Inhibition of histone deacetylases protects septic mice from lung and splenic apoptosis

Song

Korean J Physiol Pharmacol

et al. 2016

CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

Section: Discussionmentioning

confidence: 68%

Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats

Song

Korean J Physiol Pharmacol

et al. 2016

“…HDAC inhibitors have long been used as psychotropic medications, and recently have been utilized in the treatment of cancers and lymphoma. Recent emerging data suggests that HDAC inhibitors may be protective in animal models of sepsis (100). HDACs act on multiple targets, so it will be difficult to identify any protective mechanisms.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Function in Sepsis

Arulkumaran

Deutschman

Pinsky

et al. 2016

Shock

143

123

Mitochondria are an essential part of the cellular infrastructure, being the primary site for high energy adenosine triphosphate (ATP) production through oxidative phosphorylation. Clearly, in severe systemic inflammatory states, like sepsis, cellular metabolism is usually altered and end organ dysfunction not only common but predictive of long term morbidity and mortality. Clearly, interest is mitochondrial function both as a target for intracellular injury and response to extrinsic stress have been a major focus of basic science and clinical research into the pathophysiology of acute illness. However, mitochondria have multiple metabolic and signaling functions that may be central in both the expression of sepsis and its ultimate outcome. In this review, the authors address five primary questions centered on the role of mitochondria in sepsis. This review should be used as both a summary source in placing mitochondrial physiology within the context of acute illness and as a focal point for addressing new research into diagnostic and treatment opportunities these insights provide.

“…The proteins in the supernatant were measured using BCA Protein Assay Kit (Thermo Fisher Scientific, Rockford, IL, USA). Immunoblotting was performed as described in our previous reports [19, 23]. Samples (30–50 μg of protein) were electrophoresed on 10 or 14 % SDS-PAGEs and transferred to PVDF membrane.…”

Section: Methodsmentioning

confidence: 99%

Critical role of endogenous histamine in promoting end-organ tissue injury in sepsis

Hattori

Yamazaki

Ohashi

et al. 2016

ICMx

Self Cite

BackgroundHistamine assumes an important role as a major mediator in various pathologic disorders associated with inflammation and immune reactions. However, the involvement of histamine in the pathological conditions and symptoms of sepsis remains entirely unknown. In this study, we establish that histamine is identified as a contributory mediator to promoting the development of organ injury in sepsis.MethodsHistidine decarboxylase (HDC) gene knockout (HDC−/−) mice, histamine H1-/H2-receptor gene-double knockout (H1R−/−/H2R−/−) mice, and their littermate wild-type (WT) C57BL/6J mice underwent cecal ligation and puncture (CLP) or sham operation. Some WT mice were injected intraperitoneally with d-chlorpheniramine and famotidine 60 min before CLP to block H1- and H2-receptors, respectively.ResultsIn mice rendered septic by CLP, tissue histamine levels were elevated in association with increased HDC expression. Sepsis-induced abnormal cytokine production and multiple organ injury (lung, liver, and kidney) were significantly less pronounced in HDC−/− mice as compared with WT controls, and HDC deficiency had improved survival in sepsis. This benefit corresponded with a significant reduction in activation levels of the nuclear factor (NF)-κB signaling pathway. H1R−/−/H2R−/− mice apparently behaved similar to HDC knockout mice in reducing sepsis-related pathological changes. Pharmacological interventions with H1- and H2-receptor antagonists indicated that both H1- and H2-receptors were involved in septic lung and liver injury, whereas only H2-receptors contributed to septic kidney injury.ConclusionsIn the setting of sepsis, histamine, through activation of H1- and H2-receptors, serves as an aggravating mediator to contribute to the development of sepsis-driven major end-organ failure.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-016-0109-y) contains supplementary material, which is available to authorized users.