Department of Pediatric Surgery, Women and Children's Hospital, Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Department of Pediatric Surgery, Women and Children's Hospital, Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Burn, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Pediatric Surgery, Chongqing Health Center for Women and Children, Chongqing, China.
J Surg Res. 2022 Dec;280:429-439. doi: 10.1016/j.jss.2022.07.041. Epub 2022 Aug 29.
Hypoxia-inducible factor (HIF) 1α is essential for the pathogenesis of necrotizing enterocolitis (NEC). HIF-1α is stabilized by glutaredoxin-1 (Grx1) deletion. The precise role of HIF-1α in the intestinal microcirculation in NEC is not well defined. We aimed to determine the role of HIF-1α in the regulation of the intestinal microcirculation during the development of NEC.
Experimental NEC was induced in full-term C57BL/6 mice and Grx1 pups through the formula gavage and hypoxia technique. HIF-1α signaling was blocked using the HIF-1α inhibitor, YC-1 [3-(5-hydroxymethyl-2-furyl)-1-benzyl indazole]. Intestinal tissues were collected at predetermined time points for the assessment of the intestinal microcirculation and HIF-1α activity and signaling.
We found that NEC induction impaired the intestinal microcirculation, but the impairment of the intestinal blood flow and capillary density was ameliorated in Grx1 mice. This amelioration was associated with tripeptide glutathione-protein adducts in the intestinal tissue. Grx1 ablation also promoted vascular endothelial growth factor A production in the intestinal tissue. This intestinal microvascular improvement was not found in HIF-1α-inhibited mice, suggesting that HIF-1α was involved in the intestinal microcirculatory perfusion.
The current data demonstrated that HIF-1α signaling is involved in the intestinal microvascular modification during the pathogenesis of NEC, suggesting that targeting HIF-1α might be a promising strategy for NEC treatment.
缺氧诱导因子 1α（HIF-1α）是坏死性小肠结肠炎（NEC）发病机制的关键。Grx1（谷氧还蛋白-1）缺失可稳定 HIF-1α。HIF-1α 在 NEC 肠道微循环中的确切作用尚未明确。我们旨在确定 HIF-1α 在 NEC 发展过程中对肠道微循环的调节作用。
通过配方灌胃和低氧技术，在足月 C57BL/6 小鼠和 Grx1 幼鼠中诱导实验性 NEC。使用 HIF-1α 抑制剂 YC-1（3-（5-羟甲基-2-呋喃基）-1-苄基吲唑）阻断 HIF-1α 信号。在预定时间点采集肠组织，评估肠道微循环和 HIF-1α 活性和信号。
我们发现 NEC 诱导会损害肠道微循环，但 Grx1 小鼠的肠道血流和毛细血管密度损害得到改善。这种改善与肠道组织中的三肽谷胱甘肽蛋白加合物有关。Grx1 缺失还促进了肠道组织中血管内皮生长因子 A 的产生。在 HIF-1α 抑制的小鼠中未发现这种肠道微血管改善，表明 HIF-1α 参与了肠道微循环灌注。
目前的数据表明，HIF-1α 信号参与了 NEC 发病过程中的肠道微血管改变，提示靶向 HIF-1α 可能是 NEC 治疗的一种有前途的策略。
