Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin production is increased in rodents by administration of endotoxin or cytokines. To investigate whether circulating leptin is related to cytokine release and survival in human sepsis, plasma concentrations of leptin, interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, soluble TNF receptor type I, IL-1 receptor antagonist (IL-1ra), and the inflammatory modulator IL-10 were measured as soon as severe sepsis (n=28) or septic shock (n=14) developed and every 6 h for 24 h. Patients with sepsis or septic shock had leptin concentrations 2.3- and 4.2-fold greater, respectively, than the control group. There was an independent association for leptin with IL-1ra and IL-10 in both patient groups. By discriminant analysis, leptin and IL-6 were independent predictors of death. These findings suggest that increases in leptin levels may be a host defense mechanism during sepsis.
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PMID:Relationship of plasma leptin to plasma cytokines and human survivalin sepsis and septic shock. 1043 92

Due to intensive research in the field of cytokines during the last decade the knowledge of cytokine mediated processes has increased intensively. Modulation or even inhibition of the inflammatory cascade gave hope to effective therapeutic possibilities in sepsis or autoimmune diseases, particularly in rheumatoid arthritis (RA). Interestingly the application of biological immunomodulating substances could not increase the prognosis in sepsis, sometimes even deterioration occurred. However, in inflammatory bowel diseases and RA substantial efficacy could be revealed. Since blockade of II-1 or II-2 led to some beneficial results, but also sometimes to significant toxicity, TNF-alpha blockade gave hope to constitute a promising therapeutical target. Since the efficacy of a monoclonal anti-TNF-alpha antibody and a recombinant soluble TNF receptor p75 fusion protein had been demonstrated in animal studies and in vitro, these results could be confirmed in controlled multicenter trials, showing significant improvement of patients according to Paulus and/or ACR criteria. However, a final assessment of therapeutical TNF-alpha blockade in RA cannot be given yet, since the tolerability in long-term application, particularly with respect to the risk of infections and the induction of malignancies and antibodies (e.g. drug induced lupus erythematosus) has to be observed carefully for longer times. Also the cost effectiveness of this new therapeutic approach needs further investigations.
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PMID:[Anti-TNF-alpha therapy as a new option in treatment of rheumatoid arthritis?]. 1063 66

Cytokines are small regulatory peptides with diverse functions. They regulate the immune system and modulate the inflammatory response, both of which are implicated in vesico-ureteric reflux (VUR) and associated reflux nephropathy (RN). The cytokine profile in VUR and RN has yet to be fully investigated. Blood was obtained from three subject groups immediately after induction of anaesthesia: group A [subjects with VUR and established RN, (N=9)]; group B [VUR alone but no associated RN, (N=6)]; and group C [age- and sex-matched controls with no history of urinary sepsis, (N=14)]. Serum cytokine levels of tumour-necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), soluble TNF receptor-1 (sTNF-R1), and interleukin-8 (IL-8) were measured using standard ELISA technique. Serum levels of IL-6 were higher in group A subjects (1.798-4.638 pg/ml, median 3.253 pg/ml) than controls (1.531-2.078 pg/ml, median 1.798 pg/ml). There was no significant difference in levels in group B subjects (1.498-3. 048 pg/ml, median 1.948 pg/ml) and controls. These same relationships were observed for levels of TNF-alpha (group A: 8. 501-14.471 pg/ml, median 13.483 pg/ml; group B: 7.088-10.650 pg/ml, median 8.886 pg/ml; group C: 6.746-13.344 pg/ml, median 7.671 pg/ml) and sTNF-R1 (group A: 690.34-5780.74 pg/ml, median 1197.38 pg/ml; group B: 366.65-1401.62 pg/ml, median 592.82 pg/ml; C: 313.49-636.33 pg/ml, median 504.17 pg/ml). IL-8 was not significantly elevated in any of the study groups (A or B) compared with control group C (group A: 27.08-56.38 pg/ml, median 31.35 pg/ml; group B: 29.90-35. 87 pg/ml, median 31.35 pg/ml; group C: 25.05-30.22 pg/ml, median 29. 90 pg/ml). These results suggest there may be an immunological basis to RN.
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PMID:Serum cytokine profile in reflux nephropathy. 1066 39

The role of cytokines and reactive oxygen species (ROS) in multiple and not fully explained pathogenesis of sepsis was presented. Close attention was paid to the contribution of inflammatory cytokines (TNF-alpha, IL-1, IL-6, IL-8) to the enhanced phagocyte-derived oxidative metabolism and the activation of respiratory burst. The pleiotropic interaction of these and the other cytokines creating so-called cytokine network was described, among other things in order to express the phagocytic and endothelial receptors. The significant role of polymorphonuclear leucocytes (PMNLs) and macrophages in the pathogenesis of sepsis was outlined, presenting not only their bactericidal activity but immunoregulatory effect connected with cytokine release as well. The significance of T cells cooperating with PMNLs was presented as well. The participation of antiinflammatory cytokines (IL-10, IL-13) and cytokine inhibitors e.g. soluble TNF receptor (sTNFR) and IL-1 receptor antagonist (IL-1 ra) was mentioned; all of them appear in septic patients and are thought to be natural regulators of immunological response in vivo. The key role of ROS generated by the activated phagocytes during sepsis has been outlined; it is proposed that the hypermetabolic response to sepsis results from enhanced ROS generation and so-called oxidant stress is a consequence of the imbalance between their generation and detoxification. The consequences of the action of oxygen free radicals resulting in lipid peroxidation followed by host auto-injury were also described. At the end a possibility of immunotherapy of sepsis connected with the application of pentoxifylline (PTXF) as TNF-alpha inhibitor was recommended to take into consideration.
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PMID:[The role of cytokines and reactive oxygen species in the pathogenesis of sepsis]. 1076 55

