Cell type-specific effect of hypoxia and platelet-derived growth factor-BB on extracellular matrix turnover and its consequences for lung remodeling
Cell type-specific effect of hypoxia and platelet-derived growth factor-BB on extracellular matrix turnover and its consequences for lung remodeling
复制标题
DOI：
10.1074/jbc.m602178200
复制
发表时间：
2007-01-12
影响因子：
4.8
通讯作者：
Roth, Michael
中科院分区：
文献类型：
--
作者：
Karakiulakis, George;Papakonstantinou, Eleni;Roth, Michael
缺氧与几种炎性肺疾病（如纤维化、慢性阻塞性肺病和哮喘）中的细胞外基质重塑相关。在人类细胞培养模型中，我们评估了细胞外基质的缺氧和血小板源性生长因子（PDGF）的修饰是否涉及基质金属蛋白酶（MMPs）的作用，从而影响细胞增殖。采用酶谱法和酶联免疫吸附法检测人肺成纤维细胞和肺血管平滑肌细胞（VSMCs）中MMP的表达及其活性，酶联免疫吸附法检测可溶性I型胶原的合成。在这两种细胞类型中，缺氧上调MMP-1，-2和-9前体的表达，而没有随后的激活。MMP-13仅在成纤维细胞中因缺氧而增加。PDGF-BB通过激活Erk 1/2丝裂原活化蛋白（MAP）激酶抑制所有缺氧依赖性MMP的合成和分泌。缺氧和PDGF-BB通过Erk 1/2和p38 MAP激酶诱导可溶性I型胶原的合成。缺氧诱导的细胞增殖被PDGF-BB抗体或Erk 1/2抑制阻断，但不被成纤维细胞中MMP或p38 MAP激酶抑制阻断。在VSMC中，缺氧诱导的增殖涉及Erk 1/2和p38 MAP激酶，并通过成纤维细胞条件培养基或可溶性胶原I型通过Erk 1/2进一步增加。总之，缺氧以细胞类型特异性方式控制组织重塑和增殖。此外，成纤维细胞可能通过诱导可溶性I型胶原的合成而间接影响VSMC的增殖。
Hypoxia is associated with extracellular matrix remodeling in several inflammatory lung diseases, such as fibrosis, chronic obstructive pulmonary disease, and asthma. In a human cell culture model, we assessed whether extracellular matrix modification by hypoxia and platelet-derived growth factor (PDGF) involves the action of matrix metalloproteinases (MMPs) and thereby affects cell proliferation. Expression of MMP and its activity were assessed by zymography and enzyme-linked immunosorbent assay in human lung fibroblasts and pulmonary vascular smooth muscle cells (VSMCs), and synthesis of soluble collagen type I was assessed by enzyme-linked immunosorbent assay. In both cell types, hypoxia up-regulated the expression of MMP-1, -2, and -9 precursors without subsequent activation. MMP-13 was increased by hypoxia only in fibroblasts. PDGF-BB inhibited the synthesis and secretion of all hypoxia-dependent MMP via Erk1/2 mitogen-activated protein (MAP) kinase activation. Hypoxia and PDGF-BB induced synthesis of soluble collagen type I via Erk1/2 and p38 MAP kinase. Hypoxia-induced cell proliferation was blocked by antibodies to PDGF-BB or by inhibition of Erk1/2 but not by the inhibition of MMP or p38 MAP kinase in fibroblasts. In VSMCs, hypoxia-induced proliferation involved Erk1/2 and p38 MAP kinases and was further increased by fibroblast-conditioned medium or soluble collagen type I via Erk1/2. In conclusion, hypoxia controls tissue remodeling and proliferation in a cell type-specific manner. Furthermore, fibroblasts may affect proliferation of VSMC indirectly by inducing the synthesis of soluble collagen type I.