Attenuation of Alcoholic Hepatitis by Transgenic Expression of M3 Protein

Zili Zhang, MD, PhD, Principal Investigator
Jay Kolls, MD

Abstract
Recently we have established a mouse alcoholic hepatitis model demonstrating that repeated EtOH insults potentiate the ability of LPS to cause leukocyte recruitment in the liver. Our in vitro studies find that chronic EtOH induces CXC and CC chemokine expression and augments LPS-induced chemokine production in mouse Kupffer cells. Therefore, we hypothesize that EtOH induces chemokine expression and synergistically increases LPS-induced chemokine production in the liver, leading to leukocyte infiltration on the process oh hepatic inflammation.

To test this hypothesis, this project has the following Specific Aims:

Specific Aim I. Define the role of CXC and CC chemokines in EtOH-induced hepatic leukocyte infiltration.

1. Does EtOH induce the expression of Macrophage Inflammatory Protein-2 (MIP-2), a CXC chemokine, and Regulated upon Activation, Normal T Expressed, and presumably Secreted (RANTES), a CC chemokine, in mouse liver?

2. Does EtOH synergistically increase LPS-induced production of MIP-2 and RANTES in mouse liver?

3. Does EtOH cause less severe hepatic injury and leukocyte infiltration in interleukin-8 (IL-8) receptor knockout and CCR5 knockout mice than that in wild-type mice?

Specific Aim II. Does neutralization of chemokine activity prevent EtOH-induced hepatic leukocyte infiltration?

4. Does delivery of an exogenous M3 gene prevent EtOH-induced leukocyte infiltration in mouse liver?

Long-term objective of this proposed study is to further elucidate the pathogenesis of alcoholic hepatitis and to development innovative treatment strategies.

Sponsor: American Liver Foundation
Duration: 07/03 - 06/06