Hemorrhagic shock is a frequent cause of
liver failure and often leads to a fatal outcome. Several studies have revealed that
p38 MAPK is a key mediator in hemorrhagic damage of the primary organs through the activation of proinflammatory
cytokines such as
tumor necrosis factor (TNF)-α and
interleukin (IL)-1β. However, the precise role of these factors in liver damage following
hemorrhagic shock is unclear. In this study, we used
FR167653, a specific inhibitor of
p38 MAPK phosphorylation, to examine the role of
p38 MAPK in liver damage occurring up to 5 hours after a hemorrhagic episode in a rat model. Activation of
p38 MAPK in the liver as well as an increase in hepatic
mRNA expression and serum concentrations of TNF-α and IL-1β occurred during the early phase after
hemorrhage. Increased serum levels of hepatic
enzymes, as well as histological damage and activated neutrophil accumulation in the liver, were observed in the late phase following
hemorrhagic shock.
FR167653 inhibited the
inflammation-related hepatic injury following
hemorrhagic shock. Bacterial
lipopolysaccharide (LPS) derived from the gut appeared to have little effects on the hepatic damage. These results demonstrate that
p38 MAPK activation is induced by hepatic
ischemia during
hemorrhagic shock and plays an important role both in the hepatic expression of proinflammatory
cytokines and in the development of
inflammation-related liver damage.