Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia.
Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia.
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DOI：
10.1084/jem.193.9.1027
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发表时间：
2001-05-07
期刊：
影响因子：
--
通讯作者：
Colgan SP
中科院分区：
文献类型：
--
作者：
Furuta GT;Turner JR;Taylor CT;Hershberg RM;Comerford K;Narravula S;Podolsky DK;Colgan SP
肠等粘膜器官由丰富而复杂的底层脉管系统支持。因此，肠道，特别是屏障保护性上皮细胞，很容易受到与血流减少和伴随的组织缺氧相关的损伤。我们试图确定在肠道缺氧期间保护上皮屏障的补偿机制。对 T84 结肠上皮细胞的初步研究表明，屏障功能对缺氧引起的变化有独特的抵抗力。对肠道特异性屏障保护因子的研究表明，人肠三叶因子 (ITF) 基因启动子具有一个先前未被认识的缺氧诱导因子 (HIF)-1 结合位点。缺氧导致 ITF mRNA 和蛋白质的平行诱导。使用 ITF 特异性 HIF-1 共有基序进行电泳迁移率变动分析，产生缺氧诱导的 DNA 结合活性，而用针对 HIF-1 α 链的反义寡核苷酸加载细胞会导致 ITF 缺氧诱导能力丧失。此外，添加抗ITF抗体会导致暴露于缺氧的上皮细胞屏障功能丧失，而向血管内皮细胞添加重组人ITF部分保护内皮细胞免受缺氧引起的屏障破坏。这些体内研究的扩展揭示了缺氧引起 ITF 缺失小鼠肠道通透性的显着增加。 HIF-1 依赖性 ITF 诱导可能为缺氧期间屏障功能的维持提供适应性联系。
Mucosal organs such as the intestine are supported by a rich and complex underlying vasculature. For this reason, the intestine, and particularly barrier-protective epithelial cells, are susceptible to damage related to diminished blood flow and concomitant tissue hypoxia. We sought to identify compensatory mechanisms that protect epithelial barrier during episodes of intestinal hypoxia. Initial studies examining T84 colonic epithelial cells revealed that barrier function is uniquely resistant to changes elicited by hypoxia. A search for intestinal-specific, barrier-protective factors revealed that the human intestinal trefoil factor (ITF) gene promoter bears a previously unappreciated binding site for hypoxia-inducible factor (HIF)-1. Hypoxia resulted in parallel induction of ITF mRNA and protein. Electrophoretic mobility shift assay analysis using ITF-specific, HIF-1 consensus motifs resulted in a hypoxia-inducible DNA binding activity, and loading cells with antisense oligonucleotides directed against the α chain of HIF-1 resulted in a loss of ITF hypoxia inducibility. Moreover, addition of anti-ITF antibody resulted in a loss of barrier function in epithelial cells exposed to hypoxia, and the addition of recombinant human ITF to vascular endothelial cells partially protected endothelial cells from hypoxia-elicited barrier disruption. Extensions of these studies in vivo revealed prominent hypoxia-elicited increases in intestinal permeability in ITF null mice. HIF-1–dependent induction of ITF may provide an adaptive link for maintenance of barrier function during hypoxia.
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影响因子：
3.5
作者：
Kramer, MF;Gunaratne, P;Ferreira, GC
通讯作者：
Ferreira, GC
DOI：
10.1084/jem.188.8.1433
发表时间：
1998-10-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lennon PF;Taylor CT;Stahl GL;Colgan SP
通讯作者：
Colgan SP
DOI：
10.1073/pnas.85.5.1529
发表时间：
1988-03-01
影响因子：
11.1
作者：
SAMBUY, Y;RODRIGUEZBOULAN, E
通讯作者：
RODRIGUEZBOULAN, E
影响因子：
56.9
作者：
Mashimo, H;Wu, DC;Fishman, MC
通讯作者：
Fishman, MC
DOI：
10.1073/pnas.95.1.178
发表时间：
1998-01-06
影响因子：
11.1
作者：
Kanai, M;Mullen, C;Podolsky, DK
通讯作者：
Podolsky, DK