Compensatory Anti-inflammatory Response Research Articles

What is the pathophysiology of the septic host upon admission?

The enormous case-fatality rate of severe sepsis and septic shock has resulted in considerable efforts being made towards understanding their complex mechanisms of pathogenesis. This has been done with the hope that agents that interfere with the pathways of pathogenesis and modulate the immune response of the host may be candidates for therapy. Disappointing results from most trials of immunomodulators in sepsis have led to understanding that the progression of patients to multiple organ dysfunction syndrome involves blunting of the pro-inflammatory cytokine storm. Instead, the compensatory anti-inflammatory response syndrome (CARS) develops, which is characterised by immunoparalysis. Components of this syndrome are impaired phagocytosis by neutrophils, decreased expression of HLA-DR on monocytes, impairment of ex vivo cytokine stimulation of monocytes, CD4 lymphopenia due to apoptosis of lymphocytes and predominance of anti-inflammatory T h2 and regulatory T-cell responses over pro-inflammatory T h1 and T 17 responses. CARS is not the sole explanation for the failure of trials of immunomodulators in sepsis. Recent data from the Hellenic Sepsis Study Group demonstrate that components of CARS upon transition from sepsis to severe sepsis/shock differ in relation to the underlying type of infection. These data underscore that the pathogenesis of sepsis presents considerable heterogeneity from one patient to another. That heterogeneity should be taken into consideration when deciding to administer an immunomodulator.

P22 Derangements in energy, amino-acid and gut microbial metabolism in hepatic encephalopathy: a metabolomic approach

IntroductionHepatic encephalopathy (HE) pathogenesis is related to gut microbial products, which lead to deranged cerebral bioenergetics. Biofluid MR spectroscopy (MRS) can be used to determine changes in bioenergetics, gut microbial...

Admission levels and early changes in serum interleukin-10 are predictive of poor outcome in acute liver failure and decompensated cirrhosis

Immunoparesis contributes to prognosis in acute liver failure (ALF) and decompensated cirrhosis, a phenomenon thought to be mediated by the anti-inflammatory cytokine interleukin (IL)-10. We investigated the prognostic value of admission IL-10 levels and their evolution during the early phase of treatment in intensive care, in comparison to the pro-inflammatory cytokines IL-6 and tumour necrosis factor (TNF)-alpha. We measured these cytokines within 48 h of admission in 51 ALF and 39 decompensated cirrhosis patients admitted to intensive care, and obtained follow-up measurement a median of 2 days later in 35 patients. Levels of all cytokines were higher in those with a poor outcome. IL-10 performed as well as TNF-alpha and IL-6 in the whole cohort (area under receiver operator curve 0.73 vs 0.66 and 0.72). However IL-10 outperfomed pro-inflammatory cytokines in the subgroups with ALF (0.80 vs 0.63 and 0.70) and acetaminophen-induced ALF (0.92 vs 0.67 and 0.81). Levels of all cytokines rose significantly in non-surviving patients (n=15); IL-10 by a factor of 2, TNF-alpha by 2.6 and IL-6 by 1.13. No significant changes were seen in the surviving patients. In ALF, IL-10 was an independent predictor of outcome in multivariate analysis. The magnitude of the compensatory anti-inflammatory response at admission, and its development during the early phase of treatment, predicts outcome as well as the pro-inflammatory response in acute hepatic syndromes and supports a vital role for this immunological phenomenon in the outcome of these patients.

PWE-056 A compensatory anti-inflammatory response syndrome triggered by neutrophil-induced oxidative stress is associated with chronic low grade hepatic encephalopathy in patients with advanced cirrhosis

