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
-
- Animals
- Gastrointestinal Microbiome*
- Intestinal Diseases*/chemically induced
- Intestinal Diseases*/metabolism
- Intestinal Diseases*/microbiology
- Intestinal Diseases*/pathology
- Enterocytes/metabolism*
- Enterocytes/microbiology
- Enterocytes/pathology
- Anti-Inflammatory Agents, Non-Steroidal*/adverse effects
- Anti-Inflammatory Agents, Non-Steroidal*/pharmacology
- ATP-Binding Cassette Transporters/antagonists & inhibitors
- ATP-Binding Cassette Transporters/metabolism
- Zebrafish*/metabolism
- Zebrafish*/microbiology
- Glafenine/adverse effects*
- Glafenine/pharmacology
- Inflammation/chemically induced
- Inflammation/metabolism
- Inflammation/microbiology
- Inflammation/pathology
- PubMed
- 31391308 Full text @ Proc. Natl. Acad. Sci. USA
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.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping