目的 探讨富马酸氯马斯汀(clemastine fumarate, CLE)对大鼠高原缺氧肺损伤的影响。方法 按照随机数字表法,将40只8周龄雄性SD大鼠分为对照组(C组)、高原缺氧肺损伤组(HH组)、地塞米松治疗组(DXM组)、氯马斯汀治疗组(CLE组),每组10只。将HH组、DXM组和 CLE组以低压低氧模式放入动物实验舱,DXM组入舱前1 h开始每6 h肌注2 mg/kg DXM,CLE组入舱前2 h按0.9 mg/kg肌注CLE,入舱10 h后按0.9 mg/kg追加一次用药,完成造模。立即处死大鼠,测肺组织湿/干重比(W/D);HE染色观察肺组织病理学变化;PCR检测肺组织中白细胞介素1β(IL-1β)、肿瘤坏死因子α(TNF-α)、Toll样受体4(TLR4)和核因子κB(NF-κB)的mRNA水平;Western blot法检测IL-1β、TNF-α、TLR4和NF-κB蛋白表达水平。结果 与C组比较,HH组、DXM组、CLE组肺组织W/D比值明显升高(P<0.05),肺组织中IL-1β、TNF-α、TLR4、NF-κB的mRNA转录水平和蛋白表达水平均明显升高(P<0.05)。与HH组比较,DXM组和CLE组肺组织W/D比值明显降低(P<0.05),肺组织中IL-1β、TNF-α、TLR4、NF-κB的mRNA转录水平和蛋白表达水平均明显降低(P<0.05)。结论 富马酸氯马斯汀可以减轻大鼠高原缺氧肺损伤程度。
Abstract
Objective To explore the effect of clemastine fumarate on hypoxic lung injury in rats at high altitude.Methods Forty eight-week-old male SD rats were equally divided into the control group (group C), high altitude hypoxia lung injury group (HH group), dexamethasone treatment group (DXM group) and clemastine fumarate treatment group (CLE group) using the random number table method. The HH group, DXM group and CLE group were put into an animal experiment cabin separately in a low-pressure and hypoxic mode. The DXM group was intramuscularly injected with 2 mg/kg DXM every 6 hours starting from one hour before entry. The CLE group was intramuscularly injected with 0.9 mg/kg 2 h before entry, and another dose of 0.9mg/kg was given 10 hours after entry into the cabin, thus completing the establishment of the model. The rats in each group were immediately sacrificed before the wet/dry weight ratio (W/D) of the upper lobes of right lungs was measured. HE staining was performed on the tissues of the lower lobes of right lungs. The mRNA levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB) in lung tissues were detected by PCR. Expression levels of IL-1β, TNF-α, TLR4 and NF-κB were determined by Western blot.Results Compared with the control group, the W/D ratios of the HH group, DXM group and CLE group were significantly increased (P<0.05), so were the mRNA transcription and protein expression levels of IL-1β, TNF-α, TLR4 and NF-κB in lung tissues (all P<0.05). Compared with the HH group, the W/D ratios of DXM group and CLE group were significantly decreased (P<0.05), so were mRNA transcription and protein expression levels of IL-1β, TNF-α, TLR4 and NF-κB (all P<0.05).Conclusions Clemastine fumarate can reduce the degree of high altitude hypoxic lung injury in rats.
关键词
富马酸氯马斯汀 /
肺损伤 /
高原病 /
缺氧
Key words
clemastine fumarate /
lung injury /
altitude sickness /
hypoxia
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参考文献
[1] Bärtsch P, Gibbs J S. Effect of altitude on the heart and the lungs[J]. Circulation, 2007, 116(19): 2191-2202.
[2] West J B. Paralysis and blindness during a balloon ascent to high altitude[J]. High Alt Med Biol, 2004, 5(4): 453-456.
