PUBLICATION

Epithelial delamination is protective during pharmaceutical-induced enteropathy

Authors
Espenschied, S.T., Cronan, M.R., Matty, M.A., Mueller, O., Redinbo, M.R., Tobin, D.M., Rawls, J.F.
ID
ZDB-PUB-190809-3
Date
2019
Source
Proceedings of the National Academy of Sciences of the United States of America   116(34): 16961-16970 (Journal)
Registered Authors
Cronan, Mark, Espenschied, Scott "Ted", Matty, Molly, Rawls, John F., Tobin, David
Keywords
MDR efflux pump, NSAID, intestine, microbiota, zebrafish
MeSH Terms
  • Anti-Inflammatory Agents, Non-Steroidal*/adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal*/pharmacology
  • ATP-Binding Cassette Transporters/antagonists & inhibitors
  • ATP-Binding Cassette Transporters/metabolism
  • Glafenine/adverse effects*
  • Glafenine/pharmacology
  • Zebrafish*/metabolism
  • Zebrafish*/microbiology
  • Animals
  • Inflammation/chemically induced
  • Inflammation/metabolism
  • Inflammation/microbiology
  • Inflammation/pathology
  • Intestinal Diseases*/chemically induced
  • Intestinal Diseases*/metabolism
  • Intestinal Diseases*/microbiology
  • Intestinal Diseases*/pathology
  • Enterocytes/metabolism*
  • Enterocytes/microbiology
  • Enterocytes/pathology
  • Gastrointestinal Microbiome*
(all 21)
PubMed
31391308 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
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.
Genes / Markers
Figures
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ct3aGtTransgenic Insertion
ct520aGtTransgenic Insertion
gl24TgTransgenic Insertion
    mb10TgTransgenic Insertion
      nc1TgTransgenic Insertion
        nz117TgTransgenic Insertion
          pd1000TgTransgenic Insertion
            pd1028TgTransgenic Insertion
              xt18TgTransgenic Insertion
              xt24TgTransgenic Insertion
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                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                No data available
                Fish
                No data available
                Antibodies
                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                CitrineEFGCitrine
                DsRedEFGDsRed
                EGFPEFGEGFP
                GAL4EFGGAL4
                GFPEFGGFP
                mCherryEFGmCherry
                TomatoEFGTomato
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                Mapping
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                Citation
                Espenschied, S.T., Cronan, M.R., Matty, M.A., Mueller, O., Redinbo, M.R., Tobin, D.M., Rawls, J.F. (2019) Epithelial delamination is protective during pharmaceutical-induced enteropathy. Proceedings of the National Academy of Sciences of the United States of America. 116(34):16961-16970.