1 Department of Physiology, School of Basic Science, Guangzhou Medical University, Guangzhou 510182, China ; 2 Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China ; 3 School of Life Science, Sun Yat-Sen University, Guangzhou 510275, China.
J Thorac Dis. 2014 Jun;6(6):818-28. doi: 10.3978/j.issn.2072-1439.2014.03.31.
To evaluate the dominant role in rat pulmonary artery (PA) remodeling induced by chronic smoking exposure (CSE).
Thirty-five male Sprague-Dawley (SD) rats were exposed to 36 cigarettes per day, 6 days per week, for 1, 3, or 5 months. Another 35 SD rats were sham-exposed during the same period. Hemodynamic measurement, evaluation of the right ventricular hypertrophy index (RVHI) plus right ventricle-to-weight ratio, and hematoxylin eosin staining was performed. Wall thickness, artery radius, luminal area, and total area were measured morphometrically. Western blotting assessed expression of PPAR-γ BMP4, BMPR2, and TRPC1/4/6 in the artery and lung. Store-operated calcium entry (SOCE) and [Ca(2+)]i were measured using Fura-2 as dye.
Mean right ventricular pressure increased after 3 months of smoking exposure and continued to increase through 5 months. Right ventricular systolic pressure (RVSP) increased after 3 months of exposure and then stabilized. RVHI increased after 5 months; right ventricle-to-weight ratio was elevated after 3 months and further increased after 5 months. Wall thickness-to-radius ratio does-dependently increased after 3 months through 5 months, in parallel with the decreased luminal area/total area ratio after 5 months. Other changes included the development of inflammatory responses, enlargement of the alveolar spaces, and reductions in the endothelial lining of PAs, proliferative smooth muscle cells, fibroblasts, and adventitia. Moreover, BMP4 and TRPC1/4/6 expression increased to varying degrees in the arteries and lungs of smoking-exposed animals, whereas BMPR expression and SOCE increased only in the arteries, and PPAR-γ was downregulated in both the arteries and lungs.
In SD rats, smoking exposure induces pulmonary vascular remodeling. The consequences of increased SOCE include increase in TRPC1/4/6, probably via augmented BMP4 expression, which also contribute to inflammatory responses in the lung. Moreover, interactions between BMP4 and PPAR-γ may play a role in preventing inflammation under normal physiological conditions.
评估慢性吸烟暴露（CSE）对大鼠肺动脉（PA）重塑的主导作用。
35 只雄性 Sprague-Dawley（SD）大鼠每天暴露于 36 支香烟中，每周 6 天，暴露 1、3 或 5 个月。另外 35 只 SD 大鼠在同一时期进行假暴露。进行血流动力学测量、右心室肥厚指数（RVHI）加右心室与体重比的评估以及苏木精-伊红染色。形态计量学测量壁厚度、动脉半径、管腔面积和总面积。Western blot 评估动脉和肺中 PPAR-γ、BMP4、BMPR2 和 TRPC1/4/6 的表达。使用 Fura-2 作为染料测量储存操作钙内流（SOCE）和[Ca2+]i。
暴露于吸烟 3 个月后平均右心室压力增加，并持续增加至 5 个月。暴露 3 个月后右心室收缩压（RVSP）增加，然后稳定。5 个月后 RVHI 增加；暴露 3 个月后右心室与体重比升高，5 个月后进一步升高。壁厚度-半径比在 3 个月至 5 个月期间独立增加，与 5 个月后管腔面积/总面积比降低平行。其他变化包括炎症反应的发展、肺泡腔的扩大以及 PA 内皮衬里、增殖性平滑肌细胞、成纤维细胞和外膜的减少。此外，BMP4 和 TRPC1/4/6 的表达在吸烟暴露动物的动脉和肺中不同程度地增加，而 BMPR 的表达和 SOCE 仅在动脉中增加，PPAR-γ 在动脉和肺中均下调。
在 SD 大鼠中，吸烟暴露会引起肺血管重塑。SOCE 的增加导致 TRPC1/4/6 的增加，可能是通过增强 BMP4 的表达，这也有助于肺中的炎症反应。此外，BMP4 和 PPAR-γ 之间的相互作用可能在正常生理条件下发挥作用，以防止炎症。
