Our laboratory has been actively studying the pathogenesis of alcoholic liver disease, focusing on the role of E-selectin in alcoholic fatty liver and liver inflammation, and therapeutic potential of IL-22 for the treatment of alcoholic liver disease Alcoholic liver disease (ALD) is associated with infiltration of neutrophils, but the mechanisms underlying neutrophil recruitment to the liver and the roles of neutrophils in the pathogenesis of ALD remain unclear. E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a cell adhesion molecule expressed only on endothelial cells activated by cytokines and LPS. During inflammation, E-selectin plays an important part in recruiting leukocytes to the site of injury. Because high hepatic expression of E-selectin has been reported in patients with ALD, we hypothesized that E-selectin could play a role in ethanol-induced liver damage. To investigate the contribution of E-selectin to the pathogenesis of ALD, wild-type (WT) and E-selectin deficient (SELE-/-) mice were fed a Lieber-DeCarli diet containing 5% ethanol for 10 days then gavaged with a single dose of ethanol (5g/kg body weight) and sacrificed 9 hours later. Chronic plus binge ethanol feeding markedly up-regulated the expression of E-selectin in the liver. SELE-/- mice were resistant to chronic plus binge ethanol feeding-induced elevation of serum ALT and AST compared with wild-type mice, whereas the level of steatosis was similar in both groups. Moreover, chronic plus binge ethanol feeding induced up-regulation of several pro-inflammatory cytokines, chemokines, and adhesion molecules in wild-type mice, but such up-regulation was markedly reduced in SELE-/- mice. Finally, SELE-/- mice were resistant to chronic plus binge ethanol feeding-induced neutrophil infiltration in the liver compared with wild-type mice. In conclusion, the hepatic expression of E-selectin is markedly up-regulated after chronic plus binge ethanol feeding in mice and such up-regulated E-selectin plays an important role in alcohol-induced neutrophil recruitment, liver inflammation, and injury in the early stage of ALD. We are also exploring the therapeutic potential of IL-22 for the treatment of alcoholic liver disease. We have demonstrated that IL-22 treatment has many beneficial effects in ameliorating alcoholic fatty liver and injury. In addition, we are also collaborating with Drs. George Kunos and Pal Pacher from NIAAA to investigate the role of the endocannabinoid system in alcoholic liver disease.

Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2012
Total Cost
$1,301,353
Indirect Cost
Name
National Institute on Alcohol Abuse and Alcoholism
Department
Type
DUNS #
City
State
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Zip Code
He, Yong; Gao, Bin (2017) A small specific-sized hyaluronic acid ameliorates alcoholic liver disease by targeting a small RNA: New hope for therapy? Hepatology 66:321-323
Xu, Ming-Jiang; Zhou, Zhou; Parker, Richard et al. (2017) Targeting inflammation for the treatment of alcoholic liver disease. Pharmacol Ther 180:77-89
Li, Man; He, Yong; Zhou, Zhou et al. (2017) MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47phox-oxidative stress pathway in neutrophils. Gut 66:705-715
Ramirez, Teresa; Li, Yong-Mei; Yin, Shi et al. (2017) Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. J Hepatol 66:601-609
Wang, Wei; Xu, Ming-Jiang; Cai, Yan et al. (2017) Inflammation is independent of steatosis in a murine model of steatohepatitis. Hepatology 66:108-123
Gao, Bin; Xu, Ming-Jiang; Bertola, Adeline et al. (2017) Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance. Gene Expr 17:173-186
Gao, Bin; Tsukamoto, Hidekazu (2016) Inflammation in Alcoholic and Nonalcoholic Fatty Liver Disease: Friend or Foe? Gastroenterology 150:1704-9
Matyas, Csaba; Varga, Zoltan V; Mukhopadhyay, Partha et al. (2016) Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis. Am J Physiol Heart Circ Physiol 310:H1658-70
Oh, Yumin; Park, Ogyi; Swierczewska, Magdalena et al. (2016) Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells. Hepatology 64:209-23
Mathews, Stephanie; Feng, Dechun; Maricic, Igor et al. (2016) Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration. Cell Mol Immunol 13:206-16

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