Prostaglandins and the inflammatory response

Prostaglandins not only mediate the classic signs of inflammation but also help to regulate the function of cellular constituents in an inflammatory reaction. Clinical and experimental evidence of the role of prostaglandins as mediators is highlighted.     

Genetic determinants of the inflammatory response

PURPOSE OF REVIEW: Despite substantial advances in our understanding of the biology of sepsis and inflammation, improvements in clinical outcomes have been more sporadic and, with few notable exceptions, are related to improvements in supportive care rather than to specific therapies. As a result, morbidity, mortality, and cost remain high. Investigation into the genetic determinants of this response span a broad spectrum and include those aimed at deciphering the mechanisms and involved pathways on a molecular level, to those aiming to identify how genetic variation may be clinically important. While it is clear that gene sequencing and manipulation of experimental models have provided insight into the biology of the inflammatory response to infection, these technologies and their application to the study of naturally occurring human genetic variation have yet to provide the same insight or clinical benefit. The purpose of this review is to summarize what is known about the genetic determinants of the inflammatory response. We make particular reference to this broad scope of investigation introduced above but with a focus on the present status of studies examining the role of human genetic variation in the risk for and outcome from severe bacterial infection, or sepsis. RECENT FINDINGS: Using the examples of two candidate genes tumor necrosis factor-alpha (TNF-alpha) and toll-like receptor 4 (TLR4), we illustrate the spectrum of studies concerning the genetic determinants of the inflammatory response. We highlight recent literature across this spectrum, focusing on genetic association studies examining the relationships between SNPs in these genes and sepsis risk and outcome. We then review the literature addressing discordant findings in basic experimental observations and studies of clinical association. SUMMARY: Naturally occurring genetic variants in important inflammatory mediators such as TNF-alpha and TLR4 appear to alter inflammatory responses in numerous experimental and a few clinical models of inflammation. However, inconsistencies exist in the literature regarding the association between these genetic variants and disease (eg, sepsis) susceptibility and prognosis. The main limitations relate to the translation of experimental observations into reproducible genotype-phenotype associations. The reasons for these are multifactorial and include deficiencies in study design (insufficient sample size), and the complexities introduced by background genetic heterogeneity.     

Burn size determines the inflammatory and hypermetabolic response

Background  

Increased burn size leads to increased mortality of burned patients. Whether mortality is due to inflammation, hypermetabolism or other pathophysiologic contributing factors is not entirely determined. The purpose of the present study was to determine in a large prospective clinical trial whether different burn sizes are associated with differences in inflammation, body composition, protein synthesis, or organ function.     

The epidemiology of the systemic inflammatory response

Objective: To examine the incidence, risk factors, aetiologies and outcome of the various forms of the septic syndromes (the systemic inflammatory response syndrome [SIRS] sepsis, severe sepsis, and septic shock) and their relationships with infection.¶Design: Review of published cohort studies examining the epidemiology of the septic syndromes, with emphasis on intensive care unit (ICU) patients.¶Results: The prevalence of SIRS is very high, affecting one-third of all in-hospital patients, and > 50 % of all ICU patients; in surgical ICU patients, SIRS occurs in > 80 % patients. Trauma patients are at particularly high risk of SIRS, and most these patients do not have infection documented. The prevalence of infection and bacteraemia increases with the number of SIRS criteria met, and with increasing severity of the septic syndromes. About one-third of patients with SIRS have or evolve to sepsis. Sepsis may occur in approximately 25 % of ICU patients, and bacteraemic sepsis in 10 %. In such patients, sepsis evolves to severe sepsis in > 50 % of cases, whereas evolution to severe sepsis in non-ICU patients is about 25 %. Severe sepsis and septic shock occur in 2 %–3 % of ward patients and 10 %–15 % or more ICU patients, depending on the case-mix; 25 % of patients with severe sepsis have shock. There is a graded severity from SIRS to sepsis, severe sepsis and septic shock, with an associated 28-d mortality of approximately 10 %, 20 %, 20 %–40 %, and 40 %–60 %, respectively. Mortality rates are similar within each stage, whether infection is documented or not, and microbiological characteristics of infection do not substantially influence outcome, although the source of infection does. While about three of four deaths occur during the first months after sepsis, the septic syndromes significantly impact on long-term outcome, with an estimated 50 % reduction of life expectancy over the following five years. The major determinants of outcome, both short-term and long-term, of patients with sepsis are the severity of underlying diseases and comorbidities, the presence of shock and organ failures at onset of sepsis or evolving thereafter. It has been estimated that two-thirds of the overall mortality can be attributed to sepsis.¶Conclusions: The prevalence of sepsis in ICU patients is very high, and most patients have clinically or microbiologically documented infection, except in specific subset of patients. The prognosis of septic syndromes is related to underlying diseases and the severity of the inflammatory response and its sequelae, reflected in shock and organ dysfunction/failures.     

