Epithelial delamination is protective during pharmaceutical-induced enteropathy.
Scott T Espenschied1, Mark R Cronan1, Molly A Matty1
1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710.
Summary
Intestinal epithelial cell shedding is a protective, unfolded protein response (UPR) to drug-induced damage. This process, mediated by multidrug resistance (MDR) efflux pumps, helps limit inflammation and preserve gut health.
Area of Science:
- Gastroenterology
- Cell Biology
- Pharmacology
Background:
- Intestinal epithelial cell (IEC) shedding is a key response to gut injury, but its precise mechanisms and functions remain unclear.
- Chronic intestinal damage models are crucial for understanding these processes.
- The role of inflammation and microbial interactions in IEC shedding requires further investigation.
Purpose of the Study:
- To investigate the mechanisms and protective functions of IEC shedding in response to chemical injury.
- To identify the cellular targets responsible for Glafenine-induced enteropathy.
- To explore the role of multidrug resistance (MDR) efflux pumps in intestinal homeostasis.
Main Methods:
- Utilized zebrafish larvae to model chronic intestinal damage using the NSAID Glafenine.
- Analyzed the induction of the unfolded protein response (UPR) and inflammatory pathways in IECs.
- Assessed the impact of microbial colonization on Glafenine-induced inflammation and IEC shedding.
- Investigated the off-target effects of Glafenine on multidrug resistance (MDR) efflux pumps and tested other MDR inhibitors.
Main Results:
- Glafenine induced UPR and inflammation in IECs, leading to cell delamination.
- Microbial colonization augmented Glafenine-induced inflammation and altered microbiota composition.
- IEC shedding was identified as a UPR-dependent protective mechanism that restricted inflammation and enhanced survival.
- Glafenine's off-target inhibition of MDR efflux pumps was implicated, as other MDR inhibitors also induced IEC delamination.
Conclusions:
- IEC delamination is a protective, UPR-mediated response to chemical injury, crucial for limiting inflammation.
- Multidrug resistance (MDR) efflux pumps are essential cellular targets involved in Glafenine-induced enteropathy.
- MDR efflux pumps play a critical role in maintaining intestinal homeostasis.
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