瑞舒伐他汀减轻野百合碱诱发的大鼠肺动脉高压

发布时间：2018-03-17 17:41

本文选题：瑞舒伐他汀　切入点：肺动脉高压　出处：《郑州大学》2016年博士论文　论文类型：学位论文

【摘要】：研究背景肺动脉高压(Pulmonary arterial hypertension,PAH)患者远端肺小动脉通常出现特征性的病理改变,这些特征性的病理改变往往包括血管内膜增生并纤维化、丛样病变、中膜增生肥厚、肌化以及血栓形成。肺小动脉的这种持续性病理改变终将导致以血管管腔逐渐闭塞为基本特征的恶性肺动脉血管病变。弥漫性的微血管管腔闭塞最终导致肺动脉血管阻力渐进性增加。长期进行性的肺动脉压升高导致右心功能衰竭。临床常用的治疗药物对PAH有很大的个体差异,总体治疗效果不佳,患者的运动耐量和生存率受到严重影响。随着对PAH机制的阐明,近年来研发的药物如前列腺类似物(前列环素),内皮素受体拮抗剂(波生坦)和磷酸二脂酶5抑制剂(西地那非)在重度PAH患者的血流动力学生活质量及改善预后方面显示了一定的临床效果,但PAH患者长期的预后仍然不容乐观。近年来随着对PAH病理生理机制的研究的进一步深入,认为内皮细胞功能障碍导致的内皮细胞结构、功能以及代谢的改变在肺动脉循环压力升高的发生和发展中起着关键作用。基因突变(微卫星不稳定性、骨形态发生蛋白受体2突变、激活素样激酶1突变)、活性氧、自身免疫、剪切力以及Ang1-Tie2-BMPR1a-BMPR2信号通路缺陷通常会引起肺动脉内皮损伤。损伤的内皮出现功能障碍,导致肺动脉内膜屏障破坏、内膜下暴露于可溶性生长因子、体液失调、内皮细胞紊乱不受控制性增殖、高凝以及细胞因子/生长因子的释放,参与了肺动脉血管的病理性收缩与重构。内皮细胞损伤后,合成引起血管舒张的物质(NO、PGI2)减少,而释放内皮素-1(Endothelin-1,ET-1)、血管紧张素(Angiotensin,Ang)等血管收缩物质增多,结果导致肺血管收缩。损伤的内皮出现屏障功能异常,一些来自血液中和激活的内皮细胞本身释放的细胞活性因子被激活,导致肺动脉中层平滑肌细胞出现增生肥大。肺动脉压力进行性增加促使肺动脉平滑肌细胞和血管外膜出现适应性增生和肥厚。发生于肺动脉的内皮功能异常还增加各种促栓物质的生成并减少抗栓活性因子的合成分泌,最终使肺循环产生了易栓环境并导致部分肺微循环的血栓形成,微循环血栓形成会使肺动脉管腔出现进一步狭窄,最终导致肺动脉压力的升高。因此,恢复正常的内皮功能是治疗PAH的病理生理基础。内皮祖细胞(EPC)是内皮细胞的前体细胞,来源于骨髓,能在体循环分化为成熟内皮细胞并参与损伤血管内皮的修复。研究表明内皮祖细胞可在某些药物的刺激动员下,由骨髓释放进入外周循环,定向迁移归巢到血管出现损伤的部位,因此在修复损伤的血管内皮细胞,维护正常血管内皮功能中起重要作用。大量证据表明PAH患者中EPCs水平和功能均降低。一些研究已经表明3-羟基-3-甲基-戊二酰辅酶A还原酶抑制剂对EPCs和e NOS有潜在的调节作用。3-羟基-3-甲基-戊二酰辅酶A还原酶抑制剂可以动员骨髓EPC的增殖和迁移,增强EPC修复损伤血管内皮细胞的能力。3-羟基-3-甲基-戊二酰辅酶A还原酶抑制剂还可上调和激活e NOS的表达(参与调节血管功能的一个关键酶)产生内皮衍生舒张因子。目的观察瑞舒伐他汀对MCT诱导的PAH大鼠EPCs和e NOS表达的影响。方法六十只Sprague-Dawley(SD)大鼠均分为三组:对照组(A组)、PAH+瑞舒伐他汀组(B组),和PAH组(C组)。MCT(60mg/kg ip)腹腔注射诱导PAH。B组大鼠Rosuvastatin(10mg/(kg.day),阿斯利康公司提供)灌胃共6周。治疗前及治疗6周后从各组大鼠股动脉抽取外周血(5毫升)。用M199培养基(含10%胎牛血清)常规分离和培养获得EPC的单个核细胞,6周后取小的和中等大小的肺动脉进行组织学分析。本研究采用RT-PCR和Western blotting检测肺动脉e NOS在m RNA和蛋白水平的表达的变化。结果与A组相比,B组和C组循环EPC的数量和肺动脉e NOS在m RNA和蛋白水平表达均降低(P0.05),且B组和C组之间有统计学差异(P0.05)。与C组相比,B组大鼠肺动脉血管病理检测重塑现象减弱。结论1.Rosuvastatin可以增加MCT诱导的PAH大鼠EPCs的数量;2.Rosuvastatin可以上调MCT诱导的PAH大鼠e NOS的表达;3.Rosuvastatin可以改善MCT诱导的PAH大鼠肺动脉重塑,减轻PAH。
[Abstract]:The research background of pulmonary arterial hypertension (Pulmonary arterial, hypertension, PAH) in patients with distal pulmonary arteries usually appear pathological change, these pathological characteristic changes often include vascular intimal hyperplasia and fibrosis, plexiform lesions, membrane hypertrophy, muscle and thrombosis. The pulmonary pathological changes will lead to persistent the vascular lumen occlusion gradually as the basic characteristics of malignant pulmonary vascular disease. The microvascular lumen diffuse occlusion resulting in pulmonary vascular resistance progressively increased. The long-term pressure of pulmonary artery leads to right heart failure. Commonly used in the treatment of drug clinical individual difference of PAH, the treatment effect is poor. The patient's exercise tolerance and survival rate were seriously affected. With the elucidation of the mechanisms of PAH in recent years, research and development of drugs such as prostate analogues (prostacyclin), Endothelin receptor antagonist (bosentan) and two phosphate lipase 5 inhibitor (sildenafil) shows certain clinical efficacy in patients with severe PAH hemodynamics in quality of life and improve the prognosis, but long-term prognosis of PAH patients is still not optimistic. In recent years, with the further study of PAH pathophysiology, that endothelial cells the structure leads to endothelial cell dysfunction, plays a key role in the occurrence and development of functional and metabolic changes in pulmonary arterial pressure increased circulation. Gene mutation (microsatellite instability, bone morphogenetic protein receptor 2 mutations, activin like kinase 1 mutation), ROS, autoimmunity, shear stress and Ang1-Tie2-BMPR1a-BMPR2 signaling pathway defects usually caused by pulmonary artery endothelial injury. The injury of endothelial dysfunction, leading to pulmonary artery endothelial barrier damage in membrane exposed to soluble Growth factor, humoral disorders, endothelial cell disorders, uncontrolled proliferation, high coagulation and release of cytokines / growth