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

Ting Zhao, Yongqing Li, Roderick T. Bronson, Baoling Liu, George C. Velmahos, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)235-242
Number of pages8
JournalSurgery (United States)
Volume156
Issue number2
DOIs
StatePublished - Aug 2014
Externally publishedYes

ASJC Scopus subject areas

  • Surgery

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