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