Compensatory Anti-inflammatory Response Syndrome Research Articles

A comparison of elderly and adult multiple organ dysfunction syndrome in the rat model

Multiple organ dysfunction syndrome (MODS) in the elderly is the most common cause of mortality in critically ill elderly patients, and it is different from MODS in the adult in clinic. Rare studies have been done on its pathogenesis and the comparison between adult and elderly MODS animal models. This work aimed at exploring the mechanisms mediating elderly MODS and compared this with adult MODS. Male Sprague–Dawley aged and adult rats were intraperitoneally injected with zymosan for incitement of MODS. Aged rats receiving zymosan showed severer pulmonary, cardiac and renal dysfunctions than adult rats. Likewise, the tissue lesions under light microscope in major organs of zymosan treated aged rats were much worse than those of zymosan treated adult rats. Moreover, zymosan treated aged rats showed 142% and 64% greater increase in pulmonary alveolar macrophages (AMs) apoptotic rate and serum TNF-α level, respectively, whereas 43% smaller increase in serum IL-10 level compared to zymosan treated adult rats. Furthermore, lung injury was much worse than that in other organs in zymosan treated aged rats. Overall, these results suggest that zymosan can be used in aged rats to incite MODS in the elderly. In the animal model of elderly MODS, there are (1) severer injury in lung, heart and kidney vs adult; (2) easier to develop severe systemic inflammatory response syndrome (SIRS) instead of compensatory anti-inflammatory response syndrome (CARS) compared to the adult; and (3) severer inflammation in lung than other organs indicative of the possible roles of lung in triggering MODS in the elderly.

Postoperative immunosuppression cascade and immunotherapy using lymphokine-activated killer cells for patients with esophageal cancer: Possible application for compensatory anti-inflammatory response syndrome

Immunological parameters were measured in order to elucidate a postoperative immunosuppression mechanism in transthoracic esophagectomy for patients with esophageal cancer. Moreover, lymphokine-activated killer (LAK) cells were transferred just after the surgery to overcome the postoperative immunosuppression. Fifteen consecutive patients who underwent transthoracic esophagectomy were subjected to the postoperative measurement of immunological parameters. Ten patients who underwent open cholecystectomy served as controls. Heparinized venous blood was obtained pre- and postoperatively, and serum levels of cytokines IL-6 and IL-10 and immunosuppressive acidic protein (IAP) were measured. Peripheral blood lymphocytes were harvested and analyzed by flow cytometry for phenotype detection and by a mixed lymphocyte reaction for detecting concanavalin (Con)-A-induced or -non-induced suppressor activity. Another 29 consecutive patients who underwent transthoracic esophagectomy were randomly enrolled in a postoperative immunotherapy trial either with or without lymphokine-activated killer cells. It was found that, in the esophagectomy group, IL-6 and IL-10 increased postoperatively and peaked on day 1, followed by an increase in IAP, peaked again on day 4, with a profound decrease in helper and cytotoxic T-cell subsets, followed by increases in Con-A-induced (on day 7 or later) and spontaneous (on day 10) suppressor activities. These changes were minimal in the cholecystectomy group. LAK cell transfer restored the postoperative decrease in the helper and cytotoxic T-cell population, and there was a trend of reduction for postoperative remote infection such as pneumonia and surgical site infection in the LAK therapy group. Taken together, we would like to propose the existence of a postoperative immunosuppression cascade consisting of increases in cytokines and immunosuppressive proteins, decreases in helper and cytotoxic T-cell populations, and the development of suppressor T-cell activities in surgery for esophageal cancer. Postoperative adoptive transfer of LAK cells may be a novel clinical application in surgery for esophageal cancer as a means of treating this postoperative immunosuppressive condition that may be identical to the status of compensatory anti-inflammatory response syndrome (CARS).

