Role of mast Cell chymase in the development of pulmonary hypertension associated with congenital heart diseases

先天性心脏病（CHD）合并肺血管病（PVD）的分子机制尚不清楚。提示血管紧张素转换酶在肺血管病理中起重要作用的证据使我们推测肥大细胞糜酶，另一种血管紧张素I转换酶，也有可能促进CHD中PVD的发展。23例年龄3个月至45岁的患有心房或心室或两者的间隔缺损的患者，肺动脉血流和压力增加，肺血管阻力范围为1.3 ~ 8.1单位m^2。肥大细胞和肥大细胞糜酶在矫正手术期间获得的肺活检组织中进行了化学鉴定。肺循环正常组（n=10）与肺循环正常组（n=23）相比，肥大细胞总数有显著性差异（P<0.01）。CHD患者肺组织中含糜酶的肥大细胞与对照组相比有显著性差异。在患者中，72%的肺肥大细胞含有糜蛋白酶，而对照组仅为15%（p<0.0001）。含凝乳酶的肥大细胞主要出现在血管壁的中膜和外膜。重要的是，血管紧张素II在存在糜酶的血管周围病变中被化学检测到，但在糜酶稀疏的病变中未检测到。此外，含糜酶的肥大细胞的数量与肺血管阻力相关（r=0.64）。这些发现提示肥大细胞糜酶在CHD患者早期PVD的发生中可能发挥作用。

The molecular mechanism involved in pulmonary vascular disease (PVD) associated with congenital heart disease (CHD) remains uncertain. Evidence suggesting that angiotensin converting enzyme plays an important role in pulmonary vascular pathology led us to hypothesize that mast cell chymase, another angiotensin I converting enzyme, also had the potential to contribute to the development of PVD in CHD.Twenty-three patients ranging from age 3 months to 45 years with atrial or ventricular or both septal defects with increased pulmonary arterial blood flow and pressure, with pulmonary vascular resistance ranging from 1.3 to 8.1 unit m^2, were studied. Mast cells and mast cell chymase were immunohistochemically identified in the lung biopsy tissues obtained during corrective surgery. There was a significant difference in numbers of total mast cells between patients (n=23) and controls (n=10) with normal pulmonary circulation (p<0.01). Moreover, chymase-containing mast cells in the lung tissues of CHD patients showed striking differences from those of controls. In the patients, 72% of lung mast cells contained chymase, compared to only 15% in controls (p<0.000l). Chymase-containing mast cells predominantly appeared in the media and adventitia of vessel walls. Importantly, angiotensin II was immunohistochemically detected in perivascular lesions where chymase was present, but not in the lesions where chymase was sparsely seen. Furthermore, the number of chymase-containing mast cells was correlated with pulmonary vascular resistance (r=0.64). These findings suggest a possible role of mast cell chymase in the development of early-stage PVD in CHD patients.