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J Surg Res. 2014 Aug;190(2):647-54. doi: 10.1016/j.jss.2014.01.056. Epub 2014 Feb 4.

Selective inhibition of histone deacetylase 6 alters the composition of circulating blood cells in a lethal septic model.

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Division of Trauma, Emergency Surgery and Surgical Critical Care, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts.
Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Chemical Biology Program, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan. Electronic address:



Phagocytes, especially monocytes, macrophages, and dendritic cells, play a pivotal role in the innate and adaptive immune responses during sepsis. We have shown that inhibition of histone deacetylase 6 improves survival and increases bacterial clearance in a mouse model of cecal ligation and puncture (CLP). The aim of this study was to determine whether this effect was associated with changes in the number and composition of different blood cell types in the circulation.


C57BL/6J mice were subjected to CLP, and 1 h later given an intraperitoneal injection of either Tubastatin A dissolved in dimethyl sulfoxide, or dimethyl sulfoxide only. Sham-operated animals were treated in an identical fashion but not subjected to CLP. Forty-eight hours later, peripheral blood was obtained via cardiac puncture and analyzed using a HemaTrue veterinary hematology analyzer.


Tubastatin A administration increased the number of circulating monocytes in the sham-operated and the CLP animals. In comparison with the sham, CLP animals displayed an increase in the granulocyte percentage in white blood cells and decrease in the lymphocyte number and percentage, with a resultant increase in the granulocyte-to-lymphocyte ratio. Treatment of CLP animals with Tubastatin A decreased the granulocyte percentage and restored the lymphocyte number and percentage, which decreased the granulocyte-to-lymphocyte ratio. In the sham animals, Tubastatin A increased red blood cell number, hematocrit, and hemoglobin. This effect was not seen in CLP animals.


Tubastatin A treatment has significant impact on the composition of circulating blood cells. It increases the number of circulating monocytes and the red blood cell mass in sham-operated animals. In the CLP animals, it increases the monocyte count, decreases the percentage of granulocytes, restores the lymphocyte population, and decreases the granulocyte-to-lymphocyte ratio. These results may explain why Tubastatin A treatment improves survival in the septic models.


Blood; Granulocyte; Histone deacetylase 6; Lymphocyte; Sepsis; Tubastatin A

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