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Protective Effect of Tubastatin A in CLP-Induced Lethal Sepsis

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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.

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Funding

This work was funded by a grant from NIH RO1 GM084127 to H.B.A. Data was presented at the 12th Annual Academic Surgical Congress, Clinical Congress Las Vegas, NV (February 2017).

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Authors and Affiliations

  1. Department of Surgery, North Campus Research Complex, University of Michigan, Rm 363N, Bldg 26, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA

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

  2. Xiangya Hospital, Central South University, Changsha, Hunan, China

    Qiufang Deng & Baihong Pan

  3. Department of Pathology, Loyola University Medical Center, Maywood, IL, USA

    Xiuzhen Duan

  4. Department of Human Genetics/Epidemiology, University of Michigan, Ann Arbor, MI, USA

    Nan Lin

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  1. Qiufang Deng
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Contributions

Q.D., T.Z., Y.L., and H.B.A. designed this study, for which H.B.A. secured funding. Q.D. and T.Z. performed the experiments and collected and analyzed data. B.L. and B.P provided experimental support. N.L. performed statistical analysis. E.C. presented the data at the 12th Annual Academic Surgical Congress. Q.D., T.Z., I.S.D., A.M.W., U.F.B., and Y.L. wrote the manuscript, which was critically reviewed and revised by Y.L. and H.B.A. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yongqing Li.

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The protocol for this study was approved by the University of Michigan Institutional Animal Care and Use Committee. All experiments complied with animal welfare and research regulations.

Conflict of Interest

The authors declare that they have no competing interests.

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Deng, Q., Zhao, T., Pan, B. et al. Protective Effect of Tubastatin A in CLP-Induced Lethal Sepsis. Inflammation 41, 2101–2109 (2018). https://doi.org/10.1007/s10753-018-0853-0

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