Thrombin and TNF-α/IL-1β synergistically induce fibroblast-mediated collagen gel degradation
Thrombin and TNF-α/IL-1β synergistically induce fibroblast-mediated collagen gel degradation
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DOI：
10.1165/rcmb.2005-0026oc
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发表时间：
2006-12-01
影响因子：
6.4
通讯作者：
Rennard, Stephen I.
中科院分区：
文献类型：
--
作者：
Fang, Qiuhong;Liu, Xiangde;Rennard, Stephen I.
已经存在的和新合成的细胞外基质的降解被认为在组织重塑中起重要作用。本研究评价了凝血酶和TNF-α/IL-1 β是否可以协同诱导在三维胶原凝胶中培养的人胎肺成纤维细胞（HFL-1）和成人支气管成纤维细胞降解胶原。TNF-α/IL-1 β单独诱导基质金属蛋白酶（MMPs）-1、-3和-9的产生，这些酶以潜伏形式释放。随着凝血酶的加入，潜在的MMPs转化为活性形式，这导致胶原蛋白凝胶降解。凝血酶对MMP的部分活化是在无细胞存在下直接活化MMP-1、MMP-2、MMP-3和MMP-9所致。此外，凝血酶和TNF-α/ IL-1 β的组合抑制了金属蛋白酶组织抑制剂-1的产生。这些结果表明，凝血酶和TNF-α/IL-1 β协同作用，通过增加MMIP的产生和活化来诱导三维胶原凝胶的降解，并且这种作用通过凝血酶直接活化MMP和通过凝血酶间接活化成纤维细胞来介导。通过这些机制，凝血酶可能导致许多以组织重塑为特征的慢性肺部疾病。
Degradation of preexisting and newly synthesized extracellular matrix is thought to play an important role in tissue remodeling. The current study evaluated whether thrombin and TNF-alpha/IL-1 beta could collaboratively induce Collagen degradation by human fetal lung fibroblasts (HFL-1) and adult bronchial fibroblasts cultured in three-dimensional Collagen gels. TNF-alpha/IL-1 beta alone induced production of matrix metalloproteinases (MMPs)-1, -3, and -9, which were released in latent form. With the addition of thrombin, the latent MMPs were converted into active forms and this resulted in Collagen gel degradation. Part of the activation of MMPs by thrombin resulted from direct activation of MMP-1, MMP-2, MMP-3, and MMP-9 in the absence of cells. In addition, tissue inhibitor of metalloproteinase-1 production was inhibited by the combination of thrombin and TNF-alpha/ IL-1 beta. These results suggest that thrombin and TNF-alpha/IL-1 beta synergize to induce degradation of three-dimensional Collagen gels through increasing the production and activation of MMIPs, and that this effect is mediated through both direct activation of MMPs by thrombin and indirectly by thrombin activation of fibroblasts. Through such mechanisms, thrombin could contribute to many chronic lung disorders characterized by tissue remodeling.