Toll-like receptor-4 antagonist eritoran tetrasodium for severe sepsis

The human innate immune system initiates inflammation in response to bacterial molecules, particularly Gram-negative bacterial endotoxin. The steps by which endotoxin exposure leads to systemic inflammation include binding to Toll-like receptor-4 that specifically recognizes endotoxin and subsequently triggers cellular and molecular inflammatory responses. Severe sepsis is a systemic inflammatory response to infection that induces organ dysfunction and threatens a person's survival. Severe sepsis is frequently associated with increased blood levels of endotoxin. It is a significant medical problem that effects approximately 700,000 patients every year in the USA, resulting in 250,000 deaths. Eritoran tetrasodium is a nonpathogenic analog of bacterial endotoxin that antagonizes inflammatory signaling by the immune receptor Toll-like receptor-4. Eritoran is being evaluated for the treatment of patients with severe sepsis.     

脓毒症与铁代谢的研究进展

脓毒症是一种由感染引起的常见的全身炎症反应综合征,具有高发病率和高病死率的特征,已成为重要的公共健康问题之一。脓毒症及其发病机制和治疗也一直是研究重点。2016年,脓毒症被重新定义为由宿主对感染的反应失调引起的危及生命的器官功能障碍模式。近年来,针对脓毒症患者的免疫反应及代谢变化开展了大量临床及实验研究,其中铁代谢与脓毒症的关系也是研究重点之一。铁在调节免疫功能和微生物生长方面有着关键作用,已有研究证明铁代谢的变化会影响感染的风险。本文旨在对铁代谢与脓毒症及脓毒症诱导的多器官功能障碍的关系等作简要概述,以期对脓毒症的预后预测及治疗提供新的方向。     

To be,or not to be immunocompetent

Several data support the view that impairment of the inflammatory-immune response is a hallmark of severe sepsis and the level and time of recovery to immunocompetence has a major impact on the clinical outcome of ICU patients. Recent studies demonstrate that improvement of anti-tumour immune response by targeting negative regulatory molecules, such as CD25, chronic T-lymphocyte activation antigen 4, and programmed death-1 receptor (PD-1)/PD-1 L, offers a novel opportunity to prevent or even reverse progression of tumour growth in experimental models and patients. Likewise, severe sepsis is associated with enhanced expression of those negative regulatory molecules, suggesting a novel approach to reverse immunoparalysis in sepsis. Consequently, targeting negative molecules in sepsis can reverse immunoparalysis and improve survival in experimental sepsis, as shown by Chang and colleagues in a recent issue of Critical Care. This opens new opportunities to overcome overwhelming downregulation of the adaptive immune response to prevent and/or improve recovery from sepsis.     

The puzzle of sepsis: fitting the pieces of the inflammatory response with treatment

Sepsis is a complex syndrome characterized by simultaneous activation of inflammation and coagulation in response to microbial insult. These events manifest as systemic inflammatory response syndrome (SIRS)/sepsis symptoms through release of proinflammatory cytokines, procoagulants, and adhesion molecules from immune cells and/or damaged endothelium.Conventional treatments have focused on source control, antimicrobials, vasopressors, and fluid resuscitation; however, a new treatment paradigm exists: that of treating the host response to infection with adjunct therapies including early goal directed therapy, drotrecogin alfa (activated), and immunonutrition. The multimechanistic drotrecogin alfa (activated) has been shown to reduce mortality in the severely septic patient when combined with traditional treatment. Therapies targeting improved oxygen and blood flow and reduction of apoptosis and free radicals are under investigation. Early sepsis diagnosis through detection of pro calcitonin, C reactive protein, sublingual CO2, and genetic factors may be beneficial. Ultimately, intervention timing may be the most important factor in reducing severe sepsis mortality.     

Role of host defense peptides of the innate immune response in sepsis

Innate immune response and its effector molecules have received growing attention in research. Host defense peptides are known to be antimicrobially active. Recently, the peptides have been recognized as potent signaling molecules for cellular effectors of both innate and adaptive immunity. Mammalian peptides in particular revealed immunomodulatory functions, including endotoxin-binding and -neutralizing capacity, chemotactic activities, induction of cytokines and chemokines, promotion of wound healing, and angiogenesis. In sepsis, they present a family of natural substances that can be used in combination with antibiotics to complete a broad-spectrum antimicrobial regimen with endotoxin-neutralizing properties. Although there are side effects, host defense peptides have the potential to be significant reinforcements to the currently available therapeutic options in the future. In this review, we analyze the role of host defense peptides in infection and immune response, and discuss recent efforts to establish host defense peptides as potent novel therapeutic agents for the treatment of sepsis.     

