Epithelial delamination is protective during pharmaceutical-induced enteropathy.

Autor:	Espenschied ST; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710., Cronan MR; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710., Matty MA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710., Mueller O; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710., Redinbo MR; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.; Department of Biochemistry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599., Tobin DM; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710.; Department of Medicine, Duke University School of Medicine, Durham, NC 27710.; Department of Immunology, Duke University School of Medicine, Durham, NC 27710., Rawls JF; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710; john.rawls@duke.edu.; Department of Medicine, Duke University School of Medicine, Durham, NC 27710.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Aug 20; Vol. 116 (34), pp. 16961-16970. Date of Electronic Publication: 2019 Aug 07.
DOI:	10.1073/pnas.1902596116
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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