title: Selective inhibition of histone deacetylase 6 alters the composition of circulating blood cells in a lethal septic model.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Trauma, Emergency Surgery and Surgical Critical Care, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
authors.forename: Ihab
authors.initials: I
authors.lastname: Halaweish
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Chemical Biology Program, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.affiliation: Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan. Electronic address: alamh@med.umich.edu.
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010976:Platelet Count; D011897:Random Allocation; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology
chemical_list: D006454:Hemoglobins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C553587:tubastatin A; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Blood; Granulocyte; Histone deacetylase 6; Lymphocyte; Sepsis; Tubastatin A