CCL2 as a trigger of manifestations of compensatory anti-inflammatory response syndrome in mice with severe systemic inflammatory response syndrome

Patients with compensatory anti-inflammatory response syndrome (CARS) are at a higher risk for infection with various opportunistic pathogens. CARS develops commonly in association with the manifestation of systemic inflammatory response syndrome (SIRS). In the present study, the role of SIRS-associated soluble factors on the CARS development was examined in mice with pancreatitis, a carrier of typical SIRS. Following the production of SIRS-related cytokines [tumor necrosis factor alpha and interleukin (IL)-1beta], CC chemokine ligand 2 (CCL2), IL-4, and IL-10 (typical CARS cytokines) were detected in the sera of mice with pancreatitis. CCL2 has been described as an essential chemokine for the T helper cell type 2 manifestation. CARS effector cells (cells with an ability to produce IL-4 and IL-10) were not generated from normal T cells after stimulation with SIRS-related cytokines. However, these cells were generated from normal T cells after cultivation with peripheral blood neutrophils (PMN) from SIRS mice in a dual-chamber transwell. Normal T cells did not convert to CARS effector cells after transwell cultures with PMN from normal mice. CCL2 was detected in culture fluids of PMN from SIRS mice, and PMN from normal mice did not produce CCL2 into their culture fluids. CARS effector cells did not appear in PMN-depleted SIRS mice or SIRS mice treated with anti-CCL2 monoclonal antibody, and these cells were demonstrated in PMN-depleted SIRS mice after treatment with recombinant murine CCL2. These results indicate that CCL2 produced by PMN from SIRS mice is an active molecule on the SIRS-associated CARS manifestation.

T-CELL RESPONSE IN TAUROCHOLATE PANCREATITIS IN MICE: CTLA-4 A NEW SEVERITY MARKER FOR ACUTE NECROTISING PANCREATITIS?

Introduction: Acute necrotising pancreatitis is characterised by an overwhelming inflammatory immune response syndrome (SIRS). This could be followed by a compensatory anti-inflammatory response syndrome (CARS) which may facilitate pancreatic infection. Since the role, if any, of T cells in acute pancreatitis has not been defined, we have determined the expression of the inhibitory T-cell surface molecule CTLA-4 (CD152) in murine models of acute pancreatitis. Methods: Pancreatitis was induced in C57BL6 mice either by 7 hourly injections of caerulein (50 μg/h, i.p.) or by retrograde taurocholate (TC) injections into the pancreatic duct (2%, 3% and 4%). All animals were sacrificed after 12 hours. Serum was evaluated for amylase levels and cytokine secretion (TNFα, IFNγ, IL-6, IL-10, IL-12 and MCP-1). Flow cytometry was employed to evaluate T-cell activation. Granulocyte infiltration was detected by MPO activity measurements and GR-1 staining. Apoptosis was detected by direct 3-OH-nick-end-labelling in the thymus. Splenic CTLA-4 expression was either determined by FACS analysis or antibody labelling of cryosections. Results: TC concentrations of 4% resulted in an overall mortality rate of 85% (50% for 3% TC, 0% for 2% TC), while all caerulein treated animals survived. Pro-inflammatory cytokines, as well as granulocyte activation and tissue infiltration were significantly elevated in taurocholate pancreatitis compared to the caerulein model. Thymus cell apoptosis was found to be significantly increased in taurocholate pancreatitis. Furthermore, we observed a linear correlation of increased CTLA-4 expression with mortality. Conclusion: We show that, also in mice, retrograde duct injection with taurocholate is a feasible and gradable model of experimental pancreatitis. When compared to a milder model (caerulein) taurocholate-induced pancreatitis involves T-cell activation and a possible shift from SIRS to CARS as indicated by increased expression of the inhibitory surface molecule CTLA-4. Further studies will need to clarify whether CTLA-4 could serve as a new marker for pancreatitis severity.

