上皮细胞分层在药物诱导的肠病中具有保护作用。
Epithelial delamination is protective during pharmaceutical-induced enteropathy.
机构信息
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710.
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
出版信息
Proc Natl Acad Sci U S A. 2019 Aug 20;116(34):16961-16970. doi: 10.1073/pnas.1902596116. Epub 2019 Aug 7.
Intestinal epithelial cell (IEC) shedding is a fundamental response to intestinal damage, yet underlying mechanisms and functions have been difficult to define. Here we model chronic intestinal damage in zebrafish larvae using the nonsteroidal antiinflammatory drug (NSAID) Glafenine. Glafenine induced the unfolded protein response (UPR) and inflammatory pathways in IECs, leading to delamination. Glafenine-induced inflammation was augmented by microbial colonization and associated with changes in intestinal and environmental microbiotas. IEC shedding was a UPR-dependent protective response to Glafenine that restricts inflammation and promotes animal survival. Other NSAIDs did not induce IEC delamination; however, Glafenine also displays off-target inhibition of multidrug resistance (MDR) efflux pumps. We found a subset of MDR inhibitors also induced IEC delamination, implicating MDR efflux pumps as cellular targets underlying Glafenine-induced enteropathy. These results implicate IEC delamination as a protective UPR-mediated response to chemical injury, and uncover an essential role for MDR efflux pumps in intestinal homeostasis.
肠上皮细胞（IEC）脱落是对肠道损伤的基本反应，但潜在的机制和功能一直难以确定。在这里，我们使用非甾体抗炎药（NSAID）加洛芬胺在斑马鱼幼虫中模拟慢性肠道损伤。加洛芬胺诱导 IEC 中的未折叠蛋白反应（UPR）和炎症途径，导致分层。微生物定植增强了加洛芬胺诱导的炎症，并与肠道和环境微生物组的变化相关。IEC 脱落是对加洛芬胺的 UPR 依赖性保护反应，可限制炎症并促进动物存活。其他 NSAID 不会诱导 IEC 分层；然而，加洛芬胺还会抑制多药耐药（MDR）外排泵的非靶向抑制。我们发现一组 MDR 抑制剂也诱导了 IEC 分层，这表明 MDR 外排泵是加洛芬胺诱导的肠病的细胞靶点。这些结果表明 IEC 脱落是化学损伤的保护性 UPR 介导反应，并揭示了 MDR 外排泵在肠道稳态中的重要作用。
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