Protective effects of PX478 on gut barrier in a mouse model of ethanol and burn injury.
Protective effects of PX478 on gut barrier in a mouse model of ethanol and burn injury.
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DOI：
10.1002/jlb.3a0820-323rr
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发表时间：
2021-06
影响因子：
5.5
通讯作者：
Choudhry MA
中科院分区：
文献类型：
--
作者：
Morris NL;Cannon AR;Li X;Choudhry MA
乙醇仍然是烧伤后病理学的混杂因素，与受损的肠屏障有关。先前，我们证明了乙醇和烧伤损伤减少了肠道氧输送（缺氧），并改变了小肠上皮细胞中microRNA（miR）的表达。低氧已显示影响miR和miR生物发生组分的表达。因此，我们研究了缺氧是否影响miR生物合成组分（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。小鼠在接受~12.5%全身表面全厚度烧伤前4 h灌胃乙醇（~2.9 g/kg）。在损伤时，用含或不含5 mg/kg PX-478（缺氧诱导因子-1 α抑制剂）的生理盐水复苏小鼠。损伤后一天，将小鼠安乐死，并评估miR及其生物发生组分的表达以及细菌生长、紧密连接蛋白、肠转运和渗透性。与假手术组相比，乙醇联合烧伤显著降低了drosha、ago-2、miR（−7a和−150）、occludin、闭合小带-1、claudin-4、闭合小带-1、粘蛋白-2和-4的表达以及肠道转运。此外，与假手术相比，联合损伤后肠道通透性、细菌总数和肠杆菌科细菌数量增加。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治疗还改善了肠道运输并降低了生态失调和渗透性。这些数据表明，PX-478改善了miR生物发生和miR表达，并恢复了屏障完整性，同时减少了乙醇和烧伤后的细菌生态失调。
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.