低氧性肺动脉高压研究进展

低氧性肺动脉高压（hypoxic pulmomary artery hypertension,HPH）是临床常见的病理生理过程,也是慢性阻塞性肺疾病、慢性肺心病、高原肺动脉高压（高原心脏病）等多种心肺疾病发生发展的关键病理环节.HPH的形成包括低氧性肺血管收缩反应（hypoxic pulmonary vasoconstriction,HPV）和低氧性肺血管重塑（hypoxic pulmonary vascularstructure remodeling,HPSR）两个主要发病环节.近年来,国内外对HPH发病机制和治疗的研究取得了较大进步,现就相关方面的研究进展作一综述.     

胶原与低氧性肺动脉高压

肺血管壁中含有Ⅰ、Ⅱ、Ⅳ、Ⅴ等多种胶原，近年来研究认为低氧性肺动脉高压发生时各种胶原均增多。本就正常血管壁胶原类型及功能、低氧性肺动脉高压发生时肺血管壁胶原改变及其可能原因进行综述。     

低氧肺动脉高压大鼠的肺动脉组织凋亡

目的 研究bcl-2、bax凋亡相关基因在低氧处理大鼠肺动脉中的表达,探讨低氧肺动脉高压的发病机制及防治措施.方法 36只Wistar大鼠随机分为3组,分别为正常对照组、低氧肺动脉高压组、低浓度一氧化碳(CO)组,每组12只,采用原位细胞凋亡、原位杂交、免疫组化等方法检测肺动脉的凋亡状况.结果 ①原位凋亡检测示,正常对照组、低氧肺动脉高压组、低浓度CO组的凋亡率分别为8.1%,37.6%,76.5%,三者间差异显著;②原位杂交显示,正常对照组bax、bcl-2杂交呈弱阳性表达.低氧肺动脉高压组bax杂交呈弱阳性表达,低浓度CO组呈强阳性表达,但bcl-2杂交可见低氧肺动脉高压组呈强阳性表达,低浓度CO组呈弱阳性表达;③免疫组织化结果表明,低浓度CO组bcl-2、bax蛋白均有升高,以bax为著.低氧肺动脉高压组虽然也有表达,但程度较弱,且bcl-2表达处于优势.结论 低浓度CO可以调节bcl-2、bax凋亡基因的表达,从而促进肺动脉组织的凋亡.     

舒肺颗粒对大鼠低氧性肺动脉高压的影响

目的观察舒肺颗粒对大鼠低氧性肺动脉高压的影响。方法将30只雄性Wistar大鼠分为常压对照组、低氧对照组和低氧/中药给药组。以常压低氧复制肺动脉高压模型。观察右心室肥厚指数、肺小动脉管壁厚度的变化。结果低氧/中药给药组应用舒肺颗粒后大鼠肺血管厚度、右心室肥厚指标显著低于低氧对照组(P<0.05),并可抑制低氧所致的大鼠右心室肥厚(P<0.05)。结论舒肺颗粒在防治低氧性肺动脉高压中具有一定的应用前景。     

葛根素对低氧性肺动脉高压大鼠肺动脉压力及结构的影响

目的观察大鼠在低氧状态下出现的肺动脉高压和肺小动脉结构的重构，以及葛根素对这两个病理变化的干预效应。方法雄性SD大鼠24只，随机分为对照组、低氧组和葛根素干预组。低氧组和葛根素干预组在常压低氧舱内建立肺动脉高压模型，葛根素干预组大鼠每天腹腔注射葛根素500mg／kg，测定各组平均肺动脉压，并取大鼠左肺沿肺门横断取材，石蜡包埋切片，进行苏木素伊红（HE）染色，观察肺小动脉形态学变化。结果①对照组和葛根素干预组大鼠平均肺动脉压均明显低于低氧组[（15．01±1．47）mmHg、（20．43±2．86）mmHg、（29．74±2．32）mmHg，P〈0．01]。②对照组大鼠肺小血管管壁较薄、管腔较大，低氧组大鼠肺小动脉普遍增厚，管腔狭窄，葛根素干预组的肺小动脉管壁及血管管腔狭窄程度较低氧组显著减轻。结论慢性缺氧可导致肺动脉壁增厚、管腔狭窄等血管重构病理改变；葛根素能在一定程度上抑制低氧肺动脉高压的形成和发展及肺血管结构的重构。     

