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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines are low molecular weight proteins that act in an autocrine, paracrine and endocrine fashion to regulate and integrate immune effector cell function. Cytokine production is tightly controlled by a complex network of co-stimulatory and feedback loops. The systemic concentrations of some cytokines, most notably tumor necrosis factor and various interleukins, correlate with the extent of inflammation, and the severity of critical illness and patient outcome. Thus, cytokine expression is often monitored and/or manipulated as a therapeutic target in studies of sepsis and other inflammatory conditions. Unfortunately, some therapies designed to modify cytokine response have failed to improve outcomes in sepsis, and some of these therapies have actually been harmful. Several common clinical conditions, as well as, therapeutic interventions significantly influence cytokine expression. Furthermore, the magnitude and extent of these effects may be greater than those produced by immunomodulating therapies. In contrast, other conditions may not produce clinically significant changes in cytokine expression, and must simply be considered when interpreting studies designed to determine the effects of immunomodulation. Some conditions may even result in changes in the inflammatory response and may thus add to the inflammatory burden of a critically ill patient. This review provides intensivists and other clinicians with an overview of the effects of altered physiologic conditions on cytokine expression. This information is important so that studies measuring cytokines can be correctly interpreted and clinical circumstances in which cytokine manipulation is undesirable can perhaps be avoided.
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PMID:Unintended immunomodulation: part I. Effects of common clinical conditions on cytokine biosynthesis. 1080 8

Cytokine mediators and leukocyte-endothelial cell adhesion molecules are critical and interdependent components of the acute inflammatory response in sepsis. We hypothesized that the administration of monoclonal antibodies to intercellular adhesion molecule-1 (CD54) or E- and L-selectin (CD62E/L) would decrease serum levels of the proinflammatory cytokines interleukin-1beta (IL-1), IL-6, and IL-8 and tumor necrosis factor receptor (TNFR-1) in baboons during sepsis. Adult male baboons received infusions of 1 x 10(9) colony forming units (CFU)/kg heat-killed Escherichia coli (E. coli) followed 12 h later by live E. coli (1 x 10(10) CFU/kg). At the time of live bacterial infusion, six septic animals were treated with a monoclonal antibody to CD54 and six with an antibody to CD62E and L (1 mg/kg). Eight untreated septic animals served as controls. Sequentially drawn serum samples were assayed for IL-1, IL-6, IL-8, and TNFR-1 using enzyme-linked immunoassay (ELISA). Data were compared using Mann-Whitney U tests and Chi-square analyses. Median survival was decreased in both treatment groups compared to controls (P < 0.05). Peak IL-1 level was higher than controls in septic animals treated with anti-CD54 but not anti-CD62E/L (P < 0.05, P = NS, respectively). Elevations in IL-6, IL-8, and TNFR-1 were increased and prolonged in both antibody treated groups compared to controls (P < 0.05). These results provide the first in vivo evidence that leukocyte-endothelial adhesion molecules CD54 and CD62E/L regulate cytokine production in sepsis.
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PMID:Proinflammatory cytokines increase in sepsis after anti-adhesion molecule therapy. 1080 17

A novel approach to the treatment of surgical sepsis has been tried: cytokine-based immunotherapy. Human recombinant interleukin-2 (IL-2) and a mixture of native cytokines obtained by arteriovenous perfusion of xenospleen were used as a source of proinflammatory cytokines. Extracorporeal immunotherapy of 62 patients with surgical sepsis with mononuclear cells treated by autologous IL-2 resulted in a significant decrease of endotoxicosis and effective immunocorrection. Cytokine-based immunotherapy notably decreased the mortality of patients with generalized surgical infection--to 14.6%, which was lower than the expected mortality (35%) and the mortality in the control group (34.5%).
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PMID:[Cytokines in the treatment of a generalized surgical infection]. 1083 32

The pathogenesis of septic shock is mainly due to unregulated tumour necrosis factor-alpha (TNF-alpha) production. Procalcitonin (PCT) and calcitonin gene-related peptide (CGRP) are alternative transcription products of the calcitonin gene. Since high PCT levels have been described in human sepsis, and since CGRP inhibits TNF synthesis in rats, we examined the role of these peptides in the regulation of the inflammatory response during septic shock. LPS-induced TNF production was assessed using a human whole blood model. In this model, PCT (10(-7) M) and CGRP (10(-6) M) significantly inhibit TNF production by 27 and 24 % respectively. The effect of CGRP was reversed by CGRP 8-37 (10 microM), an antagonist of CGRP receptor. No effect on interleukin (IL)-1, IL-6 and IL-8 was found. This is the first description of an anti-inflammatory role for PCT and CGRP in humans.
Cytokine 2000 Jun
PMID:Procalcitonin and calcitonin gene-related peptide decrease LPS-induced tnf production by human circulating blood cells. 1135 14

