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

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.

SUBMITTER: Chopyk DM

PROVIDER: S-EPMC6824060 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Chopyk Daniel M DM Stuart Johnasha D JD Zimmerman Matthew G MG Wen Jing J Gumber Sanjeev S Suthar Mehul S MS Thapa Manoj M Czaja Mark J MJ Grakoui Arash A

Hepatology communications 20190715 11

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 ...[more]

PMID: 31701068

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Project description:Intestinal crypt progenitor/stem (ICPS) cell apoptosis and vascular endothelial cell apoptosis are responsible for the initiation and development of ionizing radiation (IR)-evoked gastrointestinal syndrome. The signaling mechanisms underlying IR-induced ICPS cell apoptosis remain largely unclear. Our findings provide evidence that ?-arrestin-2 (?arr2)-mediated ICPS cell apoptosis is crucial for IR-stimulated intestinal injury. ?Arr2-deficient mice exhibited decreased ICPS cell and intestinal Lgr5(+) (leucine-rich repeat-containing G-protein-coupled receptor 5-positive) stem cell apoptosis, promoted crypt proliferation and reproduction, and protracted survival following lethal doses of radiation. Radioprotection in the ICPS cells isolated from ?arr2-deficient mice depended on prolonged nuclear factor-?B (NF-?B) activation via direct interaction of ?arr2 with I?B? and subsequent inhibition of p53-upregulated modulator of apoptosis (PUMA)-mediated mitochondrial dysfunction. Unexpectedly, ?arr2 deficiency had little effect on IR-induced intestinal vascular endothelial cell apoptosis in mice. Consistently, ?arr2 knockdown also provided significant radioresistance by manipulating NF-?B/PUMA signaling in Lgr5(+) cells in vitro. Collectively, these observations show that targeting the ?arr2/NF-?B/PUMA novel pathway is a potential radiomitigator for limiting the damaging effect of radiotherapy on the gastrointestinal system. Significance statement: acute injury to the intestinal mucosa is a major dose-limiting complication of abdominal radiotherapy. The issue of whether the critical factor for the initiation of radiation-induced intestinal injury is intestinal stem cell apoptosis or endothelial cell apoptosis remains unresolved. ?Arrs have recently been found to be multifunctional adaptor of apoptosis. Here, we found that ?-arrestin-2 (?arr2) deficiency was associated with decreased radiation-induced ICPS cell apoptosis, which prolonged survival in abdominally irradiated mice. Moreover, ?arr2 deficiency-mediated intestinal progenitor/stem cell radioprotection relied on protracted NF-?B activation and subsequent suppression of PUMA induction. Our results suggest that ICPS cell apoptosis is the factor involved in the initiation and development of radiation-induced gastrointestinal syndrome. ?Arr2 is a potential target for lessening radiation-induced ICPS cell apoptosis.

Dataset Information

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

Publications

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

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