1 signaling pathway.
Key words
dexmetomidine /
Nrf2/HO-1 signaling pathway /
lipopolysaccharide induced acute lung injury /
oxidative stress /
inflammatory reaction
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
References
[1] LONG ME, MALLAMPALLI RK, HOROWITZ JC.Pathogenesis of pneumonia and acute lung injury[J]. Clin Sci (Lond), 2022, 136(10): 747-769.
[2] PARK BD, FAUBEL S.Acute kidney injury and acute respiratory distress syndrome[J]. Crit Care Clin, 2021, 37(4): 835-849.
[3] MEI B, LI J, ZUO Z.Dexmedetomidine attenuates sepsis-associated inflammation and encephalopathy via central α2A adrenoceptor[J]. Brain Behav Immun, 2021, 91: 296-314.
[4] 孔岚, 白玉. 右美托咪定对胸腔镜肺癌根治术患者围手术期炎症反应及氧化应激反应的影响[J]. 医药导报, 2019, 38(7): 910-913.
[5] 饶习敏, 顾延会, 刘晓丽, 等. 盐酸氨溴索对脂多糖诱导急性肺损伤大鼠肺血管重塑的改善作用及机制[J]. 中国老年学杂志, 2024, 44(05): 1112-1118.
[6] LUO L, HUANG F, ZHONG S, et al.Astaxanthin attenuates ferroptosis via Keap1-Nrf2/HO-1 signaling pathways in LPS-induced acute lung injury[J]. Life Sci, 2022, 311(Pt A): 121091.
[7] XIAO K, HE W, GUAN W, et al.Mesenchymal stem cells reverse EMT process through blocking the activation of NF-κB and Hedgehog pathways in LPS-induced acute lung injury[J]. Cell Death Dis, 2020, 11(10): 863.
[8] TANG J, XU L, ZENG Y, et al.Effect of gut microbiota on LPS-induced acute lung injury by regulating the TLR4/NF-kB signaling pathway[J]. Int Immunopharmacol, 2021, 91: 107272.
[9] HOU L, ZHANG J, LIU Y, et al.MitoQ alleviates LPS-mediated acute lung injury through regulating Nrf2/Drp1 pathway[J]. Free Radic Biol Med, 2021, 165: 219-228.
[10] XIA L, ZHANG C, LV N, et al.AdMSC-derived exosomes alleviate acute lung injury via transferring mitochondrial component to improve homeostasis of alveolar macrophages[J]. Theranostics, 2022, 12(6): 2928-2947.
[11] ZHU H, WANG S, SHAN C, et al.Mechanism of protective effect of xuan-bai-cheng-qi decoction on LPS-induced acute lung injury based on an integrated network pharmacology and RNA-sequencing approach[J]. Respir Res, 2021, 22(1): 188.
[12] DHLAMINI Q, WANG W, FENG G, et al.FGF1 alleviates LPS-induced acute lung injury via suppression of inflammation and oxidative stress[J]. Mol Med, 2022, 28(1): 73.
[13] KAYE AD, CHERNOBYLSKY DJ, THAKUR P, et al.Dexmedetomidine in enhanced recovery after surgery (ERAS) protocols for postoperative pain[J]. Curr Pain Headache Rep, 2020, 24(5): 21.
[14] 孙颜, 王向辉, 任丹琪, 等. 右美托咪定对老年患者胸腔镜肺癌根治术后肺部并发症及炎症反应的影响[J]. 临床与病理杂志, 2022, 42(10): 2510-2515.
[15] YAMAZAKI S, YAMAGUCHI K, SOMEYA A, et al.Anti-Inflammatory Action of Dexmedetomidine on Human Microglial Cells[J]. Int J Mol Sci, 2022, 23(17): 10096.
[16] 姜远旭, 詹美俊, 幸志强, 等. 右美托咪定通过α7nAChR介导的TLR4/NF-κB通路减轻脂多糖诱导的急性肺损伤[J]. 解放军医学杂志, 2021, 46(3): 231-237.
[17] GUO Y, LIU Y, ZHAO S, et al.Oxidative stress-induced FABP5 S-glutathionylation protects against acute lung injury by suppressing inflammation in macrophages[J]. Nat Commun, 2021, 12(1): 7094.
[18] HONG H, LOU S, ZHENG F, et al.Hydnocarpin D attenuates lipopolysaccharide-induced acute lung injury via MAPK/NF-κB and Keap1/Nrf2/HO-1 pathway[J]. Phytomedicine, 2022, 101: 154143.
[19] KANG JY, XU MM, SUN Y, et al.Melatonin attenuates LPS-induced pyroptosis in acute lung injury by inhibiting NLRP3-GSDMD pathway via activating Nrf2/HO-1 signaling axis[J]. Int Immunopharmacol, 2022, 109: 108782.
[20] 阮丹, 朱金月, 罗波, 等. 柚皮素通过调控Nrf2/HO-1信号通路对百草枯中毒大鼠急性肺损伤保护的作用[J]. 中国急救医学, 2021, 41(6): 524-528
PDF(3281 KB)
