Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability.

• Type of Material: Article
• Authors: Daniel M. Chopyk, Emory University; Johnasha D. Stuart, Emory University; Matthew G. Zimmerman, Emory University; Jing Wen, Emory University; Sanjeev Gumber, Emory University; Mehul S. Suthar, Emory University; Manoj Thapa, Emory University; Mark J. Czaja, Emory University; Arash Grakoui, Emory University
• Language: English
• Date: 2019-11
• Publisher: Wiley Open Access: Creative Commons Attribution Non-Commercial No Derivatives
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/hep4.1406
• Title of Journal or Parent Work: Hepatology Communications
• ISSN: 2471-254X
• Volume: 3
• Issue: 11
• Start Page: 1435
• End Page: 1449
• Grant/Funding Information: Supported by National Institutes of Health (grants R01AI124680, R01AI126890, and R01AI136533 to A.G.; R01DK044234 to M.J.C.); Office of Research Infrastructure Programs/Office of the Director (P51OD011132 to A.G.; formerly National Center For Research Resources number P51RR000165 to the Yerkes National Primate Research Center); National Institute of Alcohol Abuse and Alcoholism, Ruth L. Kirschtein National Research Service Award Individual Predoctoral Fellowship (F31AA024960 to D.M.C.); National Institute of General Medical Sciences Institutional Research and Academic Career Development Award (2K12GM000680‐16 to J.D.S.); National Institute of Diabetes and Digestive and the Kidney Diseases Mentored Career Development Award (K01DK109025 to M.T.).; This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core.
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

Acetaminophen (APAP)-induced liver injury is the most common cause of acute liver failure (ALF) in the Western world. APAP toxicity progresses to multiorgan dysfunction and thus has broader whole-body implications. Importantly, greater 30-day mortality has been observed in liver transplant recipients following ALF due to APAP-related versus non-APAP-related causes. Reasons for this discrepancy have yet to be determined. Extrahepatic toxicities of APAP overdose may represent underappreciated and unaddressed comorbidities within this patient population. In the present study, rapid induction of apoptosis following APAP overdose was observed in the intestine, an organ that greatly influences the physiology of the liver. Strikingly, apoptotic cells appeared to be strictly restricted to the intestinal crypts. The use of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) reporter mice confirmed that the LGR5-positive (+) crypt base stem cells were disproportionately affected by APAP-induced cell death. Although the apoptotic cells were cleared within 24 hours after APAP treatment, potentially long-lived consequences on the intestine due to APAP exposure were indicated by prolonged deficits in gut barrier function. Moreover, small intestinal cell death was found to be independent of tumor necrosis factor receptor signaling and may represent a direct toxic insult to the intestine by exposure to high concentrations of APAP. Conclusion: APAP induces intestinal injury through a regulated process of apoptotic cell death that disproportionately affects LGR5+ stem cells. This work advances our understanding of the consequences of APAP toxicity in a novel organ that was not previously considered as a significant site of injury and thus presents potential new considerations for patient management.