Abstract
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.
Highlights
The liver, which plays a crucial role in metabolism and homeostasis, is one of the organs that is most susceptible to injury arising from hemorrhagic shock, the outcome of which is often fatal [1]
Changes in systemic blood pressure and hepatic blood flow caused by hemorrhage There were no significant differences in mean arterial blood pressure (MBP) between the Sham group and FR group throughout the experiment (Fig. 1A, Fig. 1C)
Several investigators have studied the role of p38 MAPK activation on liver damage following ischemia/reperfusion, dermal burns, and hemorrhage with resuscitation [4,5,21,22]
Summary
The liver, which plays a crucial role in metabolism and homeostasis, is one of the organs that is most susceptible to injury arising from hemorrhagic shock, the outcome of which is often fatal [1]. P38 MAPK has been postulated to be one of the key factors promoting the expression of pro-inflammatory cytokines such as TNF-a and IL-1b [7] These cytokines play an important role in inflammatory organ damage by promoting the recruitment of neutrophils which release reactive oxygen species and proteases [8,9,10]. We previously hypothesized that p38 MAPK activation might play an important role in the progression of liver damage following hemorrhagic shock, but this possibility was not tested experimentally. The role of p38 MAPK activation in the development of inflammatory liver damage following hemorrhagic shock was examined by the use of FR167653, which is a specific inhibitor of p38 MAPK phosphorylation. Our experimental model provided a novel paradigm to explore the cause of liver damage following hemorrhagic shock
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