Cyclic AMP-mobilizing agents and glucocorticoids modulate human smooth muscle cell migration
Cyclic AMP-mobilizing agents and glucocorticoids modulate human smooth muscle cell migration
复制标题
DOI：
10.1165/rcmb.2002-0254oc
复制
发表时间：
2003-07-01
影响因子：
6.4
通讯作者：
Panettieri, RA
中科院分区：
文献类型：
--
作者：
Goncharova, EA;Billington, CK;Panettieri, RA
平滑肌增生和细胞迁移是气道和肺血管疾病的特征。调控肺平滑肌迁移的精确细胞和分子机制尚不清楚。在这项研究中，我们研究了camp动员剂和类固醇对平滑肌细胞迁移的影响。血小板衍生生长因子（PDGF）、转化生长因子-a、血管内皮生长因子和碱性成纤维细胞生长因子显著刺激肺血管平滑肌（PVSM）细胞的细胞迁移。PDGF、转化生长因子-a和碱性成纤维细胞生长因子也能促进气道平滑肌（ASM）的迁移，但血管内皮生长因子对其无影响。有趣的是，平滑肌有丝分裂原凝血酶不刺激两种细胞类型的迁移。在两种细胞类型中，能够提高细胞内cAMP的药物抑制基础（未受刺激的）细胞迁移，而它们对pdgf刺激的迁移的影响则更加多变。前列腺素E-2、沙美特罗和4型磷酸二酯酶抑制剂西洛莫司特抑制基础ASM和PVSM迁移30-60%。前列腺素E-2和西洛莫司特也能抑制pdgf刺激的ASM和PVSM细胞的迁移，但沙美特罗没有作用。地塞米松或氟替卡松对ASM细胞进行预孵育，可抑制基础和pdgf刺激的迁移，并使沙美特罗对pdgf诱导的细胞迁移具有抑制作用。单独使用类固醇不会刺激cAMP生成或cAMP/ pka依赖性基因转录（CRE-Luc活性），但会略微增强沙美特罗刺激的CRE-Luc活性。总的来说，这些发现表明camp动员剂和类固醇可能通过不同的机制调节人类平滑肌细胞的迁移。
Hyperplasia and cell migration of smooth muscle are features of both airway and pulmonary vascular diseases. The precise cellular and molecular mechanisms that regulate smooth muscle migration in the lungs remain unknown. In this study, we examined the effect of cAMP-mobilizing agents and steroids on smooth muscle cell migration. Platelet-derived growth factor (PDGF), transforming growth factor-a, vascular endothelial growth factor, and basic fibroblast growth factor significantly stimulated cell migration in pulmonary vascular smooth muscle (PVSM) cells. Airway smooth muscle (ASM) migration was also stimulated by PDGF, transforming growth factor-a, and basic fibroblast growth factor, but vascular endothelial growth factor was without effect. Interestingly, the smooth muscle mitogen thrombin did not stimulate migration of either cell type. Agents capable of elevating intracellular cAMP inhibited basal (unstimulated) cell migration in both cell types, whereas their effects on PDGF-stimulated migration were more variable. Prostaglandin E-2, salmeterol, and the phosphodiesterase type 4 inhibitor cilomolast inhibited basal ASM and PVSM migration by 30-60%. Prostaglandin E-2 and cilomolast also inhibited PDGF-stimulated migration of ASM and PVSM cells, but salmeterol was without effect. Preincubation of ASM cells with dexamethasone or fluticasone inhibited basal and PDGF-stimulated migration, and enabled an inhibitory effect of salmeterol on PDGF-induced cell migration. Steroids alone did not stimulate cAMP production or cAMP/PKA-dependent gene transcription (CRE-Luc activity), but slightly augmented salmeterol-stimulated CRE-Luc activity. Collectively, these findings demonstrate that cAMP-mobilizing agents and steroids modulate human smooth muscle cell migration, likely by distinct mechanisms.