Epithelial delamination is protective during pharmaceutical-induced enteropathy.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Espenschied, ST; Cronan, MR; Matty, MA; Mueller, O; Redinbo, MR; Tobin, DM; Rawls, JF
Published Date
- August 20, 2019
Published In
Volume / Issue
- 116 / 34
Start / End Page
- 16961 - 16970
PubMed ID
- 31391308
Pubmed Central ID
- PMC6708343
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.1902596116
Language
- eng
Conference Location
- United States