Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 10, Issue 3, 2010

Sepsis remains a challenge for intensive care physicians and is one of the leading causes of death nowadays. This syndrome comprises a spectrum of conditions ranging from systemic inflammatory response syndrome (SIRS) to septic shock and multisystem organ failure (MSOF), the deadly forms of the disease. Although definite advances have been made in the knowledge regarding its pathogenesis and treatment and a decline in mortality has been observed, the annual incidence of the disease is increasing 8.7% in the United States, which results in augmented health care costs. The economic burden of sepsis is nearly $17 billion annually in the United States, with mortality ranging from 20% to 50% of severely affected patients. This enhance in the incidence in recent years is probably due to progressive aging of the population, improvements in critical care support and in immunosuppressive therapies so that individuals with immunosuppression now have increased life expectancy [1]. Thus, there is a clear need to further investment in order to better understand the integrative mediator pathways of inflammation, vascular dysfunction and cellular repair amenable to therapeutic intervention in sepsis. The pathogenesis of sepsis is complex and a fascinating area of investigation; our understanding of its underlying mechanisms has improved markedly in recent years, despite several pieces of the sepsis' puzzle are yet to be discovered. In sepsis, protective and deleterious responses are closely related. Certainly, this is an important reason for the failure of many pathogenesis-oriented target adjunctive therapies. It is now well accepted that this disease results from a triggering of body's defense mechanisms by pathogens and their products. The extension of this activation as well as the regulation of this complex pathogen-host interaction is the key for poor outcome or survival [2]. The mechanisms implicated in development of organ dysfunction during sepsis are progressively being revealed. Compounds such as cytokines, eicosanoids and more recently, nitric oxide (NO) and reactive oxygen species (ROS) have been clearly related to MSOF [3]. In sepsis, large amounts of NO are present in vasculature and may be partially responsible for vascular hiporeactivity and microvascular damage which are common features of this condition. In addition, new players have been described in the field of vascular dysfunction, such as platelet-derived microparticles, which are associated with apoptosis of vascular cells and cardiac failure [4]. However, the correlation of these pathways to outcome is so far poorly understood. Mitochondria seem to be another important piece in the puzzle of sepsis' pathogenesis. Patient studies have shown that the degree of mitochondrial dysfunction relates to eventual outcome [5]. Associated mechanisms may include damage to mitochondria or inhibition of the electron transport chain enzymes from NO and other reactive oxygen species (the effects of which are amplified by co-existing tissue hypoxia). During sepsis, a decrease in energy supply due to mitochondrial inhibition or injury may trigger this hibernation/estivation-like state with organ “shut-down” as an adaptation to harmful environment. Likewise, organ recovery may depend on restoration of normal mitochondrial respiration (mitochondrial biogenesis), which seems to be related to NO production. The pathway that correlates the same molecule to organ injury and recovery is another attractive aspect of sepsis' pathogenesis. Therefore, stimulation of mitochondrial biogenesis could offer a new therapeutic approach for patients in MSOF. In this issue of Endocrine, Metabolic & Immune Disorders - Drug Targets journal we intend to provide an update on the most recent discoveries regarding sepsis pathogenesis. Mechanisms of sepsis-related organ dysfunction such as the ones described above and several others will be discussed by the invited authors, which will support most of the topics discussed on their own research data, thus offering a wide scope of information concerning several pathogenetic and therapeutic aspects of this disease.

The continuous antigenic triggering has greatly contributed to the evolution of the immune system and, therefore, animals have developed cells able to cope with a broad variety of microbial antigens and or their toxins, e.g., endotoxins. At the same time, intestinal commensals have evolved along with human progress and introduction of new foods, thus empowering both regional and systemic immune response. In this review, some important steps in the evolution of the immune system will be analyzed such as organization of lymphoid organs, formation of germinal centers, leukocyte attraction to tissue, function of Toll like receptors and role of antimicrobial peptides. In particular, the major phylogenetic acquisitions of living organisms in the assessment of the immune machinery will be emphasized. Finally, fish will be taken into consideration as animal models of human diseases also in view of drug design strategies. Special attention will be focused on vaccinated salmon and zebrafish models.

