Wright J L, Churg A
Department of Pathology, University of British Columbia, University Hospital, 2211 Wesbrook Mall, Vancouver, BC, Canada.
J Appl Physiol (1985). 2008 May;104(5):1462-9. doi: 10.1152/japplphysiol.00520.2007. Epub 2008 Mar 20.
The pathogenesis of cigarette smoke-induced pulmonary hypertension is not understood. We have previously shown that smoke rapidly and persistently, but discoordinately, upregulates gene expression of mediators that control vasoconstriction, vasoproliferation, and vasorelaxation in small intrapulmonary arteries. To investigate the possibility that smoke also induces endothelial dysfunction, a finding common to other forms of pulmonary hypertension, we exposed guinea pigs to smoke or air (control) daily for 2 wk and then prepared precision-cut lung slices. After exposure to endothelin-1, a vasoconstrictor, intra-acinar arteries in lung slices derived from smoke-exposed animals constricted more rapidly (greater constriction at a given concentration of endothelin) than did vessels from air-exposed animals. To examine relaxation responses, arteries were constricted with the vasoconstrictor U-46619 and then relaxed with progressively increasing doses of acetylcholine. Vessels from smokers had a delayed response to acetylcholine compared with vessels from controls. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester reduced relaxation in both control and smoke-exposed arteries, whereas the NO donor sodium nitroprusside increased relaxation of the smoke-exposed arteries, confirming that endothelial dysfunction with decreased effective NO production is present. These findings show that precision cut lung slices can be used to examine the physiological effects of cigarette smoke on intra-acinar pulmonary arteries and indicate that even relatively short-term exposure to smoke produces endothelial dysfunction with a resulting tendency to earlier constriction and later relaxation in cigarette smokers. These changes may be important in the development of pulmonary hypertension.
香烟烟雾所致肺动脉高压的发病机制尚不清楚。我们之前已经表明，烟雾能迅速且持续但不协调地上调控制肺内小动脉血管收缩、血管增殖和血管舒张的介质的基因表达。为了研究烟雾是否也会诱发内皮功能障碍（这是其他形式肺动脉高压的一个常见发现），我们将豚鼠每天暴露于烟雾或空气（对照）中，持续2周，然后制备精密肺切片。暴露于血管收缩剂内皮素-1后，来自烟雾暴露动物的肺切片中的腺泡内动脉比来自空气暴露动物的血管收缩更快（在给定浓度的内皮素下收缩更强）。为了检测舒张反应，用血管收缩剂U-46619使动脉收缩，然后用逐渐增加剂量的乙酰胆碱使其舒张。与对照组血管相比，吸烟组动物的血管对乙酰胆碱的反应延迟。一氧化氮合酶抑制剂N(G)-硝基-L-精氨酸甲酯降低了对照组和烟雾暴露组动脉的舒张，而一氧化氮供体硝普钠增加了烟雾暴露组动脉的舒张，证实存在内皮功能障碍且有效一氧化氮生成减少。这些发现表明，精密肺切片可用于检测香烟烟雾对腺泡内肺动脉的生理影响，并表明即使相对短期暴露于烟雾也会导致内皮功能障碍，从而使吸烟者的血管有更早收缩和更晚舒张的倾向。这些变化可能在肺动脉高压的发生发展中起重要作用。