Missing effects of zinc in a porcine model of recurrent endotoxemia

BackgroundChronic human sepsis often is characterised by the compensatory anti-inflammatory response syndrome (CARS). During CARS, anti-inflammatory cytokines depress the inflammatory response leading to secondary and opportunistic infections. Proved in vitro as well as in vivo, zinc's pro-inflammatory effect might overcome this depression.MethodsWe used the model of porcine LPS-induced endotoxemia established by Klosterhalfen et al. 10 pigs were divided into two groups (n = 5). Endotoxemia was induced by recurrent intravenous LPS-application (1.0 μg/kg E. coli WO 111:B4) at hours 0, 5, and 12. At hour 10, each group received an intravenous treatment (group I = saline, group II = 5.0 mg/kg elementary zinc). Monitoring included hemodynamics, blood gas analysis, and the thermal dilution technique for the measurement of extravascular lung water and intrapulmonary shunt. Plasma concentrations of IL-6 and TNF-alpha were measured by ELISA. Morphology included weight of the lungs, width of the alveolar septae, and rate of paracentral liver necrosis.ResultsZinc's application only trended to partly improve the pulmonary function. Compared to saline, significant differences were very rare. IL-6 and TNF-alpha were predominately measured higher in the zinc group. Again, significance was only reached sporadically. Hemodynamics and morphology revealed no significant differences at all.ConclusionThe application of zinc in this model of recurrent endotoxemia is feasible and without harmful effects. However, a protection or restoration of clinical relevance is not evident in our setting. The pulmonary function just trends to improve, cytokine liberation is only partly activated, hemodynamics and morphology were not influenced. Further pre-clinical studies have to define zinc's role as a therapeutic tool during CARS.

Damage Control Orthopaedics

In some groups of polytrauma patients, particularly those with chest injuries, head injuries, and those with mangled extremities, early total care of major bone fractures may be potentially harmful. Delaying all orthopaedic surgery, however, is also not always the best approach. In these situations, damage control orthopaedics, which emphasizes the stabilization and control of the injury rather than repair will add little additional physiologic insult to the patient and is a treatment option that should be considered.

Immature anti-inflammatory response in neonates.

The inflammatory response plays a major role in the induction of several neonatal diseases. We hypothesize that an imbalance between the pro- and anti-inflammatory response is crucial for the previously shown enhanced production of proinflammatory cytokines in term and preterm infants during infection. To test this hypothesis, we compared the capacity to produce the main anti-inflammatory cytokines IL-10 and TGF-beta in term infants, preterm infants and adults at different levels of synthesis by quantitative real time reverse-transcribed PCR, flow cytometry, as well as enzyme-linked immunoassay. Term and preterm infants showed a profoundly diminished IL-10 mRNA-expression and IL-10 production after stimulation. In addition, the amount of TGF-beta-positive lymphocytes was significantly less in neonates than adults. Furthermore, there was a considerably lower inhibition of production of IL-1alpha, IL-6, IL-8 and TNF-alpha by the use of recombinant IL-10 in term and preterm infants compared with adults. These results demonstrate not only a diminished anti-inflammatory capacity but also a reduced response to anti-inflammatory stimuli in term and preterm infants. From these data we conclude that neonates display an immature compensatory anti-inflammatory response syndrome (CARS) which may predispose preterm infants to harmful effects of proinflammatory cytokines resulting in severe organ sequelae during infection.

Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing?

Accumulating data suggest that deficiencies in the production of proinflammatory cytokines result in defective activation of the host defense against invading pathogens, and are associated with an increased susceptibility to infections. In this Opinion, we challenge the view that overproduction of proinflammatory cytokines is a major mechanism in the susceptibility to septic shock. By contrast, we propose that innate deficiency in cytokine release during acute severe infections leads to a rapid multiplication of the invading microorganism, leading to a secondary reaction of the host consisting of systemic inflammatory and anti-inflammatory reactions [systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS)], which could ultimately lead to shock and death. In addition, cytokine deficiencies also contribute to susceptibility to infections in some the patients with recurrent or rare infections.

Early postoperative compensatory anti-inflammatory response syndrome is associated with septic complications after major surgical trauma in patients with cancer.

Patients who undergo major surgery for cancer are at high risk of postoperative infection. Postoperative immunosuppression may be due to dysregulation of cytokine production. The aim of this study was to investigate the association between changes in serum proinflammatory and anti-inflammatory cytokine concentrations and postoperative septic complications after major surgery. Serial blood samples were collected from 30 consecutive patients for determination of serum cytokine levels. Healthy volunteers were used as the control group. Eleven patients developed no complications (group 1), 14 developed sepsis or severe sepsis (group 2), and five developed septic shock (group 3). On day 1 the patients in groups 2 and 3 had significantly higher levels of interleukin (IL) 6 than those in group 1. IL-6 levels remained high until day 5. Tumour necrosis factor (TNF), IL-1, interferon (IFN) gamma and IL-12 levels were not affected by surgical trauma or by the occurrence of septic complications. After operation the circulating IL-1 receptor antagonist (IL-1ra) concentration was increased in all groups, but patients in group 3 had significantly higher levels of IL-1ra than those in group 1. IL-1ra levels correlated with IL-6 levels. The pattern of IL-10 levels was similar to that of IL-1ra levels. Serum concentrations of proinflammatory cytokines (TNF, IL-1, IFN-gamma and IL-12) were not affected by operation or the occurrence of septic complications. The postoperative increase in IL-6 concentration was associated with septic morbidity, while raised IL-1ra concentration was associated with postoperative septic shock.

