Oxidative stress and the pathogenesis of cholestasis.

Cholestasis is a reduction in bile flow that occurs from a variety of causes in humans. This produces hepatocellular injury and fibrosis. Considering that there are limited therapies for this disease, there has been interest in understanding the mechanism by which cholestasis produces injury. Studies have demonstrated that oxidative stress occurs in livers of humans with cholestasis. In vitro studies have demonstrated that bile acids kill hepatocytes by a mechanism that depends upon reactive oxygen species (ROS). Further studies, however, have demonstrated that this mechanism is of limited importance in vivo. Cholestasis also initiates an inflammatory response resulting in accumulation of neutrophils in the liver. Inhibition of neutrophil function reduces oxidative stress and liver injury suggesting that neutrophils are an important source of damaging ROS in vivo. Furthermore, inhibition of ROS during cholestasis reduces fibrosis. Collectively, these studies suggest that ROS are important for pathologic changes that occur during cholestasis.