Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of studies have suggested that the inflammatory and chemotactic autocoid platelet activating factor (PAF), together with various cytokines, plays an important role in the pathophysiology of trauma, sepsis, and shock. However, little is known about PAF's contribution to the immunosuppression associated with hemorrhage. The aim of our study was, therefore, to determine if the use of a PAF-antagonist following hemorrhage has any salutary effects on splenocyte lymphokine production. To study this, mice were bled to and maintained at a mean arterial pressure of 35 mm Hg for 60 min. The mice were then segregated into three groups and were resuscitated with shed blood plus lactated Ringer's solution (2x the volume of shed blood), containing either a potent PAF-antagonist (Ro 24-4736, a thienodiazepine) in dimethyl sulfoxide (DMSO) or DMSO-vehicle. Sham-operated mice received either DMSO-vehicle in saline or saline alone. Twenty-four hours thereafter the animals were sacrificed and splenocyte cultures established and stimulated for 48 hr with Con A (2.5 micrograms/ml). Supernatant lymphokine levels were determined by bioassay. The cellular release of interleukin-2 and -3 (IL-2 and IL-3) by splenocytes was significantly depressed in the nontreated or vehicle-treated hemorrhaged animals compared to shams. Treatment with the PAF-antagonist Ro 24-4736 restored IL-2 and IL-3 release values to levels comparable to those of the sham-operated animals. Thus, (1) PAF appears to play a significant role in hemorrhage-induced immunosuppression and (2) the use of a PAF-antagonist to uncouple the PAF-generated feedback loops prevents the depression in splenocyte function following hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:PAF-antagonist administration after hemorrhage-resuscitation prevents splenocyte immunodepression. 764 95

Although studies indicate that polymicrobial sepsis produces marked depression in lymphocyte functions, it remains unclear whether this dysfunction is due to the chronic exposure of immune cells to endotoxin (ETX; a product of the gram-negative bacterial cell wall) at levels typically encountered in the septic state. The aim of this study, therefore, was to determine whether the changes in lymphokine release seen during polymicrobial sepsis are comparable to those observed with chronic ETX infusion. To assess this, splenocytes were harvested from C3H/HeN mice (ETX-sensitive) at 1 or 24 hr following cecal ligation and puncture (CLP; to induce polymicrobial sepsis), Sham CLP (Sham), or laparotomy followed by peritoneal implantation of a mini-osmotic pump which delivered either saline vehicle (Sal-pump) or ETX (ETX-pump; 0.025 micrograms lipopolysaccharide/25 g body wt/24 hr). Splenocytes were then stimulated with concanavalin A (2.5 micrograms/ml/48 hr) and their capacity to release interleukin (IL)-2, interferon (IFN)-gamma, IL-4, and IL-10 was determined by bioassay or ELISA. The results indicated that there were no changes in lymphokine release capacity at 1 hr after CLP or ETX-pump implantation. However, prolonged sepsis (i.e., at 24 hr) caused a marked suppression of IL-2 and IFN-gamma release (immune-enhancing lymphokines characteristic of Th1-cells), while enhancing the release of immunosuppressive Th2-cell products IL-4 and IL-10. Chronic exposure to ETX at a level comparable to that seen in CLP caused no depression in lymphokine (IL-2/IFN-gamma) release. This implies that a bacterial component other than ETX mediates the differential alterations observed in lymphokine release during prolonged polymicrobial sepsis.
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PMID:Polymicrobial sepsis but not low-dose endotoxin infusion causes decreased splenocyte IL-2/IFN-gamma release while increasing IL-4/IL-10 production. 801 14

Topics include treatment of multiple sclerosis (MS) with T cell receptor (TCR) peptides, rheumatoid arthritis (RA) with IL-1ra, IL-2 toxin conjugate, or antibodies to TNF, to CD4, or to ICAM-1, sepsis and five other diseases with IL-1ra, and treatment of experimental animal diseases with soluble receptors, IL-12, TGF-beta2, or small molecule antagonists of cytokines.
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PMID:Clinical and preclinical studies presented at the Keystone Symposium on Arthritis, Related Diseases, and Cytokines. 821 99

Experimental acute pyelonephritis in monkeys led to death in some of the animals following renal E. coli inoculation. It was found that both the inflammatory response and cytokine activation were much more severe in these monkeys as compared with others that survived. IL-1 was decreased just before death, and there were early increases in IL-2 and IL-6 serum concentrations, but no significant increase in TNF values. The data suggest that death in sepsis is due in part to excessive cytokine release because of a decrease in the protective activity of IL-1.
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PMID:Events leading to septic death from experimental acute pyelonephritis in the monkey. 834 80

