慢性阻塞性肺疾病患者肺动脉高压时肺动脉平滑肌细胞的增殖与凋亡

目的探讨慢性阻塞性肺疾病（COPD）患者肺动脉高压及肺血管重塑的机制。方法将患者分为非COPD非肺动脉高压组（A组）、COPD非肺动脉高压组（B组）和COPD并肺动脉高压组（C组），应用免疫组织化学方法检测肺动脉平滑肌细胞增殖细胞核抗原（PCNA），用原位缺口末端DNA碎片标记技术检测肺动脉平滑肌细胞凋亡。结果A组肺小动脉管壁较薄，管腔较大；B组管壁厚度增加，管腔变窄，其程度介于A组和C组之间；C组肺小动脉管壁明显增厚，管腔明显变窄，平滑肌细胞增生肥大，呈现明显的肺血管重塑现象；图像分析结果表明。B组及C组管壁厚度占外径的百分比（WT％）和血管壁横断面积占血管总面积的百分比（WA％）分别为（20±4）和（35±5）％、（28±5）和（50±6）％，明显高于A组的（16±3）和（25±3）％。C组与B组相比，WT％及WA％明显增高。3组肺小动脉壁平滑肌细胞均存在一定比例的增殖与凋亡，B组和C组肺小动脉平滑肌细胞增殖指数（PI）为（19±5）和（38±7）％，明显高于A组的（8±2）％；两组凋亡指数为（4．5±1．3）和（3．1±1．3）％，均明显低于A组的（6．9±1．9）％；B组肺动脉平滑肌细胞增殖指数低于C组，而凋亡指数高于C组。C组及B组氧分压与肺动脉平滑肌细胞增殖指数成负相关（r=-0．519，P=0．003），与肺动脉平滑肌细胞凋亡指数成正相关（r=0．441，P=0．015）。结论肺动脉平滑肌细胞增殖增加和凋亡减少。由此引起增殖与凋亡失衡是COPD患者肺血管重塑及发生肺动脉高压的主要机制；缺氧是引起肺动脉平滑肌细胞增殖增加和凋亡减少的主要原因之一。

Apoptosis versus proliferation activities of pulmonary artery smooth muscle cells in pulmonary arterial hypertension associated with chronic obstructive pulmonary disease

OBJECTIVE: To investigate the apoptosis versus proliferation activities of pulmonary artery smooth muscle cells (PASMC) in pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD) and pulmonary vascular structural remodeling. METHODS: Forty-five patients were divided into three groups: patients without COPD and PH (non-COPD group, n = 15), COPD patients without PH (COPD with non-PH group, n = 15) and patients with PH associated with COPD (COPD with PH group, n = 15). Lung tissue samples were obtained from surgically resected specimens. The remodeling of pulmonary arteries were observed under microscope, and the changes of morphology-the ratio of the thickness of the wall to the external diameter of the pulmonary arterioles (WT%) and the ratio of the area of the wall to that of the pulmonary arterioles (WA%) were analyzed by computer-based image analysis system. The proliferation of PASMC was detected by proliferating cell nuclear antigen (PCNA) with immunohistochemical technique, and TUNEL (terminal deoxynu-cleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-digoxigenin nick end labeling) was used for the detection of the apoptosis of PASMC. RESULTS: In the COPD with non-PH group, the arterial walls were thicker and the lumens narrower than that of the non-COPD group. In the COPD with PH group, the walls were thicker and the lumens narrower than that of the COPD with non-PH group. In the COPD with non-PH group and the COPD with PH group, the WT% and WA% (20 +/- 4)% and (35 +/- 5)%; (28 +/- 5)% and (50 +/- 6)%, respectively] were higher than those of the non-COPD group (16 +/- 3)% and (25 +/- 3)% (P < 0.01), and the WT% and WA% of the COPD with PH group were higher than those of the COPD with non-PH group (P < 0.01). Both proliferative and apoptotic PASMC were found in the patients of the three groups. The proliferation indexes (PI) of the COPD with non-PH group and the COPD with PH group (19 +/- 5)% and (38 +/- 7)%] were significantly higher than that of the non-COPD group (8 +/- 2)%, P < 0.01], while the apoptosis indexes (AI) (4.5 +/- 1.3)% and (3.1 +/- 1.3)%] were lower than that of the non-COPD group (6.9 +/- 1.9)%, P < 0. 01]. The PI of the COPD with non-PH group was lower than that of the COPD with PH group; the AI was higher than that of the COPD with PH group (P < 0.05). The PaO(2) of the COPD with non-PH group and the COPD with PH group was negatively related with the PI (r = -0.519, P = 0.003), but positively related to the AI of the PASMC (r = 0.441, P = 0.015). CONCLUSION: The imbalance of the increased proliferation and decreased apoptosis of PASMC may contribute to the pulmonary vascular structural remodeling and pulmonary arterial hypertension in patients of COPD. Hypoxia is one of the main causes of increased proliferation and decreased apoptosis of the PASMC.