Endothelial cell damage of glomeruli and kidney arterioles seems to play a pivotal role in several pathologic situations, such as Gram-negative sepsis, glomerulonephritis, and acute renal failure. Bacterial lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) have been identified as potent inducers of apoptotic cell death in bovine glomerular endothelial cells. Both agents elicited apoptotic DNA laddering within 12 to 24 h. Basic fibroblast growth factor (bFGF) was generally described as a protective factor for endothelial cells against radiation-, TNF-alpha-, and UV-light-induced programmed cell death. Therefore, whether bFGF also affects apoptosis of microvascular endothelial cells was questioned. Surprising was that simultaneous treatment of glomerular endothelial cells with bFGF and either LPS or TNF-alpha left LPS-induced death unaffected, whereas TNF-alpha-induced death induction was potentiated, amounting to 48.9+/-6.3% versus 22.4+/-4.3% DNA degradation with TNF-alpha alone. Comparably, acidic FGF also selectively potentiated TNF-alpha-induced apoptosis. In mechanistic terms, bFGF synergistically increased TNF-alpha-induced mitochondrial permeability transition, the release of cytochrome c from mitochondria to the cytosol, and upregulation of the proapoptotic protein Bak and significantly enhanced activation of caspase-8 protease activity. In contrast, stress-activated protein kinase and nuclear factor kappaB activation, which represent primary signals of TNF/TNF receptor interaction, downregulation of the antiapoptotic protein Bcl-x(L), and caspase-3-like protease activation, were unaffected. As bFGF did not affect LPS-induced apoptotic cell death, bFGF also left LPS-induced Bak upregulation and Bcl-x(L) downregulation unaffected. The results point to a selective bFGF-mediated enhancement of distinct proapoptotic pathways induced by TNF-alpha in glomerular endothelial cells.
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PMID:Basic fibroblast growth factor selectively enhances TNF-alpha-induced apoptotic cell death in glomerular endothelial cells: effects on apoptotic signaling pathways. 1109 43

CD14 is a receptor for cell wall components of Gram-negative and Gram-positive bacteria that has been implicated in the initiation of the inflammatory response to sepsis. To determine the role of CD14 in LPS-induced effects in humans, 16 healthy subjects received an i.v. injection of LPS (4 ng/kg) preceded (-2 h) by i.v. IC14, a recombinant chimeric mAb against human CD14, at a dose of 1 mg/kg over 1 h, or placebo. In subjects receiving IC14, saturation of CD14 on circulating monocytes and granulocytes was >90% at the time of LPS injection. IC14 attenuated LPS-induced clinical symptoms and strongly inhibited LPS-induced proinflammatory cytokine release, while only delaying the release of the anti-inflammatory cytokines soluble TNF receptor type I and IL-1 receptor antagonist. IC14 also inhibited leukocyte activation, but more modestly reduced endothelial cell activation and the acute phase protein response. The capacity of circulating monocytes and granulocytes to phagocytose Escherichia coli was only marginally reduced after infusion of IC14. These data provide the first proof of principle that blockade of CD14 is associated with reduced LPS responsiveness in humans in vivo.
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PMID:IC14, an anti-CD14 antibody, inhibits endotoxin-mediated symptoms and inflammatory responses in humans. 1120 21

Tumor necrosis factor-alpha (TNF-alpha) is a key mediator of inflammatory responses and gram-negative bacterial sepsis, but the role that it plays during Salmonella enterica species bacterial infections in swine has not yet been elucidated. To facilitate studies on the role of TNF-alpha on the pathology associated with Salmonella infections in pigs, recombinant soluble porcine TNF receptor type I (rspTNF-RI) and soluble TNF receptor type I fused to the Fc region of porcine IgG1 (rspTNF-RI-IgG) were expressed in insect cells using a baculovirus expression system. The proteins were secreted into the cell culture media and purified by anti-soluble porcine TNF-RI antibody and protein G affinity chromatography, respectively. The yield of protein using this method was approximately 1.5mg rspTNF-RI and 4mg rspTNF-RI-IgG/L of cell culture medium. In in vitro assays, rspTNF-RI-IgG was approximately 10-fold (0.97 vs. 10.00pmol/ml) more effective than rspTNF-RI at completely inhibiting the cytotoxic activity of 500U of recombinant porcine TNF-alpha on 3 x 10(4) WEHI 164 murine fibrosarcoma, clone 13, cells. Compared to previously described methods, this method yields significantly more biologically active rspTNF-RI.
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PMID:Development of a baculovirus expression system for soluble porcine tumor necrosis factor receptor type I and soluble porcine tumor necrosis factor receptor type I-IgG fusion protein. 1200 91

