Kohshi Hattori

Pleiotropic Benefits of Metformin: Macrophage Targeting Its Anti-inflammatory Mechanisms

Metformin is a biguanide family member used in the treatment of type 2 diabetes and one of the most widely prescribed antidiabetes drugs. This drug increases the peripheral uptake of glucose, decreases hepatic glucose production, and reduces insulin resistance in liver and skeletal muscle. The exact molecular mechanisms responsible for its effect on glucose homeostasis are still not completely understood but may include the triggering of the AMPK pathway (1), although it has been indicated that the acute inhibitory effects of high doses of metformin on hepatic gluconeogenesis are independent of AMPK activation (2). Interestingly, experimental and clinical studies have shed new light on an array of potential benefits of metformin, not only in the treatment of diabetes. Notably, accumulating evidence suggests that the cardiovascular protective role of metformin is largely beyond its hypoglycemic action and is ascribed to pleiotropic effects (3–5). Previous studies have described the anti-inflammatory effects of metformin on different types of cells, including human vascular endothelial cells and smooth muscle cells (6,7). Recent reports have also demonstrated that metformin can attenuate lipopolysaccharide (LPS)-induced or oxidized LDL–induced proinflammatory responses in monocytes and macrophages (8,9). Although the crucial mechanisms underlying the anti-inflammatory effects of metformin remain to be fully elucidated, the current concept of atherosclerosis as an inflammatory disorder may imply that such anti-inflammatory properties could contribute, at least in part, to the anti-atherosclerotic …

Anti-Inflammatory Profile of Levosimendan in Cecal Ligation-Induced Septic Mice and in Lipopolysaccharide-Stimulated Macrophages.

Objectives: The calcium sensitizer levosimendan is used in treatment of decompensated heart failure and may also exhibit anti-inflammatory properties. We examined whether treatment with levosimendan is substantially beneficial in mice with cecal ligation and puncture–induced polymicrobial sepsis, and its arbitration mechanism was explored in the mouse macrophage cell line RAW264.7. Design: Laboratory and animal/cell research. Setting: University research laboratory. Subjects: BALB/c mice (8–10 wk old) and mouse macrophage cell line RAW264.7 cells. Interventions: Levosimendan (0.5 &mgr;g/kg/min) was administered to mice through an osmotic pump that was implanted into the peritoneal cavity immediately following surgery. In RAW264.7 cells, levosimendan was added to the culture medium 30 minutes before lipopolysaccharide. Measurements and Main Results: When levosimendan was continuously administered to cecal ligation and puncture–induced septic mice, a significant improvement of left ventricular function was found without any change in heart rate, and hypotension was significantly mitigated. Furthermore, levosimendan conferred substantial protection against sepsis-associated inflammation in mice, as indicated by reduced lung injury and decreased blood proinflammatory and chemotactic cytokine levels. These beneficial effects of levosimendan led to a significant improvement of survival in mice after cecal ligation and puncture. In endotoxin-stimulated RAW264.7 macrophages, treatment with levosimendan and pimobendan suppressed overproduction of proinflammatory and chemotactic cytokines. Levosimendan and pimobendan were without effect on activation of the nuclear factor-&kgr;B, mitogen-activated protein kinase, and Akt pathways. Instead, levosimendan and pimobendan prevented high mobility group box 1 release from the nucleus to the extracellular space in macrophages. This was associated with inhibition of the Rho kinase signaling pathway. The elevated serum high mobility group box 1 levels in cecal ligation and puncture–induced septic mice were also inhibited by continued administration of levosimendan and pimobendan. Conclusions: We define a novel mechanism for the anti-inflammatory action of levosimendan and suggest that the pharmacological profiles of levosimendan as both an inotrope and an anti-inflammatory agent could contribute to its clinical benefit in patients with sepsis with heart problems.

Control of Macrophage Dynamics as a Potential Therapeutic Approach for Clinical Disorders Involving Chronic Inflammation

Macrophages are a well recognized player of both innate and adaptive immunity and have emerged as a key regulator of systemicmetabolism, hematopoiesis, vasculogenesis, apoptosis, malignancy, and reproduction. Such pleiotropic roles of macrophages are mirrored by their protean features. Upon environmental. challenges, macrophages redistribute and differentiate in situ and contribute to the multiple disease states by exerting protective and pathogenic effects. The environmental challenges include cytokines, chemokines, lipid mediators, and extrinsic insults, such as food and pathogenic bacteria. In addition, homeostasis and the activation state of macrophages are influenced by various metabolites from a commensal microbe that colonizes epithelial and mucosal surfaces, such as the lungs, intestines, and skin. In this review, we describe macrophage differentiation, polarization, and various functions in chronic disease states, including chronic inflammatory bowel disease, tumorigenesis, metabolism and obesity, and central nervous system demyelinating disorders. Controlling the macrophage dynamics to affect the pathologic states is considered to be an important therapeutic approach for many clinical disorders involving chronic inflammation.

