Dekkers Bart G J, Schaafsma Dedmer, Nelemans S Adriaan, Zaagsma Johan, Meurs Herman
Department of Molecular Pharmacology, University Centre for Pharmacy, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Am J Physiol Lung Cell Mol Physiol. 2007 Jun;292(6):L1405-13. doi: 10.1152/ajplung.00331.2006. Epub 2007 Feb 9.
Changes in the ECM and increased airway smooth muscle (ASM) mass are major contributors to airway remodeling in asthma and chronic obstructive pulmonary disease. It has recently been demonstrated that ECM proteins may differentially affect proliferation and expression of phenotypic markers of cultured ASM cells. In the present study, we investigated the functional relevance of ECM proteins in the modulation of ASM contractility using bovine tracheal smooth muscle (BTSM) preparations. The results demonstrate that culturing of BSTM strips for 4 days in the presence of fibronectin or collagen I depressed maximal contraction (E(max)) both for methacholine and KCl, which was associated with decreased contractile protein expression. By contrast, both fibronectin and collagen I increased proliferation of cultured BTSM cells. Similar effects were observed for PDGF. Moreover, PDGF augmented fibronectin- and collagen I-induced proliferation in an additive fashion, without an additional effect on contractility or contractile protein expression. The fibronectin-induced depression of contractility was blocked by the integrin antagonist Arg-Gly-Asp-Ser (RGDS) but not by its negative control Gly-Arg-Ala-Asp-Ser-Pro (GRADSP). Laminin, by itself, did not affect contractility or proliferation but reduced the effects of PDGF on these parameters. Strong relationships were found between the ECM-induced changes in E(max) in BTSM strips and their proliferative responses in BSTM cells and for E(max) and contractile protein expression. Our results indicate that ECM proteins differentially regulate both phenotype and function of intact ASM.
细胞外基质（ECM）的变化和气道平滑肌（ASM）质量的增加是哮喘和慢性阻塞性肺疾病气道重塑的主要促成因素。最近有研究表明，ECM蛋白可能对培养的ASM细胞的增殖和表型标志物的表达产生不同影响。在本研究中，我们使用牛气管平滑肌（BTSM）制剂研究了ECM蛋白在调节ASM收缩性方面的功能相关性。结果表明，在纤连蛋白或I型胶原存在的情况下，将BSTM条培养4天会降低乙酰甲胆碱和氯化钾引起的最大收缩（E(max)），这与收缩蛋白表达降低有关。相比之下，纤连蛋白和I型胶原均增加了培养的BTSM细胞的增殖。血小板衍生生长因子（PDGF）也观察到类似的效果。此外，PDGF以累加方式增强了纤连蛋白和I型胶原诱导的增殖，而对收缩性或收缩蛋白表达没有额外影响。纤连蛋白诱导的收缩性降低被整合素拮抗剂Arg-Gly-Asp-Ser（RGDS）阻断，但未被其阴性对照Gly-Arg-Ala-Asp-Ser-Pro（GRADSP）阻断。层粘连蛋白本身不影响收缩性或增殖，但降低了PDGF对这些参数的影响。在BTSM条中ECM诱导的E(max)变化与其在BSTM细胞中的增殖反应之间，以及E(max)与收缩蛋白表达之间发现了密切关系。我们的结果表明，ECM蛋白对完整ASM的表型和功能具有不同的调节作用。
