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

Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 710)


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.


Septic Shock HDAC Inhibitor Hemorrhagic Shock Innate Immune Signaling Protein Acetylation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Apoptosis signal regulating kinase 1


Bcl-xl/Bcl-2 associated death promoter


B-cell lymphoma 2


Beta2-adrenergic receptor


Bone morphogenetic protein 7


Colon ascendant stent peritonitis


Cyclic AMP (cAMP) response element binding protein (CREBP) binding protein


Chemokine (C-C motif) ligand 2


Cytokine-induced neutrophil chemoattractant


Cecal ligation puncture


Damage-associated molecular patterns


Deoxyribonucleic acid


Dual specificity protein phosphatase 5


Enzyme-linked immunosorbent assay


Endoplasmic reticulum


Extracellular signal regulated kinase


Filamentous actin


Fresh whole blood


Glycogen synthase kinase-3β






Histone acetylases


Histone deacetylase A1


Histone deacetylases


Histone deacetylase inhibitors


High mobility group box 1


Hemorrhagic shock

Hsp 70

Heat shock protein 70

Hsp 90

Heat shock protein 90


Intercellular adhesion molecule-1




Insulin-like growth factor 1


IκB kinase




Interleukin-1 receptor associated kinase 1


Interferon regulatory factor 3


Intravenous (injection into a vein)


c-Jun N-terminal kinase




Membrane-associated guanylate kinase


Mean arterial pressure


Mitogen-activated protein kinase


Myocyte enhancer factor 2


MAP kinase phosphatase 1


Mouse mammary tumor virus


Multi-organ dysfunction syndrome




Mitogen and stress-activated protein kinase 1


Myeloid differentiation factor 88


Nicrotinamide adenine dinucleotide


Nuclear factor kappa B


Pathogen-associated molecular patterns


p300/CREB-binding protein-associated factor


Peritoneal contamination and infection


p300 histone acetyl transferase


Peroxisome proliferator-activated receptor γ coactivator-1α


Phosphoinositide 3 kinase


Phosphatidylinositol 4,5-bisphosphate


Phosphatidyl-inositol,3,4,5 triphosphate


Protein kinase B


Phosphatase and tensin homolog


Reactive oxygen species


Ribosomal S6 kinase 2


Suberoylanilide hydroxamic acid


Stress-activated protein kinase (SAPK)/extracellular signal-regulated kinase (ERK) kinase


Systemic inflammatory response syndrome




Superior mesenteric artery


Reverse transcription polymerase chain reaction


Trx binding protein 2


Transcription factors


Tight junction


Toll-like receptor 4


Tumor necrosis factor α


TNF receptor associated factor 6


Tribbles 3




Trichostatin A


Vascular cell adhesion molecule-1


Valproic acid


Vascular smooth muscle cells


Wild type



Dr. Alam acknowledges grant support from the National Institutes of Health (RO1 GM084127), Defense Advanced Research Projects Agency (W911NF-06-1-0220), Office of Naval Research (N000140910378), and the US Army Medical Research Material Command (GRANTT00521959).


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical CareMassachusetts General Hospital/Harvard Medical SchoolBostonUSA
  2. 2.Division of Trauma, Emergency Surgery, and Surgical Critical CareMassachusetts General HospitalBostonUSA

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