Introduction The systemic inflammatory response syndrome (SIRS) exacerbates hepatic encephalopathy (HE) in patients with cirrhosis. SIRS is a proinflammatory response tasked with killing infectious organisms through activation of the immune system, whereas CARS is a global deactivation of the immune system aimed at restoring homeostasis. The timing and magnitude of CARS may impact on patient outcomes. This study aimed to characterise the relationship between neutrophil oxidative stress, plasma cytokine profile and ammonia in a cohort of patients with advanced cirrhosis undergoing assessment for liver transplantation (LT). Patients specifically referred for LT with chronic HE (n=7) were compared to those who had no history of overt HE (n=17) and healthy controls (HC) (n=8). Methods Neutrophils were isolated at the time of LT assessment and 72 h following LT (n=6/24). Quantification of spontaneous oxidative burst (OB) was determined by measuring the percentage of neutrophils producing reactive oxidants at rest. Formation of oxidative reactants was monitored by oxidation of dihydrorhodamine (DHR 123) to rhodamine. To identify neutrophils, cells were stained with anti- CD16-PE IgG1 and analysed by flow cytometry. Clinical data, blood biochemistry, arterial ammonia and a full set of microbial cultures were collected. Cytokine analysis for TNF-α, IL-1s, IL-6, IL-8, IL-10 and IL-17 were performed by ELISA. Results There were no differences in MELD score, neutrophil count, ammonia (p=0.85) or empirical antibiotic use between those with chronic HE and those without. Neutrophil spontaneous OB was elevated in those with HE (30% (9–77) vs 13% (9–41), p=0.04) compared to those without. Patients with chronic HE had markedly decreased proinflammatory cytokines (TNF-α, p=0.02; IL-6, p=0.009 and IL-17, p=0.01) compared to those without HE but not the neutrophil-specific cytokine IL-8, upregulated in response to oxidative stress. The anti-inflammatory cytokine IL-10 was low in patients with HE compared to those without HE (6 (5–65) vs 207 (34–369) pg/ml, p=0.02) and HCs. Cirrhotic cytokine profiles and elevated spontaneous OB returned to HC levels post-LT. Conclusion These data suggest that patients with advanced cirrhosis and chronic HE have neutrophil-induced oxidative stress which triggers CARS rather than SIRS with time. IL-10 may protect against chronic HE and oxidative stress.

Immune depression in musculoskeletal trauma

The immune responses after musculoskeletal trauma are physiological reactions of the organism to restore homeostasis. An imbalance between the early systemic inflammatory response syndrome and the later compensatory anti-inflammatory response syndrome may be responsible for organ dysfunction and increased susceptibility to infections. Cytokines are known to be integral components of the immune response, and the balance or imbalance of the different cytokines partly controls the clinical course in the patients. The major pro-inflammatory cytokines include tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and IL-8. These cytokines are predominantly produced by monocytes and macrophages, they mediate overlapping effects, and their actions can be additive. TNF-alpha and IL-1beta are early regulators of the immune response, and both induce the release of secondary pro-inflammatory cytokines. IL-10 is an anti-inflammatory cytokine which reduces the synthesis of pro-inflammatory mediators. The extent of traumatic damage correlates with the immunological changes and determines a graded depression of leucocytes to express cytokines on edotoxin exposure. Correspondingly, it has become clinically evident that in unstable traumatised patients, the recommendation today is damage control orthopaedics, i.e. initial stabilisation of long bone fractures by external fixation followed by definitive stabilisation at about 1 week.

Importance of the compensatory anti‐inflammatory response following severe sepsis on cirrhosis†

The recent review by Gustot et al.1 did not emphasize the important, common, and frequently lethal phase of illness that is immunoparesis, caused by the compensatory anti-inflammatory response syndrome (CARS). A term coined by Bone et al.,2 CARS describes prolonged elevations in anti-inflammatory mediators and immune dysregulation with defects in both the innate and adaptive immune responses. Studies in patients without cirrhosis have shown that the severity of this phase determines outcome beyond the initial “cytokine storm” associated with the systemic inflammatory response syndrome (SIRS).3, 4 In cirrhosis, it is common for patients to suffer repeated episodes of nosocomial sepsis following an initial episode of infection. Defects in both innate and adaptive5 arms of the immune response have been demonstrated, and there is increasing evidence that monitoring of monocyte function by assessing the expression of antigen presentation apparatus, such as human leukocyte antigen-DR is of prognostic value.6, 7 Early studies in the animal model of cirrhosis have determined that Toll-like receptor expression is up-regulated,8 predisposing the organism to an exaggerated SIRS, followed by an equally exaggerated and prolonged CARS. In the current era, when organ support strategies are capable of allowing patients to weather the “cytokine storm,” we believe further emphasis should be placed on this harmful sequel to severe sepsis.

