依达拉奉对慢性阻塞性肺疾病模型大鼠的干预作用

Effect of Edaravone on Chronic Obstructive Pulmonary Disease Rat Models

目的研究依达拉奉对慢性阻塞性肺疾病(COPD)模型大鼠的治疗作用及其机制。方法将雄性健康SD大鼠随机分为空白对照组,模型对照组,N-乙酰半胱氨酸(NAC)组,依达拉奉小、中、大剂量组(Eda1、Eda2、Eda3组)。除空白对照组外,其他大鼠制备COPD模型。NAC组和依达拉奉各剂量组每次造模前均分别腹腔注射NAC20 mg·kg^(-1)和依达拉奉10,20,40 mg·kg^(-1),模型对照组每次造模前腹腔注射等量0.9%氯化钠溶液。空白对照组气管滴注及腹腔注射0.9%氯化钠溶液。连续4周后测定大鼠肺功能、血浆丙二醛(MDA)水平和超氧化物歧化酶(SOD)活力,测定支气管肺泡灌洗液(BALF)上清液肿瘤坏死因子α(TNF-α)、白细胞介素8(IL-8)水平,免疫组化方法检测各组大鼠右上肺组织基质金属蛋白酶(MMP-9、MMP-12)、组织金属蛋白酶抑制因子(TIMP-1)表达情况。结果与空白对照组比较,模型对照组血浆MDA、SOD、TNF-α水平和MMP-9、MMP-12及TIMP-1表达及MMP-9/TIMP-1和MMP-12/TIMP-1显著升高(P<0.05)。与模型对照组比较,NAC组、依达拉奉中、大剂量组血浆MDA水平、MMP-9、MMP-12和TIMP-1表达、MMP-9/TIMP-1和MMP-12/TIMP-1显著降低(P<0.05)。与模型对照组比较,NAC组SOD活力降低(P<0.05),NAC组、依达拉奉各剂量组BALF中TNF-α水平均降低(P<0.05)。结论依达拉奉可通过抗氧化、抑制炎症细胞聚集和炎症因子释放、平衡蛋白酶/抗蛋白酶表达而发挥抗大鼠COPD作用。

Objective To study the effect of edaravone on chronic obstructive pulmonary disease（COPD）in rats and the possible mechanism.MethodsHealthy male SD rats were randomly divided into blank control group,model control group,N-acetylcysteine group,edaravone low,middle and high dose groups（Eda1,Eda2,Eda3 groups）.Except for the blank control group,rats of each group were administered with intratracheal instillation of lipopolysaccharide and exposed to cigarette smoke to establish COPD mode.The rats in NAC group,Eda1 group,Eda2 group and Eda3 group was intraperitoneally injected with 20 mg·kg^-1NAC,10 mg·kg^-1Eda,20 mg·kg^-1Eda,40 mg·kg^-1Eda,respectively,before exposure to cigarette smoke.The rats in model control group were intraperitoneally injected with the same amount of 0.9%sodium chloride solution before exposure to cigarette smoke.The rats in blank control group were not exposed to cigarette smoke,same amount of 0.9%sodium chloride solution was intratracheally instilled and intraperitoneally injected.After four weeks,the lung function and the level of malondialdehyde and superoxide dismutase in plasma were measured.The levels of tumor necrosis factor-αand interleukin-8 in the supernatant of bronchoalveolar lavage fluid were measured.The expression of matrix metalloproteinase（MMP-9,MMP-12）and tissue inhibitor of metalloproteinase-1 were detected by immunohistochemistry.ResultsAs compared with the blank control group,the levels of MDA,SOD,TNF-αand the expression of MMP-9,MMP-12 and TIMP-1,and the ratio of MMP-9/TIMP-1 and MMP-12/TIMP-1 were significantly increased in model control group（P〈0.05）.Compared with model control group,NAC and medium and high dose of edaravone could significantly decrease the levels of MDA and the expression of MMP-9,MMP-12 and TIMP-1 in rat plasma and the ratio of MMP-9/TIMP-1 and MMP-12/TIMP-1（P〈0.05）.NAC could significantly inhibit the increase of SOD activity（P〈0.05）.NAC and all doses of edaravone could decrease the level of TNF-αin BALF of rats（P〈0.05）.ConclusionEdaravone can exert anti-COPD effect by antioxidant,inhibiting the infiltration of inflammatory cell and releasing inflammatory factors,and balancing protease/anti-protease expression.