肾上腺髓质素缓解低氧性肺动脉高压大鼠肺动脉中胶原堆积的研究

Adrenomedullin alleviates collagen accumulation in pulmonary arteries of rats with hypoxic pulmonary hypertension

摘要:

目的：观察长期应用肾上腺髓质素（adrenomedullin, ADM）对慢性低氧性肺动脉高压大鼠肺血管胶原代谢的影响，以探讨ADM对慢性低氧性肺血管结构重建的作用及其可能机制。方法：19只雄性Wistar大鼠随机分为对照组（n=6）、低氧组（n=7）、低氧+ADM组（n=6）。对于低氧+ADM组大鼠，通过微量渗透泵皮下持续给予ADM（300 ng/h）2周。低氧2周后，以右心导管法测定肺动脉平均压，检测右心室与左心室加室间隔比值，观测肺血管显微变化。用免疫组化法检测肺动脉中胶原I、胶原III和转化生长因子（TGF）-β的表达。结果：低氧2周后，大鼠肺动脉平均压明显升高(P<0.01)，右心室与左心室加室间隔的比值明显增加(P<0.01)，肺小血管肌化程度和肺动脉相对中膜厚度较对照组均明显增高（P<0.01），同时肺动脉胶原I、胶原III和TGF-β表达增强。与低氧组大鼠相比，低氧+ADM组大鼠肺动脉平均压明显降低（P<0.01），右心室与左心室加室间隔的比值明显下降（P<0.01），肺小血管肌化程度和肺动脉相对中膜厚度较低氧组均明显降低（均P<0.01），同时肺动脉胶原I、胶原III和TGF-β表达减弱。结论：外源性补充ADM可能通过抑制肺动脉TGF-β表达，减少肺动脉壁胶原异常堆积，对低氧性肺动脉高压和肺血管结构重建发挥调节作用。

Abstract:

OBJECTIVE: To observe the effect of adrenomedullin (ADM) on the pulmonary vascular collagen metabolism in hypoxic rats in order to study the effect of ADM on chronic hypoxic pulmonary vascular structural remodeling and its possible mechanism. METHODS: Nineteen male Wistar rats were randomly divided into three groups: normal control (n=6), hypoxia (n=7) and ADM-treated hypoxia (n=6). ADM was subcutaneously administered into rats of the ADM-treated hypoxia group by mini-osmotic pump (300 ng/h) for two weeks. After two weeks of hypoxic challenge, mean pulmonary arterial pressure (mPAP) was evaluated using a right cardiac catheterization procedure. The ratio of right ventricular mass to left ventricular plus septal mass ［RV/ (LV+S)］ was measured. The changes of pulmonary vascular microstructure were observed. Meanwhile, the expression levels of collagen I, collagen III and transforming growth factor (TGF)-β in pulmonary arteries were detected by immunohistochemical assay. RESULTS: mPAP and RV/(LV+S) increased significantly in the hypoxia group compared with normal controls (P<0.01). The muscularization of small pulmonary vessels and the relative medial thickness of pulmonary arteries increased obviously in the hypoxia group compared with those in the normal control group (P<0.01). Meanwhile, the expression levels of collagen I, collagen III and TGF-β of pulmonary arteries in the hypoxia group increased markedly compared with those in the normal control group. However, mPAP and RV/(LV+S) were significantly reduced in the ADM-treated hypoxia group compared with those in the hypoxia group (P<0.01). ADM ameliorated pulmonary vascular structural remodeling of hypoxic rats, with a decrease in the expression of collagen I, collagen III and TGF-β of pulmonary arteries. CONCLUSIONS: ADM might play a regulatory role in the development of hypoxic pulmonary hypertension and hypoxic pulmonary vascular remodeling, through inhibiting the expression of TGF-β and alleviating the collagen accumulation of pulmonary arteries.