111. Pharmacological Resuscitation: Cell Protective Mechanisms of Histone Deacetylase Inhibition in Lethal Hemorrhagic Shock

Abstract

Hemorrhage is the leading cause of death in civilian and combat trauma, and effective resuscitation strategies have the potential of saving many lives. At a cellular level, hemorrhagic shock and resuscitation can alter gene expression and affect the regulation of subsequent downstream survival pathways. Histone proteins are known regulators of transcription, and we have previously shown that treatment with histone deacetylase inhibitors (HDACI) can enhance nuclear acetylation, promote gene transcription, attenuate organ injury, and improve survival in animal models of lethal hemorrhage, even in the absence of fluid resuscitation. However, the precise mechanisms responsible for these protective properties of HDACI are not well understood. In the current study, we explored whether treatment with valproic acid (VPA), an HDACI, would protect against c-Jun N-terminal kinase (JNK) and caspase-3 mediated apoptosis following lethal hemorrhagic shock.