内源性一氧化碳/血红素氧合酶体系在缺氧性肺动脉高压形成中的作用

目的 研究内源性一氧化碳／血红素氧合酶（CO／HO）体系在慢性低氧环境中的变化规律，探讨CO／HO体系在缺氧性肺动脉高压形成中的作用。方法 将第1批大鼠随机分为对照组、低氧1d组、低氧3d组、低氧7d组、低氧14d组；第2批大鼠随机分为对照组、低氧组、低氧＋锌原卟啉（ZnPP）均。均以右心导管法测定肺动脉压力；称量并计算右心室与左心室加室间隔的比例；应用双波长分光光度法间接测定大鼠血浆及肺组织匀浆中CO含量；应用免疫组织化学技术对第一批大鼠肺内HO－1蛋白表达进行定位及半定量分析。结果 大鼠低氧7－14d开始形成稳定的肺动脉高压，伴右心室肥大；血浆及肺组织心浆中CO含量分别于低氧1d和低氧14d时两次明显增高（P＜0．01）；低氧1－3d肺泡及肺泡间质巨噬细胞和炎性细胞（F＝8．72，P＜0．001）；低氧＋ZnPP组大鼠肺动脉平均压明显高于对照组及低氧组，血浆及肺组织匀浆中CO含量明显 于氏氧组（P均＜0．01）。结论 内源性CO／HO体系在慢性低氧刺激下明显增高，且呈时间依赖性的双峰现象，其中第2次代偿性增高与肺动脉压力的变化密切相关，HO－1抑制剂的干预研究进一步表明，内源性CO／HO体系对缺氧性肺动脉高压形成具有积极的调节作用。

Role of endogenous carbon monoxide/heme oxygenase (CO/HO) system in the development of hypoxic pulmonary hypertension

Objective To explore the changing regularity of endogenous CO/HO system under chronic hypoxic condition, and the role of CO/HO on the development of hypoxic pulmonary hypertension Methods The first forty two Wistar rats were randomly divided into five groups, hypoxia 0,1,3,7,14 days respectively The second eighteen Wistar rats were randomly divided into control group, hypoxic group and hypoxic with ZnPP group Pulmonary artery mean pressure(mPAP) of each rat was evaluated using right cardiac catheterization The heart was excised and weighed, and the right to left heart weight ratio was determined The indirect production of CO in plasma and pulmonary tissue homogenates was detected by the double wavelength spectrophotometer The lung tissue of the first rats were inflation fixed, and the expressions and localization of HO 1 were studied by immunohistochemistry Results Steady pulmonary hypertension and right ventricular hypertrophy were detected after 7 to 14 days of hypoxia compared with control ( P <0 01) The production of CO in the lung tissue homogenates and plasma significantly increased after exposure to hypoxic condition 1 day and 14 days, respectively( P <0 01) In control rat lungs,HO 1 staining was primarily detected in alveolar macrophages After 1 and 3 days of hypoxia, increased numbers of inflammatory cells were present in the lung and the macrophages stained intensely for HO 1 After 7 and 14 days of hypoxia,HO 1 staining presented in the thickened smooth muscle layer in many small pulmonary arteries was increased significantly( F =8 72, P <0 001) Treatment with ZnPP, an inhibitor of HO, decreased the production of CO in the lung tissue homogenates and plasma and enhanced the mPAP compared with rats exposed to hypoxic condition alone( P <0 01) Conclusion The endogenous CO/HO system in pulmonary arteries under chronic hypoxic condition increased in a time dependent two peak manner, the second increase having a very intimate correlation with the pulmonary artery pressure Endogenous CO/HO serves as an important regulatory system in hypoxic pulmonary hypertension The mechanisms underlying this effect might involve a direct vasodilating and antiproliferative action of endogenous CO, as well as an indirect effect of CO on the production of vasoconstrictors