Protective Effect of Tubastatin A in CLP-Induced Lethal Sepsis
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ORIGINAL ARTICLE
Protective Effect of Tubastatin A in CLP-Induced Lethal Sepsis Qiufang Deng,1,2 Ting Zhao,1 Baihong Pan,1,2 Isabel S. Dennahy,1 Xiuzhen Duan,3 Aaron M. Williams,1 Baoling Liu,1 Nan Lin,4 Umar F. Bhatti,1 Eric Chen,1 Hasan B. Alam,1 and Yongqing Li1,5
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. KEY WORDS: HDAC6; lung; spleen; macrophages; innate immune cells; sepsis.
INTRODUCTION 1
Department of Surgery, North Campus Research Complex, University of Michigan, Rm 363N, Bldg 26, 2800 Plymouth Road, Ann Arbor, MI 48109, USA 2 Xiangya Hospital, Central South University, Changsha, Hunan, China 3 Department of Pathology, Loyola University Medical Center, Maywood, IL, USA 4 Department of Human Genetics/Epidemiology, University of Michigan, Ann Arbor, MI, USA 5 To whom correspondence should be addressed at Department of Surgery, North Campus Research Complex, University of Michigan, Rm 363N, Bldg 26, 2800 Plymouth Road, Ann Arbor, MI 48109, USA. E-mail: [email protected]
Sepsis is the most common cause of death in hospitalized patients that results in millions of deaths yearly [1]. Sepsis has been newly defined as Blife-threatening organ dysfunction caused by a dysregulated host response to infection^ [2]. Septic shock is further described as a subclass of sepsis in which the level of physiologic derangements increases the risk of mortality [3]. Multiple organ failure (MOF) accounts for the large majority of early deaths in septic shock [4]. One of the first org
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