Creating a Pro-survival and Anti-inflammatory Phenotype by Modulation of Acetylation in Models of Hemorrhagic and Septic Shock

Abstract

Shock, regardless of etiology, is characterized by decreased tissue perfusion resulting in cell death, organ dysfunction, and poor survival. Current therapies largely focus on restoring tissue perfusion through resuscitation but have failed to address the specific cellular dysfunction caused by shock. Acetylation is rapidly emerging as a key mechanism that regulates the expression of numerous genes (epigenetic modulation through activation of nuclear histone proteins), as well as functions of multiple cytoplasmic proteins involved in key cellular functions such as cell survival, repair/healing, signaling, and proliferation. Cellular acetylation can be increased immediately through the administration of histone deacetylase inhibitors (HDACI). A series of studies have been performed using: (1) cultured cells; (2) single-organ ischemia-reperfusion injury models; (3) rodent models of lethal septic and hemorrhagic shock; (4) swine models of lethal hemorrhagic shock and multi-organ trauma; and (5) tissues from severely injured trauma patients, to fully characterize the changes in acetylation that occur following lethal insults and in response to treatment with HDACI. These data demonstrate that: (1) shock causes a decrease in acetylation of nuclear and cytoplasmic proteins; (2) hypoacetylation can be rapidly reversed through the administration of HDACI; (3) normalization of acetylation prevents cell death, decreases inflammation, attenuates activation of pro-apoptotic pathways, and augments pro-survival pathways; (4) the effect of HDACI significantly improves survival in lethal models of septic shock, hemorrhagic shock, and complex poly-trauma without need for conventional fluid resuscitation or blood transfusion; and (5) improvement in survival is not due to better resuscitation but due to an enhanced ability of cells to tolerate lethal insults. As different models of hemorrhagic or septic shock have specific strengths and limitations, this chapter will summarize our attempts to create “pro-survival and anti-inflammatory phenotype” in various models of hemorrhagic shock and septic shock.

Effect of pharmacologic resuscitation on the brain gene expression profiles in a swine model of traumatic brain injury and hemorrhage

“…This study supports our previous results, which showed that VPA administration protects neurons against hypoxiainduced apoptotic cell death 28 and activates innate cell survival pathways. 29 Another mechanism of cell survival lies in the autogenic strengthening and remodeling of cell structural components in response to injury. We found significant overexpression of NEFL and SIX4, two genes that play an important role in the regeneration, differentiation, and maturation of neuronal cells.…”

Trichostatin A protects against intestinal injury in rats with acute liver failure

“…Recently, studies have proven that HDACi have anti-inflammatory and cell-protective effects in traumatic brain injury, stroke, and ischemia reperfusioninduced oxidative damage. [13][14][15] Trichostatin A (TSA), one of the HDAC inhibitors, selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes.…”

Selective inhibition of histone deacetylase 6 promotes survival in a rat model of hemorrhagic shock

“…Even the patients that survive the acute episode of blood loss often develop multiple organ dysfunction syndrome (MODS) due to tissue hypoxia and systemic inflammation (2, 3). Tissue hypoxia with resultant anaerobic metabolism has long been considered a leading etiology of post-shock MODS (4).…”