Divergent adaptive and innate immunological responses are observed in humans following blunt trauma

BackgroundThe immune response to trauma has traditionally been modeled to consist of the systemic inflammatory response syndrome (SIRS) followed by the compensatory anti-inflammatory response syndrome (CARS). We investigated these responses in a homogenous cohort of male, severe blunt trauma patients admitted to a University Hospital surgical intensive care unit (SICU). After obtaining consent, peripheral blood was drawn up to 96 hours following injury. The enumeration and functionality of both myeloid and lymphocyte cell populations were determined.ResultsNeutrophil numbers were observed to be elevated in trauma patients as compared to healthy controls. Further, neutrophils isolated from trauma patients had increased raft formation and phospho-Akt. Consistent with this, the neutrophils had increased oxidative burst compared to healthy controls. In direct contrast, blood from trauma patients contained decreased naïve T cell numbers. Upon activation with a T cell specific mitogen, trauma patient T cells produced less IFN-gamma as compared to those from healthy controls. Consistent with these results, upon activation, trauma patient T cells were observed to have decreased T cell receptor mediated signaling.ConclusionsThese results suggest that following trauma, there are concurrent and divergent immunological responses. These consist of a hyper-inflammatory response by the innate arm of the immune system concurrent with a hypo-inflammatory response by the adaptive arm.

Early Inflammatory Response in Patients With Ruptured Abdominal Aortic Aneurysm

Multiorgan failure is the main cause of death in patients operated for ruptured abdominal aortic aneurysm (rAAA). The systemic inflammatory response plays a central role in the generation and maintenance of multiorgan dysfunction. The aim of the current study was to investigate the inflammatory response preoperatively in patients with ruptured and nonruptured AAA in relation to the clinical outcome. A total of 95 patients about to undergo repair of AAA (43 ruptured with shock, 12 ruptured without shock, and 40 elective) and 41 controls without aneurysm matched by age, gender, and smoking habits were investigated by inflammatory markers. There were significantly higher levels of interleukin 6 (IL-6; proinflammatory cytokine) and IL-10 (anti-inflammatory cytokine) in patients operated for ruptured compared to nonruptured AAA. In conclusion, the current data indicate that rupture of an AAA activates the inflammatory system with a compensatory anti-inflammatory response.

Triggering receptor expressed on myeloid cells-1 expression on monocytes is associated with inflammation but not with infection in acute pancreatitis

IntroductionAcute pancreatitis (AP) is usually a mild and self-limiting disease, but some patients develop a severe form that is associated with high mortality. In AP, local inflammation is followed first by the systemic inflammatory response syndrome and then by the compensatory anti-inflammatory response syndrome, which is defined by low human leukocyte antigen (HLA)-DR expression on monocytes, increased concentration of the anti-inflammatory cytokine IL-10, and decreased monocyte function. Our aim was to measure the expression of triggering receptor expressed on myeloid cells (TREM)-1 (a proposed marker of infection or inflammation) and HLA-DR on monocytes, and the serum concentrations of IL-6 (a proinflammatory cytokine) and IL-10 in patients with AP to determine whether these markers can identify patients at high risk of developing severe AP or infection.MethodsFifty healthy volunteers, 18 patients with mild AP, and 11 patients with severe AP were included in this study. Samples were taken at admission and one and three days later. TREM-1 and HLA-DR expression was evaluated by flow cytometry, and soluble TREM-1, IL-6 and IL-10 concentrations were measured by ELISA.ResultsTREM-1 expression was higher in patients with AP than in healthy volunteers, but there was no difference between patients with mild and severe AP. TREM-1 expression was not associated with mortality or with the presence of infection. Soluble TREM-1 concentration in serum was higher in non-survivors than in survivors. HLA-DR expression was lower and IL-6 concentration higher in patients with severe AP and in infected patients.ConclusionsIncreased TREM-1 expression was associated with the presence of inflammation but not infection in AP. In patients with AP, low HLA-DR expression and high IL-6 concentration could predict severity and infection in samples taken shortly after admission.