Recent advances in the pathophysiology and molecular basis of sepsis-associated organ dysfunction: Novel therapeutic implications and challenges.

ABSTRACT Sepsis is one of the most common reasons for critically ill patients to be admitted to an intensive care unit and, despite advances in overall medical care, it represents a major clinical problem and remains the leading cause of death in the critically ill patient population. Although sepsis has been defined as a systemic inflammatory syndrome, in which there is an identifiable focus of infection, clinical trials aimed at anti‐inflammatory therapeutic approaches have largely failed to identify an effective therapeutic target to improve clinical outcomes in sepsis. Very recently, the third international consensus definitions have been advocated for sepsis and septic shock. Thus, sepsis is now defined as life‐threatening organ dysfunction due to a dysregulated host response to infection. A better understanding of the molecular mechanisms involved in the pathogenesis of sepsis and its resultant organ failure has been sought, and the development of therapies targeted at preventing or limiting molecular events associated with the progress of fatal organ failure, hence leading to improvement of outcomes, is urgently needed. This review article provides an overview of possible pathogenic mechanisms underlying the development of multiple organ dysfunction in sepsis and discusses pharmacological agents regarded as promising in treatment of this disorder.

Diminished responsiveness to dobutamine as an inotrope in mice with cecal ligation and puncture-induced sepsis: attribution to phosphodiesterase 4 upregulation

Dobutamine has been used in septic shock for many years as an only inotrope, but its benefit has been questioned. We weighed the effects of dobutamine and milrinone as inotropes in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. CLP-induced septic mice exhibited significant cardiac inflammation, as indicated by greatly increased mRNAs of proinflammatory cytokines and robust infiltration of inflammatory cells in the ventricular myocardium. Elevations of plasma cardiac troponin-I showed cardiac injury in CLP mice. Noninvasive echocardiographic assessment of cardiac function revealed that despite preserved left ventricular function in the presence of fluid replacement, the dobutamine inotropic response was significantly impaired in CLP mice compared with sham-operated controls. By contrast, milrinone exerted inotropic effects in sham-operated and CLP mice in an equally effective manner. Surface expression levels of β1-adrenoceptors and α-subunits of three main G protein families in the myocardium were unaffected by CLP-induced sepsis. Plasma cAMP levels were significantly elevated in both sham-operated and CLP mice in response to milrinone but only in sham-operated controls in response to dobutamine. Of phosphodiesterase (PDE) isoforms, PDE4D, but not PDE3A, both of which are responsible for cardiac cAMP hydrolysis, was significantly upregulated in CLP mouse myocardium. We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis, and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of a PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support.NEW & NOTEWORTHY Advisability of the usefulness of dobutamine in septic shock management is limited. Here, we reveal that the effect of dobutamine as a positive inotrope is impaired in mice with cecal ligation and puncture-induced sepsis without changes in cardiac β1-adrenoceptor signaling as a result of cAMP breakdown achieved by upregulated phosphodiesterase 4D.

Accuracy and Trending Ability of the Fourth-Generation FloTrac/Vigileo System in Patients With Low Cardiac Index.

OBJECTIVES To determine the accuracy and trending ability of the fourth-generation FloTrac/Vigileo in patients with low cardiac index by comparing FloTrac/Vigileo-derived cardiac index with that measured by 3-dimensional echocardiography. DESIGN Prospective clinical study. SETTING Cardiac surgery operating room in a single cardiovascular center. PARTICIPANTS Twenty-five patients undergoing elective cardiac resynchronization therapy lead implantation. INTERVENTIONS FloTrac/Vigileo-derived cardiac index and 3-dimensional echocardiography-derived cardiac index were determined simultaneously before and after phenylephrine bolus and cardiac resynchronization therapy using 3-dimensional echocardiography-derived cardiac index as the reference method. MEASUREMENTS AND MAIN RESULTS Cardiac index measured by the fourth-generation FloTrac/Vigileo had a wide limit of agreement with that measured by 3-dimensional echocardiography, with a percentage error of 59.1%. The tracking ability of the unit after both phenylephrine administration and cardiac resynchronization therapy were measured by concordance rate, and both were below the acceptable limit (72.7% and 85%, respectively). CONCLUSIONS The degree of accuracy of the fourth-generation FloTrac/Vigileo in patients with low cardiac index was not acceptable, and high systemic vascular resistance in patients with low cardiac index may have contributed to this inaccuracy. The tracking ability of the fourth-generation FloTrac/Vigileo after phenylephrine administration or cardiac resynchronization therapy was below acceptable limits.

Regulation of the Cardiovascular System by Histamine

Histamine mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in the central nervous system. Histamine also exerts a series of actions upon the cardiovascular system but may not normally play a significant role in regulating cardiovascular function. During tissue injury, inflammation, and allergic responses, mast cells (or non-mast cells) within the tissues can release large amounts of histamine that leads to noticeable cardiovascular effects. Owing to intensive research during several decades, the distribution, function, and pathophysiological role of cardiovascular H1- and H2-receptors has become recognized adequately. Besides the recognized H1- and H2-receptor-mediated cardiovascular responses, novel roles of H3- and H4-receptors in cardiovascular physiology and pathophysiology have been identified over the last decade. In this review, we describe recent advances in our understanding of cardiovascular function and dysfunction mediated by histamine receptors, including H3- and H4-receptors, their potential mechanisms of action, and their pathological significance.

