目的 探究右美托咪定（dexmedetomidine,DEX）调控Nrf2/HO-1信号通路对脂多糖诱导急性肺损伤（acute lung injury,ALI）模型氧化应激和炎症反应的作用机制。方法 将小鼠随机分为空白对照组（Control组）、ALI小鼠模型组（ALI组）、右美托咪定干预组（DEX组）、右美托咪定联合Nrf2抑制剂ML385组（DEX+ML385组）。计算肺组织湿/干重比,检测肺组织病理学变化（HE染色）、肺组织中氧化应激指标及肺泡灌洗液中炎症因子水平,蛋白质印迹法检测肺组织中核因子E2相关因子2（nuclear factor erythroid 2-related factor,Nrf2）、血红素氧化酶-1（hemeoxygenase-1,HO-1）蛋白表达。结果 ALI组小鼠肺组织湿/干重比值、肺损伤病理学评分、BALF中总细胞、中性粒细胞、巨噬细胞计数、肿瘤坏死因子（tumor necrosis factor,TNF）-α、白细胞介素（interleukin,IL）-6、IL-1β、IL-18含量、肺组织中丙二醛（malondialdehyde,MDA）含量和髓过氧化物酶（myeloperoxidase,MPO）活性均高于Control组,肺组织中谷胱甘肽过氧化物酶（glutathion peroxidase,GSH-Px）含量、超氧化物歧化酶（superoxide dismutase,SOD）活性及Nrf2、HO-1蛋白表达均低于Control组;和ALI组相比,DEX组小鼠肺组织湿/干重比值、肺损伤病理学评分、支气管肺泡灌洗液中总细胞、中性粒细胞、巨噬细胞计数、TNF-α、IL-6、IL-1β、IL-18含量、肺组织中MDA含量和MPO活性明显降低,肺组织中GSH-Px含量、SOD活性及Nrf2、HO-1蛋白表达明显增加;DEX+AL385组小鼠肺组织W/D值、肺损伤病理学评分、支气管肺泡灌洗液中总细胞、中性粒细胞、巨噬细胞计数、TNF-α、IL-6、IL-1β、IL-18含量、肺组织中MDA含量和MPO活性明显高于DEX组,肺组织中GSH-Px含量、SOD活性及Nrf2、HO-1蛋白表达明显低于DEX组。结论 右美托咪定可改善脂多糖诱导急性肺损伤小鼠抗氧化能力,抑制炎症反应,从而对肺组织发挥保护作用,其作用机制可能和激活Nrf2/HO-1信号通路有关。
Abstract
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.
关键词
右美托咪定 /
Nrf2/HO-1信号通路 /
脂多糖诱导急性肺损伤 /
氧化应激 /
炎症反应
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}}
参考文献
[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
基金
2023年度四川省中医药管理局中医药科研专项课题“浮针疗法治疗骨质疏松性骨折经皮锥体成形术（PVP）后残余痛的效果观察”（2023MS010）
PDF(3281 KB)
