Hemorrhage is the leading cause of death in civilian and combat trauma, and effective resuscitation strategies have the potential of saving many lives. However, conventional resuscitation can exacerbate cellular injury caused by hemorrhagic shock. At a sub-cellular level, hemorrhagic shock and resuscitation can alter gene expression, and impair the regulation of subsequent downstream survival pathways. Nuclear histone proteins are known regulators of gene transcription, and we have previously shown that treatment with histone deacetylase inhibitors (HDACI) enhances gene transcription through specific hyperacetylation at multiple lysine residues ("epigenetic regulation"), attenuates organ damage, and improves early survival after lethal hemorrhage. Emerging evidence also suggests that acetylation of non-histone proteins may play an equally important regulatory role in cellular processes, independent of transcription. Thus, administration of HDACI (with or without conventional fluid resuscitation) appears to be a very promising strategy for the treatment of lethal hemorrhage. However, before these exciting findings can be translated into clinical practice, the most effective HDACI treatment (e.g. agent, dose, and timing), and the precise mechanisms of action must be clearly identified. LONG TERM GOALS: Develop strategies to minimize cellular injury and improve survival after lethal hemorrhage.
SPECIFIC AIM 1 : Identify the histone deacetylase inhibitor (HDACI) treatment that induces the most pronounced acetylation, when given after lethal non-resuscitated hemorrhage? Sub aim 1: Identify the optimal doses of HDACI for achieving maximum protein acetylation.
Sub aim 2 : Determine whether protein hyperacetylation can be sustained for longer duration through repeated administration of HDACI.
Sub aim 3 : Determine whether combining agents from different HDACI groups can enhance protein acetylation.
SPECIFIC AIM 2 : Establish whether addition of HDACI to resuscitation fluids is advantageous? Sub aim 1: Ascertain whether addition of HDACI to conventional fluids attenuates markers of cellular injury and improves survival? Sub aim 2: Determine whether HDACI treatment can be combined with hypertonic fluid resuscitation to achieve synergistic effects? SPECIFIC AIM 3: Determine the dominant mechanisms that are responsible for exerting the protective effects of HDACI.
Sub aim 1 : Identify the genes whose transcription is altered by the acetylation of histone proteins ("epigenetic mechanisms"), and study its impact on downstream proteins.
Sub aim 2 : Identify whether the protective effects of HDACI are due to direct acetylation of non-histone proteins.

Public Health Relevance

Conventional methods of treating massive blood loss have proven to be ineffective, and may even worsen the outcome. Our research has shown that survival can be dramatically improved by enhancing the essential protective mechanisms that are naturally present in the cells.
The aim of our project is to refine this novel approach, and develop effective strategies for the treatment of lethal blood loss.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Zhao, Yili; Zhou, Peter; Liu, Baoling et al. (2015) Protective effect of suberoylanilide hydroxamic acid against lipopolysaccharide-induced liver damage in rodents. J Surg Res 194:544-50
Li, Yongqing; Liu, Zhengcai; Liu, Baoling et al. (2014) Citrullinated histone H3: a novel target for the treatment of sepsis. Surgery 156:229-34
Zhao, Ting; Li, Yongqing; Bronson, Roderick T et al. (2014) Selective histone deacetylase-6 inhibition attenuates stress responses and prevents immune organ atrophy in a lethal septic model. Surgery 156:235-42
Hwabejire, John O; Lu, Jennifer; Liu, Baoling et al. (2014) Valproic acid for the treatment of hemorrhagic shock: a dose-optimization study. J Surg Res 186:363-70
Zhao, Ting; Li, Yongqing; Liu, Baoling et al. (2014) Selective inhibition of histone deacetylase 6 alters the composition of circulating blood cells in a lethal septic model. J Surg Res 190:647-54
Liu, Zhengcai; Li, Yongqing; Chong, Wei et al. (2014) Creating a prosurvival phenotype through a histone deacetylase inhibitor in a lethal two-hit model. Shock 41:104-8
Zhou, P; Wu, E; Alam, H B et al. (2014) Histone cleavage as a mechanism for epigenetic regulation: current insights and perspectives. Curr Mol Med 14:1164-72
Jin, Guang; Liu, Baoling; You, Zerong et al. (2014) Development of a novel neuroprotective strategy: combined treatment with hypothermia and valproic acid improves survival in hypoxic hippocampal cells. Surgery 156:221-8
Zhao, Ting; Li, Yongqing; Liu, Baoling et al. (2014) Histone deacetylase inhibitor treatment attenuates coagulation imbalance in a lethal murine model of sepsis. Surgery 156:214-20
Zhao, Ting; Li, Yongqing; Liu, Baoling et al. (2013) Novel pharmacologic treatment attenuates septic shock and improves long-term survival. Surgery 154:206-13

Showing the most recent 10 out of 22 publications