A primary goal of this laboratory is to elucidate the mechanisms by which alcohol and other hepatotoxicants cause liver injury. Recently, for example, we discovered that antibiotics prevent injury following chronic exposure to alcohol, that female rats develop fatty liver much earlier than males, and that hypoxia markers detect oxygen gradients in the liver. Elevated levels of endotoxin activate Kupffer cells to release substances such as eicosanaoids, TNF and other cytokines, prostaglandins, and free radicals.
Prostaglandins increase oxygen uptake and most likely participate in a hypermetabolic state.
The increase in oxygen demand leads to hypoxia in the liver, and on reperfusion, free radicals are formed, leading to tissue damage in oxygen-poor pericentral regions of the liver lobule. Thurman, R. G. Mechanisms of hepatic toxicity. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Enomoto, N., Ikejima, K., Bradford, B., Rivera, C., Kono, H., Brenner, D., and Thurman, R. G. Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin. R.G. Estrogen increases sensitivity of Kupffer cells to endotoxin.