Alagappan V K T, McKay S, Widyastuti A, Garrelds I M, Bogers A J J C, Hoogsteden H C, Hirst S J, Sharma H S
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Cell Biochem Biophys. 2005;43(1):119-29. doi: 10.1385/CBB:43:1:119.
Airflow obstruction in chronic airway disease is associated with airway and pulmonary vascular remodeling, of which the molecular mechanisms are poorly understood. Paracrine actions of angiogenic factors released by resident or infiltrating inflammatory cells following activation by proinflammatory cytokines in diseased airways could play a major role in the airway vascular remodeling process. Here, the proinflammatory cytokines interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha were investigated on cell cultures of human airway smooth muscle (ASM) for their effects on mRNA induction and protein release of the angiogenic peptide, vascular endothelial growth factor (VEGF). IL-1beta (0.5 ng/mL) and TNF-alpha (10 ng/mL) each increased VEGF mRNA (3.9 and 1.7 kb) expression in human ASM cells, reaching maximal levels between 16 and 24 and 4 and 8 h, respectively. Both cytokines also induced a time-dependent release of VEGF, which was not associated with increased ASM growth. Preincubation of cells with 1 microM dexamethasone abolished enhanced release of VEGF by TNF-alpha. The data suggest that human ASM cells express and secrete VEGF in response to proinflammatory cytokines and may participate in paracrine inflammatory mechanisms of vascular remodeling in chronic airway disease.
慢性气道疾病中的气流阻塞与气道和肺血管重塑有关，但其分子机制尚不清楚。在患病气道中，促炎细胞因子激活后，驻留或浸润的炎症细胞释放的血管生成因子的旁分泌作用可能在气道血管重塑过程中起主要作用。在此，研究了促炎细胞因子白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α对人气道平滑肌（ASM）细胞培养物的影响，观察它们对血管生成肽血管内皮生长因子（VEGF）的mRNA诱导和蛋白释放的作用。IL-1β（0.5 ng/mL）和TNF-α（10 ng/mL）均增加了人ASM细胞中VEGF mRNA（3.9和1.7 kb）的表达，分别在16至24小时和4至8小时达到最高水平。两种细胞因子还诱导了VEGF的时间依赖性释放，这与ASM生长增加无关。用1 microM地塞米松预孵育细胞可消除TNF-α诱导的VEGF释放增加。数据表明，人气道平滑肌细胞对促炎细胞因子作出反应，表达并分泌VEGF，可能参与慢性气道疾病中血管重塑的旁分泌炎症机制。