Mathematical models of the acute inflammatory response

PURPOSE OF REVIEW: Trauma and infection elicit an acute inflammatory response. In certain circumstances the degree of the acute inflammatory response may result in pathologic manifestations, namely, sepsis and multiple organ failure. Despite an extensive series of clinical trials designed to modulate inflammation in sepsis, only one compound, activated protein C, has emerged from more than 250 failed trials. There is a growing recognition that the complexity of the acute inflammatory response precludes the efficient development of therapies for sepsis and multiple organ failure until systems approaches are brought to bear on this problem. RECENT FINDINGS: Work carried out by the authors' groups suggests that mathematical modeling can provide a means by which in vitro and in vivo data can be synthesized into system-level analytic models of the acute inflammatory response. The authors have focused on agent-based modeling and modeling with ordinary differential equations. Some of the advantages and disadvantages of these modeling approaches are presented, and methods for calibration and validation of these models are discussed. Finally, the usefulness of mathematical models to evaluate the prospective therapeutic strategies in clinical trials of sepsis and trauma is examined. SUMMARY: Simulations using various methods can shed insight into the pathophysiology of the acute inflammatory response and may lead to better design of clinical trials in sepsis and trauma.     

Mechanisms of the systemic inflammatory response.

The purpose of inflammation is to combat various agents that may injure the tissues. Conditions such as CPB can often cause systemic inflammation and dysfunction of major organs. Pulmonary, renal, myocardial and intestinal function may suffer various degrees of impairment during and after cardiac surgery. Although changes in major organs usually remain clinically insignificant, severe organ failure is not uncommon. The process of systemic inflammation proceeds through activation of serum proteins, activation of leucocytes and endothelial cells, secretion of cytokines, leucocyte-endothelial cell interaction, leucocyte extravasation and tissue damage. Several anti-inflammatory strategies have already been used, some of which have given promising results pertaining to further reduction in the rate of the inflammation-related complications in cardiac surgical patients.     

Neutropenia and the development of the systemic inflammatory response syndrome

OBJECTIVE: To determine outcome and natural course of systemic inflammatory response syndrome (SIRS) stages in adult febrile neutropenic patients. DESIGN AND SETTING: Retrospective cohort study in the medicine department and intensive care unit of a university hospital. PATIENT: Adults with cancer-related neutropenia and community-acquired fever. MEASUREMENTS AND RESULTS: Patients were classified on admission according to SIRS parameters, tumor type, and degree of neutropenia. Records of clinical and laboratory data during hospitalization were reviewed. Univariate and logistic regression analyses were performed. Seventy-nine events in 62 patients were analyzed. Overall mortality rate was 20.2% (16/79). Mortality increased as SIRS stage worsened on admission. No patients with stage 2 SIRS died (neutropenia and fever alone) but 11.1% of patients with SIRS 3, 43.4% with SIRS 4, 66.6% with sepsis induced hypotension, and 90% with septic shock. SIRS stage on admission was an independent predictor of death and was related directly to rate of progression to shock, i.e., none of the patients with SIRS 2, 2.7%(1/36) of those with SIRS 3, and 30.4% (7/23) of those admitted with SIRS 4. CONCLUSIONS: Mortality and progression to septic shock increased as more SIRS criteria were met on admission. SIRS stages could serve as a risk-assessing model in febrile neutropenic patients.     

Polymorphisms related to SIRS and inflammatory response

Recently, susceptibility and outcome of disease are proved to depend on some gene polymorphisms. Here, we review of gene polymorphisms and its contributions to systemic inflammatory response syndrome (SIRS) and inflammation. The relationships of many polymorphisms, such as TNF, IL-1, PAI-1, TLR, etc. and infections have been studied. Gene polymorphisms of some cytokines are reported to increase expression and production of these cytokines, prevalence rate, morbidity and mortality. These polymorphism informations will be very useful for the prevention and therapy in infected diseases, and recognition of patients that need intensive therapy. From analysis of each patient's gene polymorphism, therapy will be changed case by case. Judging from the difference of races and polymorphisms, Japanese need multi-center large scaled studies in Japan.     

Clopidogrel-induced systemic inflammatory response syndrome

Clopidogrel bisulfate, a widely used inhibitor of platelet aggregation, is considered at least as safe as aspirin. We describe a patient who developed a systemic inflammatory response syndrome consisting of high fever, tachycardia, cellulitis-like rash, impaired liver function, and mild leukopenia after receiving clopidogrel before coronary angiography and stent implantation. The reaction resolved promptly after withdrawal of the drug and recurred shortly after a rechallenge dose was administered, thus making the diagnosis of a clopidogrel-induced reaction highly probable. Recognition of this clopidogrel-induced syndrome is extremely important, both for rapid discontinuation of the offending drug and for avoidance of unnecessary drug therapy or invasive procedures.     