Tumor necrosis factor (TNF) is a major mediator of apoptosis as well as inflammation and immunity, and it has been implicated in the pathogenesis of a wide spectrum of human diseases, including sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases. The interaction of TNF with TNF receptor-1 (TNF-R1) activates several signal transduction pathways. A common feature of each pathway is the TNF-induced formation of a multiprotein signaling complex at the cell membrane. Over the past decade, many of the components and mechanisms of these signaling pathways have been elucidated. We provide an overview of current knowledge of TNF signaling and introduce an STKE Connections Map that depicts a canonical view of this process.
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PMID:TNF-R1 signaling: a beautiful pathway. 1204 Jan 73

As reported in the literature, the mortality rates for patients with Acute Hepatic Failure (AHF) approaches 80% in cases in which liver transplantation is not possible. Post-transplant mortality mostly depends on the severity of the neurological condition at the time of the operation (20% in I-II degree coma patients and 44% in III degree coma patients). The primary indications for liver transplantation in AHF are Fulminant Hepatitis (FH)(93%), Subfulminant Hepatitis (5%) and other indications (2%). Other causes of AHF are Primary Non-Function (PNF) and Delayed Function (DF), which occur in 7-10%. Therefore it becomes necessary to monitor the patients with a Liver Support Device to be able to improve the clinical condition of the patients before liver transplantation (LT). In our experience we used the Molecular Adsorbent Recirculating System (MARS) (MARS Monitor; Teraklin AG, Rostock Germany), which enables the selective removal of albumin-bound substances accumulating in liver failure by the use of albumin-enriched dialysate. The system is used as a bridging device to orthotopic liver transplantation (OLT) of patients with FHF. We studied 34 patients, including 16 males and 18 females: 9 were affected by Primary-Non-Function (PNF), nine by Fulminant Hepatitis (FH), six by Delayed-Non-Function (DNF), and ten by Acute on Chronic Hepatic Failure (AOCHF). The average age of the patients was 41.8 years and the average number of applications was 6.4; the median length of application was about eight hours. The parameters that we monitored, before and after each treatment, were neurological status (EEG, cerebral CT, Glasgow Coma Score), haemodynamic parameters, acid base equilibrium, and blood gas analysis. We also monitored hepatic and renal function. In addition, the clinical conditions of the patients were monitored using kidney and liver ultrasound/ultrasonography (US). Inclusion criteria were bilirubin > 15 mg/dL, ammonia > 160 micro g/dL and a Glasgow Coma Score between 6 and 11. The reduction of bilirubin and ammonia were very significant (P < 0.01), whereas the changes of International Normalized Ratio (INR) were not significant. Also the modifications of albumin, total protein, sodium, potassium and calcium were not significant. In conclusion, four out of nine patients with PNF are alive without a second transplantation and were discharged after about 48 days; four out of nine underwent OLT, while one out of nine died; five out of six patients with DF are alive without a second transplantation, and they were discharged after an average time of 55.5 days, one out of six died; six out of nine patients with fulminant hepatitis underwent OLT and four of these are alive, while two died due to sepsis; three patients are alive without OLT. Four patients with AOCHF underwent OLT and are alive, three patients are alive and on a waiting list, two died while on a waiting list and one patient who experienced reactivation of HBV infection during chemotherapy for non-Hodgkin's lymphoma is alive. In spite of the limited number of cases of our study, we believe that MARS can be applied with high tolerance for a very long period of time. In addition, its repeatability allows it to be used in patients with DNF and FH as a bridge to transplant. In patients with DNF, it is used while waiting for complete recovery of the transplanted organ.
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PMID:MARS (Molecular Adsorbent Recirculating System): experience in 34 cases of acute liver failure. 1222 Mar 3

Group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress produces a polysaccharide exotoxin (CM101) which has been previously described as GBS toxin. CM101 infused i.v. into tumor-bearing mice causes rapid tumor neovascularitis, infiltration of inflammatory cells, inhibition of tumor growth and tumor apoptosis. CM101 has successfully completed phase I studies in refractory cancer patients with very encouraging results. We have now demonstrated a mechanism of action for CM101. Using a normal mouse tumor model, we have examined tumor and normal tissues which were harvested at 0, 5, 15, 30 and 60min post-infusion of either CM101 or dextran. We present evidence that CM101 is rapidly (within the first 5min) bound to the tumor neovasculature. Complement is activated by the alternative pathway (C3) and leukocytes start to infiltrate the tumor within the first 5min. Through RT-PCR and immunohistochemical techniques, we demonstrate that proinflammatory cytokines, interleukin-6 and tumor necrosis factor (TNF)-alpha, are up-regulated in infiltrating leukocytes and TNF receptor 2 is up- regulated in the targeted tumor neovasculature. Combined, these events constitute possible explanations for the observed pathophysiology of tumor ablation.
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PMID:Functional studies on the anti-pathoangiogenic properties of CM101. 1451 62


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