Novel pharmacologic treatment attenuates septic shock and improves long-term survival

Zhao, Ting C.; Li, Yongqing; Liu, Baoling; Liu, Zhengcai; Wang, Chong; Duan, Xiuzhen; DePeralta, Danielle K.; Velmahos, George C.; Alam, Hasan B.

doi:10.1016/j.surg.2013.04.003

Cited by 46 publications

(43 citation statements)

References 25 publications

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“…Our research team has demonstrated that both hemorrhage and sepsis can lead to protein hypoacetylation, whereas therapeutically targeting the alterations with HDACIs induces acetylation of histone and non-histone proteins, and is protective against lethal insults, such as hemorrhagic shock, traumatic brain injuries, endotoxemic shock, and severe sepsis. 15-18 In humans and mice, the 18 HDAC enzymes are grouped into four classes: classical HDACs, including class I, II and IV, are Zn 2+ dependent, while the classes III sirtuins act through a NAD + -dependent mechanism. HDAC6 belongs to class IIb HDAC and is unique in that it is a cytoplasmic microtubule-associated enzyme.…”

Section: Discussionmentioning

confidence: 99%

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

Zhao

Bronson

et al. 2014

Surgery

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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 H&E 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 to 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=0.0366), bone marrow depletion and atrophy (58.3±6.5 vs. 25.0±14.4%, p=0.0449), and cellular apoptosis in the splenic follicles (41.2±3.7 vs. 28.5±4.3 per 40× field, p=0.0354). Conclusions 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.

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Section: Discussionmentioning

confidence: 99%

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

Zhao

Bronson

et al. 2014

Surgery

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“…Recently, we have shown that an HDACI, suberoylanilide hydroxamic acid (SAHA), modulates the immune response, 7–9 and improves survival in a mouse model of cecal ligation and puncture (CLP). 10 Unfortunately, this non-selective HDAC inhibitor is not well tolerated, and may impair the innate immune response when given in therapeutically relevant doses. 1 …”

Section: Introductionmentioning

confidence: 99%

Citrullinated histone H3: A novel target for the treatment of sepsis

Liu²,

Liu

et al. 2014

Surgery

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INTRODUCTION We have recently demonstrated that in a rodent model of lipopolysaccharide (LPS)-induced shock, an increase in circulating citrullinated histone H3 (Cit H3) is associated with lethality of sepsis, and treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor (HDACI), significantly improves survival. However, the role of Cit H3 in pathogenesis and therapeutics of sepsis are largely unknown. The present study was designed to test whether treatment with HDACI could inhibit cellular Cit H3 production, and inhibition of peptidyalarginine deiminase (PAD, an enzyme producing Cit H3) with Cl-amidine (PAD inhibitor) or neutralization of blood Cit H3 with anti-Cit H3 antibody could improve survival in a clinically relevant mouse model of cecal ligation and puncture (CLP) induced septic shock. METHODS Three experiments were carried out. In experiment I, HL-60 neutrophilic cells grown on a coverslip were treated with LPS (100 ng/ml) in the presence or absence of SAHA (5 µmol) for 3 h, and subjected to immuno-staining with anti-Cit H3 antibody to assess effect of SAHA on Cit H3 production under a fluorescence microscope. The ratio of Cit H3 positive cells was calculated as mean ± SD (n=3). In experiment II, male C57BL/6J mice were subjected to CLP, and 1 hour later randomly divided into three groups for intraperitoneal injection as follows: (1) dimethyl sulfoxide (DMSO), (2) SAHA (50 mg/kg) in DMSO, and (3) Cl-amidine (80 mg/kg) in DMSO (n=10/group). In experiment III, male C57BL/6J mice were divided into control and treatment groups, and subjected to CLP. Two hours later, immunoglobulin (IgG) and Cit H3 antibody (20 mg/kg iv; n=5/group) were injected into the control and treatment groups, respectively. Survival was monitored for up to 10 days. RESULTS In experiment I, LPS induced Cit H3 production in the HL-60 cells, while SAHA treatment inhibited H3 citrullination significantly (p<0.05). In experiment II, all vehicle injected mice died within 3 days with increased circulating Cit H3 levels, whereas treatment with HDACI or Cl-amidine notably improved long-term survival (p< 0.01). In experiment III, administration of IgG did not improve survival, but a single treatment with Cit H3 specific antibody significantly improved survival (p<0.014). CONCLUSIONS Inhibition of HDAC or PAD significantly suppresses Cit H3 production in vitro, and improves survival in vivo. Neutralization of Cit H3 significantly improves survival in septic mice. Collectively, our findings indicate for the first time that Cit H3 could not only serve as a potential biomarker but also a novel therapeutic target in sepsis.

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“…Our lab was the first to demonstrate that administration of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), improved survival in lethal rodent models of lipopolysaccharide (LPS)-induced endotoxemia and cecal ligation and puncture (CLP)-induced severe sepsis 8–10 . Selective inhibition of HDAC6 with Tubastatin A displays even better survival outcomes in the lethal CLP-sepsis model and increases bacterial clearance in circulation (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of histone deacetylase 6 alters the composition of circulating blood cells in a lethal septic model

Zhao

Liu

et al. 2014

Journal of Surgical Research

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Background Phagocytes, especially monocytes, macrophages and dendritic cells, play a pivotal role in the innate as well as adaptive immune responses during sepsis. We have shown that inhibition of histone deacetylase (HDAC)-6 improves survival and increases bacterial clearance in a mouse model of cecal ligation and puncture (CLP). The aim of this study was to determine whether this effect was associated with changes in the number and composition of different blood cell types in the circulation. Methods C57BL/6J mice were subjected to CLP, and 1 hour later given an intraperitoneal injecton of either Tubastatin A dissolved in dimethyl sulfoxide (DMSO), or DMSO only. Sham-operated animals were treated in an identical fashion but not subjected to CLP. Forty-eight hours later peripheral blood was obtained via cardiac puncture and analyzed using a veterinary Hematrue hematology analyzer. Results Tubastatin A administration increased the number of circulating monocytes in the sham-operated as well as the CLP animals. In comparison to the sham, CLP animals displayed an increase in the granulocyte percentage in white blood cells, decrease in the lymphocyte number and percentage, with a resultant increase in the granulocyte to lymphocyte ratio. Treatment of CLP animals with Tubastatin A decreased the granulocyte percentage, and restored the lymphocyte number and percentage, which decreased the granulocyte to lymphocyte ratio. In the sham animals, Tubastatin A increased red blood cell (RBC) number, hematocrit and hemoglobin. This effect was not seen in CLP animals. Conclusions Tubastatin A treatment has significant impact on the composition of circulating blood cells. It increases the number of circulating monocytes and the RBC cell mass in sham-operated animals. In the CLP animals, it increases the monocyte count, decreases the percentage of granulocytes, restores the lymphocyte population, and decreases the granulocyte to lymphocyte ratio. These results may explain why Tubastatin A treatment improves survival in the septic models.

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Novel pharmacologic treatment attenuates septic shock and improves long-term survival

Cited by 46 publications

References 25 publications

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

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

Citrullinated histone H3: A novel target for the treatment of sepsis

Selective inhibition of histone deacetylase 6 alters the composition of circulating blood cells in a lethal septic model

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