15th Annual Semmelweis Lecture Surgical Infection Society-Europe. Injury-induced immune dysfunction: is the lymphocyte irrelevant?

immune response to serious injury is one of inflammation, which is usually termed the systemic inflammatory response syndrome (SIRS). In patients with major traumatic or thermal injury, SIRS is evident clinically shortly after initial resuscitation. In a significant minority (25–35%) of patients, SIRS persists without respite and may lead directly to the multiple organ dysfunction syndrome (MODS), particularly if infection supervenes [1,2]. In the majority of patients SIRS remits after several days without progression to early MODS. However, the patient may be left with an increased susceptibility to nosocomial infection associated with production of anti-inflammatory mediators by the immune system, a process referred to as the compensatory anti-inflammatory response syndrome (CARS) [3]. Invasive infection occurring during this period may again induce systemic inflammation, which in turn may lead to the multiple organ dysfunction syndrome (late MODS). Organ dysfunction both early and late is associated with substantial mortality [1,2]. Since cells of the innate immune system are the chief source of inflammatory mediators and cellular and humoral components of innate immunity are major effectors in the early defense against invading microorganisms, it is not surprising that the majority of research into the immune consequences of injury has focused on the innate immune system. The adaptive immune system, by contrast, ordinarily responds only when activated by antigen-presenting cells of the innate immune system. Whereas the T-cell receptors and antibodies of the adaptive immune system demonstrate amazing diversity and exquisite precision for individual antigenic epitopes, several days of clonal expansion following initial activation are ordinarily required for a significant response to become evident. Thus, at first glance, the adaptive immune system appears to be ill suited to play a role in host defense early after injury, although later participation might be anticipated. Yet, the macrophages and dendritic cells of the innate immune system and the Tand B-lymphocytes of the adaptive immune system are in intimate contact with one another in the secondary lymphoid organs and mucosa-associated lymphoid tissue. Thus, interactions between the two immune systems are continuous and likely to be of biological significance after injury as well as in the uninjured state. I will attempt to summarize the available evidence that the T-cells and B-cells of the adaptive immune system and their products participate along with the innate immune system in both the SIRS and CARS responses following major injury. The pivotal cell in the adaptive immune sysSURGICAL INFECTIONS Volume 3, Number 4, 2002 © Mary Ann Liebert, Inc.

From SIRS and CARS to SLIRS and LISIS - New concepts for understanding the development of organ failure after clinical insults

In the early phase after clinical insults (planned and unplanned injuries), both local and systemic inflammatory responses occur in the body. These are biological defense responses to insults. These responses are indispensable for the survival of organisms and therefore, have delicate backup, fail-safe, and feedback systems. The activation of the feedback system for locally-induced proinflammatory cytokines results in the predominance of anti-inflammatory cytokines in the systemic circulation. The more marked local inflammatory responses are, the more severe systemic anti-inflammatory responses become. To understand the vulnerable state of organ failure after insults, the author proposes to classify the pathologic condition after insults into SLIRS (systemic and local inflammatory response syndrome) in the early phase and LISIS (local inflammation-induced systemic immunosuppression syndrome) in the subsequent phase to avoid confusion with previous held concepts of SIRS (systemic inflammatory response syndrome) and CARS (compensatory anti-inflammatory response syndrome). The development of post-insult organ failure should be considered in terms of the course with time and both local and systemic states. Uniform measures for mediators are inadequate.