Sepsis is one of the major health problems all over the word. Its pathophysiological mechanisms are not completely understood, but coagulation alterations are a hallmark of this syndrome. There is a clear exacerbation of coagulation and a suppression of control mechanisms of this process, including a reduction in fibrinolysis with consequent impairment of fibrin removal. The leading cause of these alterations is the proinflammatory state of those patients, characterized by high cytokine levels, increase in adhesion molecules expression, endothelial and platelets activation, release of microparticles and other related phenomena. Moreover, coagulation and inflammation are linked in a variety of pathways with mutual activation that ultimately contributes for its maintenance. The components of this process will be herein discussed as well as therapeutical alternatives that have excessive coagulation as a target.

Sepsis and multiple organ failure remain leading causes of death in intensive care patients. Recent advances in our understanding of the pathophysiology of these syndromes include a likely prominent role for mitochondria. Patient studies have shown that the degree of mitochondrial dysfunction is related to the eventual outcome. Associated mechanisms include damage to mitochondria or inhibition of the electron transport chain enzymes by nitric oxide and other reactive oxygen species (the effects of which are amplified by co-existing tissue hypoxia), hormonal influences that decrease mitochondrial activity, and downregulation of mitochondrial protein expression. Notably, despite these findings, there is minimal cell death seen in most affected organs, and these organs generally regain reasonably normal function should the patient survive. It is thus plausible that multiple organ failure following sepsis may actually represent an adaptive state whereby the organs temporarily 'shut down' their normal metabolic functions in order to protect themselves from an overwhelming and prolonged insult. A decrease in energy supply due to mitochondrial inhibition or injury may trigger this hibernation/estivation-like state. Likewise, organ recovery may depend on restoration of normal mitochondrial respiration. Data from animal studies show histological recovery of mitochondria after a septic insult that precedes clinical improvement. Stimulation of mitochondrial biogenesis could offer a new therapeutic approach for patients in multi-organ failure. This review will cover basic aspects of mitochondrial function, mechanisms of mitochondrial dysfunction in sepsis, and approaches to prevent, mitigate or speed recovery from mitochondrial injury.

The sepsis syndrome represents an improper immune response to pathogens and is associated with an unacceptably high rate of mortality. Although supportive care is of benefit to the septic patient, there are no viable therapeutics available that target the immune system suitable for the whole septic population. Recently, using a physiologically relevant murine mouse model, the cannabiniod 2 receptor has been shown to play a critical role in the host response to sepsis. Here, the structure, expression, signaling, and function of the CB2 receptor on leukocytes will be reviewed. Further, the effects mediated by the CB2 receptor during sepsis will be reviewed. Altogether, alterations in inflammation and the host response during sepsis by the CB2 receptor support its use as a possible therapeutic agent.

In the last few years, an important body of knowledge has been developed showing the pathophysiological relevance of the sublingual microcirculation in the development of multiorgan failure associated with sepsis. In addition to the compelling experimental evidence, the development of new videomicroscopic techniques allows now the evaluation of the microcirculation in critically ill patients. Consequently, the sublingual microcirculation can be easily monitored at bedside. Therefore, studies performed in the sublingual area show that severe microcirculatory sublingual alterations are present in septic patients. Moreover, these alterations have an important prognostic value. Finally, sublingual microvascular alterations can be modified by therapeutic interventions. In this article, we review relevant information related to the pathophysiology of the microcirculation in health and disease with special reference to the behavior of the mesenteric territory during shock states and the alterations of sublingual microcirculation in septic patients as well as their responses to different therapeutic approaches.

Septic shock is characterized by vasodilation and hypotension despite increased vasoconstrictors. While nitric oxide is known to be responsible for vasodilation, failure of vascular smooth muscle to constrict may be due in part to low plasma levels of vasopressin, a neurohypophyseal hormone. In the initial phase of septic shock, vasopressin concentration usually increases but then decreases to a significantly lower concentration after onset of septic shock. In this review, we discuss the neural mechanisms for the regulation of vasopressin secretion during septic shock.

Metabolic acidosis is very common in critically ill septic patients. Acidosis may be a result of the underlying pathophysiology, but it also may be the result of the way in which those patients are managed. Chloride-associated acidosis is frequent and is potentially aggravated during fluid resuscitation. The severity of metabolic acidosis is associated with poor clinical outcomes; however, it remains uncertain whether or not there is a causal relationship between acidosis and the pathophysiology of septic syndromes. Several experimental findings have demonstrated the impact of acidosis modulation on the release of inflammatory mediators and cardiovascular function. Treatment of metabolic acidosis is based on control of the underlying process and support of organ dysfunction, although the use of intravenous chloridepoor balanced solutions seems an attractive option to prevent the worsening of metabolic acidosis during fluid resuscitation.

