Selective induction of integrin β1 by hypoxia-inducible factor: implications for wound healing
Selective induction of integrin β1 by hypoxia-inducible factor: implications for wound healing
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DOI：
10.1096/fj.08-125344
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发表时间：
2009-05-01
期刊：
影响因子：
4.8
通讯作者：
Colgan, Sean P.
中科院分区：
文献类型：
--
作者：
Keely, Simon;Glover, Louise E.;Colgan, Sean P.
由于局部血管损伤和组织需氧量增加，伤口愈合发生在相对缺氧的微环境中。这些特征与慢性炎症（如克罗恩病和溃疡性结肠炎）的伤口愈合和纤维化特别相关。在这些研究中，我们试图在肠粘膜下层模型中确定缺氧对伤口修复机制的贡献。最初的研究表明，缺氧促进伤口愈合，正如肠道成纤维细胞介导的胶原凝胶收缩增加所模拟的那样。在转录谱结果的指导下，我们确定了缺氧对成纤维细胞整合素β 1 （ITGB1）的选择性诱导。进一步的分析表明，缺氧以及缺氧诱导因子（HIF）的药理激活剂可诱导成纤维细胞β 1整合素mRNA、蛋白和功能提高多达4倍。对β 1整合素基因启动子的克隆和分析显示，在缺氧条件下，启动子活性增加了10 +/- 0.8倍，随后的研究在ITGB1基因启动子中发现了HIF的功能DNA结合区。对ITGB1启动子内HIF结合位点的突变分析导致ITGB1缺氧诱导能力显著丧失。作为原理证明，在小鼠结肠炎模型中的研究显示结肠炎疾病严重程度与组织ITGB1表达之间存在相关性（R-2=0.80）。综上所述，这些结果表明缺氧通过依赖于HIF的转录机制诱导成纤维细胞ITGB1的表达和功能。-Keely， S., Glover， L. E., MacManus， C. F., Campbell， E. L., Scully， M. M., Furuta， G. T., Colgan， S. P.：低氧诱导因子选择性诱导整合素β 1：对伤口愈合的影响。中华医学杂志，23 (2009):1338-1346
Because of localized vascular damage and increased tissue oxygen demand, wound healing occurs in a relatively hypoxic microenvironment. These features are particularly relevant to wound healing and fibrosis in chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis. In these studies, we sought to identify the contribution of hypoxia to mechanisms of wound repair in a model of the intestinal submucosa. Initial studies revealed that hypoxia promotes wound healing, as modeled by an increase in intestinal fibroblast-mediated collagen gel contraction. Guided by results from transcriptional profiling, we identified the selective induction of fibroblast integrin beta 1 (ITGB1) by hypoxia. Further analysis revealed that hypoxia, as well as pharmacological activators of hypoxia-inducible factor (HIF), induce fibroblast beta 1 integrin mRNA, protein, and function by as much as 4-fold. Cloning and analysis of the beta 1 integrin gene promoter revealed a 10 +/- 0.8-fold increase in promoter activity in response to hypoxia, and subsequent studies identified a functional DNA binding region for HIF in the ITGB1 gene promoter. Mutational analysis of the HIF binding site within the ITGB1 promoter resulted in a significant loss of ITGB1 hypoxia-inducibility. As proof of principle, studies in a murine model of colitis revealed a correlation between colitic disease severity and tissue ITGB1 expression (R-2=0.80). Taken together, these results demonstrate that hypoxia induces fibroblast ITGB1 expression and function by transcriptional mechanisms dependent on HIF.-Keely, S., Glover, L. E., MacManus, C. F., Campbell, E. L., Scully, M. M., Furuta, G. T., Colgan, S. P. Selective induction of integrin beta 1 by hypoxia-inducible factor: implications for wound healing. FASEB J. 23, 1338-1346 (2009)