Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, and Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, PR China.
Respir Res. 2010 Mar 31;11(1):36. doi: 10.1186/1465-9921-11-36.
Cigarette smoking is an important risk factor for pulmonary arterial hypertension (PAH) in chronic obstructive pulmonary disease (COPD). Chymase has been shown to function in the enzymatic production of angiotensin II (AngII) and the activation of transforming growth factor (TGF)-beta1 in the cardiovascular system. The aim of this study was to determine the potential role of chymase in cigarette smoke-induced pulmonary artery remodeling and PAH.
Hamsters were exposed to cigarette smoke; after 4 months, lung morphology and tissue biochemical changes were examined using immunohistochemistry, Western blotting, radioimmunoassay and reverse-transcription polymerase chain reaction.
Our results show that chronic cigarette smoke exposure significantly induced elevation of right ventricular systolic pressures (RVSP) and medial hypertrophy of pulmonary arterioles in hamsters, concurrent with an increase of chymase activity and synthesis in the lung. Elevated Ang II levels and enhanced TGF-beta1/Smad signaling activation were also observed in smoke-exposed lungs. Chymase inhibition with chymostatin reduced the cigarette smoke-induced increase in chymase activity and Ang II concentration in the lung, and attenuated the RVSP elevation and the remodeling of pulmonary arterioles. Chymostatin did not affect angiotensin converting enzyme (ACE) activity in hamster lungs.
These results suggest that chronic cigarette smoke exposure can increase chymase activity and expression in hamster lungs. The capability of activated chymase to induce Ang II formation and TGF-beta1 signaling may be part of the mechanism for smoking-induced pulmonary vascular remodeling. Thus, our study implies that blockade of chymase might provide benefits to PAH smokers.
吸烟是慢性阻塞性肺疾病（COPD）中肺动脉高压（PAH）的一个重要危险因素。糜酶已被证明在心血管系统中具有酶促生成血管紧张素 II（AngII）和激活转化生长因子（TGF）-β1的功能。本研究旨在确定糜酶在香烟烟雾引起的肺动脉重塑和 PAH 中的潜在作用。
将仓鼠暴露于香烟烟雾中；4 个月后，通过免疫组织化学、Western blot、放射免疫测定和逆转录聚合酶链反应检测肺形态和组织生化变化。
我们的结果表明，慢性香烟烟雾暴露显著诱导仓鼠右心室收缩压（RVSP）升高和肺小动脉中膜肥厚，同时肺中的糜酶活性和合成增加。暴露于烟雾的肺部也观察到 Ang II 水平升高和 TGF-β1/Smad 信号转导激活增强。用糜酶抑制剂 chymostatin 抑制可减少香烟烟雾引起的肺糜酶活性和 Ang II 浓度升高，并减轻 RVSP 升高和肺小动脉重塑。Chymostatin 不影响仓鼠肺中的血管紧张素转换酶（ACE）活性。
这些结果表明，慢性香烟烟雾暴露可增加仓鼠肺中的糜酶活性和表达。激活的糜酶诱导 Ang II 形成和 TGF-β1 信号的能力可能是吸烟引起的肺血管重塑的机制之一。因此，我们的研究表明，糜酶的阻断可能对吸烟引起的 PAH 有益。
