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)

Calcium functions as a critical intracellular second messenger and regulates many cellular processes such as muscle contractility, glycogen and protein turnover, hormone secretion, and vascular smooth muscle tone which are markedly abnormal during sepsis/endotoxemia. There also is increasing recognition of the role of calcium in the production of a variety of cytokines such as tumor necrosis factor alpha and interleukin-1 beta, which are important mediators of sepsis. Our hypothesis is that disturbances in cellular calcium regulation are responsible for or contribute to many of the metabolic manifestations of sepsis/endotoxemia and may be the driving force behind the development of multiorgan failure. In this article, we focus on a) new insights into calcium's regulation of the inflammatory cascade, b) the controversy concerning whether free cytosolic calcium concentration ([Ca2+]i) is increased in the disorder, and c) the potential therapeutic uses of calcium antagonists. An important message is that there are fundamental differences in the pathophysiology of the endotoxin model versus the cecal ligation and perforation (CLP) model of sepsis. Although calcium antagonists improve survival in the endotoxin model, they increase mortality in the CLP model of sepsis. Possible reasons for the differences in the effect of the drugs in the two different models and insight into the mechanisms of cell injury in endotoxin versus sepsis are presented.
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PMID:Calcium: a regulator of the inflammatory response in endotoxemia and sepsis. 868 76

We investigated the role of interleukin-10 (IL-10) in a neonatal mouse model of lethal group B streptococci (GBS) sepsis. Plasma IL-10 levels significantly increased at 24 and 48 h after GBS inoculation. Neutralization of IL-10 with specific antibodies had no effect on lethality. Administration of recombinant IL-10 at 20 or 4 h before challenge, but not at later times, resulted in decreased tumor necrosis factor alpha levels and improved survival. IL-10 could be potentially useful for the treatment of GBS sepsis.
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PMID:Interleukin-10 protects neonatal mice from lethal group B streptococcal infection. 869 23

During sepsis, there is release of various endotoxins from microorganisms which more or less activates cascade systems including release of cytokines such as tumor necrosis factor alpha and interleukin 6 and complement components. This causes impairment of vascular integrity and permeability which may progress into septic shock and a disseminated intravascular coagulation which progresses into multiorgan failure, including acute renal failure and subsequent death. Although most endotoxins and cytokines have a molecular size < 50 kD, there is little efficacy in removal of them by hemofiltration filters used for acute dialysis. The use of antibodies against different endotoxins has not been successful. The use of plasma exchange procedures (including blood exchange) to remove such toxins and cell debris, as free myoglobin and hemoglobin, has been successfully tried in smaller not controlled studies since 1984. Once when more than three organs are involved in a progressive manner, the risk of death is at least 80%. In contrast, these studies showed a survival rate of about 75% by addition of such therapeutic interventions to the conventional intensive care unit treatment. The substitution of the removed plasma products must be considered to include products important for the host defense and coagulation process and to avoid infections, bleeding, or increased coagulation. This type of removal is unselective and probably in the future will include addition of absorption techniques which may add further benefit to the outcome.
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PMID:Plasmapheresis in severe sepsis or septic shock. 871 72

Unlike the antibiotics erythromycin and penicillin G, sodium fusidate (fusidin) pretreatment (80 mg/kg of body weight) increased the survival rate of neonatal BALB/c mice challenged with Salmonella enteritidis lipopolysaccharide. Fusidin also significantly reduced the plasma tumor necrosis factor alpha levels. Hence, fusidin may prove useful in the management of bacterial sepsis in humans.
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PMID:Improved survival and antagonistic effect of sodium fusidate on tumor necrosis factor alpha in a neonatal mouse model of endotoxin shock. 880 74

We measured the levels of soluble intercellular adhesion molecule-1 (sICAM-1), CD11a, CD11b, CD18, endotoxin, and various inflammatory cytokines to clarify the relationship between adhesive molecules and cytokines in sepsis. We studied 21 patients with sepsis (sepsis group) and 13 patients with trauma not complicated by infection (trauma group). The mean sICAM-1 level was significantly higher in the sepsis group than in the trauma group. No significant difference was observed in the CD11a, CD11b, and CD18 levels between the two groups. The sICAM-1 levels significantly correlated with the levels of endotoxin, tumor necrosis factor alpha (TNF-alpha), and IL-8, but CD11a, CD11b, and CD18 levels did not correlate with endotoxin or cytokine levels. These findings suggest that ICAM-1 production is induced by endotoxins and cytokines produced in excess by inflammatory reactions and that endotoxins and cytokines are involved in qualitative, but not quantitative changes in LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18).
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PMID:Changes in adhesion molecule levels in sepsis. 882 72