Pathophysiology of Sepsis and Recent Patents on the Diagnosis, Treatment and Prophylaxis for Sepsis

Despite advances in the development of powerful antibiotics and intensive care unit, sepsis is still life threatening and the mortality rate remains unchanged for the past three decades. Recent prospective trials with biological response modifiers have shown a modest clinical benefit. The pathological basis of sepsis is initially an excessive inflammatory response against invading pathogens, leading to systemic inflammatory response syndrome (SIRS). Evidence reveals that a variety of inflammatory mediators orchestrate the intense inflammation through complicated cellular interactions. More recent data indicate that most septic patients survive this stage and then subjected to an immunoparalysis phase, termed compensatory anti-inflammatory response syndrome (CARS), which is more fatal than the initial phase. Sepsis is a complicated clinical syndrome with multiple physiologic and immunologic abnormalities. In this review, we summarize the recent understandings of the pathophysiology of sepsis, and introduce recent patents on diagnosis, treatment and prophylaxis for sepsis.

Compensatory anti-inflammatory response syndrome

The concept of 'Compensatory anti-inflammatory response syndrome' (CARS) was proposed in 1997 by Roger Bone (1941-1997) to qualify the consequences of the counter-regulatory mechanisms initiated to limit the overzealous inflammatory process in patients with infectious (sepsis) or non-infectious systemic inflammatory response syndrome (SIRS). One major consequence of CARS is the modification of the immune status that could favour the enhanced susceptibility of intensive care patients to nosocomial infections. Indeed, most animal 'two-hit' models illustrate an enhanced sensitivity to infection after a first insult. However, this observation is highly dependent on the experimental procedure. Numerous functions of circulating leukocytes are altered in sepsis and SIRS patients, as well as in animal models of sepsis or SIRS. However, this is rather a reprogramming of circulating leukocytes, since there is not a global defect of the immune cells functions. Furthermore, within tissues, leukocytes are rather primed or activated than immunosuppressed. Thus, CARS may be considered as an adapted compartmentalized response with the aim to silence some acute proinflammatory genes, and to maintain the possible expression of certain genes involved in the anti-infectious process.

Systemic inflammatory response following acute traumatic brain injury

The early, delayed, and systemic effects of acute traumatic brain injury (TBI) are the result of inflammatory mediators which initiate systemic inflammatory response syndrome (SIRS), subsequent complement deficits and coagulopathy. Once SIRS is triggered by acute inflammation, it can detrimentally self-propagate. Systemic inflammation causes tissue damage leading to further inflammation and damage, leaving the body in a vicious cycle of hyperinflammation. Therefore, important inflammatory mediators like interleukin (IL)-1 beta, IL-6 and tumour necrosis factor (TNF) alpha, are targeted in compensatory anti-inflammatory response syndrome (CARS) in an attempt to control the development of SIRS. The hypothalamus-pituitary (HPA)-axis and sympathetic nervous system (SNS) efferent limbs in CARS provide negative feedback for the production of inflammatory mediators. However, in the case of acute TBI, the activation of CARS often leads to the complication of immunosuppression which may result in multi-organ dysfunction syndrome (MODS) and mortality. In light of this, the activation of the SIRS following acute TBI does not bode well. If left uncontrolled, multiple systems will be implicated making it difficult to remedy.

Statins and sepsis: good bullet, disappearing target.

Despite several decades of research and phenomenal advances in technology and therapeutics, sepsis remains a catastrophic enigma. As a frequent cause of death, sepsis now rivals acute myocardial infarction. The longstanding therapeutic principles of early antibiotics use and supportive care have been difficult to improve upon. The authors conducted a concise review of pertinent literature on the pathophysiologic mechanisms of sepsis and the pharmacologic effects of statins. They conclude that, though statins possess anti-inflammatory and lipid-lowering properties, these effects may not be advantageous throughout the changing immunoresponse that can occur in sepsis syndrome. Based on the available information, statin therapy seems advantageous before the onset of sepsis and during sepsis resolution--but not during the compensatory anti-inflammatory response that may occur. Thus, the authors recommend that, until the status of a patient's changing immune response can be clearly determined, the uninterrupted use of statin therapy throughout the full spectrum of sepsis should be avoided.

