Ethanol remains a confounder in postburn pathology, which is associated with an impaired intestinal barrier. Previously, we demonstrated that ethanol and burn injury reduce intestinal oxygen delivery (hypoxia) and alters microRNA (miR) expression in small intestinal epithelial cells. Hypoxia has been shown to influence expression of miRs and miR biogenesis components. Therefore, we examined whether hypoxia influences expression of miR biogenesis components (drosha, dicer, and argonaute-2 [ago-2]) and miRs (-7a and -150) and whether these changes impacted other parameters following ethanol and burn injury. Mice were gavaged with ethanol (∼2.9 g/kg) 4 h before receiving a ∼12.5% total body surface full thickness burn. Mice were resuscitated at the time of injury with normal saline with or without 5 mg/kg PX-478, a hypoxia-inducible factor-1α inhibitor. One day following injury mice were euthanized, and the expression of miRs and their biogenesis components as well as bacterial growth, tight junction proteins, intestinal transit, and permeability were assessed. Ethanol combined with burn injury significantly reduced expression of drosha, ago-2, miRs (-7a and -150), occludin, zonula occludens-1, claudin-4, zonula occludens-1, mucins-2 and -4, and intestinal transit compared to shams. Furthermore, there was an increase in intestinal permeability, total bacteria, and Enterobacteriaceae populations following the combined injury compared to shams. PX-478 treatment improved expression of drosha, ago-2, miRs (-7a and -150), occludin, claudin-4, zonula occludens-1, and mucin-2. PX-478 treatment also improved intestinal transit and reduced dysbiosis and permeability. These data suggest that PX-478 improves miR biogenesis and miR expression, and restores barrier integrity while reducing bacterial dysbiosis following ethanol and burn injury.

中文翻译：

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PX478对乙醇烧伤小鼠模型肠道屏障的保护作用

乙醇仍然是烧伤后病理学的混杂因素，这与肠道屏障受损有关。以前，我们证明乙醇和烧伤会减少肠道氧气输送（缺氧）并改变小肠上皮细胞中的 microRNA (miR) 表达。低氧已被证明会影响 miRs 和 miR 生物发生成分的表达。因此，我们检查了缺氧是否影响 miR 生物发生成分（drosha、dicer 和 argonaute-2 [ago-2]）和 miR（-7a 和 -150）的表达，以及这些变化是否影响乙醇和烧伤后的其他参数。在接受约 12.5% 的全身表面全层烧伤之前，给小鼠灌胃乙醇 (约 2.9 g/kg) 4 小时。小鼠在受伤时用生理盐水复苏，含或不含 5 mg/kg PX-478，一种缺氧诱导因子-1α抑制剂。受伤后一天对小鼠实施安乐死，并评估 miRs 的表达及其生物发生成分以及细菌生长、紧密连接蛋白、肠道转运和渗透性。乙醇联合烧伤显着降低drosha、ago-2、miRs（-7a和-150）、occludin、zonula occludens-1、claudin-4、zonula occludens-1、mucins-2和-4以及肠道转运的表达与骗局相比。此外，肠道通透性、细菌总数和 与假手术相比，ago-2、miR（-7a 和 -150）、occludin、小带 occludens-1、claudin-4、小带 occludens-1、mucins-2 和 -4 以及肠道转运。此外，肠道通透性、细菌总数和 与假手术相比，ago-2、miR（-7a 和 -150）、occludin、小带 occludens-1、claudin-4、小带 occludens-1、mucins-2 和 -4 以及肠道转运。此外，肠道通透性、细菌总数和与假手术相比，联合损伤后的肠杆菌科细菌种群。PX-478 处理改善了 drosha、ago-2、miR（-7a 和 -150）、occludin、claudin-4、zonula occludens-1 和 mucin-2 的表达。PX-478 治疗还改善了肠道转运并减少了生态失调和通透性。这些数据表明 PX-478 可改善 miR 生物发生和 miR 表达，并恢复屏障完整性，同时减少乙醇和烧伤后的细菌失调。