Cardioprotective and functional effects of levosimendan and milrinone in mice with cecal ligation and puncture-induced sepsis

Levosimendan and milrinone may be used in place of dobutamine to increase cardiac output in septic patients with a low cardiac output due to impaired cardiac function. The effects of the two inotropic agents on cardiac inflammation and left ventricular (LV) performance were examined in mice with cecal ligation and puncture (CLP)-induced sepsis. CLP mice displayed significant cardiac inflammation, as indicated by highly increased pro-inflammatory cytokines and neutrophil infiltration in myocardial tissues. When continuously given, levosimendan prevented but milrinone exaggerated cardiac inflammation, but they significantly reduced the elevations in plasma cardiac troponin-I and heart-type fatty acid-binding protein, clinical markers of cardiac injury. Echocardiographic assessment of cardiac function showed that the effect of levosimendan, given by an intravenous bolus injection, on LV performance was impaired in CLP mice, whereas milrinone produced inotropic responses equally in sham-operated and CLP mice. A lesser effect of levosimendan on LV performance after CLP was also found in spontaneously beating Langendorff-perfused hearts. In ventricular myocytes isolated from control and CLP mice, levosimendan, but not milrinone, caused a large increase in the L-type calcium current. This study represents that levosimendan and milrinone have cardioprotective properties but provide different advantages and drawbacks to cardiac inflammation/dysfunction in sepsis.

Role of G protein-coupled receptor kinase 2 in oxidative and nitrosative stress-related neurohistopathological changes in a mouse model of sepsis-associated encephalopathy

Sepsis‐associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein‐coupled receptor 2 (GRK2), first identified as a G protein‐coupled receptor (GPCR) regulator, in the regulation of non‐G protein‐coupled receptor‐related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE. When mouse MG6 microglial cells were challenged with lipopolysaccharide (LPS), GRK2 cytosolic expression was highly up‐regulated. The ablation of GRK2 by small interfering RNAs (siRNAs) prevented an increase in intracellular reactive oxygen species generation in LPS‐stimulated MG6 cells. Furthermore, the LPS‐induced up‐regulation of inducible nitric‐oxide synthase expression and increase in nitric oxide production were negated by GRK2 inhibitor or siRNAs. However, GRK2 inhibition was without effect on overproduction of tumor necrosis factor‐α, interleukin (IL)‐6, and IL‐1β in LPS‐stimulated MG cells. In mice with cecal ligation and puncture‐induced sepsis, treatment with GRK2 inhibitor reduced high levels of oxidative and nitrosative stress in the mice brains, where GRK2 expression was up‐regulated, alleviated neurohistological damage observed in cerebral cortex sections, and conferred a significant survival advantage to CLP mice. Altogether, these results uncover the novel role for GRK2 in regulating cellular oxidative and nitrosative stress during inflammation and suggest that GRK2 may have a potential as an intriguing therapeutic target to prevent or treat SAE.

Accuracy and trending ability of the fourth-generation FloTrac/Vigileo System™ in patients undergoing abdominal aortic aneurysm surgery

PurposeThe fourth-generation FloTrac/Vigileo™ improved its algorithm to follow changes in systemic vascular resistance index (SVRI). This revision may improve the accuracy and trending ability of CI even in patients who undergo abdominal aortic aneurysm (AAA) surgery which cause drastic change of SVRI by aortic clamping. The purpose of this study is to elucidate the accuracy and trending ability of the fourth-generation FloTrac/Vigileo™ in patients with AAA surgery by comparing the FloTrac/Vigileo™-derived CI (CIFT) with that measured by three-dimensional echocardiography (CI3D).MethodsTwenty-six patients undergoing elective AAA surgery were included in this study. CIFT and CI3D were determined simultaneously in eight points including before and after aortic clamp. We used CI3D as the reference method.ResultsIn the Bland–Altman analysis, CIFT had a wide limit of agreement with CI3D showing a percentage error of 46.7%. Subgroup analysis showed that the percentage error between CO3D and COFT was 56.3% in patients with cardiac index < 2.5 L/min/m2 and 28.4% in patients with cardiac index ≥ 2.5 L/min/m2. SVRI was significantly higher in patients with cardiac index < 2.5 L/min/m2 (1703 ± 330 vs. 2757 ± 798; p < 0.001). The tracking ability of fourth generation of FloTrac/Vigileo™ after aortic clamp was not clinically acceptable (26.9%).ConclusionsThe degree of accuracy of the fourth-generation FloTrac/Vigileo™ in patients with AAA surgery was not acceptable. The tracking ability of the fourth-generation FloTrac/Vigileo™ after aortic clamp was below the acceptable limit.