Prognostic value of phagocytic activity of neutrophils and monocytes in sepsis. Correlation to CD64 and CD14 antigen expression

The role of the phagocytic function of monocytes and neutrophils in sepsis has been poorly investigated. The present study evaluated the impact of the phagocytic activity of neutrophils and monocytes on the outcome of patients with severe sepsis. Thirty-one patients and 30 healthy individuals were enrolled in the study. The phagocytic activity of monocytes and neutrophils was evaluated during 24 h after admission and the results were correlated to the expression of CD64 on neutrophils and monocytes, CD14 antigen on monocytes, the Simplified Acute Physiology Score II and the patients' survival. A reduced phagocytic activity of neutrophils during the first 24 h after admission was a negative predictor for survival. Increased expression of CD64 antigen on polymorphonuclear cells (PMNs) and monocytes was favourably correlated to the patients' survival. In multivariate analysis the phagocytic activity of PMNs was the only independent predictor factor for survival. Patients with PMN phagocytic activity <37% had lower expression of CD64 on monocytes and PMNs and worse outcome, while those with phagocytic activity >37% had higher expression of CD64 on monocytes and PMNs and better outcome. Reduced phagocytic activity of neutrophils may represent a state of neutrophil inactivation similar to that previously described for monocytes during the compensatory anti-inflammatory response.

Cardiac RAGE in Sepsis

See related article, pages 1239–1246 Sepsis is a systemic inflammatory response syndrome triggered by infection. The hallmarks of clinical sepsis are a broad range of systemic and organ function aberrations, including core temperature (hypothermia or hyperthermia), cardiac (rate and contractility), and respiratory and hematologic perturbations. When sepsis results in at least 1 organ failure or dysfunction, it is classified as severe sepsis. Severe sepsis with hypotension unresponsive to fluid resuscitation defines septic shock. Sepsis syndrome afflicts almost 750 000 patients in the United States each year, at a cost of almost $17 billion, and causes more than 200 000 deaths annually. The incidence of sepsis syndrome continues to rise along with the increase in life span and several other important risk factors. Sepsis without organ dysfunction is a relatively benign condition, and spontaneous recovery with conservative measures results in low in-hospital mortality (5% to 10%). Severe sepsis and septic shock carry high mortality, 30% to 50%, in spite of all that modern treatment offers.1–3 Genetic predisposing factors have been proposed including mutations in cytokine genes such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6. Most of these polymorphisms, implicated in increasing severity of sepsis, are associated with increases in these proinflammatory cytokines. Abnormalities in Toll-like receptor-4 and its signaling kinase, IRAK-4, have been associated with worse outcomes. The alarming increase in pathogens resistant to antibiotics that, in the past, were very effective in prevention and treatment of sepsis no doubt contributes to increases in severe sepsis prevalence in the elderly. The key mechanisms believed to initiate and propagate …

Immunological aspects of minimally invasive oncologic surgery

In the last few decades minimally invasive surgery has evolved to complement more traditional open surgical approaches. Pioneers of laparoscopic surgery have continually striven to replicate open surgical techniques with a view to maintaining equivalent surgical outcomes with the added benefits of shorter hospital stays, earlier return to full activity and fewer long-term wound complications. Having established the safety and feasibility of minimally invasive surgery, the focus moved to assuring such surgeries had equivalence in terms of oncological outcomes. Currently there is interest in exploring areas where laparoscopy might provide advantages over open surgery. The effect on immune response following surgery and how it relates to oncological outcomes is one potential area, and is reviewed here. Major surgery is associated with profound alterations in host immunity, with an initial elevation in cytokine production giving way to a compensatory anti-inflammatory response. This suppresses normal defence mechanisms rendering the host more susceptible to infection, dampening immune defence mechanisms active in malignancy. Minimally invasive surgery is associated with better preservation of systemic immune responses following major surgery. Laparoscopy results in better overall preservation of immune function than open surgery. There is, however, depression of local immune responses locally at the level of the peritoneum. Whether findings in the experimental animal translate into true benefit for patients remains to be seen.

