The involvement of endotoxin in early alcohol-induced liver injury is well established; supporting the hypothesis, that pathogenesis involves aspects of innate immunity and inflammatory mediators. A number of reports have clearly demonstrated that Kupffer cells play a critical role in the pathogenesis due to ethanol. Specifically, it was shown that mice deficient in the endotoxin receptor CD14, which is primarily expressed on Kupffer cells, were resistant to chronic alcohol-induced liver injury. These data suggest that CD14 signaling may be a critical component in alcohol-related liver injury. The overall hypothesis is that LPS from the gut activates Kupffer cells causing an increase in oxidant production and subsequent TNF-alpha release. This hypothesis is strongly supported by a number of studies using gene therapy, knockout and transgenic animals, as well as an in vivo mouse intragastric ethanol-feeding model. Despite a great amount of new information regarding the role of endotoxin in ethanol-induced liver injury, critical gaps still exist in our understanding. For example, the signaling mechanisms involved in LPS- induced oxidant production, the regulation of CD14 and related signaling components in pathogenesis, and the molecular mechanisms determining gender- related differences in injury remain unknown. The purpose of this application is to address the following underlying hypotheses: 1. PI3 kinase mediates LPS-induced NADPH oxidase generation of superoxide in Kupffer cells. 2. Oxidant-sensitive transcription factors NF-kappaB and AP-1 regulate CD14 expression following acute ethanol administration. 3. Gender differences in regulation of innate immune response and transcription factor activation are key to increased susceptibility to ethanol-induced pathogenesis in females.
The aims below will use gene delivery techniques and knockout mouse technology to address these critical questions related to roles of LPS, PI3 kinase activation, and CD14 expression in both acute ethanol and chronic ethanol toxicity.
Showing the most recent 10 out of 27 publications