Significant immunomodulatory effects of Pseudomonas aeruginosa quorum-sensing signal molecules: possible link in human sepsis

Pathogenic bacteria use quorum-sensing signal molecules to co-ordinate the expression of virulence genes. Animal-based studies have demonstrated the immunomodulatory effects of quorum-sensing signal molecules. In the present study, we have examined the impact of these molecules on normal human immune function in vitro and compared this with immune changes in patients with sepsis where quorum-sensing signal molecules were detected in the sera of patients. Quorum-sensing signal molecules inhibited normal dendritic cell and T-cell activation and proliferation, and down-regulated the expression of co-stimulatory molecules on dendritic cells; in MLDCRs (mixed lymphocyte dendritic cell reactions), secretion of IL (interleukin)-4 and IL-10 was enhanced, but TNF-alpha (tumour necrosis factor-alpha), IFN-gamma (interferon-gamma) and IL-6 was reduced. Quorum-sensing signal molecules induced apoptosis in dendritic cells and CD4(+) cells, but not CD8(+) cells. Dendritic cells from patients with sepsis were depleted and ex vivo showed defective expression of co-stimulatory molecules and dysfunctional stimulation of allogeneic T-lymphocytes. Enhanced apoptosis of dendritic cells and differential CD4(+) Th1/Th2 (T-helper 1/2) cell apoptotic rate, and modified Th1/Th2 cell cytokine profiles in MLDCRs were also demonstrated in patients with sepsis. The pattern of immunological changes in patients with sepsis mirrors the effects of quorum-sensing signal molecules on responses of immune cells from normal individuals in vitro, suggesting that quorum-sensing signal molecules should be investigated further as a cause of immune dysfunction in sepsis.     

脓毒症患儿CD4+CD25+调节性T细胞的变化

目的 观察不同免疫状态下脓毒症婴幼儿外周血CD4+CD25+Foxp3high调节性T细胞(Treg细胞)及相关分子的变化,探讨婴幼儿脓毒症免疫功能紊乱的可能机制.方法 分别收集2007年5月至2007年11月深圳市儿童医院重症监护室收治的婴幼儿脓毒症36例血液标本,另选16例健康同龄儿童作为正常对照进行前瞻性研究;排除既往患有自身免疫性疾病、免疫缺陷病、遗传代谢病及肿瘤的患儿,排除近6个月曾使用影响免疫功能的药物.本研究获得深圳市儿童医院伦理委员会的同意.以外周血CD14+单核细胞HLA-DR表达>30%或<30%为阈值,将患儿分为免疫激活组(DR-H组)和免疫抑制组(DR-L组),用流式细胞术检测CD14+单核细胞HLA-DR表达率,CD4+CD25+Foxp3highTreg细胞比例;实时荧光定量PCR(Real time-PCR)检测CD4+T细胞Foxp3、CTLA-4、GITR、IL-10mRNA表达.统计方法采用单因素方差分析,P<0.05为差异具有统计学意义.结果 急性期DR-L组CD4+CD25+Foxp3highTreg细胞比例明显高于对照组及DR-H组(P<0.05).DR-L组Foxp3、CTLA-4、IL-10等相关分子基因表达高于对照组及DR-H组(P<0.05),DR-L组GITR基因表达高于DR-H组.结论 CD4+CD25+Foxp3highTreg细胞数量异常增加可能与婴幼儿脓毒症免疫抑制状态有关.     

VX-166: a novel potent small molecule caspase inhibitor as a potential therapy for sepsis

Introduction  

Prevention of lymphocyte apoptosis by caspase inhibition has been proposed as a novel treatment approach in sepsis. However, it has not been clearly demonstrated that caspase inhibitors improve survival in sepsis models when dosed post-insult. Also, there are concerns that caspase inhibitors might suppress the immune response. Here we characterize VX-166, a broad caspase inhibitor, as a novel potential treatment for sepsis.     

