辛伐他汀在慢性阻塞性肺疾病大鼠模型中的早期干预作用

摘要

目的 探讨早期给予辛伐他汀干预对慢性阻塞性肺疾病(COPD)大鼠模型的影响及机制.方法 将42只大鼠(Wistar,清洁级)随机分为空白组、模型组和他汀组,每组14只.采用烟熏加气道内滴入脂多糖法复制COPD大鼠模型,他汀组在造模2周后加用辛伐他汀(5 mg/kg)灌胃治疗.观察大鼠一般表现;监测体重变化;采用生物素双抗体夹心酶联免疫吸附法测定血清及支气管肺泡灌洗液(BALF)中白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)水平;血球计数仪计数BALF中白细胞计数;免疫组织化学染色法测定肺组织中基质金属蛋白酶(MMP-9)的表达;图像分析系统分析各组大鼠病理改变.结果 模型组及他汀组大鼠体重较空白组减轻(P＜0.01).血清和BALF中IL-6、TNF-α水平,模型组及他汀组较空白组增加(P＜0.05),他汀组较模型组降低(P＜0.05).肺组织中MMP-9表达,模型组较空白组增高(P＜0.01),他汀组较模型组降低(P＜0.05).模型组及他汀组大鼠肺组织符合COPD病理学改变,他汀组组织损伤、重塑及炎症浸润程度较模型组降低.结论 香烟吸入联合呼吸系统感染可加重肺部及全身炎性反应程度,增加蛋白酶过度表达,参与COPD的发生发展.早期给予辛伐他汀治疗,可在一定程度上减轻肺组织损伤及重塑,降低炎性反应程度,缓解蛋白酶系统亢进.%Objective To explore the effects of early stage administration of Simvastatin on chronic obstructive pulmonary disease (COPD) rat model and its mechanism.Methods 42 SPF Wistar rats were randomly divided into three groups (n=14):blank group,model group and Simvastatin group.COPD rat models were replicated with the method of inhaling cigarette smoke and intratracheal instillation of LPS.Simvastatin group rats were gave lavage treatment with Simvastatin (5 mg/kg) after 2 weeks when COPD model was established.Usual manifestations and body weights of rats from the three groups were monitored.The levels of IL-6 and TNF-α in serum and BALF were measured by double antibody sandwich enzyme-linked immuno sorbent assay (ELISA).Leukocyte in BALF was counted by haemocytometer.The expression of MMP-9 in the lung tissues was measured by immunohistochemically.Pathological examination of lung tissues from every group was analyzed by image analysis system.Results Body weights of rats from the model group and Simvastatin group were significantly reduced compared with those of the blank group (P ＜ 0.01).Levels of IL-6 and TNF-α in serum and BLAF were higher in the model group and Simvastatin group than the blank group (P ＜ 0.05).Compared with model group,the levels in Simvastatin group were decreased (P ＜ 0.05).The expression of MMP-9 in lung tissues,model group was increased than the blank group (P ＜ 0.05),Simvastatin group was lower than the model group (P ＜ 0.05).The pathologic characteristics of COPD was observed in the lung tissues from Simvastatin group and model group.Copmared with the model group,lung tissue injury,remodeling and inflammatory infiltration in Simvastation group was attenuated.Conclusion Cigarettes inhalation combined with respiratory infections can aggravate pulmonary and systemic inflammation,and up-regulate the expression of proteases,all of which are involved in the genesis and development of COPD.Simvastatin therapy as an early intervention can alleviate the lung tissue injury and remodeling to a certain degree,attenuate pulmonary and systemic inflammation and alleviate the overactivation of proteasesystem.