Regulators of intestinal epithelial migration in sepsis

• Type of Material: Article
• Authors: Mei Meng, Shandong University; Nathan Klingensmith, Emory University; Zhe Liang, Emory University; John Lyons, Emory University; Katherine T. Fay, Emory University; Ching-wen Chen, Emory University; Mandy Ford, Emory University; Craig Coopersmith, Emory University
• Language: English
• Date: 2019-01-01
• Publisher: Lippinscott, Williams and Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 by the Shock Society.
• Final Published Version (URL): http://dx.doi.org/10.1097/SHK.0000000000001117
• Title of Journal or Parent Work: Shock
• Volume: 51
• Issue: 1
• Start Page: 88
• End Page: 96
• Grant/Funding Information: This work was supported by funding from the National Institutes of Health (GM072808, GM095442, GM104323, GM109779, GM113228, GM117895), National Natural Science Foundation of China (81401571), Natural Science Foundation of Shandong Province of China (ZR2014HM014)
• Keywords: APOPTOSIS; PATHOBIOME; GUT; permeability; PATHOGENESIS; integrity; sepsis; Life Sciences & Biomedicine; JAM-A; CELL-MIGRATION; proliferation; BrdU; Bcl-2; enterocyte; Hematology; migration; INJURY; Peripheral Vascular Disease; PROLIFERATION; MICROBIOME; MORTALITY; Apoptosis; Cardiovascular System & Cardiology; gut; General & Internal Medicine; cecal ligation and puncture; Science & Technology; Critical Care Medicine; intestine; Surgery; DYSFUNCTION
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

The gut is a continuously renewing organ, with cell proliferation, migration, and death occurring rapidly under basal conditions. As the impact of critical illness on cell movement from crypt base to villus tip is poorly understood, the purpose of this study was to determine how sepsis alters enterocyte migration. Wild-type, transgenic, and knockout mice were injected with 5-bromo-2'deoxyuridine (BrdU) to label cells in S-phase before and after the onset of cecal ligation and puncture and were sacrificed at predetermined endpoints to determine distance proliferating cells migrated up the crypt-villus unit. Enterocyte migration rate was decreased from 24 to 96h after sepsis. BrdU was not detectable on villi 6 days after sham laparotomy, meaning all cells had migrated the length of the gut and been exfoliated into its lumen. However, BrdU positive cells were detectable on villi 10 days after sepsis. Multiple components of gut integrity altered enterocyte migration. Sepsis decreased crypt proliferation, which further slowed enterocyte transit as mice injected with BrdU after the onset of sepsis (decreased proliferation) had slower migration than mice injected with BrdU before the onset of sepsis (normal proliferation). Decreasing intestinal apoptosis via gut-specific overexpression of Bcl-2 prevented sepsis-induced slowing of enterocyte migration. In contrast, worsened intestinal hyperpermeability by genetic deletion of JAM-A increased enterocyte migration. Sepsis therefore significantly slows enterocyte migration, and intestinal proliferation, apoptosis and permeability all affect migration time, which can potentially be targeted both genetically and pharmacologically.