IL-2 with or without autologous lymphokine-activated killer (LAK) cells, administered early after ABMT for AML may eradicate residual disease and reduce relapses. This paper reports 14 patients who received IL-2 or IL-2 plus LAK cells after ABMT for AML in first relapse or at a later stage, in two separate trials. Patients with AML in first relapse (n = 9), second CR (n = 3) or second relapse (n = 2) underwent ABMT after busulfan (BU), CY and total body irradiation (n = 11) or BU/CY alone (n = 3), with marrow that was (n = 6) or was not (n = 8) purged with 4-HC. In a previously-reported Phase I trial, eight patients received IL-2 (Roche) by continuous infusion at 0.3-3.0 x 10(6) U/m2/day x 5 days and, after 6 days of rest, 0.3 x 10(6) U/m2/day x 10 days. In a subsequent trial, five patients received IL-2 at 3.0 x 10(6) U/m2/day x 5 days, underwent leukapheresis for 3 days and received their LAK cells plus IL-2 (0.3 x 10(6) U/m2/day x 10 days). A sixth patient received only 2 days of IL-2, developed sepsis and died of multiorgan failure. All other patients had mild to moderate toxicity which was reversible. All patients developed neutrophilia, lymphocytosis and thrombocytopenia. IL-2 with or without LAK therapy was initiated 21-91 days (median 51 days) after ABMT. Severe thrombocytopenia (< 10 x 10(9)/l) occurred during the apheresis days.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-2 with or without lymphokine-activated killer cells as consolidative immunotherapy after autologous bone marrow transplantation for acute myelogenous leukemia. 840 64

It has previously been shown by this laboratory that immunomodulation of thermally injured animals with low-dose interleukin-1 (IL-2) and indomethacin (Indo) improves survival following septic challenge. Lymphokine-activated killer (LAK) cells have been shown to be effective in certain viral infections and to act in synergy with IL-2 in the treatment of certain types of cancer. We have studied the effect of LAK cells in combination with IL-2 and Indo in a murine model of thermal injury and sepsis. Male A/J mice received a 25% scald burn injury or sham burn and were randomized into five groups: (a) sham/vehicle, (b) burn/vehicle, (c) burn/IL-2 (250 U) + Indo (5 micrograms), (d) burn/LAK cells (2 x 10(6) cells), or (e) burn/LAK cells+IL-2+Indo and were treated accordingly for 6 days following injury. LAK cells were generated by in vitro IL-2 treatment of syngeneic spleen cells for 72 hr and cytotoxic activity was confirmed by standard 51Cr release assay using natural killer (NK)-sensitive and NK-resistant targets. In the groups receiving LAK cells they were administered on Day 1 and Day 6 postinjury. On Day 10, septic challenge by cecal ligation and puncture (CLP) or splenectomy, for in vitro studies, was performed. Five-day survival after CLP was 80% in the sham/vehicle group compared to 0% in the burn/vehicle group (P < 0.01). IL-2/Indo and LAK/IL-2/Indo improved survival to 25% (P < 0.05) and 57.1% (P < 0.01), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lymphokine activated killer cells enhance IL-2 prevention of sepsis-related death in a murine model of thermal injury. 841 66

Interleukin 10 (IL-10) indirectly prevents antigen-specific T-cell activation, which is associated with downregulation of the antigen presentation and accessory cell functions of monocytes, macrophages, Langerhans cells and dendritic cells. In addition, IL-10 inhibits T-cell expansion by directly inhibiting IL-2 production by these cells. These properties of IL-10, together with its capacity to downregulate the production of proinflammatory cytokines and chemokines by activated monocytes, polymorphonuclear leucocytes and eosinophils, indicate that IL-10 is a potent immunosuppressant in vitro. IL-10 has similar activities in vivo. It inhibits lipopolysaccharide or staphylococcal enterotoxin B induced lethal shock in mice. In addition, IL-10 deficient mice develop chronic inflammatory bowel disease, which could be reduced, or prevented by IL-10 treatment. IL-10 also prevented the development of colitis in a SCID mouse model. Collectively, these data indicate that IL-10 has great potential therapeutical utility in the treatment of diseases, such as chronic inflammation, autoimmune diseases, transplant rejection, graft-versus-host disease and sepsis.
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PMID:Immunosuppressive and anti-inflammatory properties of interleukin 10. 854 Oct 28