低氧致炎与低氧性肺动脉高压

低氧性肺动脉高压（hypoxic pulmonary hypertension,HPH）对人的长期严重危害依然未得到很好解决,是一治疗极为棘手、高致死率和高致残率的病理生理综合征,被认为是“假恶性”肿瘤.低氧性肺血管结构重建（hypoxic pulmonary vascular structural remodeling,HPVSR）和低氧性肺血管收缩（hypoxic pulmonary vasoconstriction,HPV）是HPH形成的两大基本病理生理特征.肺血管内皮细胞（pulmonary vascular endothelial cell,PVEC）、肺血管平滑肌细胞（pulmonary vascular smooth muscle cell,PVSMC）和肺成纤维细胞是构成肺血管壁的主要细胞,这些细胞结构和功能的异常变化是导致HPVSR和HPV的主要原因.     

扎鲁司特对低氧性肺动脉高压大鼠的影响

探讨扎鲁司特降低低氧性肺动脉高压的作用机制。方法将Ｗｉｓｔａｒ大鼠４０只随机分为４组,每组１０只：（１）正常对照组;（２）低氧性肺动脉高压模型组;（３）扎鲁司特预防组;（４）扎鲁司特治疗组。各组实验完毕,分别用心导管法测定平均肺动脉压（ｍＰＡＰ）,检测ＮＯ＾－２／ＮＯ＾－３胶原、过氧化脂质、超氧化物歧化酶。     

肝素对大鼠常压低氧性肺动脉高压形成的影响

肺动脉高压是许多呼吸疾病的并发症,如进一步发展可导致肺心病的发生。目前有文献报道,低氧性肺动脉高压的形成与内皮素(ＥＴ)1、一氧化氮(ＮＯ)[1]含量变化有关。肝素在临床用于抗凝治疗已有较长时间,已证明无明显副作用。近年来还发现肝素具有调节ＥＴ1、ＮＯ[2]的作用。而肝素对低氧性肺动脉高压的影响,目前国内报道尚少,现将我们的研究结果报告如下。一、材料与方法1.材料:雄性Ｗｉｓｔａｒ大鼠30只,体重200～250ｇ,首都医科大学动物科学部提供(合格证:医动字第013084号)。2.试剂与仪器:普通肝素钠由江苏常州生化制药有限公司提供(批号9…     

脂联素改善间歇性低氧性肺动脉高压大鼠离体肺动脉舒张功能及其机制

目的 研究重组人球状脂联素（gAd）对低氧性肺动脉高压（HPH）大鼠离体肺动脉舒张功能的影响并研究其作用机制。方法 将24只雄性SD大鼠随机分为正常对照组、HPH 2周组（HPH2W）、HPH 4周组（HPH4W）,每组8只。正常对照组动物在正常环境中饲养,低氧组大鼠以间歇性低压低氧法建立HPH模型。低氧组模型建立后,以右心导管法测定平均肺动脉压（mPAP)、平均右心室压(mRVP),称重测量右心室/左心室+室间隔（RV/LV+S）、右心室/体质量（RV/BW）;ELISA检测试剂盒检测血清gAd及NO浓度。右肺下叶肺组织经HE染色后观察肺小动脉血管显微结构的改变。取大鼠左、右肺动脉干制备血管环,行离体灌流实验,观察不同浓度的乙酰胆碱及硝普钠诱导的血管舒张作用。取HPH4W组动物肺外肺动脉干,分组进行孵育（HPH4W组:Krebs液孵育;HPH4W+gAd组:gAd 2 μg/ml孵育;HPH4W+gAd+L-NAME组:gAd 2 μg/ml+L-NAME 0.5 mmol/L孵育）,孵育后观察不同浓度的乙酰胆碱及硝普钠诱导的血管舒张作用,然后收集作用于血管环的灌流液,检测NO产物。取HPH4W组大鼠肺动脉血管按上述分组进行孵育,然后行Western blot检测AMPK、Akt、eNOS等信号蛋白分子的表达及磷酸化水平。结果 与正常对照组相比,HPH组大鼠的mPAP、mRVP、RV/LV+S、RV/BW均显著增高（P<0.05）;血清gAd、NO水平下降（P<0.05）;光镜下肺动脉平滑肌及弹力纤维层增生,管壁增厚,管腔狭窄。与正常对照组比较,HPH组大鼠肺动脉对乙酰胆碱诱导的血管舒张作用明显减弱(P<0.05),正常对照组最大舒张率69.94%,HPH2W组最大舒张率48.79%,HPH4W组最大舒张率仅42.09%。经gAd体外孵育后,血管环内皮依赖的舒张作用明显增强,HPH4W组最大舒张率可达到46.35%,加入L-NAME组的血管环舒张作用被显著阻断。各组大鼠对硝普钠诱导的血管舒张均有良好反应,无统计学意义。经gAd孵育后的血管环组织AMPK、Akt、eNOS磷酸化水平、灌流液NO产物均增加（P<0.05）,L-NAME可阻断gAd增强eNOS磷酸化和NO水平的作用。结论 gAd对间歇性低氧性肺动脉高压大鼠的肺动脉内皮依赖性的血管舒张功能具有确切的直接保护作用。AMPK/Akt/eNOS/NO信号通路可能是gAd发挥肺动脉保护作用的分子机制。     