Severe acute necrotizing pancreatitis is a disease that is caused by premature activation of pancreatic enzymes. Cytokine release contributes to systemic manifestations such as systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), adult respiratory distress syndrome (ARDS), and sepsis. Diagnosis is based on a history of abdominal pain, laboratory values such as serum amylase and lipase levels, and CT scan. Medical management focuses on fluid and electrolyte balance, antibiotic therapy, pain control, and decreasing systemic complications. Surgery is indicated when infectious pancreatic necrosis has been identified. This article addresses incidence and etiology; pathophysiology; clinical manifestations; diagnostics; and medical and surgical patient care management.
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PMID:Necrotizing pancreatitis: pathophysiology, diagnosis, and acute care management. 1086 31

The precise regulatory mechanisms of amplification and downregulation of the pro- and anti-inflammatory cytokines in the inflammatory response have not been fully delineated. Although activated protein C (APC) and its precursor protein C (PC) have recently been reported to be promising therapeutic agents in the management of meningococcal sepsis, direct evidence for the anti-inflammatory effect remains scarce. We report that APC inhibits in vitro the release of tumor necrosis factor (TNF) and macrophage migration inhibitory factor (MIF), two known cytokine mediators of bacterial septic shock, from lipopolysaccharide (LPS)-stimulated human monocytes. The THP-1 monocytic cell line, when stimulated with LPS and concomitant APC, exhibited a marked reduction in the release of TNF and MIF protein in a concentration-dependent manner compared to cells stimulated with LPS alone. This effect was observed only when incubations were performed in serum-free media, but not in the presence of 1-10% serum. Serum-mediated inhibition could only be overcome by increasing APC concentrations to far beyond physiological levels, suggesting the presence of endogenous serum-derived APC inhibitors. Inhibition of MIF release by APC was found to be independent of TNF, as stimulation of MIF release by LPS was unaltered in the presence of anti-TNF antibodies. Our data confirm that the suggested anti-inflammatory properties of APC are due to direct inhibition of the release of the pro-inflammatory monokine TNF, and imply that the anti-inflammatory action of APC is also mediated via inhibition of MIF release.
Eur Cytokine Netw 2000 Sep
PMID:Activated protein C inhibits tumor necrosis factor and macrophage migration inhibitory factor production in monocytes. 1102 25

Recent studies suggest that increased activation-induced lymphocyte apoptosis (AICD) is detected in mouse splenocytes during polymicrobial sepsis which may contribute to lymphocyte immune dysfunction [i.e., decreased interleukin (IL-)2 and interferon-gamma (IFN-gamma) production] leading to the associated morbidity seen in those animals. Thus, we wanted to examine the hypothesis that immune suppressive agents, such as IL-4, IL-10 or prostaglandin E2(PGE2), known to be elevated in septic animals, also contribute to this increase in AICD. Here we demonstrate that the inclusion of monoclonal antibody (mAb) to IL-10, but not anti-IL-4 or ibuprofen (IBU), blunted this sepsis induced increase in splenocyte AICD. Additionally, septic mice deficient in the IL-10 gene product (-/-) showed neither an increase in AICD nor a loss of IL-2/IFN-gamma release capacity. Interestingly, mAb to IL-10 did not altered the extent of AICD in a Th2-cell line, but exogenous IL-10 did potentiate Th1-like cell line AICD. This was consistent with the finding that the increased AICD seen in septic mouse splenocytes was restricted largely to the CD4+ cells producing IL-2 (Th1-cells) and that mAb to IL-10 treatment suppressed this change. Furthermore, IL-10 appears to mediate its AICD effect by upregulation of the Fas receptor and Fas receptor signaling protein components, but not by altered expression of Bcl/Bax/Bad family members, in septic mouse splenocytes. To the extent that these processes contribute in a pathological fashion to the animal's capacity to survive sepsis we have previously observed that in vivo post-treatment of mice with mAb IL-10 markedly attenuated septic mortality. Collectively, these data indicate that in the septic mouse the Th2 cytokine IL-10 not only serves to actively induce Th1 lymphocyte immune dysfunction but also plays a role in their apoptotic depletion. These processes in turn appear to contribute to the animal's inability to ward off lethal septic challenge.
Cytokine 2001 Apr 07
PMID:IL-10 mediation of activation-induced TH1 cell apoptosis and lymphoid dysfunction in polymicrobial sepsis. 1129 91