Effects of melatonin on<Emphasis Type="Italic">Candida</Emphasis> sepsis in an experimental rat model

As an immunomodulator, melatonin reportedly exhibits protective effects in severe sepsis/shock induced by bacterial lipopolysaccharides in animal models. The present study was conducted to evaluate the possible protective effects of melatonin against experimental Candida sepsis in rats. A total of 40 adult male Wistar rats were randomly assigned to 4 groups: control, melatonin-treated control, septic, and melatonin-treated septic. Melatonin (200 microg/kg/d, intraperitoneally) injections were begun a week prior to sepsis induction and were continued daily for 3 wk until the end of the study. Cyclophosphamide was administered to animals in all groups as an immunosuppressive agent as a single dose 4 d prior to yeast inoculation. To cause sepsis, the Candida albicans (ATCC 10259) strain was administered intravenously. Amphotericin B was given as an antimycotic therapeutic agent as a single dose to septic rats. Plasma levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), vascular cell adhesion molecule-1, and E-selectin were measured on the first and 15th days of sepsis. IL-6, TNF-alpha, vascular cell adhesion molecule-1, and E-selectin levels of septic rats were higher than those of controls. Melatonin reduced IL-6 levels and shortened time to improvement in animals with Candida sepsis. Levels of TNF-alpha and adhesion molecules in melatonin-treated septic rats were decreased compared with those in septic rats, but this difference was not statistically significant. In light of the current results, investigators conclude that melatonin may have therapeutic benefits in Candida sepsis and in classic antimycotic treatment because of its immune regulatory effects.     

Development of TLR9 agonists for cancer therapy

In vertebrates, the TLRs are a family of specialized immune receptors that induce protective immune responses when they detect highly conserved pathogen-expressed molecules. Synthetic agonists for several TLRs, including TLR3, TLR4, TLR7, TLR8, and TLR9, have been or are being developed for the treatment of cancer. TLR9 detects the unmethylated CpG dinucleotides prevalent in bacterial and viral DNA but not in vertebrate genomes. As discussed in this Review, short synthetic oligodeoxynucleotides containing these immune stimulatory CpG motifs activate TLR9 in vitro and in vivo, inducing innate and adaptive immunity, and are currently being tested in multiple phase II and phase III human clinical trials as adjuvants to cancer vaccines and in combination with conventional chemotherapy and other therapies.     

Toward resolving the challenges of sepsis diagnosis

Sepsis in the United States has an estimated annual healthcare cost of 16.7 billion dollars and leads to 120,000 deaths. Insufficient development in both medical diagnosis and treatment of sepsis has led to continued growth in reported cases of sepsis over the past two decades with little improvement in mortality statistics. Efforts over the last decade to improve diagnosis have unsuccessfully sought to identify a "magic bullet" proteic biomarker that provides high sensitivity and specificity for infectious inflammation. More recently, genetic methods have made tracking regulation of the genes responsible for these biomarkers possible, giving current research new direction in the search to understand how host immune response combats infection. Despite the breadth of research, inadequate treatment as a result of delayed diagnosis continues to affect approximately one fourth of septic patients. In this report we review past and present diagnostic methods for sepsis and their respective limitations, and discuss the requirements for more timely diagnosis as the next step in curtailing sepsis-related mortality. We also present a proposal toward revision of the current diagnostic paradigm to include real-time immune monitoring.     

Pneumonia models and innate immunity to respiratory bacterial pathogens

Preclinical sepsis models have been used for decades to study the pathophysiologic processes during sepsis and shock. Although these studies revealed promising immunomodulating agents for the treatment of sepsis, clinical trials evaluating the efficacy of these new agents in patients with sepsis were disappointing. The main reason for this unsatisfactory experience might be that unlike the clinical situation, most of these preclinical models are devoid of a localized infectious source from which the infection disseminates. Studies on the effects of several immunomodulating strategies have demonstrated strikingly opposite results when sepsis models with a more natural route of infection, such as pneumonia, were used. In this review, we will give insights into pneumonia models and discuss results and differences in the innate immune responses during distinct pulmonary infection models.     