C-type natriuretic peptide ameliorates monocrotaline-induced pulmonary hypertension in rats

C-type natriuretic peptide (CNP) has been shown to act as a local regulator of vascular tone and remodeling. We investigated whether CNP ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Rats received a continuous infusion of CNP or placebo. Significant pulmonary hypertension developed 3 weeks after MCT. However, infusion of CNP significantly attenuated the development of pulmonary hypertension and vascular remodeling. Neither systemic arterial pressure nor heart rate was altered. Interestingly, CNP enhanced Ki-67 expression, a marker for cell proliferation, in pulmonary endothelial cells and augmented lung tissue content of endothelial nitric oxide synthase. CNP significantly suppressed apoptosis of pulmonary endothelial cells, decreased the number of monocytes/macrophages, and inhibited expression of plasminogen activator inhibitor type 1, a marker for fibrinolysis impairment, in the lung. In addition, CNP significantly increased the survival rate in MCT rats. Finally, infusion of CNP after the establishment of pulmonary hypertension also had beneficial effects on hemodynamics and survival. In conclusion, infusion of CNP ameliorated MCT-induced pulmonary hypertension and improved survival. These beneficial effects may be mediated by regeneration of pulmonary endothelium, inhibition of endothelial cell apoptosis, and prevention of monocyte/macrophage infiltration and fibrinolysis impairment.     

Combination of sildenafil and simvastatin ameliorates monocrotaline-induced pulmonary hypertension in rats

Sildenafil, a phosphodiesterase-5 inhibitor, and simvastatin, a cholesterol lowering drug, both have therapeutic effects on PAH; however, the combination of these drugs has not been tested in the treatment of PAH. The purpose of this study was to determine whether the combination of sildenafil and simvastatin is superior to each drug alone in the prevention of MCT-induced PAH. Phosphorylated Smad levels were decreased in lung tissue in MCT-injected rats, whereas ERK protein levels were increased. This indicates a possible role for an increase in mitogenic ERK activity in addition to decreased proapoptotic Smad signaling in the MCT model of PAH. Combination sildenafil and simvastatin treatment prevented the MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH), exerted an anti-proliferative effect on pulmonary artery smooth muscle cells (PASMC). Our results indicate that combination therapy with sildenafil and simvastatin attenuated the development of pulmonary hypertension more than either treatment alone.     

A combination of oral sildenafil and beraprost ameliorates pulmonary hypertension in rats

Sildenafil, an oral phosphodiesterase type-5 inhibitor, has vasodilatory effects through a cyclic guanosine 3', 5'-monophosphate-dependent mechanism, whereas beraprost, an oral prostacyclin analog, induces vasorelaxation through a cAMP-dependent mechanism. We investigated whether the combination of oral sildenafil and beraprost is superior to each drug alone in the treatment of pulmonary hypertension. Rats were randomized to receive repeated administration of saline, sildenafil, beraprost, or both of these drugs twice a day for 3 weeks. Three weeks after monocrotaline (MCT) injection, there was significant development of pulmonary hypertension. The increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight were significantly attenuated in the Sildenafil and Beraprost groups. Combination therapy with sildenafil and beraprost had additive effects on increases in plasma cAMP and cyclic guanosine 3', 5'-monophosphate levels, resulting in further improvement in pulmonary hemodynamics compared with treatment with each drug alone. Unlike MCT rats given saline, sildenafil, or beraprost alone, all rats treated with both drugs remained alive during 6-week follow-up. These results suggest that combination therapy with oral sildenafil and beraprost attenuates the development of MCT-induced pulmonary hypertension compared with treatment with each drug alone.     

