摘要目的 应用重组人Ⅱ型肿瘤坏死因子受体抗体融合蛋白——依那西普(ECP)对野百合碱(MCT)诱导的大鼠肺动脉高压(PAH)模型进行干预,观察ECP在该模型中的疗效,并对其机制进行初步探讨.方法 用MCT建立动物模型,并用ECP对模型进行预防干预和治疗干预,分别在建模第2、4周时,通过右心导管技术测量大鼠的肺动脉平均压(mPAP),与模型组比较,判断干预是否有效;并通过肺脏病理组织苏木素-伊红(HE)染色进行肺小动脉血管壁增厚定量测定(R值),及免疫组织化学染色测定肿瘤坏死因子(TNF)-α和白细胞介素(IL)-6的表达量,探讨ECP的干预机制.结果 ECP预防组mPAP(14±6)mm Hg与2周模型组(29±8)mm Hg相比显著降低(P＜0.01),ECP治疗组mPAP(36±22)mmHg与4周模型组(66±28)mm Hg相比有下降趋势;肺脏病理组织HE染色显示ECP预防组测定的R值(0.273±0.019)与2周模型组(0.203±0.039)相比显著增高(P＜0.01),提示肺小血管壁厚度程度减轻;免疫组织化学染色显示野百合碱模型中大鼠肺组织中有大量炎性细胞浸润,并且有大量TNF-α和IL-6的表达,ECP预防组较2周模型组的TNF-α和IL-6染色减少.结论 ECP可降低MCT诱导的大鼠PAH模型的肺动脉压力,其机制与抑制巨噬细胞分泌炎症因子,减轻肺小动脉血管炎症和血管壁增厚程度相关.

abstractsObjective To evaluate the efficacy of etanercept(ECP)in monocrotaline(MCT)-induced pulmonary arterial hypertension(PAH)rat model.Methods Rats received MCT(60 mg/kg i.p.)once to estabiish the PAH model.The treatment groups received ECP for prophylactic intervention or remedial intervention.At the end of week 2 and week 4.the mean pulmonary arterial pressure(mPAP)and"R value"of the prophylactic treatment group or remedial treatment group were compared between the 2-week model group or 4-week model group respectively.The expression of TN F-α and IL-6 in the rat lung tissues Was determined using immunohistochemistry staining.Results Prophylactic ECP intervention could significantly reduce the mPAP(compared with the 2-week model group,P＜0.0 1),the remedial group also showed a tendency of mPAP-reduction.We got the same results when using R value to assess the efficacy of the two treatment groups.The immunohistochemistry staining showed that there were massive expressions of TNF-α and IL-6 in the lung tissues of the model groups and decreased staining in both treatment groups.Conclusion Inhibition of TNF-α with ECP in MCT-induced PAH model can result in a significant reduction of mPAP and the thickness of small pulmonary arteries.TNF-α may play a key role in the progression of MCT-induced PAH model.TNF-α antagonists may be useful in the management of connective tissue disease associated PAH.