The inflammatory response to surgery and trauma

PURPOSE OF REVIEW: The inflammatory or stress response to injury has evolved to ensure survival. This review will examine this response in otherwise healthy patients. Additionally, the impact of several common comorbid conditions on the inflammatory response will be considered. What will become evident is that the stress response may be exaggerated in some conditions and suppressed in others. Rapid identification of both an abnormal response and its cause will allow clinicians to maximize a patient's healing potential. RECENT FINDINGS: Recent work has shown that an altered inflammatory response has marked effects on both immune competence and the endocrine system. Investigations are ongoing to delineate the mechanism of lymphocyte dysfunction. With regard to critical care endocrinopathies, the effects of insulin and hyperglycemia on inflammation and wound healing are being investigated. SUMMARY: An understanding of the stress response will aid the clinician in preparing for expected responses, recognizing and perhaps correcting deviations from the norm and accounting for potential complications that arise in the face of preexisting disease. Deviations from the normal time course may represent the effects of preexisting medical illness, treatment or postoperative/injury complications.     

Procoagulant and inflammatory response of virus-infected monocytes

BACKGROUND: Monocytes play a prominent role in inflammation, coagulation and atherosclerosis by their ability to produce tissue factor (TF) and cytokines. The aim of the present study was to establish whether virus-infected monocytes initiate coagulation. In addition, the production of cytokines by monocytes may accelerate the chronic process of atherosclerosis and may contribute to coronary syndromes by eliciting plaque instability. MATERIALS AND METHODS: Monocytes were isolated by Vacutainer(R), BD Biosciences, Alphen aan den Rijn, Netherlands and subsequent magnetic cell sorting (MACS(R), Milteny Biotec, Bergish Gladbach, Germany). Coagulation times in normal pooled plasma and Factor VII-deficient plasma were measured after infection with cytomegalovirus (CMV), Chlamydia pneumoniae (Cp) and influenza A\H1N1. Anti-TF antibodies were added to neutralize TF expressed on monocytes. Interleukins (IL) 6, 8 and 10 were measured in the supernatants. RESULTS: Chlamydia pneumoniae- and CMV-infected monocytes decreased the clotting time by 60%, and influenza-infected monocytes by 19%, as compared to uninfected monocytes. Procoagulant activity was absent when Factor VII-deficient plasma or anti-TF antibodies were used. Monocytes produced both IL-6 and IL-8 after infection with CMV (317 pg mL-1 and 250 pg mL-1) or Cp (733 pg mL-1 and 268 pg mL-1). Similar results were obtained for influenza virus-infected monocytes, but the levels of both cytokines were 3-5-fold higher (1797 pg mL-1 and 725 pg mL-1). Interleukin-10 was not produced by infected monocytes. CONCLUSION: The procoagulant activity of virus-infected monocytes is TF-dependent. Although influenza infection did not generate a significant reduction in clotting time, the pronounced expression of IL-6 and IL-8 may induce local and/or systemic inflammatory reactions, which may be associated with plaque rupture and atherosclerosis. The lack of production of the anti-inflammatory cytokine IL-10 may even accelerate these processes.     

Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy

Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.During normal aging, there are significant alterations in immune functions and tissue responses to stimuli. Aging is associated with a low-grade proinflammatory state and a diminished capacity to mount specific adaptive immune responses resulting in susceptibility to pathology after infectious episodes (Boparai and Korc-Grodzicki, 2011). Immunotherapy (IT) in the treatment of cancer has recently resulted in significant clinical responses and is being increasingly applied (Dougan and Dranoff, 2009). However, as cancer also predominantly occurs within the elderly population (Repetto and Balducci, 2002), these immune alterations that occur with aging potentially also render cancer patients more likely to be susceptible to systemic toxicities after application of systemic IT or in response to infection (Repetto and Balducci, 2002; Brüünsgaard and Pedersen, 2003; Ferrucci et al., 2005; Franceschi, 2007; Chung et al., 2009). Elevated serum levels of proinflammatory cytokines, such as IL-1α, IL-1β, IL-6, and TNF, have been observed with increasing age and are believed to be due to an age-related redox imbalance that activates multiple proinflammatory signaling pathways (Franceschi et al., 2000; Brüünsgaard and Pedersen, 2003; Ferrucci et al., 2005; Chung et al., 2009). The mechanisms underlying the causes and contributors to the age-related proinflammatory state remain unclear. Of concern is that the majority of preclinical studies assessing potential immunotherapeutic regimens use younger mice, which likely fail to replicate human clinical cancer treatment conditions with regard to age. Therefore, understanding the impact of age on IT responses and outcome is critical as significant toxicities can be observed with systemic IT (McInnes et al., 1997; Suntharalingam et al., 2006; Waldmann, 2006; Berger et al., 2009; Attarwala, 2010; Di Giacomo et al., 2010; Weber et al., 2012).Our studies demonstrate that as opposed to young mice, applying systemic IT in aged mice resulted in rapid and lethal responses due to the induction of a proinflammatory cytokine storm and multiorgan pathology. The elevated cytokine responses occurred with numerous immunostimulatory regimens with proinflammatory cytokine production being mediated by macrophages. TNF was a critical mediator for the increased morbidity, as TNF blockade resulted in partial protection from these lethal systemic toxicities and pathology. Application of TNF blockade also led to successful administration of IT while preserving anti-tumor responses in aged mice. These data indicate that aging results in a heightened predisposition to inflammatory responses by macrophages, which leads to increased susceptibility to multiorgan pathology upon challenge.