Wright Joanne L, Tai Hsin, Churg Andrew
Dept. of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5.
J Appl Physiol (1985). 2006 Feb;100(2):672-8. doi: 10.1152/japplphysiol.00274.2005. Epub 2005 Oct 6.
The pathogenesis of pulmonary hypertension in patients with chronic obstructive pulmonary disease is not understood. We have previously shown increased levels of mediators that control vasoconstriction (endothelin-1), vascular cell proliferation (endothelin-1 and vascular endothelial growth factor), and vasodilation (endothelial nitric oxide synthase) in the intrapulmonary arteries of animals exposed to cigarette smoke. To determine whether these mediators could be implicated in the structural remodeling of the arterial vasculature and increased pulmonary arterial pressure caused by chronic cigarette smoke exposure, guinea pigs were exposed to daily cigarette smoke for 6 mo. Pulmonary arterial pressures were measured. Intrapulmonary artery structure was analyzed by morphometry, artery mediator protein expression by immunohistochemistry, and artery mediator gene expression by laser capture microdissection and real-time RT-PCR. We found that the smoke-exposed animals developed increases in pulmonary arterial pressure and increased muscularization of the small pulmonary arteries. Gene expression and protein levels of all three mediators were increased, and pulmonary arterial pressure correlated both with the levels of mediator production and with the degree of arterial muscularization. We conclude that chronic smoke exposure produces increased vasoactive mediator expression in the small intrapulmonary arteries and that these mediators are associated with vascular remodeling as well as increased pulmonary arterial pressure. These findings support the idea that hypertension in chronic obstructive pulmonary disease is a result of direct cigarette smoke-mediated effects on the vasculature and suggest that interference with endothelin and VEGF production and activity or augmentation of nitric oxide levels may be beneficial.
慢性阻塞性肺疾病患者肺动脉高压的发病机制尚不清楚。我们之前已经表明，在暴露于香烟烟雾的动物肺内动脉中，控制血管收缩的介质（内皮素-1）、血管细胞增殖的介质（内皮素-1和血管内皮生长因子）以及血管舒张的介质（内皮型一氧化氮合酶）水平升高。为了确定这些介质是否与慢性香烟烟雾暴露引起的动脉血管结构重塑和肺动脉压力升高有关，将豚鼠每天暴露于香烟烟雾中6个月。测量肺动脉压力。通过形态计量学分析肺内动脉结构，通过免疫组织化学分析动脉介质蛋白表达，通过激光捕获显微切割和实时逆转录聚合酶链反应分析动脉介质基因表达。我们发现，暴露于烟雾的动物肺动脉压力升高，小肺动脉肌化增加。所有三种介质的基因表达和蛋白水平均升高，肺动脉压力与介质产生水平以及动脉肌化程度均相关。我们得出结论，慢性烟雾暴露导致肺内小动脉血管活性介质表达增加，并且这些介质与血管重塑以及肺动脉压力升高有关。这些发现支持了这样一种观点，即慢性阻塞性肺疾病中的高血压是香烟烟雾对血管的直接介导作用的结果，并表明干扰内皮素和血管内皮生长因子的产生及活性或提高一氧化氮水平可能是有益的。
