Protective Effect of Tubastatin A in CLP-Induced Lethal Sepsis

Qiufang Deng, Ting Zhao, Baihong Pan, Isabel S. Dennahy, Xiuzhen Duan, Aaron M. Williams, Baoling Liu, Nan Lin, Umar F. Bhatti, Eric Chen, Hasan B. Alam, Yongqing Li*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

We have found earlier that Tubastatin A (TubA), a selective inhibitor of histone deacetylase 6 (HDAC6), improves survival in a mouse model of lethal cecal ligation and puncture (CLP)-induced sepsis. However, the underlying mechanisms have not been fully established. This study sought to test the hypothesis that TubA could affect both lung and splenic functions. C57BL/6J mice were subjected to CLP, and randomized to receive either TubA (70 mg/kg) dissolved in dimethyl sulfoxide (DMSO), or DMSO alone, 1 h following CLP. Sham animals acted as control. Twenty-four hours later, lung tissue was harvested for pathological examination, and splenic tissue was harvested for bacterial colonization. In a parallel study, the spleen was collected 48 h following CLP, and single cell suspension was prepared. Splenocytes then underwent flow cytometry to analyze the immune cell population. RAW264.7 macrophages were treated with lipopolysaccharide (LPS) with or without the presence of TubA (10 μM) at 37 °C for 3 h to assess the effect on macrophage phagocytosis. We found that acute lung injury secondary to lethal sepsis was attenuated by TubA. Treatment with TubA restored the percentage of B lymphocytes, and significantly increased percentages of innate immune cells and macrophages compared to the vehicle-treated CLP group. Moreover, TubA significantly decreased the bacterial load in the spleen, and improved the phagocytic ability of RAW264.7 murine macrophages in vitro. Such findings may help to explain the beneficial effects of TubA treatment in a model of lethal sepsis, as previously reported.

Original languageEnglish (US)
Pages (from-to)2101-2109
Number of pages9
JournalInflammation
Volume41
Issue number6
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

Keywords

  • HDAC6
  • innate immune cells
  • lung
  • macrophages
  • sepsis
  • spleen

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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