Original Article
Remodeling of rat pulmonary artery induced by chronic smoking exposure
Abstract
Objective: To evaluate the dominant role in rat pulmonary artery (PA) remodeling induced by chronic smoking exposure (CSE).
Methods: 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 [Ca2+]i were measured using Fura-2 as dye.
Results: 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.
Conclusions: 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.
Methods: 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 [Ca2+]i were measured using Fura-2 as dye.
Results: 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.
Conclusions: 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.