Bench-to-bedside review: understanding genetic predisposition to sepsis

Sepsis is a complex syndrome that develops when the initial, appropriate host response to an infection becomes amplified, and is then dysregulated. Among other factors, the innate immune system is of central importance to the early containment of infection. Death from infection is strongly heritable in human populations. Hence, genetic variations that disrupt innate immune sensing of infectious organisms could explain the ability of the immune system to respond to infection, the diversity of the clinical presentation of sepsis, the response to current medical treatment, and the genetic predisposition to infection in each individual patient. Such genetic variations may identify patients at high risk for the development of sepsis and organ dysfunction during severe infections. Single base variations, known as single nucleotide polymorphisms (SNPs), are the most commonly used variants. There has been great interest in exploring SNP in those genes involved in the inflammatory cascade resulting from the systemic inflammatory response to micro organisms. The rationale for studying gene SNPs in critical illnesses seeks to identify potential markers of susceptibility, severity, and clinical outcome; seeks to identify potential markers for responders and non-responders in clinical trials, and seeks to identify targets for therapeutic intervention. In this review, we focus on the current state of association studies of those genes governing the powerful bacterial infection-induced inflammation and provide guidelines for future studies describing disease associations with genetic variations based on current recommendations. We envision a time in the near future when genotyping will be include in the standard evaluation of critically ill patients and will help to prioritize a therapeutic option.     

B cells enhance early innate immune responses during bacterial sepsis

Microbes activate pattern recognition receptors to initiate adaptive immunity. T cells affect early innate inflammatory responses to viral infection, but both activation and suppression have been demonstrated. We identify a novel role for B cells in the early innate immune response during bacterial sepsis. We demonstrate that Rag1(-/-) mice display deficient early inflammatory responses and reduced survival during sepsis. Interestingly, B cell-deficient or anti-CD20 B cell-depleted mice, but not α/β T cell-deficient mice, display decreased inflammatory cytokine and chemokine production and reduced survival after sepsis. Both treatment of B cell-deficient mice with serum from wild-type (WT) mice and repletion of Rag1(-/-) mice with B cells improves sepsis survival, suggesting antibody-independent and antibody-dependent roles for B cells in the outcome to sepsis. During sepsis, marginal zone and follicular B cells are activated through type I interferon (IFN-I) receptor (IFN-α/β receptor [IFNAR]), and repleting Rag1(-/-) mice with WT, but not IFNAR(-/-), B cells improves IFN-I-dependent and -independent early cytokine responses. Repleting B cell-deficient mice with the IFN-I-dependent chemokine, CXCL10 was also sufficient to improve sepsis survival. This study identifies a novel role for IFN-I-activated B cells in protective early innate immune responses during bacterial sepsis.     

Soluble adhesion molecules as markers for sepsis and the potential pathophysiological discrepancy in neonates,children and adults

Sepsis is a severe and life-threatening systemic inflammatory response to infection that affects all populations and age groups. The pathophysiology of sepsis is associated with aberrant interaction between leukocytes and the vascular endothelium. As inflammation progresses, the adhesion molecules that mediate these interactions become shed from cell surfaces and accumulate in the blood as soluble isoforms that are being explored as potential prognostic disease biomarkers. We critically review the studies that have tested the predictive value of soluble adhesion molecules in sepsis pathophysiology with emphasis on age, as well as the underlying mechanisms and potential roles for inflammatory shedding. Five soluble adhesion molecules are associated with sepsis, specifically, E-selectin, L-selectin and P-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. While increased levels of these soluble adhesion molecules generally correlate well with the presence of sepsis, their degree of elevation is still poorly predictive of sepsis severity scores, outcome and mortality. Separate analyses of neonates, children and adults demonstrate significant age-dependent discrepancies in both basal and septic levels of circulating soluble adhesion molecules. Additionally, a range of both clinical and experimental studies suggests protective roles for adhesion molecule shedding that raise important questions about whether these should positively or negatively correlate with mortality. In conclusion, while predictive properties of soluble adhesion molecules have been researched intensively, their levels are still poorly predictive of sepsis outcome and mortality. We propose two novel directions for improving clinical utility of soluble adhesion molecules: the combined simultaneous analysis of levels of adhesion molecules and their sheddases; and taking age-related discrepancies into account. Further attention to these issues may provide better understanding of sepsis pathophysiology and increase the usefulness of soluble adhesion molecules as diagnostic and predictive biomarkers.     

