Selective histone deacetylase-6 inhibition attenuates stress responses and prevents immune organ atrophy in a lethal septic model

Surgery. 2014 Aug;156(2):235-42. doi: 10.1016/j.surg.2014.03.033. Epub 2014 Jun 16.

Abstract

Background: An overproduction of corticosterone during severe sepsis results in increased apoptosis of immune cells, which may result in relative immunosuppression and an impaired ability to fight infections. We have previously demonstrated that administration of tubastatin A, a selective inhibitor of histone deacetylase-6 (HDAC6), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice. The purpose of this study was to characterize the effects of this treatment on sepsis-induced stress responses and immune function.

Methods: C57BL/6J mice were subjected to CLP, and 1 hour later given an intraperitoneal injection of either tubastatin A dissolved in dimethyl sulfoxide (DMSO), or DMSO only. Blood samples were collected to measure the levels of circulating corticosterone and adrenocorticotropic hormone (ACTH). Thymus and long bones (femur and tibia) were subjected to hematoxylin and eosin staining, and immunohistochemistry was utilized to detect cleaved-caspase 3 in the splenic follicles as a measure of cellular apoptosis.

Results: All vehicle-treated CLP animals died within 3 days, and displayed increased corticosterone and decreased ACTH levels compared with the sham-operated group. These animals also developed atrophy of thymic cortex with a marked depletion of thymocytes. Tubastatin A treatment significantly attenuated the stress hormone abnormalities. Treated animals also had significantly lower percentages of thymic atrophy (95.0 ± 5.0 vs 42.5 ± 25.3; P = .0366), bone marrow depletion and atrophy (58.3 ± 6.5 vs 25.0 ± 14.4%; P = .0449), and cellular apoptosis in the splenic follicles (41.2 ± 3.7 vs 28.5 ± 4.3 per 40× field; P = .0354).

Conclusion: Selective inhibition of HDAC6 in this lethal septic model was associated with a significant blunting of the stress responses, with attenuated thymic and bone marrow atrophy, and decreased splenic apoptosis. Our findings identify a novel mechanism behind the survival advantage seen with tubastatin A treatment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Animals
  • Apoptosis / drug effects
  • Atrophy
  • Bone Marrow / drug effects
  • Bone Marrow / immunology
  • Bone Marrow / pathology
  • Corticosterone / blood
  • Disease Models, Animal
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Histone Deacetylases / metabolism*
  • Hydroxamic Acids / therapeutic use*
  • Indoles / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Sepsis / drug therapy*
  • Sepsis / immunology
  • Sepsis / pathology
  • Spleen / drug effects
  • Spleen / immunology
  • Spleen / pathology
  • Stress, Physiological / drug effects
  • Thymus Gland / drug effects
  • Thymus Gland / immunology
  • Thymus Gland / pathology

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • tubastatin A
  • Adrenocorticotropic Hormone
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Histone Deacetylases
  • Corticosterone