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.

Fig. 11.1

Effect of HDACI on cell survival signaling pathway in hemorrhagic shock. HDACI induce phosphorylation of AKT by inhibition of TRB3 and PTEN. While AKT stimulates transcription of cell survival genes through several other pathways, phosphorylated AKT phosphorylates GSK-3β. Phosphorylated GSK-3β becomes inactivated form, which cannot degrade β-catenin. HDACI can also directly inhibit GSK-3β. Moreover, HDACI induce acetylation and nuclear translocation of β-catenin, leading to downstream survival gene transcription. P phosphorylation, Ac acetylation

Fig. 11.2

Effect of HDACI on gut-lymph-lung axis in response to hemorrhagic shock. Hemorrhagic shock causes destruction of the gut barrier due to tight junction protein (e.g., claudin-3) loss. Bactria, endotoxin, and inflammatory cytokines enter into circulation and lung. In the lung tissue, MAPKs are stimulated and neutrophils infiltrated, resulting in acute lung injury. HDACI block these processing by inhibition of tight junction protein loss in gut and inactivation of MAPKs in lung

Fig. 11.3

HDACI modulate a paracrine between leukocytes and endothelial cells. The interaction between leukocytes and endothelial cells seems to form a paracrine loop. On one hand, IL-1 and TNF-a produced by infiltrating inflammatory cells such as neutrophils and macrophages can induce endothelial cells to express cytokines and adhesion molecules. On the other hand, endothelial cells play an essential role in speeding up this process via their ability to express cell surface adhesion molecules that mediate interactions with leukocytes in the bloodstream. HDACI break the loop by suppressing TNF-a induced VCAM-1 expression and reducing immune cells adhesion to endothelial cells

Fig. 11.4

TLR4 signaling – a converged immune response pathway for hemorrhagic shock and septic shock. TLR4 not only serves as a key sensor of pathogen-associated molecular patterns (PAMPs), but also is proposed recently to act as a receptor for some endogenous molecules called “alarmins”. HDACI block TLR4 signaling at multiple steps; therefore they can inhibit immune response for both hemorrhagic shock and septic shock