The Increased Expression of TREM-1 on Monocytes Is Associated With Infectious and Noninfectious Inflammatory Processes

Inflammation is the response of an organism to tissue injury or infection. It is usually limited to the affected tissue, but sometimes the inflammatory mediators reach the bloodstream and act systemically. A compensatory anti-inflammatory response syndrome, in which expression of major histocompatibility complex class II (MHC-II) molecules are decreased, regulates the resulting systemic inflammatory response syndrome (SIRS). SIRS and compensatory anti-inflammatory response syndrome can lead to the development of sepsis. Triggering receptor expressed on myeloid cells (TREM)-1 has been proposed as a biomarker of the presence of sepsis. In this study, we investigated whether TREM-1 is increased only in septic patients, and not in patients with systemic inflammatory response but no infection. We also looked for a possible correlation between TREM-1 and MHC-II expression levels and the patients' progress. Fifty-eight surgical patients, 14 septic patients and 50 healthy volunteers, were included in this study. TREM-1 and MHC-II expression on blood monocytes was determined by flow cytometry. TREM-1 expression was increased in all patients after surgery, and its expression was higher in patients with preexisting SIRS. No association was found with the presence of infection. In septic patients, the increase in TREM-1 expression was transitory. MHC-II expression was decreased in both surgical and septic patients, and this decrease was greater in patients with a worse outcome. Increased TREM-1 expression on monocytes is associated with both infectious and noninfectious inflammatory processes, and the levels of MHC-II expression is better correlated with the patient outcome.

Severe sepsis and Toll-like receptors

Severe sepsis dominates the mortality of non-cardiac intensive care units. The ingenious Toll-like receptor (TLR) system can recognise many infectious organisms through relatively few receptors to trigger pro-inflammatory and anti-inflammatory cytokine release. Further complexity arises from positive and negative signalling feedback loops. Severe sepsis may be a consequence of an inappropriately excessive response or inadequate endogenous negative feedback. Therapies targeting these pathways are currently being evaluated. Alternatively, in clinical scenarios such as compensatory anti-inflammatory response syndrome, chronic viral sepsis or inadequate vaccine function, TLR signalling may be inadequate. TLR agonists may augment the innate response and are being investigated.

Immune-modulating enteral formulations: Optimum components, appropriate patients, and controversial use of arginine in sepsis

Nutrients have traditionally been viewed as a means to provide basic calories to sustain homeostasis. However, critically ill, surgical, and trauma patients are in a constant dynamic state between systemic inflammatory response (SIRS) and compensatory anti-inflammatory response (CARS). Results from ongoing research strongly support the use of specific nutrients to modulate the immune and/or metabolic response. These agents can now be considered therapeutic tools in the management of complex hypermetabolic diseases. The principle of using nutrients as a therapeutic strategy rather than just as "nutritional support" requires a shift in the current dogma. The most common nutrients found in currently available enteral immune-modulating formulas are omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid), antioxidants, nucleotides, glutamine, and arginine. Multiple individual reports and at least five meta-analyses using combinations of immune-modulating nutrients have reported almost uniform beneficial results. However, certain conflicting hypotheses continue to revolve around the use of arginine in septic patients.

Chronic Sepsis Mortality Characterized by an Individualized Inflammatory Response

Late mortality in septic patients often exceeds the lethality occurring in acute sepsis, yet the immunoinflammatory alterations preceding chronic sepsis mortality are not well defined. We studied plasma cytokine concentrations preceding late septic deaths (days 6-28) in a murine model of sepsis induced by polymicrobial peritonitis. The late prelethal inflammatory response varied from a virtually nonexistent response in three of 14 to a mixed response in eight of 14 mice to the concurrent presence of nearly all measured cytokines, both proinflammatory and anti-inflammatory in three of 14 mice. In responding mice a consistent prelethal surge of plasma MIP-2 (1.6 vs 0.12 ng/ml in survivors; mean values), MCP-1 (2.0 vs 1.3 ng/ml), soluble TNF receptor type I (2.5 vs 0.66 ng/ml), and the IL-1 receptor antagonist (74.5 vs 3.3 ng/ml) was present, although there were infrequent increases in IL-6 (1.9 vs 0.03 ng/ml) and IL-10 (0.12 vs 0.04 ng/ml). For high mobility group box 1, late mortality was signaled by its decrease in plasma levels (591 vs 864 ng/ml). These results demonstrate that impeding mortality in the chronic phase of sepsis may be accurately predicted by plasma biomarkers, providing a mechanistic basis for individualized therapy. The pattern of late prelethal responses suggest that the systemic inflammatory response syndrome to compensatory anti-inflammatory response syndrome transition paradigm fails to follow a simple linear pattern.