It is now clear that several members of the nuclear receptor superfamily are co-expressed by macrophages, lymphocytes and other cell types that are involved in the regulation of inflammatory and immune responses. Peroxisome proliferator-activated receptors (PPAR) and nuclear liver X receptors (LXR) are members of this family known to be activated by lipid derived endogenous ligands (such as fatty acids, eicosanoids and cholesterol) and pharmacological ones. Here we review the biology of these nuclear receptors and highlight recent work that show that their activation can ameliorate inflammatory conditions, especially due to their effect on macrophage functions. The data discussed herein show the potential beneficial effect of targeting these nuclear receptors in order to improve the outcome of septic patients.

Corticosteroids have been proposed for decades as adjunctive therapy of severe infections. These drugs have complex mechanisms of action involving anti-inflammatory and vasoactive properties. However, due to discordant results from clinical studies, the use of corticosteroids to treat patients with severe infections is still a matter of intense debate in the scientific and medical community. In the present article, we review the underlying mechanisms related to the potential benefits of corticosteroids and their impact on clinical management of severe sepsis.

Sepsis remains one of the leading causes of death in intensive care units. Progressive cardiovascular failure is an important cause of the mortality. Septic patients with myocardial dysfunction have significantly higher mortality compared with patients without cardiovascular impairment. Myocardial dysfunction in sepsis is characterized by decreased contractility and impaired myocardial compliance. Experimental studies of sepsis showed heterogeneity of microvascular perfusion, as well as impaired myocardial oxygen extraction. The underlying cellular mechanisms include increased neutrophil adhesion to the endothelium, production of reactive free radicals and oxidants, and endothelial dysfunction. Superoxide, nitric oxide and peroxynitrite cardiac formation has been demonstrated in septic hearts, which has been implicated in the pathogenesis of the myocardial depression and cell death in sepsis. Nitric oxide, carbon monoxide and hydrogen sulfide are gaseotransmitters that may exert protective effects in the septic heart.

Sepsis is a complex clinical situation responsible for thousands of deaths annually in intensive care units around the globe. Despite all our progress in providing medical care to critically ill patients, mortality of severe forms of sepsis did not decrease as expected. Part of this phenomenon is due to our defective understanding about the host immune response to aggression by a microorganism, including the part played by the pattern-recognition receptors (PRRs) in this process. PRRs are part of the innate immunity responsible for detecting non-self antigens and trigger the initial inflammatory response. The best known PRRs are the tol-like receptors (TLRs). In this article, we review some of our knowledge regarding the role of TLRs in sepsis, both in experimental models and in human patients. The improvement in our knowledge about the mediators and signaling pathways that control this immune response is crucial for the development of better markers of disease and new therapeutic targets, leading us to improve the way we treat septic patients.

Acute critical illness is characterized by a hypermetabolic and catabolic response where profound endocrine, metabolic and immunologic changes are initiated and sustained through the activation, in part, of beta-adrenergic receptors. The modulation of beta-adrenergic receptor mediated endocrine, immunological and metabolic control may be beneficial in sepsis through a number of mechanisms. However, the complex interaction between beta-adrenoreceptormediated, apparently disparate systems may confer both positive and negative clinical outcomes. Chronic cardiac failure and sepsis/critical illness share several similar endocrine, immunologic and metabolic pathological features. Beneficial beta-adrenergic modulation of various pathophysiological changes has been demonstrated in both experimental and clinical heart failure. Investigations in critical illness rarely take into account the role of beta-adrenoreceptor stimulation in patients with such co-morbidities, who are among the most vulnerable to sepsis. Despite similar phenotypes and possibly common mechanisms, few clinical studies have explored whether beta-adrenoreceptor modulation may confer outcome benefit during critical illness. Recent experimental and observational clinical data illustrate that carefully monitored, patient/subject-specific beta-adrenoreceptor modulation may provide a useful intervention to ameliorate the detrimental effects of hyperacute and/or prolonged beta-adrenergic receptor stimulation. Most notably, human studies demonstrate that (non-specific) beta-adrenoreceptor blockade does not increase inflammation, sepsis, or infectious episodes. Furthermore, hemodynamically tailored beta-1 adrenoreceptor antagonism improves outcome in experimental sepsis through novel cardiac and non-cardiac mechanisms. Understanding the dynamic complexity of beta-adrenergic physiology during critical illness offers further insights into the mechanisms underlying maladaptive metabolic and immunologic changes and potentially novel therapeutic interventions.