Current Drug Targets - Volume 8, Issue 4, 2007

A comprehensive understanding of severe sepsis, enough to develop a unified approach to treatment remains the “Holy Grail” for the critical care medical community. In simple terms sepsis is a bloodstream infection with progressive severity to produce vascular inflammatory perturbations leading to vascular collapse, organ dysfunction, and death. Sepsis consumes the host blood leukocyte response, endothelial responses and related cytokine responses. A formal clinical definition of “Severe Sepsis” was developed in 1992 by the joint American College of Chest Physicians/Society of Critical Care Medicine. This definition relies on criteria of clinical signs of a systemic inflammatory response (SIRS criteria) and the presence of at least one organ failure. As a disease state, severe sepsis afflicts 750,000 patients in the U.S annually and causes 250,000 deaths. Previous anti-cytokine approaches (e.g. antibody to TNF, anti-IL-1, etc...) in clinical trials were too specific and unsuccessful in achieving meaningful severe sepsis survival. Subsequently, agents addressing the inflammation-coagulation axis have been moderately successful in providing a survival advantage for severe sepsis patients. However, practical physiologic approaches of cardiovascular volume support, intensive insulin strategies, and other intensive organ support in the critical care unit have made a difference for some severe sepsis patients. This is a battle that is far from over. In this issue of Current Drug Targets seven reviews address various aspects of sepsis. The first five manuscripts evaluate specific drug targets in sepsis: 1.) apoptosis, 2.) endothelium, 3.) vascular permeability, 4.) cancer and sepsis and a specific target of intermediary metabolism 5.) phosphoenol pyruvate/ethyl pyruvate. Two other reviews take a more clinical approach to cover important subpopulations of sepsis, 6.) bioterrorism agents and 7.) the solid organ transplant population. In sepsis the host innate immune response calls in monocytes whose cytokine responses direct neutrophil and other leukocyte traffic. T-cells provide secondary responses and antiviral help. The stress response including steroids can reduce T-cell number leading to a degree of immune incompetence. Wesche-Soldato et al. review the leukocyte contribution to the host immune response with emphasis on T-cell apoptosis mechanisms and new promising drug targets aimed at this leukocyte subpopulation. Bill Aird reviews the role of the endothelium in sepsis, a complex regulatory organ essential for maintaining vascular-organ homeostasis and interfacing both coagulation and the progressive inflammation encountered in this condition. Natural anticoagulants and anti-inflammatory drug targets highlight a portion of the potential treatment targets within the endothelium. Vascular permeability occurs early in sepsis and intravascular volume loss accounts for concerning lung acute respiratory distress and the hypotension of distributive shock. Endotoxin, Tumor necrosis factor alpha and Thrombin (FIIa) incite this early endothelial permeability. Jacobsen et al. review subcellular mechanisms and potential drug targets aimed at reducing permeability. Cancer and sepsis is a smaller subgroup. With an aging population and evolving therapies for cancer, this population may achieve some relevance. Since some tumors express Tissue Factor, Cancer Procoagulant, and secrete other procoagulant proteins, the thrombotic tendency in sepsis may play to worse outcomes for the cancer patient. The question posed suggests that anticoagulants may be worth considering in this compromised population. Intermediary metabolism has received more notoriety with the finding that intensive insulin therapy can improve severe sepsis survival. Mitch Fink presents Ethyl Pyruvate (EP) as promising fit. From biochemical to cellular, to metabolism considerations through the relevant animal models EP should be near human dosing. Although presented as a single drug, the manuscript provides an excellent example of the process from molecule to mammal......

Recent research has yielded many interesting and potentially important therapeutic targets in sepsis. Specifically, the effects of antagonistic anti-cytokine therapies (tumor necrosis factor-alpha [TNF-α], interleukin-1 [IL-1]) and anti-endotoxin strategies utilizing antibodies against endotoxin or endotoxin receptor/carrier molecules (anti-CD14 or anti-LPS-binding protein) have been studied. Unfortunately, these approaches often failed clinically, and in many cases, the efficacy of these treatments was dependent on the severity of sepsis. Recently, clinical trials using insulin to lock blood glucose levels and activated protein C treatment have showed that while they provided some survival benefit, their efficacy does not appear to be predicated solely upon anti-inflammatory effects. Here, we will review work done in animal models of polymicrobial sepsis and clinical findings that support the hypothesis that apoptosis in the immune system is a pathologic event in sepsis that can be a therapeutic target. In this respect, experimental studies looking at the septic animal suggest that loss of lymphocytes during sepsis may be due to dysregulated apoptosis and that this appears to be brought on by a variety of mediators effecting ‘intrinsic’ as well as ‘extrinsic’ cell death pathways. From a therapeutic perspective this has provided a number of novel targets for clinically successful current, as well as future therapies, such as caspases (caspase inhibition/protease inhibition), proapoptotic protein-expression (via administration and/or over-expression of Bcl-2) and the death receptor family Fas-FasL (via. FasFP [fas fusion protein] and the application of siRNA against a number pro-apoptotic factors).

The endothelium plays an important role in health and disease. Endothelial dysfunction contributes to sepsis pathophysiology. An important goal is to develop novel therapies that reverse endothelial dysfunction in sepsis. This review will consider the role of the endothelium in sepsis and will highlight its untapped therapeutic potential.

