Chronic ethanol exposure can result in hepatic injury. This injury is exacerbated in part through an LPS- dependent signaling cascade. Our lab found that chronic ethanol exposure increases the IPS response of Kupffer cells leaing to the activation LPS-induced activation of p38. Ultimately the activation of p38 will lead to TNFa mRNA stability. LPS and TNFa stimulate the production of reactive oxygen species. The ROS causes the redox-sensing molecule thioredoxin (Trx) to dissociate from ASK1 leading to apoptosis. Glutathione is another redox-sensing molecule that protects the cell against oxidative damage. As a result of ethanol-induced oxidative stress, mitochondrial levels of GSH drastically deplete.
The specific aims of this proposal will determine (1) effects of chronic ethanol on LPS dependent signal transduction leading to increased p38 phosphorylation (2) identify how Trx and GSH contribute to increased p38 activation in response chronic ethanol exposure (3) if overexpression of Trx-1 protects mice from ethanol-induced liver injury. Results from our studies will further our understanding of cellular antioxidant systems and possibly the prevention of ethanol-induced liver disease.
| Cohen, Jessica I; Nagy, Laura E (2011) Pathogenesis of alcoholic liver disease: interactions between parenchymal and non-parenchymal cells. J Dig Dis 12:3-9 |
| Cohen, Jessica I; Chen, Xiaocong; Nagy, Laura E (2011) Redox signaling and the innate immune system in alcoholic liver disease. Antioxid Redox Signal 15:523-34 |
| Cohen, Jessica I; Roychowdhury, Sanjoy; McMullen, Megan R et al. (2010) Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice. Gastroenterology 139:664-74, 674.e1 |