To investigate the effect of cyclooxygenase inhibition in experimental Gram-negative sepsis, indomethacin was administered to mice at different times (1 or 5 days, or 1 h) before sublethal infection with an intravenous inoculum of Pseudomonas aeruginosa Early indomethacin exposure did not alter the outcome of infection, yet treatment at the time of bacterial challenge resulted in a high mortality rate. Polymerase chain reaction-assisted mRNA amplification in the spleens of infected mice revealed that tumor necrosis factor alpha (TNF-alpha) messenger was selectively expressed by the drug-treated and infected mice during the 24 h preceding death. Higher TNF-alpha levels were found in sera from these mice, whose macrophages produced increased levels of nitric oxide in vitro. Both pentoxifylline, an inhibitor of TNF-alpha synthesis, and an inhibitor of nitric oxide production improved survival in the indomethacin-treated and infected mice, although no such effect followed the administration of TNF-neutralizing antibodies. These data support the notion that cyclooxygenase inhibitors may exert both positive and negative effects in Gram-negative sepsis, the latter presumably involving overproduction of TNF-alpha.
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PMID:Evidence for tumor necrosis factor alpha as a mediator of the toxicity of a cyclooxygenase inhibitor in Gram-negative sepsis. 883 21

Intravenous injection of Candida albicans into mice produced elevated serum tumor necrosis factor alpha (TNF-alpha) levels. We hypothesized that immunostimulants released in vivo from C. albicans during fungal sepsis might contribute to the elevated levels of TNF-alpha in serum. We tested this hypothesis in mice with C. albicans mannan (CAM). Increased serum TNF-alpha levels were observed following intravenous and intraperitoneal injections of CAM. Injection of CAM into mice resulted in increased serum TNF-alpha concentrations that reached 1,200 pg/ml of blood, compared with 2,400 microg/ml of blood following injection of 10 microg of endotoxin. The response to CAM was concentration dependent, requiring a minimum dose of 20 microg of CAM per g of body weight. Sera from mice were tested 30, 60, 90, and 120 min after intravenous injections with CAM. TNF-alpha concentrations were minimal 30 and 120 min after intravenous injection and maximal 60 and 90 min after CAM injection. The relative distribution of CAM in vivo in decreasing order was determined to be as follows: blood > liver > lung > spleen, 90 min following injection of a single 5-mg dose of CAM. CAM was confirmed as the stimulating substance by utilizing anti-CAM antibodies in vivo to block the response. Rabbit anti-mannan antibodies administered by intraperitoneal injection 24 h before CAM injection significantly suppressed (P < 0.05) the accumulation of TNF-alpha in the sera. Dexamethasone administered to mice before intravenous injection of mannan significantly reduced (40 to 90% reduction; P < 0.05) the concentrations of TNF-alpha in the sera of treated mice. Thus, when in vivo CAM clearance mechanisms are exceeded, sufficient CAM may become available to stimulate TNF-alpha production, making CAM an important part of pathogenesis in Candida sepsis.
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PMID:Intravenous injection of Candida-derived mannan results in elevated tumor necrosis factor alpha levels in serum. 889 Feb 7

