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目的:观察早期应用重组Ⅱ型肿瘤坏死因子受体抗体融合蛋白(rhTNFR-Fc)对野百合碱(monocrotaline,MCT)诱导的大鼠肺动脉高压(pulmonary arterial hypertension,PAH)的作用,并探讨其机制。方法:成年雄性SD大鼠24只,随机分为正常对照组(C组)、rhTNFR-Fc组(R组)、MCT模型组(M组)、MCT+rhTNFR-Fc组(M+R组)。建立MCT诱导的PAH模型,测定各组平均肺动脉压(mPAP)、右心肥厚指数,检测各组肺小动脉血管管壁厚度占血管外径的百分比(WT%),应用ELISA法测定各组肺组织匀浆白介素-6(interleukin-6,IL-6)、肿瘤坏死因子-α(tumor necrosis factor-alpha,TNF-α)水平,Western blot法测定肺组织核因子-κB(NF-κB)蛋白水平。结果:①M组大鼠mPAP、右心肥厚指数及WT%值较C组显著升高,差异具有统计学意义(P<0.05),rhTNFR-Fc可抑制MCT诱导的大鼠mPAP的升高(P<0.05)及肺小动脉管壁的增厚(P<0.05);②M组大鼠肺组织匀浆中IL-6、TNF-α水平与C组比较明显增高,差异有显著性(P<0.05),rhTNFR-Fc可抑制MCT诱导的PAH大鼠肺组织中IL-6、TNF-α的表达(P<0.05);③M组大鼠肺组织中NF-κB表达与C组比较显著增加(P<0.05),rhTNFR-Fc可抑制MCT诱导的PAH大鼠肺组织中NF-κB的表达增加(P<0.05)。结论:rhTNFR-Fc可能通过抑制NF-κB信号通路的激活及IL-6、TNF-α等炎症因子的表达防治MCT诱导的大鼠PAH。
OBJECTIVE: To observe the effect of early application of rhTNFR-Fc on monocrotaline (MCT) -induced pulmonary arterial hypertension (PAH) in rats and its mechanism . Methods: Twenty-four adult male Sprague-Dawley rats were randomly divided into four groups: normal control group (C), rhTNFR-Fc group (M group), MCT + rhTNFR-Fc group . The model of PAH induced by MCT was established. The mean pulmonary arterial pressure (mPAP) and right ventricular hypertrophy index of each group were measured. The percentage of vessel wall thickness to vessel diameter (WT%) in each group was measured. The levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were detected by Western blotting. The expressions of nuclear factor-κB Level. Results: ① The mPAP, right ventricular hypertrophy index and WT% of M group were significantly higher than those of C group (P <0.05), and rhTNFR-Fc inhibited the increase of mPAP induced by MCT (P <0.05), and thickening of pulmonary arteriole wall (P <0.05). ② The levels of IL-6 and TNF-α in lung homogenate of M group were significantly higher than those in C group ), rhTNFR-Fc inhibited the expression of IL-6 and TNF-α (P <0.05) in MCT-induced pulmonary tissue of PAH rats; ③The expression of NF- <0.05), rhTNFR-Fc can inhibit the expression of NF-κB in lung tissue of MCT-induced PAH rats (P <0.05). Conclusion: rhTNFR-Fc may prevent MCT-induced PAH by inhibiting the activation of NF-κB signaling pathway and the expression of IL-6, TNF-α and other inflammatory factors.