琥珀酸促进野百合碱诱导的心肺小动脉间质纤维化
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国家自然科学基金(81370277)


Effects of succinic acid on early interstitial fibrosis of small cardio-pulmonary arteries in monocrotaline-induced pulmonary hypertension
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    摘要:

    目的:探讨琥珀酸能否促进野百合碱诱导的肺动脉高压大鼠模型心肺小动脉间质纤维化,并初步探索其机制。方法:4~5周龄健康雄性SD大鼠30只,体重120~180 g,随机分为对照组、野百合碱(monocrotaline,MCT)组、野百合碱和琥珀酸(succinic acid,SUC) 联合使用组(MCT+SUC组),每组10只。MCT组和MCT+SUC组予腹腔注射MCT建造大鼠肺小动脉高压模型,MCT+SUC组继续予SUC干预4周。4周后,利用漂浮导管检测平均肺动脉压(mean pressure of pulmonary artery,mPAP)、右心室收缩压(right ventricular systolic pressure,RVSP)、肺动脉收缩压(systolic blood pressure,SBP)和肺动脉舒张压(diastolic blood pressure,DBP)等血流动力学指标。安乐死后取组织测定右室肥厚指数,行HE染色观察心脏和肺组织小动脉的肌化情况,Masson、天狼星红染色观测心脏和肺小动脉周围纤维化情况,Western blot和免疫组织化学检测心脏组织血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)、血小板衍生因子-BB(platelet derived growth factor,PDGF-BB)和成纤维细胞生长因子-2((fibroblast growth factor 2,FGF2)等蛋白表达水平。 结果:MCT组、MCT+SUC组大鼠均表现食量减少、倦卧等症状,MCT+SUC组大鼠出现唇周紫绀、气促等表现较早。MCT+SUC组RVSP、mPAP、肺动脉SBP和肺动脉DBP、右室肥厚指数、心肺小动脉中层增厚程度均明显大于MCT组(P均<0.05)。HE染色显示,MCT组心肺小动脉轻度增厚,MCT+SUC组心脏小动脉壁增厚程度较MCT组更加明显,局部心肌组织炎性细胞浸润增加。天狼星红染色与Masson染色结果显示,MCT+SUC组心肺小动脉周围间质内胶原纤维异常增生,MCT组心肺小动脉周围未见胶原纤维异常增生。Western blot 和免疫组织化学结果显示,MCT+SUC组和MCT组肺组织AngⅡ、PDGF-BB、FGF2蛋白表达水平变化与对照组相比均有不同程度的升高,MCT+SUC组较MCT组上升水平更加明显。结论:SUC可以促进MCT诱导的心肺小动脉间质纤维化的形成,其机制可能是上调FGF2和PDGF-BB等促纤维化的细胞因子,AngⅡ表达升高,导致心肺小动脉间质纤维化的形成。

    Abstract:

    Objective: To investigate whether succinic acid could exacerbate the early interstitial fibrosis of cardio-pulmonary arteries induced by monocrotaline in a rat model of pulmonary hypertension, and to explore its pathological and molecular mechanisms. Methods: A total of 30 healthy male SD rats aged 4 to 5 weeks and weighted 120~180 g were randomly divided into the control group(C group), the monocrotaline group(MCT group), and the monocrotaline and succinic acid group(MCT+SUC group), with 10 rats in each group. The MCT group and the MCT+SUC group were subjected to intraperitoneal injection with monocrotaline in 60 mg/kg. The MCT+SUC group was given SUC for 4 weeks. The rats in the control group and the MCT group were injected with equal volume of saline, lasting for 4 weeks. After 4 weeks, hemodynamic indices including mean pressure of pulmonary artery(mPAP), right ventricular systolic pressure(RVSP), systolic blood pressure(SBP) and diastolic blood pressure(DBP) of pulmonary artery were measured by floating catheter in all groups. The right ventricular hypertrophy index was measured after euthanasia. HE staining, Masson staining and Sirius red staining were conducted to detect the remodeling of arteriole in the heart and lung tissues. Western blot and immunohistochemistry were conducted to examine the protein level of angiotensinⅡ(AngⅡ), platelet derived growth factor(PDGF-BB), and platelet derived growth factor(FGF2) in the pulmonary hypertension rat model. Results: The rats in the MCT group and the SUC group both showed decreased activity, sleepiness and poor appetite. Lips cyanosis and shortness of breath appeared earlier in the MCT+SUC group. Hemodynamic examination exhibited that indices, including mPAP, RVSP, SBP and DBP of pulmonary artery, the right ventricular hypertrophy index, the thickening of arteriole in the heart and lung tissues were significantly higher in the MCT+SUC group than those in the MCT group(all P<0.05). HE staining showed slight thickening of the small arteries in the MCT group, the degree of thickening of the arterial wall of the MCT+SUC group was more obvious than that of the MCT group, and the infiltration of inflammatory cells in local myocardium increased. Sirius red staining and Masson staining showed abnormal proliferation of collagen fibers in the interstitial cells of the MCT+SUC group, and no abnormal collagen fibers in the MCT group. Western blot and immunohistochemistry showed that AngⅡ, FGF-2 and PDGF-BB expression levels in the MCT+SUC group and the MCT group were significantly higher than those in the control group, and the protein expressions of AngⅡ, FGF-2 and PDGF-BB in the MCT+SUC group increased more significantly than those in the MCT group. Conclusion: Succinic acid can exacerbate the formation of early fibrosis of cardiopulmonary arterioles in rats with pulmonary hypertension induced by monocrotaline. The mechanism may be due to regulating the expression of FGF-2 and PDGF-BB in the body, and eventually lead to increased expression of AngⅡ, causing interstitial fibrosis of cardio-pulmonary arteries.

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吴泽宇,石奇琪,黄河溯源,杨 磊,陆梦婷,莫绪明.琥珀酸促进野百合碱诱导的心肺小动脉间质纤维化[J].南京医科大学学报(自然科学版),2017,(9):1136-1141

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  • 收稿日期:2017-04-15
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  • 在线发布日期: 2017-09-25
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