We tested the hypothesis that, during sepsis, the balance of pro- and anti-inflammatory cytokines is related to severity and survival. Cecal ligation and puncture (CLP) with a large (18-gauge)-, intermediate (21-gauge)-, or small (26-gauge)-diameter needle, or sham laparotomy, was performed on outbred CD-1 mice. Concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and the anti-inflammatory cytokine IL-10 were measured (by enzyme-linked immunosorbent assay) in serum, peritoneal lavage fluid, and liver and lung samples at 4, 8, 24, 48, and 96 h. As the diameter of the CLP needle decreased, the mortality rate decreased (at 48 h: large, 80%; intermediate, 40%; small, 20%; P < 0.05), the TNF-alpha and IL-6 concentrations decreased, and the time-to-peak TNF-alpha expression increased. In contrast, IL-10 concentration increased compared with baseline (serum at 24 h: large, 2.3-fold +/- 1.6-fold; intermediate, 2.0-fold +/- 0.5-fold; small, 49.9-fold +/- 8.3-fold; P < 0.05). Administration of IL-10 (5 microg, intraperitoneal) prior to CLP decreased mortality (P < 0.001). Administration of polyclonal anti-IL-10 serum prior to CLP (0.5 ml intraperitoneal) had the opposite effect and increased mortality (P < 0.001) and TNF-alpha, IL-6, and TNF-alpha mRNA expression compared with controls. Thus, severe sepsis is associated with a largely unopposed inflammatory response, and a largely unopposed inflammatory response (with anti-IL-10) results in severe sepsis and death. Less severe sepsis is associated with greater anti-inflammatory mediator expression, and greater anti-inflammatory mediator expression (with IL-10) results in less severe sepsis. Thus, the balance of inflammatory mediators is related to the severity and mortality of murine sepsis.
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PMID:Balance of inflammatory cytokines related to severity and mortality of murine sepsis. 889 Feb 33

During sepsis or inflammation, the liver expresses various protective phenotypes such as the acute phase response or the heat shock response (HSR). Inducible nitric oxide synthase (NOS2) is also expressed in the liver in these conditions and may protect the liver under some circumstances and promote injury in others. We have previously reported that the acute phase response and NOS2 expression are differentially regulated, though both can be expressed simultaneously. The HSR is known to prevent expression of other genes, but its effects on NOS2 expression in the liver is unknown. Therefore, we examined how the HSR influences NOS2 expression in primary rat hepatocytes. Sodium arsenite (Ars) or hyperthermia (43 degrees C) induced the synthesis of hsp72 messenger RNA (mRNA) and protein in hepatocytes, indicating activation of the HSR. In the absence of the HSR, combinations of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) stimulated high levels of NOS2 mRNA and nitric oxide (NO) synthesis. However, treatment with Ars or heat shock significantly attenuated cytokine-induced NOS2 mRNA and NO production. The addition of the nuclear factor kappaB (NF-kappaB) inhibitor pyrrolidine dithiocarbamate also inhibited NOS2 expression, suggesting a role for NF-kappaB in the cytokine induction of NOS2 in hepatocytes. Cytokines induced the appearance of an NF-kappaB complex as shown in gel retardation assays; however, induction of the HSR by Ars partially prevented cytokine-induced formation of this band while hyperthermia had a more complete inhibition. Furthermore, preinduction of the HSR prevented the activation of the NOS2 promoter construct in hepatocytes transfected with a 1.6 kilobase NOS2 promoter linked to luciferase. These findings show that NO production in stressed cells can be modulated by the HSR, possibly through repression of NOS2 gene transcription via the inhibition of NF-kappaB.
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PMID:Heat shock response inhibits cytokine-inducible nitric oxide synthase expression in rat hepatocytes. 890 4

Elevated plasma concentrations of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) derived from cellular stimulation have been found to correlate well with the systemic inflammatory response syndrome and clinical outcome of sepsis. Consequently, biologic inactivation and extracorporeal removal of these potent mediators gain increasing attractiveness as adjunctive therapeutic options. In realization of the latter strategy the authors developed specific adsorbents by covalently linking polyclonal antibodies against IL-1 beta and TNF alpha onto microspheres. The attachment process was characterized by high retention of antigen neutralizing activity. Batch testing of the adsorbents revealed specificity, biocompatibility, and high binding capacity (20.2 and 36.9 ng/mg of particles for IL-1 beta and TNF alpha, respectively). Employment of the particles in the Microspheres Based Detoxification System (MDS) resulted in efficient purification: human plasma spiked with recombinant IL-1 beta and TNF alpha (500 pg/ml) could be cleared at 42 ml/min (IL-1 beta) and 55 ml/min (TNF alpha) at a flow rate of 200 ml/min. These clearance rates are considerably higher than the values obtained with ultrafiltration. In conclusion, the microsphere technology allows efficient extracorporeal removal of cytokines from plasma. In addition, by combined application of IL-1 beta and TNF alpha binding particles and endotoxin adsorbents, such as cationically modified cellulose, it should be feasible to interfere with the complex pathobiochemical sequelae of sepsis.
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PMID:Extracorporeal removal of proinflammatory cytokines by specific absorption onto microspheres. 894 19


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