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Creating a “Prosurvival Phenotype” Through Histone Deacetylase Inhibition

Past, Present, and Future

Halaweish, Ihab; Nikolian, Vahagn; Georgoff, Patrick; Li, Yongqing; Alam, Hasan B.

doi: 10.1097/SHK.0000000000000319
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ABSTRACT Traumatic injuries and their sequelae represent a major source of mortality in the United States and globally. Initial treatment for shock, traumatic brain injury, and polytrauma is limited to resuscitation fluids to replace lost volume. To date, there are no treatments with inherent prosurvival properties. Our laboratory has investigated the use of histone deacetylase inhibitors (HDACIs) as pharmacological agents to improve survival. This class of drugs acts through posttranslational protein modifications and is a direct regulator of chromatin structure and function, as well as the function of numerous cytoplasmic proteins. In models of hemorrhagic shock and polytrauma, administration of HDACIs offers a significant survival advantage, even in the absence of fluid resuscitation. Positive results have also been shown in two-hit models of hemorrhage and sepsis and in hemorrhagic shock combined with traumatic brain injury. Accumulating data generated by our group and others continue to support the use of HDACIs for the creation of a prosurvival phenotype. With further research and clinical trials, HDACIs have the potential to be an integral tool in the treatment of trauma, especially in the prehospital phase.

Department of Surgery, University of Michigan, Ann Arbor, Michigan

Received 21 Oct 2014; first review completed 5 Nov 2014; accepted in final form 15 Dec 2014

Address reprint requests to Hasan B. Alam, MD, Chief of General Surgery Section, University of Michigan Hospital, 1500 E. Medical Center Dr, 2920 Taubman Center/5331, Ann Arbor, MI 48109-5331. E-mail: alamh@med.umich.edu.

Dr. Alam acknowledges research support provided by numerous grants from the Office of Naval Research (including N000140910378 and N000141310071), the US Army Medical Research and Materiel Command (W81XWH-09-1-0520), the Defense Advanced Research Projects Agency (W911NF-06-1-0220), and the National Institutes of Health (R01GM084127). Dr. Alam also received a research grant from the Massey Foundation to study traumatic brain injury. The opinions and assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense at large.

The authors have no financial conflict of interest.

© 2015 by the Shock Society