Sepsis and immune response

BACKGROUND: Sepsis and secondary multiple organ failure in critically ill patients are the major cause of death, but the pathogenesis of sepsis is not clear, especially the dysfunction of the immune system. In this paper, we review the response and regulation of the immune system and the functions of a variety of inflammatory mediators in sepsis.DATA SOURCES: Studies were identified by searching MEDLINE and PubMed for articles using the keywords "sepsis", "immune response", and "inflammatory mediator" up to October 2010. Additional papers were identified by a manual search of the references from the key articles.RESULTS: This systematic review was conducted of: 1) the immune response; 2) immune regulation; 3) inflammatory mediators; 4) high-mobility group box 1 protein; 5) the complement system; and 6) the autonomic nervous system. There are no therapeutic approaches available for sepsis that target inflammatory response; the mortality of sepsis has not been significantly reduced.CONCLUSIONS: Sepsis is complex and dynamic, and it has a group of heterogeneous syndromes. Since different patients with sepsis have different etiology, susceptibility, and responses, treatment should be prescribed individually.     

Early interleukin-10 treatment improves survival and enhances immune function only in males after hemorrhage and subsequent sepsis

Recent studies have demonstrated gender differences in the immune response following hemorrhagic shock with an enhanced immune function and lower mortality following subsequent sepsis in females. Early interleukin-10 (IL-10) treatment has been shown to have beneficial effects on the depressed immune function in males, but not in females following shock. However, it remains unclear if the observed gender-related effect of IL-10 treatment results in an advantage following subsequent polymicrobial sepsis. To study this, male and female CBA/J mice (age 2-3 months) were subjected to hemorrhage (35 +/- 5 mmHg for 90 min and fluid resuscitation). At resuscitation, each received either 10 microg of recombinant murine IL-10 or placebo i.p.. At 48 h after resuscitation, either peritoneal macrophages (pMphi) and plasma were harvested, or polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Following CLP, either survival over 10 days was measured, or pMphi and plasma were harvested 4 h after CLP to assess TNF-alpha, IL-6, IL-10, and prostaglandin E2 (PGE2) release of pMphi and plasma levels of IL-10, free testosteron, and 17-beta estradiol. Early IL-10 treatment restored depressed proinflammatory immune response in males (TNF-alpha and PGE2), which was associated with an enhanced survival (P < 0.05) following subsequent sepsis as compared with placebo-treated mice (8/20 and 1/20, respectively). In contrast, the immune response and survival in females receiving IL-10 was not significantly changed, although females treated with IL-10 had a trend towards higher mortality (7/15 and 2/15, respectively; P = 0.08). Thus, early IL-10 anti-inflammatory treatment following hemorrhage has potential beneficial effects only in males associated with enhanced survival following subsequent sepsis.     

Sex differences in infection and sepsis

Sex and gender-based differences in responses to infection and sepsis are evident. Estrogens increase immune function, sometimes to the point of inducing autoimmune disease. Testosterone suppresses immune function, sometimes leading to a worsened outcome following traumatic injury. Therapies using sex hormones to improve outcomes after sepsis and hemorrhagic shock and to reduce exacerbations of autoimmune diseases are being studied. Differences in sex hormone levels may not tell the whole story. Studies of immune function in girls and boys before puberty may be helpful. Differences found early might indicate that factors other than estrogen and androgen levels are contributing. Variations in societal role acculturation and exposures that are gender based also may be involved. Clinicians must consider sex and gender when attempting to determine the risk of infection, sepsis, and immune dysfunction in populations. Clinical applications of sex and gender differences are just beginning to occur with the genesis of sex hormone-based treatments. The large-scale efficacy of such treatments has yet to be reported. Innovative strategies based on sex or gender differences in immune responses may soon be available and may lead to essential data for clinical decision making. The impact of sex and gender differences on long-term health outcomes remains to be seen.     

Immunity,inflammation and sepsis: new insights and persistent questions

Sepsis is now understood to affect a variety of changes in the host, chief among them being alterations in immune system function. Proper immune function involves a competent proinflammatory response to stimuli as well as a regulated counteracting force to restore homeostasis and prevent systemic inflammation and organ dysfunction. Broad-spectrum suppression of the inflammatory response has not been shown to be beneficial for patients suffering from septic disease. In fact, sepsis-related immune suppression has become increasingly recognized as an important contributor to late morbidity and mortality in the critically ill. Giamarellos-Bourboulis and colleagues detail the impaired ability of septic patients to produce proinflammatory cytokines upon ex vivo stimulation, and introduce altered caspase-1 activity as potentially contributory to this process. Proper understanding of the cellular and molecular events resulting in immune suppression following sepsis is important in the identification of new strategies for treatment and the ideal timing of therapy.