Sepsis is characterized physiologically by an aberrant systemic inflammatory response and microvascular dysfunction. While appropriate antibiotics and supportive care are essential in the management of the septic patient, therapies targeting specific aspects of the pathophysiology could have a significant impact on the morbidity and mortality associated with both sepsis and its sequlea, including acute lung injury (ALI). We have characterized several mediators of endothelial cell (EC) barrier function that may serve as novel therapies for sepsis-induced microvascular dysfunction including simvastatin, adenosine triphosphate (ATP), sphingosine 1-phosphate (S1P), and activated protein C (APC). Notably, APC is already available for the treatment of severe sepsis, however, to date its mechanism of action has been unclear. While distinct in many ways, we have found that these agonists have in common the ability to induce dynamic rearrangement of the EC actin cytoskeleton that corresponds to barrier protection. In addition, we have extended our in vitro findings to relevant animal models of endotoxin-induced acute lung injury and have confirmed beneficial effects of both simvastatin and S1P which are associated with evidence of decreased vascular permeability in this setting. Moreover, our data also indicate that APC effects in sepsis may be largely due to augmentation of EC barrier function affecting decreased microvascular permeability. We speculate that the administration of direct modulators of EC barrier function and microvascular permeability, such as those described here, may ultimately become the standard of care for the septic patient.

Pyruvic acid is a three-carbon α-ketocarboxylic acid that plays a central role in intermediary metabolism, being the final product of glycolysis and the starting substrate for the tricarboxylic acid cycle. Ethyl pyruvate, which is a simple aliphatic ester derived from pyruvic acid, has been shown to improve survival and ameliorate organ system dysfunction in mice with peritonitis induced by cecal ligation and perforation, even when treatment is started as late as 12-24 hours after the onset of sepsis. In studies using lipopolysaccharidestimulated RAW 264.7 murine macrophage-like cells, ethyl pyruvate inhibits activation of the pro-inflammatory transcription factor, NF-κB, and down-regulates secretion of a number of pro-inflammatory cytokines, such as TNF. In this reductionist in vitro system, ethyl pyruvate also blocks secretion of the late-appearing pro-inflammatory cytokine-like molecule, high mobility group B1 (HMGB1). In murine models of endotoxemia or sepsis, treatment with ethyl pyruvate decreases circulating levels of TNF and HMGB1. While the molecular events responsible for the salutary effects of ethyl pyruvate remain to be elucidated, one mechanism may involve covalent modification of a critical thiol residue in the p65 component of NF-κB. Ethyl pyruvate warrants evaluation as a therapeutic agent for the treatment of sepsis in humans.

The microorganisms potentially utilized as biologic weapons have a variety of pathogenic mechanisms that lead to overwhelming infection, septic shock and death. Although many of these organisms have unique pathogenic attributes, the development of generic therapies for common pathways would be exceedingly useful as countermeasures. This review will examine the features of pathogenesis leading to sepsis for key biologic threat agents (causative agents of anthrax, plague, tularemia, smallpox and viral hemorrhagic fevers), and highlight current and future therapeutic targets. For some of the biologic threat agents, such as anthrax, substantial research has yielded a number of targeted sites for intervention. For other organisms, further elucidation of the mechanisms of pathogenesis and septic shock is needed to direct therapeutic exploration.

Approximately seventy patients undergo solid organ transplantation (SOT) every day in the United States. Sepsis remains the first or second most common cause of death in transplant recipients, depending on the allograft type. The rapid diagnosis and treatment of sepsis is critical to ensure improved survival outcome in this special patient population. However, these patients frequently lack the classic systemic inflammatory response syndrome (SIRS), commonly seen in the immunocompetent patients. In order to minimize delays in the diagnosis of sepsis in SOT recipients, it is paramount to recognize the specific risk factors for infection associated with each allograft type. In addition, the particular surgical techniques involved in each type of transplantation may be closely related to the clinical manifestations of the infection process. This correlation can further advance the diagnosis and treatment of sepsis. In conclusion, precocious diagnosis, rapid initiation of antibiotics, surgical correction when necessary, and reduction of immunosuppression, are the mainstream approach to sepsis in the SOT patient. The recent developments in severe sepsis are discussed in the context of the transplant recipient.

The host inflammatory response is activated in both cancer and infection. This includes enhanced production of acute phase reactants, involvement of coagulation and inflammation and the potential for systemic effects. This overview will identify the prothrombotic links between cancer and sepsis and suggest antithrombotic agents as an approach in the specific treatment of sepsis in cancer patients.

Several studies showed that postprandial plasma triglyceride (TG) concentrations are higher in patients with coronary heart disease. TG-rich lipoprotein remnants accumulated in the postprandial state are involved in atherogenesis and in events leading to thrombosis. Lipid lowering drugs, such as 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) are of significant benefit in the primary and secondary prevention of atherosclerosis. Statins can decrease total cholesterol and low density lipoprotein cholesterol as well as TG concentrations and improve postprandial lipoprotein metabolism. Since abnormal postprandial lipemia is associated with pathological conditions, its treatment is relevant. This review considers the effect of statins on postprandial lipemia.

Peripheral arterial disease (PAD) is a common disorder usually associated with silent or symptomatic arterial disease elsewhere in the circulation and a “cluster” of cardiovascular risk factors (e.g. smoking, dyslipidemia, hypertension, and insulin resistance/ diabetes mellitus). The medical management of PAD should focus on both the relief of symptoms and prevention of secondary cardiovascular complications. This approach must include smoking cessation, optimal cholesterol levels, blood pressure and glycemic control as well as prescribing antiplatelet therapy. This review focuses on the evidence supporting the use of lipid-lowering drugs in PAD. Several trials indicate that getting low density lipoprotein-cholesterol levels to target (<2.6 mmol/l; 100 mg/dl), or even lower, is associated with improvement of symptoms and a reduction in vascular events in patients with PAD.