factors, involved in the contraction and remodeling of pulmonary arteries. The pathological injury of endothelial cells, synthesis of vasodilating substances (NO, PGI2) decreased, and release of endothelin -1 (Endothelin-1, ET-1), angiotensin (Angiotensin, Ang) and other vasoconstrictor substances increased, resulting in pulmonary vasoconstriction. Endothelial barrier function injury appeared abnormal cell activity factor from the blood and activated endothelial cells release itself is activated, leading to pulmonary artery smooth muscle cell hyperplasia and hypertrophy of pulmonary artery pressure. Increase in pulmonary artery smooth muscle cells and adventitial hyperplasia and hypertrophy. Adaptive generation occurs in pulmonary artery endothelial function abnormality increased prothrombotic substances and reduce antithrombotic activity Synthesis and secretion of inflammatory factor, the pulmonary circulation had a thrombophilic environment and caused part of the pulmonary microcirculation thrombosis, pulmonary artery lumen will make further stenosis and thrombosis in microcirculation, resulting in increased pulmonary artery pressure. Therefore, to restore normal endothelial function is the pathophysiological basis for the treatment of PAH. Endothelial progenitor cells (EPC) are precursor cells of endothelial cells, derived from bone marrow, circulating in the body can differentiate into mature endothelial cells and participate in the repair of vascular endothelial injury. The results indicate that the endothelial progenitor cells in the stimulation of certain drugs mobilization, released into the peripheral circulation of the bone marrow, directional migration homing to the vascular injury site, so in repair of injury of vascular endothelial cells, play an important role in maintaining normal endothelial function. There is plenty of evidence that the level and function of EPCs in PAH patients were decreased. Some studies have shown that 3- hydroxyl -3- - e two methyl coenzyme A reductase inhibitor on EPCs and E NOS have the potential to regulate the proliferation and migration of.3- hydroxy -3- methyl pentene two acyl coenzyme A reductase inhibitors can mobilize bone marrow EPC, increased expression of vascular endothelial cell injury ability to repair EPC.3- e two - hydroxy -3- methyl coenzyme A reductase inhibitors can up regulate and activate e NOS (a key enzyme involved in regulating vascular function) of endothelium derived relaxing factor. Objective To observe the effect of rosuvastatin on the expression of MCT in PAH rats induced by EPCs and E NOS. Methods sixty Sprague-Dawley (SD) rats were divided into three groups: control group (A group PAH+), rosuvastatin group (B group), PAH group (group C) and.MCT (60mg/kg IP) PAH.B rats were induced by intraperitoneal injection of Rosuvastatin (10mg/ (kg.day), AstraZeneca company) by gavage for 6 weeks. Before and after 6 weeks of treatment from each rat femoral artery Peripheral blood samples (5 ml). M199 medium (containing 10% fetal bovine serum) mononuclear cells and cultured EPC separation, pulmonary artery was harvested after 6 weeks of small and medium size histological analysis. This research adopts RT-PCR and Western blotting e NOS in the detection of pulmonary m expression the RNA and protein level. Results compared with A group, the expression of B group and C group the number of circulating EPC and pulmonary artery e NOS in M RNA and protein levels were decreased (P0.05), and between B group and C group had statistically significant difference (P0.05). Compared with C group, B group of rat lung arterial pathological detection remodeling weakened. Conclusion the quantity of 1.Rosuvastatin can increase the MCT of PAH rats induced by EPCs; 2.Rosuvastatin PAH expression in rats induced by MCT e NOS; 3.Rosuvastatin can improve pulmonary artery remodeling in PAH rats induced by MCT, reduce PAH.

【学位授予单位】：郑州大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R544.1

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