The Systemic Inflammatory Response to Cardiac Surgery

The Systemic Inflammatory Response to Cardiac Surgery

The immunologic response to injury

Research on the immune consequences of shock and trauma by multiple laboratories over more than 20 years has resulted in the following paradigm, which is currently accepted by most investigators in this field: serious traumatic or thermal injury is quickly followed, after initial resuscitation, by the systemic inflammatory response syndrome (SIRS) which, in a sizeable minority of patients, will lead inexorably to multiple organ dysfunction syndrome (early MODS), with an attendant high mortality. The majority of seriously injured patients survive the initial SIRS response without developing early MODS, and after a period of relative clinical stability, manifest a compensatory antiinflammatory response syndrome (CARS) with suppressed immunity and diminished resistance to infection. Resultant infection and its attendant inflammation in turn can lead to multiple organ dysfunction (late MODS) and death (Fig. 1). This paradigm has several implications of potential importance in interpreting the sometimes conflicting results of research in this area:

Sepsis syndromes: understanding the role of innate and acquired immunity.

An intact innate and acquired immune response are essential for defeating systemic microbial infections. Recognition molecules, inflammatory cells, and the cytokines they produce are the principal means for host tissues to recognize invading microbes and to initiate intercellular communication between the innate and acquired immune systems. However, activation of host innate immunity may also occur in the absence of microbial recognition, through expression of internal "danger" signals produced by tissue ischemia and necrosis. When activation of the innate immune system is severe enough, the host response itself can propel the patient into a systemic inflammatory response syndrome (SIRS), or even multiple system organ failure (MSOF) and shock. Although most patients survive the initial SIRS insult, these patients remain at increased risk of developing secondary or opportunistic infections because of the frequent onset of a compensatory anti-inflammatory response syndrome (CARS). The initial activation of the innate immune response often leads to macrophage deactivation, T-cell anergy, and the rapid apoptotic loss of lymphoid tissues, which all contribute to the development of this CARS syndrome and its associated morbidity and mortality. Initial efforts to treat the septic patient with anticytokine therapies directed at the SIRS response have been disappointing, and therapeutic efforts to modify the immune response during sepsis syndromes will require a more thorough understanding of the innate and acquired immune responses and the increased apoptosis in the lymphoid tissue.

Role of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in brain-mediated compensatory antiinflammatory response

Local infection or trauma induce a local inflammatory response. The release of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 activates an inflammatory cascade improving wound healing and antimicrobial defence. Overwhelming response, however, can result in systemic inflammatory response syndrome (SIRS) and septic shock. In order to control the potentially harmful inflammatory response, the immune system can release several antiinflammatory mediators like IL-10, IL-1 receptor antagonist (ra), and soluble TNF-α receptors. TNF-α, IL-1β and prostaglandins by themselves are powerful inducers of the compensatory antiinflammatory response syndrome (CARS). However, there are evidences that in addition to the autoregulatory pathways of the immune cells the delicate balance between pro- and antiinflammatory response is controlled by central mechanisms. Hence, a bidirectional communication between the immune and central nervous system (CNS) exists and is most evident in the increase in secretion of different neuromodulators and neurohormones that follows systemic inflammation. Moreover, in vitro studies demonstrate that these neuromediators, especially glucocorticoids and catecholamines, predominantly decrease the secretion of proinflammatory cytokines (IL-1, IL-6 and TNF-α) and increase the release of antiinflammatory mediators like IL-10 and transforming growth factor-β. Consequently, the activation of the neuroimmune pathways reduces the intensity of the immune response and prevents an overwhelming inflammatory immune reaction. If the immunoinhibitory CNS pathways are activated without systemic inflammation, however, a brain-mediated immunodepression can develop. This activation can result from the production of cytokines in the brain following infection, injury, and ischemia or in response to different stressors (life events, depression, anxiety etc) or directly from brain stem irritation. In summary, mediators of the CNS are implicated in the regulation of immune functions and play a role in both conditioning the host's response to endogenous or exogenous stimuli and generating a brain-mediated immunodepression. Biomedical Reviews 2000; 11: 29-38.

Leukocyte activation in sepsis; correlations with disease state and mortality.