Continuous hemofiltration is widely used for renal replacement therapy in patients with acute renal failure. It has been suggested that hemofiltration may also eliminate toxic mediators thought to be important in the pathophysiology of sepsis. The present study examined whether hemofiltration can activate or eliminate inflammatory mediators in patients with sepsis, and whether ultrafiltrate can alter specific functions of peripheral blood mononuclear leukocytes (PBMC) in vitro. Veno-venous hemofiltration was performed in 16 patients and in 5 healthy volunteers. Pre-filter (afferent), post-filter (efferent) and ultrafiltrate concentrations of cytokines (IL-1 beta, IL-6, IL-8, TNF alpha) and of complement components (C3, C3adesArg, C5adesArg, terminal complement complex) were measured after the beginning of hemofiltration (t0), and 60 minutes later (t60). PBMC, and monocyte and lymphocyte subfractions were incubated with ultrafiltrate, and cytokines were determined in the supernatants. Hemofiltration did not induce significant mediator activation. There was no evidence for significant cytokine elimination. However, pre-filter C3adesArg concentration showed a significant decline during hemofiltration (patients: t0 = 676.9 +/- 99.7 ng/ml, t60 = 545.4 +/- 83.2, P < 0.001; volunteers: t0 = 54.8 +/- 13.3 ng/ml, t60 = 33.9 +/- 10.7, P < 0.001). Ultrafiltrate from septic patients significantly stimulated PBMC and monocyte TNF alpha release, but suppressed lymphocyte IL-2 and IL-6 production. Ultrafiltrate from volunteers was without effect. Hemofiltration effectively eliminates certain mediators such as C3adesArg. Ultrafiltrate contains compounds with significant immunomodulatory qualities. Therefore, hemofiltration may represent a new modality for removal of immunomodulatory mediators.
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PMID:Hemofiltration in human sepsis: evidence for elimination of immunomodulatory substances. 854 15

Previous studies have demonstrated the presence of myocardial depression in clinical and experimental septic shock. This depression is associated with the presence of a circulating myocardial depressant substance with physical characteristics consistent with cytokines. The present study utilized an in vitro myocardial cell assay to examine the role of various human recombinant cytokines, including tumor necrosis factor (TNF)alpha and interleukin (IL)1beta, in depression of cardiac myocyte contractile function induced by serum from humans with septic shock. The extent and velocity of electrically paced rat cardiac myocytes in tissue culture was quantified by a closed loop video tracking system. Individually, TNF-alpha and IL-1beta each caused significant concentration-dependent depression of maximum extent and peak velocity of myocyte shortening in vitro. In combination, TNF-alpha and IL-1beta induced depression of myocardial cell contractility at substantially lower concentrations consistent with a synergistic effect. Using immunoabsorption, removal of both TNF-alpha and IL-1beta (but not either alone) from the serum of five patients with acute septic shock and marked reversible myocardial depression resulted in elimination of serum myocardial depressant activity. IL-2, -4, -6, -8, -10, and interferon gamma failed to cause significant cardiac myocyte depression over a wide range of concentrations. These data demonstrate that TNF-alpha and IL-1beta cause depression of myocardial cell contraction in vitro and suggest that these two cytokines act synergistically to cause sepsis-associated myocardial depression in humans.
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PMID:Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum. 864 98

There is accumulating evidence that inflammatory cytokines are involved in the pathophysiology of cardiac dysfunction found in sepsis, myocardial infarction and acute rejection after heart transplantation. Although there are some previous reports on cytokines and myocardial depression, myocardial energy metabolism caused by cytokines have not been established yet. The purpose of the present study is to determine if the IL-2 effect on contractile function is related to impaired energy production. In isolated perfused rabbit hearts (n = 6), we measured developed pressure, ATP and phosphocreatine by 31P-NMR spectroscopy during and after a 5 minute infusion of IL-2 (200 U/ml/min). Although there was slightly increased inorganic phosphate which might be affect on myocardial contractility reduced, high energy phosphate and intracellular pH did not change by IL-2 infusion, suggesting another mechanism for myocardial depression caused by inflammatory cytokine, IL-2.
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PMID:[Cardiac disfunction and myocardial energy metabolism caused by interleukin-2 (IL-2)]. 872 57


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