Hypoxia-inducible factor signaling provides protection in Clostridium difficile-induced intestinal injury.
Hypoxia-inducible factor signaling provides protection in Clostridium difficile-induced intestinal injury.
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DOI：
10.1053/j.gastro.2010.03.045
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发表时间：
2010-07
期刊：
影响因子：
29.4
通讯作者：
Beck PL
中科院分区：
文献类型：
--
作者：
Hirota SA;Fines K;Ng J;Traboulsi D;Lee J;Ihara E;Li Y;Willmore WG;Chung D;Scully MM;Louie T;Medlicott S;Lejeune M;Chadee K;Armstrong G;Colgan SP;Muruve DA;MacDonald JA;Beck PL
艰难梭菌是引起医院感染性腹泻的主要原因。不断增加的发病率、抗生素耐药性和更强的毒力菌株极大地增加了全球艰难梭菌相关死亡人数。艰难梭菌的先天宿主反应机制尚未解决；然而，我们假设缺氧诱导因子(HIF-1)在艰难梭菌结肠炎中发挥先天保护作用。因此，我们评估了艰难梭菌毒素对低氧诱导因子-1调节的影响，并评估了低氧诱导因子-1α在艰难梭菌介导的损伤/炎症中的作用。体外研究评估了暴露在艰难梭菌毒素下的人粘膜活检组织和Caco-2细胞中的HIF-1DNA基因、蛋白水平和α结合事件。体内研究采用艰难梭菌毒素引起的肠道损伤的小鼠回肠回肠模型。在肠道上皮细胞中定向缺失HIF-1α的小鼠被用来评估HIF-1α信号对艰难梭菌毒素的影响。暴露于艰难梭菌毒素的粘膜活检和Caco-2细胞显示HIF-1α转录和蛋白水平显著增加。在Caco-2细胞中也观察到了毒素诱导的DNA结合。一氧化氮合酶抑制剂可抑制毒素诱导的缺氧诱导因子-1α积聚。在体内，肠上皮细胞缺氧诱导因子-1α的缺失导致更严重的毒素诱导的肠道损伤和炎症。相反，用二甲氧烯丙基甘氨酸稳定低氧诱导因子-1α，可减轻毒素引起的损伤和炎症。这与HIF-1调节的保护性因子VEGFA、CD73和肠三叶因子的诱导以及促炎分子TNF和KC的下调有关。我们的研究首次描述了艰难梭菌毒素对缺氧诱导因子-1α的先天保护作用。利用HIF-1α对艰难梭菌毒素的天然保护作用可能代表着艰难梭菌相关疾病的一种新的治疗形式。
Clostridium difficile (C.difficile) is the leading cause of nosocomial infectious diarrhea. Increasing incidence, antibiotic resistance and more virulent strains have dramatically increased the number of C.difficile-related deaths worldwide. The innate host response mechanisms to C.difficile are not resolved; however, we hypothesize that hypoxia-inducible factor (HIF-1) plays an innate protective role in C.difficile colitis. Thus, we assessed the impact of C.difficile toxins on the regulation of HIF-1 and evaluated the role of HIF-1α in C.difficile-mediated injury/inflammation. In vitro studies assessed HIF-1α mRNA, protein levels and DNA binding events in human mucosal biopsies and Caco-2 cells exposed to C.difficile toxins. In vivo studies employed the murine ileal loop model of C.difficile toxin-induced intestinal injury. Mice with targeted deletion of HIF-1α in the intestinal epithelium were used to assess the impact of HIF-1α signaling in response to C.difficile toxin. Mucosal biopsies and Caco-2 cells exposed to C.difficile toxin displayed a significant increase in HIF-1α transcription and protein levels. Toxin-induced DNA binding was also observed in Caco-2 cells. Toxin-induced HIF-1α accumulation was attenuated by nitric oxide synthase inhibitors. In vivo, deletion of intestinal epithelial HIF-1α resulted in more severe toxin-induced intestinal injury and inflammation. In contrast, stabilization of HIF-1α, with dimethyloxallyl glycine, attenuated toxin-induced injury and inflammation. This was associated with an induction of HIF-1-regulated protective factors including VEGFa, CD73 and intestinal trefoil factor and down-regulation of proinflammatory molecules TNF and KC. Our study is the first to describe the innate protective role for HIF-1α in response to C.difficile toxins. Harnessing the innate protective actions of HIF-1α in response to C.difficile toxins may represent a novel form of therapy for C.difficile-associated disease.
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影响因子：
29.4
作者：
Cummins, Eoin P.;Seeballuck, Fergal;Taylor, Cormac T.
通讯作者：
Taylor, Cormac T.
影响因子：
2.8
作者：
Melo, AA;Souza, MHLP;Ribeiro, RA
通讯作者：
Ribeiro, RA
影响因子：
82.9
作者：
Mizukami, Y;Jo, WS;Chung, DC
通讯作者：
Chung, DC
影响因子：
3.1
作者：
SULLIVAN, NM;PELLETT, S;WILKINS, TD
通讯作者：
WILKINS, TD
影响因子：
64.8
作者：
Lyras, Dena;O'Connor, Jennifer R.;Howarth, Pauline M.;Sambol, Susan P.;Carter, Glen P.;Phumoonna, Tongted;Poon, Rachael;Adams, Vicki;Vedantam, Gayatri;Johnson, Stuart;Gerding, Dale N.;Rood, Julian I.
通讯作者：
Rood, Julian I.