The immune response in sepsis shows a bimodal pattern consisting of an early, frequently exaggerated inflammatory response followed by a state of hyporesponsiveness often referred to as the compensatory anti-inflammatory response syndrome (CARS). Insight into the disease state may be helpful in deciding whether to choose immune stimulatory or anti-inflammatory therapy in these patients and may determine clinical outcome. We hypothesized that poor outcome in patients with sepsis is related to the severity of CARS, as reflected in the degree of leukocyte activation. Prospective study. Intensive and respiratory care unit at a university hospital. Twenty consecutive patients with sepsis and 20 healthy age-matched volunteers. None. Analysis of surface expression of HLA-DR, CD11b, ICAM-1, CD66b, CD63 and CD64 on neutrophils and monocytes by flow cytometry and determination of plasma concentrations of lactoferrin, interleukin 6 and neopterin by ELISA at the time of diagnosis. Patient data were related to those of controls; moreover patient data between survivors and non-survivors were compared. Increased expression of all markers, except HLA-DR, was observed on both neutrophils and monocytes from patients compared to healthy controls. HLA-DR expression on monocytes was significantly decreased in patients with sepsis (p < 0.01). Expression of CD11b and HLE on neutrophils, and ICAM-1 on monocytes, were lower in patients who died compared to those who survived (p < 0.05). In sepsis, both neutrophils and monocytes are activated compared to healthy controls. Poor prognosis is associated with a lower expression of activation markers on monocytes and neutrophils, suggesting that poor outcome in these patients may be due to the compensatory anti-inflammatory response.

Leukocyte activation and cytokine production during experimental human endotoxemia

Background: At present, it is unclear whether in experimental endotoxemia, the pro-inflammatory response observed in healthy volunteers is followed by an anti-inflammatory response, as observed in patients with sepsis. We studied the evolution of a number of inflammatory parameters during a prolonged period (24 h) after infusion of endotoxin in healthy subjects. Methods: Six healthy male subjects received an infusion of endotoxin (4 ng/kg body weight). Blood was drawn before, and at various intervals up to and including 24 h after, endotoxin infusion. Circulating cytokine levels, leukocyte activation surface markers, plasma lactoferrin, and neopterin levels were measured, and clinical signs and symptoms were noted during a 24-h period. Monocyte and neutrophil activation after endotoxin infusion is investigated in relation to the inflammatory response. The extent of neutrophil and monocyte activation was correlated to clinical markers and blood levels of inflammatory mediators and cytokines. Results: Tumor necrosis factor-α appeared 30 min after infusion in the circulation, peaking (5665±1910 pg/ml) at 2 h. Interleukin-10 appeared 60 min after infusion, peaking (427±348 pg/ml) at 3 h. The expression of leukocyte activation markers increased significantly after infusion. Expression of HLA-DR on monocytes decreased significantly after 3 h ( P=0.03). There was a correlation between the TNF-α:IL-10 ratio and the CD11b:HLA-DR ratio ( P=0.03). Conclusions: During experimental human endotoxemia, an initial pro-inflammatory response is successfully compensated by an anti-inflammatory response, leading to homeostasis. This is in contrast to what happens in septic patients with compensatory anti-inflammatory response syndrome. The inflammatory balance, expressed as the cytokine pro:anti-inflammatory ratio, is reflected at a cellular level.

Immunomodulatory therapies in sepsis.

Despite advances in critical care medicine, mortality from sepsis in ICU patients remains high. In response to several infectious and non-infectious stimuli, monocytes/ macrophages release a number of mediators, including cytokines, involved in the proinflammatory response that underlies sepsis. The excessive release of these mediators results in the development of whole body inflammation, and plays an important role in the pathogenesis of sepsis and septic shock. In addition, patients with sepsis also undergo an anti-inflammatory phase (the compensatory anti-inflammatory response syndrome) and at times, a mixed response with both pro-and anti-inflammatory components (the mixed antagonistic response syndrome). The initial systemic hyperinflammation is caused by production of inflammatory cytokines, especially tumour necrosis factor-a (TNF-alpha), and also interleukin-1 (IL-1), IL-6, and interferon gamma, which act synergistically with TNF-alpha in inducing shock in animal models. However, clinical trials aimed at downregulating these mediators using antibodies against endotoxin, TNF-alpha, antagonists of IL-1 or platelet activating factor have proved to be uniformly disappointing. Not only have these agents been found to have no effect, but they may also increase mortality. One of the reasons for such failure may be the lack of precise immunological monitoring during the course of sepsis. We have recently demonstrated that sepsis shows a biphasic immunological pattern during the initial and later phase: the early hyperinflammatory phase is counterbalanced by an anti-inflammatory response which may lead to a hypoinflammatory state. The latter is associated with immunodeficiency that is characterised by monocytic deactivation, so-called immunoparalysis. Interferon gamma-1 b has an immunoregulatory effect in patients with immunoparalysis during the compensatory anti-inflammatory response syndrome, not only restoring levels of HLA-DR expression but also reestablishing the ability of monocytes to secrete cytokines such as TNF-alpha. By monitoring immune status in septic patients, targeted intervention may lead to more success in immunomodulation of sepsis.

