关键词: 瑞马唑仑, 哮喘, 氧化应激, 核转录因子E2相关因子2, 血红素加氧酶-1

Abstract: Objective To investigate the effects of remimazolam on airway inflammation and oxidative stress in a mouse model of ovalbumin(OVA)-induced bronchial asthma and explore the potential underlying mechanism of this effect. Methods Forty specific pathogen-free(SPF)male BALB/c mice(6-8 weeks old,18-20 g)were randomly divided into 4 groups(n=10 per group):control group,OVA-induced asthma group(OVA group),remimazolam intervention group(OVA+RMZL group),and dexamethasone(DEX)positive control group(OVA+DEX group).The bronchial asthma model was established via OVA sensitization followed by OVA challenge.One hour prior to each challenge,the mice in the OVA+RMZL group received an intraperitoneal injection of remimazolam(10 mg/kg),whereas the mice in the control group were administered phosphate-buffered saline(PBS,pH 7.4)instead.Airway pressure was measured via a lung function analyzer.Hematoxylin-eosin(HE)staining and periodic acid-Schiff(PAS)staining were performed to assess pathological changes and mucus secretion in lung tissues,respectively.An enzyme-linked immunosorbent assay(ELISA)was used to determine the concentrations of interleukin(IL)-4,IL-5,IL-13,and interferon-γ(IFN-γ)in bronchoalveolar lavage fluid(BALF),and OVA-specific immunoglobulin E(IgE)in serum.The levels of malondialdehyde(MDA),superoxide dismutase(SOD),and reduced glutathione(GSH)in lung tissues were detected via commercial assay kits.Reverse transcription-polymerase chain reaction(RT-PCR)and Western blotting were employed to measure the mRNA and protein expression levels of nuclear factor erythroid 2-related factor 2(Nrf2)and heme oxygenase-1(HO-1),respectively,in lung tissues.Additionally,immunohistochemistry was used to evaluate the nuclear translocation of Nrf2 in lung tissues. Results Compared with the control group,the OVA group presented a significant increase in airway pressure,scores of lung inflammation and mucus secretion,levels of T helper 2(Th2)cytokines(IL-4,IL-5,IL-13)in BALF,serum OVA-specific IgE concentration,contents of reactive oxygen species(ROS)and MDA,as well as the mRNA and protein expression levels of Nrf2,HO-1,and NAD(P)H:quinone oxidoreductase 1(NQO1)(all P<0.05).In contrast,the OVA group presented significant decreases in the BALF IFN-γ level,SOD activity,and GSH content(all P<0.05).Compared with the OVA group,both the OVA+RMZL and OVA+DEX groups presented significant reductions in airway pressure,scores of lung inflammation and mucus secretion,levels of Th2 cytokines(IL-4,IL-5,IL-13)in BALF,serum OVA-specific IgE concentration,and contents of ROS and MDA(all P<0.05).Conversely,these two intervention groups presented significant increases in the IFN-γ level,SOD activity,GSH content,and Nrf2,HO-1,and NQO1 mRNA and protein expression levels(all P<0.05). Conclusion Remimazolam can alleviate airway inflammation and ameliorate oxidative stress in the lung tissues of OVA-induced asthmatic mice.The protective effect of remimazolam may be attributed to its ability to activate the Nrf2/HO-1 signaling pathway.

Key words: Remimazolam, asthma, oxidative stress, Nrf2, HO-1