Studies have shown gender dimorphism in cell-mediated immune responses following haemorrhage, with depressed responses in young males and maintained or enhanced responses in proestrus females. However, it remains unknown whether or not the sexually dimorphic immune response to haemorrhage provides any protection against a subsequent in vivo polymicrobial septic challenge. To study this, male and proestrus female C3H/HeN mice were subjected to haemorrhage (35+/-5 mmHg for 90 min followed by fluid resuscitation) or sham operation. Twenty-four hours thereafter, all mice were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) and survival was assessed over a 10 day period. Haemorrhage prior to CLP significantly increased mortality in males as compared to shams. In contrast, mortality in females following CLP was comparable between the sham and haemorrhage groups. Plasma levels of interleukin (IL-)6, tumour necrosis factor (TNF)-alpha and prostaglandin E(2)(PGE(2)) at 5 h after CLP were significantly increased in males subjected to prior haemorrhage. In contrast, plasma levels of IL-6 and TNF-alpha in females did not increase under such conditions. PGE(2)levels were comparable in males and females following CLP, however prior haemorrhage significantly reduced PGE(2)levels in females, whereas no change was observed in males. Liver and splenic expression of cyclooxygenase-2 protein paralleled the changes in plasma PGE(2). Female sex hormones, therefore, appear to play an important role not only in maintaining immune function following haemorrhage, but also provide a survival advantage against subsequent septic challenge.
Cytokine 2001 May 07
PMID:Gender differences in the inflammatory response and survival following haemorrhage and subsequent sepsis. 1139 94

IL-18 binding protein (IL-18BP) is a circulating antagonist of the proinflammatory Th1 cytokine IL-18. It effectively blocks IL-18 by forming a 1:1 high affinity (Kd=400 pM) complex, exhibiting a very low dissociation rate. We have developed a sandwich ELISA for IL-18BPa and determined its limit of detection (62 pg/ml). Interference by IL-18 and related cytokines, as well as cross reactivity with other IL-18BP isoforms (b, c, and d) were determined. Using this ELISA, we measured serum IL-18BPa in large cohorts of healthy individuals and in septic patients. Serum IL-18BPa in healthy individuals was 2.15+/-0.15 ng/ml (range 0.5-7 ng/ml). In sepsis, the level rose to 21.9+/-1.44 ng/ml (range 4-132 ng/ml). Total IL-18 was measured in the same sera by an electrochemiluminescence assay and free IL-18 was calculated based on the mass action law. Total IL-18 was low in healthy individuals (64+/-17 pg/ml) and most of it ( approximately 85%) was in its free form. Total IL-18 and IL-18BPa were both elevated in sepsis patients upon admission (1.5+/-0.4 ng/ml and 28.6+/-4.5 ng/ml, respectively). At these levels, most of the IL-18 is bound to IL-18BPa, however the remaining free IL-18 is still higher than in healthy individuals. We conclude that IL-18BPa considerably inhibits circulating IL-18 in sepsis. Yet, exogenous administration of IL-18BPa may further reduce circulating IL-18 activity.
Cytokine 2001 Jun 21
PMID:A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. 1149 94

Interleukin-1 (IL-1) plays an important role in host defenses against microbial pathogens. Excessive production of this cytokine, however, may be responsible in part for the lethality observed during sepsis. Our studies show that interferon-gamma (IFN-gamma) downregulates lipopolysaccharide (LPS)-induced interleukin-1beta (IL-1beta) transcription in primary macrophages. This phenomenon does not occur in splenocytes or bone marrow-derived macrophages from signal transducer and activator of transcription (Stat1)-deficient mice, suggesting that Stat1, a transcription factor involved in IFN signaling, plays a critical role in this process. Moreover, nitric oxide (NO) was also involved in the downregulation of LPS-induced IL-1 by IFN, as addition of the inducible nitric oxide synthase (iNOS) inhibitor L-N(6)-(1-iminoethyl)lysine (NIL) negated the effect. Kinetic analysis of IL-1 and IFN levels in LPS-treated mice in vivo suggests that IFN-mediated inhibition of IL-1 might be an important negative feedback mechanism for limiting IL-1 generation in vivo.
J Interferon Cytokine Res 2001 Jul
PMID:IFN-gamma inhibits lipopolysaccharide-induced interleukin-1 beta in primary murine macrophages via a Stat1-dependent pathway. 1150 42


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