Mechanisms of brain-mediated systemic anti-inflammatory syndrome causing immunodepression.

Overwhelming inflammatory immune response can result in systemic inflammation and septic shock. To prevent excessive and deleterious action of proinflammatory cytokines after they have produced their initial beneficial effects, the immune system can release several anti-inflammatory mediators, including interleukin-10, interleukin-1 receptor antagonist, and soluble tumor necrosis factor receptors, thus initiating a compensatory anti-inflammatory response syndrome. However, in vivo the delicate balance between pro- and anti-inflammatory responses is additionally controlled by the central nervous system. Therefore, proinflammatory cytokines stimulate the hypothalamic-pituitary-adrenal axis and enhance sympathetic nerve system activity. The mediators of these neuroimmune pathways can again suppress immune cell functions to control systemic inflammation. The question is, however, what happens if the immunoinhibitory CNS pathways are activated without systemic inflammation? This can result from production of cytokines in the brain following infection, injury, or ischemia or in response to various stressors (e.g., life events, depression, anxiety) or directly from brainstem irritation. The answer is that this may generate a brain-mediated immunodepression. Many animal and clinical studies have demonstrated a stress and brain cytokine mediated decrease in the cellular immune response at the lymphocyte level. More recently, the importance of monocytes in systemic immunocapacity has been shown. Monocytic inactivation with decreased capability of antigen presentation and depressed secretion of proinflammatory cytokines increases the risk of infectious complications. Interestingly, cytokines in the brain and other stressors can also generate systemic immunodepression at the monocyte level. In this scenario the catecholamine-induced release of the potent anti-inflammatory cytokine interleukin-10 is a newly discovered mechanism of the brain-mediated monocyte deactivation in addition to the "well known" immunosuppressive action of glucocorticoids. Furthermore, other neuropeptides such as alpha-melanocyte-stimulating hormone and beta-endorphin which can be released in stressful situations have also inhibitory effects on immune cells. Thus mediators of the CNS are implicated in the regulation of immune functions and may play a role in both conditioning the host's response to endogenous or exogenous stimuli and generating a "brain-mediated" immunodepression.

The central role of monocytes in the pathogenesis of sepsis: consequences for immunomonitoring and treatment

Despite important advances in critical care medicine during the last two decades, the mortality rate of sepsis has remained high, probably because the pathogenesis of sepsis is still incompletely understood. Recent studies have shown that sepsis is a bimodal entity. The first phase is characterized by the systemic release of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-8, and by activation of the complement and coagulation cascades. In the second phase, anti-inflammatory mediators such as transforming growth factor-β (TGF-β), IL-10 and prostaglandin E2 (PGE2) may be released in an effort to counteract ongoing inflammation. Depending whether the pro- or anti-inflammatory response predominates, sepsis results in a systemic inflammatory response syndrome (SIRS), or a compensatory anti-inflammatory response syndrome (CARS). So far, most efforts to intervene in the immunopathogenesis of sepsis have been directed at the pro-inflammatory response. None of these interventions has been shown to improve the prognosis of sepsis, possibly because many patients were already in a state in which anti-inflammatory responses dominated.Recently, it has been shown that decreased expression of HLA-DR on monocytes in patients with sepsis constitutes a marker for CARS. We suggest that HLA-DR expression on monocytes might constitute a useful indicator of the immunological status of the individual patient with sepsis and a guide for treatment. Patients with CARS, as manifested by low HLA-DR expression, might benefit from immunostimulants, while patients with SIRS and normal or high monocyte HLA-DR expression should receive treatment directed to interfere with pro-inflammatory pathways.