Ediger T L, Toews M L
Department of Pharmacology, University of Nebraska Medical Center, Omaha68198-6260, USA.
J Pharmacol Exp Ther. 2000 Sep;294(3):1076-82.
Previous studies showed that human airway smooth muscle (HASM) cells treated with lysophosphatidic acid (LPA), a pertussis toxin (PTX)-sensitive G protein-coupled (GPC) mitogen, simultaneously with epidermal growth factor (EGF), a receptor tyrosine kinase (RTK) mitogen, exhibit markedly synergistic stimulation of mitogenesis. We now show that the RTK mitogens basic fibroblast growth factor, insulin-like growth factor-1, insulin, platelet-derived growth factor-AA, and platelet-derived growth factor-BB, as well as transforming growth factor-beta, all induced synergistic stimulation of mitogenesis in the presence of LPA. The PTX-sensitive GPC mitogens carbachol and endothelin-1 and the PTX-insensitive GPC mitogens sphingosine-1-phosphate and thrombin exhibited synergistic stimulation together with EGF. Several RTK-RTK growth factor pairs and GPC-GPC mitogen pairs were also synergistic. HASM cells showed synergistic responses to serum plus EGF but not to serum plus LPA. Testing various other cell types showed that synergism between LPA and EGF occurred in other smooth muscle cells because both vascular smooth muscle cells and mesangial cells exhibited synergism. Additionally, human fetal lung fibroblasts also showed striking synergism. These results indicate that HASM cells can respond synergistically to a wide variety of mitogen combinations and that this synergism is a feature shared with other contractile cell types.
先前的研究表明，用溶血磷脂酸（LPA，一种百日咳毒素（PTX）敏感的G蛋白偶联（GPC）促细胞分裂剂）与表皮生长因子（EGF，一种受体酪氨酸激酶（RTK）促细胞分裂剂）同时处理人气道平滑肌（HASM）细胞时，会显著协同刺激细胞增殖。我们现在表明，RTK促细胞分裂剂碱性成纤维细胞生长因子、胰岛素样生长因子-1、胰岛素、血小板衍生生长因子-AA和血小板衍生生长因子-BB，以及转化生长因子-β，在LPA存在时均能诱导协同刺激细胞增殖。PTX敏感的GPC促细胞分裂剂卡巴胆碱和内皮素-1以及PTX不敏感的GPC促细胞分裂剂鞘氨醇-1-磷酸和凝血酶与EGF一起表现出协同刺激作用。几种RTK-RTK生长因子对和GPC-GPC促细胞分裂剂对也具有协同作用。HASM细胞对血清加EGF表现出协同反应，但对血清加LPA则无协同反应。对其他多种细胞类型进行测试表明，LPA和EGF之间的协同作用发生在其他平滑肌细胞中，因为血管平滑肌细胞和系膜细胞均表现出协同作用。此外，人胎儿肺成纤维细胞也表现出显著的协同作用。这些结果表明，HASM细胞能够对多种促细胞分裂剂组合产生协同反应，并且这种协同作用是其他收缩细胞类型共有的特征。