[3] Anderson J D, Honigman B. The effect of altitude-induced hypoxia on heart disease: do acute, intermittent, and chronic exposures provide cardioprotection[J]. High Alt Med Biol, 2011, 12(1): 45-55.
[4] Hackett P H, Roach R C. High-altitude illness[J]. N Engl J Med, 2001, 345(2): 107-114.
[5] Hackett P H, Creagh C E, Grover R F, et al. High-altitude pulmonary edema in persons without the right pulmonary artery[J]. N Engl J Med, 1980, 302(19): 1070-1073.
[6] Kim T H, Yoon H J, Lim C M, et al. The role of endogenous histamine on the pathogenesis of the lipopolysaccharide (LPS)-induced, acute lung injury: a pilot study[J]. Inflammation, 2005, 29(2-3): 72-80.
[7] Smuda C, Wechsler J B, Bryce P J. TLR-induced activation of neutrophils promotes histamine production via a PI3 kinase dependent mechanism[J]. Immunol Lett, 2011, 141(1): 102-108.
[8] Hattori M, Yamazaki M, Ohashi W, et al. Critical role of endogenous histamine in promoting end-organ tissue injury in sepsis[J]. Intensive Care Med Exp, 2016, 4(1): 36.
[9] Green A J, Gelfand J M, Cree B A, et al. Clemastine fumarate fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial[J]. Lancet, 2017, 390(10111): 2481-2489.
[10] Richalet JP. Pro: corticosteroids are useful in the management of HAPE[J]. High Alt Med Biol, 2015, 16(3):186-189.
[11] Wu G, Xu G, Chen D W, et al. Hypoxia exacerbates inflammatory acute lung injury via the toll-like receptor 4 signaling pathway[J]. Front Immunol, 2018, 9: 1667.
[12] He X, Qian Y, Li Z, et al. TLR4-upregulated IL-1β and IL-1RI promote alveolar macrophage pyroptosis and lung inflammation through an autocrine mechanism[J]. Sci Rep, 2016, 6: 31663.
[13] Wang X, Zhang L, Duan W, et al. Anti-inflammatory effects of triptolide by inhibiting the NF-κB signalling pathway in LPS-induced acute lung injury in a murine model[J]. Mol Med Rep, 2014, 10(1):447-452.
[14] Zhang T Z, Wang S M. Esculin inhibits the inflammation of LPS-induced acute lung injury in mice via regulation of TLR/NF-κB pathways[J]. Inflammation, 2015, 38(4): 1529-1536.
[15] Yu X, Zhao Q, Zhang H, et al. Gambogenic acid inhibits LPS-simulated inflammatory response by suppressing NF-κB and MAPK in macrophages[J]. Acta Biochim Biophys Sin (Shanghai), 2016, 48(5): 454-461.
[16] Shen Y, Wang Q, Zhao Q, et al. Leptin promotes the immune escape of lung cancer by inducing proinflammatory cytokines and resistance to apoptosis[J]. Mol Med Rep, 2009, 2(2): 295-299.
[17] Kent O A, Mendell J T. A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes[J]. Oncogene, 2006, 25(46): 6188-6196.
[18] Rodriguez A, Vigorito E, Clare S, et al. Requirement of bic/micro RNA-155 for normal immune function[J]. Science, 2007, 316(5824): 608-611.
[19] Bakker R A, Schoonus S B, Smit M J, et al. Histamine H(1)-receptor activation of nuclear factor-kappa B: roles for G beta gamma- and G alpha(q/11)-subunits in constitutive and agonist-mediated signaling[J]. Mol Pharmacol, 2001, 60(5): 1133-1142.
[20] Talreja J, Kabir M H, B Filla M, et al. Histamine induces Toll-like receptor 2 and 4 expression in endothelial cells and enhances sensitivity to gram-positive and Gram-negative bacterial cell wall components[J]. Immunology, 2004, 113(2): 224-233.
基金
天津市科技计划(15ZXLCSY00040)
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