Potential conflict of interest: Nothing to report.
Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: A critical role for E-selectin
Article first published online: 30 SEP 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 5, pages 1814–1823, November 2013
How to Cite
Bertola, A., Park, O. and Gao, B. (2013), Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: A critical role for E-selectin. Hepatology, 58: 1814–1823. doi: 10.1002/hep.26419
See Editorial on Page 1526
- Issue published online: 30 OCT 2013
- Article first published online: 30 SEP 2013
- Accepted manuscript online: 26 MAR 2013 12:19PM EST
- Manuscript Accepted: 20 MAR 2013
- Manuscript Revised: 20 FEB 2013
- Manuscript Received: 31 OCT 2012
- This work was supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health.
Chronic plus binge ethanol feeding acts synergistically to induce liver injury in mice, but the mechanisms underlying this phenomenon remain unclear. Here, we show that chronic plus binge ethanol feeding synergistically up-regulated the hepatic expression of interleukin-1β and tumor necrosis factor alpha and induced neutrophil accumulation in the liver, compared with chronic or binge feeding alone. In vivo depletion of neutrophils through administration of an anti-Ly6G antibody markedly reduced chronic-binge ethanol feeding-induced liver injury. Real-time polymerase chain reaction analyses revealed that hepatic E-selectin expression was up-regulated 10-fold, whereas expression of other neutrophil infiltration-related adhesion molecules (e.g., P-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1) was slightly up- or down-regulated in this chronic-binge model. The genetic deletion of E-selectin prevented chronic-binge ethanol-induced hepatic neutrophil infiltration as well as elevation of serum transaminases without affecting ethanol-induced steatosis. In addition, E-selectin-deficient mice showed reduced hepatic expression of several proinflammatory cytokines, chemokines, and adhesion molecules, compared to wild-type mice, after chronic-binge ethanol feeding. Finally, the expression of E-selectin was highly up-regulated in human alcoholic fatty livers, but not in alcoholic cirrhosis. Conclusions: Chronic-binge ethanol feeding up-regulates expression of proinflammatory cytokines, followed by the induction of E-selectin. Elevated E-selectin plays an important role in hepatic neutrophil infiltration and injury induced by chronic-binge feeding in mice and may also contribute to the pathogenesis of early stages of human alcoholic liver disease. (Hepatology 2013;58:1814–1823)