Portal hypertension ameliorates arterial hypertension in spontaneously hypertensive rats

Systemic hemodynamic effects of portal hypertension in arterial hypertension and their relationship to serum bile acid levels were investigated using spontaneously hypertensive rats 2 and 15 weeks after partial portal vein ligation (SHR-PVL) or sham operation (SHR-SH) and normotensive controls. Mean arterial pressure in SHR-PVL at 2 weeks was decreased to normal due to a decrease in peripheral resistance. Mean arterial pressure and peripheral resistance in SHR-PVL at 15 weeks did not differ from SHR-SH. Resolution of this arterial hypotensive effect and systemic hyperdynamic circulation was associated with decreased portal-systemic shunting. Bile acid levels were increased in both SHR-PVL groups. These results suggest that an endogenous circulating vasodilator(s) associated with portal hypertension ameliorates the systemic vasoconstriction in SHR. Bile acids, while not direct mediators of these hemodynamic events, may be prototypic of this vasodilator. This arterial hypertensive model may aid further investigation of the mechanisms contributing to the hyperdynamic state in portal hypertension.     

Bilirubin ameliorates bleomycin-induced pulmonary fibrosis in rats

Many possible treatments for pulmonary fibrosis have been investigated, but except for some current clinical trials, none have succeeded in clinical trials. On the basis of the antioxidant action of bilirubin (BIL), we examined the effects of hyperbilirubinemia on the development of bleomycin (BLM)-induced pulmonary fibrosis in rats. The animals' plasma BIL level was kept within 3 and 10 mg/dl by repeated intravenous infusion of a high dose of BIL. We studied the inhibitory effects of hyperbilirubinemia on BLM-induced pulmonary fibrosis through histopathologic and biochemical analyses. Mortality of rats with BLM-induced pulmonary fibrosis was significantly lower in the three groups with hyperbilirubinemia. The ameliorating effect of hyperbilirubinemia on pulmonary fibrosis was shown by lung histology, as well as by a decreased lung content of hydroxyproline and reduced bronchoalveolar lavage fluid (BALF) concentration of transforming growth factor (TGF)-beta(1). The number of polymorphonuclear leukocytes and lymphocytes in BALF was also decreased in the groups with hyperbilirubinemia. Furthermore, oxidative metabolites of BIL in urine were present at significantly higher levels in BLM-treated rats with hyperbilirubinemia than in those without hyperbilirubinemia. These data suggest that the antioxidative action of BIL can attenuate BLM-induced pulmonary fibrosis, partly by inhibiting lung inflammation and production of TGF-beta1.     

Potassium depletion ameliorates hypertension in spontaneously hypertensive rats

The hemodynamic effect of moderate K+ depletion in hypertension is unknown. Since severe K+ depletion reduces systemic vascular resistance in normotensive rats, we determined the effect of K+ depletion on the natural history of hypertension in spontaneously hypertensive rats (SHR). Wistar-Kyoto rats (WKY) and SHR were fed a K+-replete, a moderately K+-depleted, or a severely K+-depleted diet. After 6 weeks, systemic vascular resistance was reduced by 25% in WKY on the severely K+-depleted diet while mean arterial pressure and systemic vascular resistance were comparable in WKY on the other two diets. In SHR on the severely K+-depleted diet for 6 weeks, muscle K+ was reduced by 23% and growth rate by 65%. In SHR on the moderately K+-depleted diet, growth rate was reduced by 23% after 3 weeks. By 6 weeks, however, muscle K+ was reduced by 5 to 6% and growth rate was comparable to that in SHR receiving the K+-replete diet. The administration of either K+-depleted diet prevented the development of hypertension (systolic blood pressure: severely depleted, 116 +/- 4; moderately depleted, 122 +/- 3; K+-replete, 155 +/- 5 mm Hg; p less than 0.001 compared with both K+-depleted groups) and reversed established hypertension (systolic blood pressure: severely depleted, 116 +/- 4; moderately depleted, 128 +/- 3; K+-replete, 171 +/- 5 mm Hg; p less than 0.001 compared with both K+-depleted groups). The protective effect of K+ depletion was mediated by a 40% reduction in systemic vascular resistance. These results suggest that K+ depletion has a potent antihypertensive effect in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)