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)

We tested the hypothesis that platelet-activating factor plays an important role in promoting endotoxin-induced lung injury by studying the effect of WEB 2086, a specific platelet-activating factor receptor antagonist, on lung vascular leak in endotoxin-treated rats. Intraperitoneal injection of Salmonella enteritidis endotoxin (2 mg/kg) increased the extravascular leakage of 125I-labeled albumin in perfused lungs at 30 min, 2 h, 6 h, and 48 h. Treatment with WEB 2086 (10 mg/kg ip) either 20 min before or 30 min after endotoxin injection significantly reduced lung injury at 2 h after endotoxin (leak index: control 0.74 +/- 0.03, endotoxin 1.79 +/- 0.14, endotoxin + pretreated WEB 1.23 +/- 0.09, endotoxin + posttreated WEB 1.21 +/- 0.13). In addition, posttreatment with WEB 2086 starting at 90 min after endotoxin injection markedly reduced lung leak at 6 h (control 0.74 +/- 0.03, endotoxin 1.29 +/- 0.14, endotoxin + WEB 0.71 +/- 0.06). The protective effect of WEB 2086 was not the result of cyclooxygenase blockade because the release of thromboxane B2 by endotoxin-treated lungs was not affected by WEB 2086. Furthermore, neither pretreatment nor posttreatment with WEB 2086 significantly reduced the endotoxin-induced increase in plasma glutathione disulfide, a marker of in vivo oxidative stress. In rats given a lethal dose of endotoxin (20 mg/kg ip), posttreatment with WEB 2086, starting at 2 h after endotoxin, significantly improved survival compared with vehicle treatment. We conclude that WEB 2086 ameliorated endotoxin-induced lung injury without reducing oxidative stress in the rat and suggest that blockade of platelet-activating factor receptor may be an important therapeutic consideration in sepsis-induced acute lung vascular injury.
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PMID:Beneficial effect of a platelet-activating factor antagonist, WEB 2086, on endotoxin-induced lung injury. 230 3

Ibuprofen is a potent cyclooxygenase inhibitor known to reduce the production of arachidonic acid metabolites. Prostacyclin and thromboxane are well-studied metabolites that play a prominent role in inflammation. Many of the effects of ibuprofen can be linked to its anti-inflammatory properties. Beneficial results from ibuprofen therapy have been documented, and more widespread use of the drug seems indicated. Conditions ranging from immunologic response to trauma and sepsis to postburn lung dysfunction to wound edema are improved by the use of ibuprofen. The fact that ibuprofen is effective in the various conditions detailed above, while other steroidal and nonsteroidal drugs are effective only in selective instances, increases the value of ibuprofen. Other properties of the drug, aside from its anti-inflammatory effects, are not as well studied and not as well known. Their importance, however, should not be overlooked. Superoxide radical tissue injury may be very important in acute injury and this phenomenon needs further study. In several studies ibuprofen has been shown to antagonize this type of injury. Similarly fibrinolysis inhibition is known to occur in burn wounds, but its role in other injuries is unknown. The antagonism of this inhibitor by ibuprofen maintains vascular patency. The clinical use of ibuprofen will increase as research further elucidates the mechanisms of tissue injury in acute situations and the many and varied mechanisms of action of ibuprofen.
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PMID:Ibuprofen in acute-care therapy. 240 73

ARDS is a complication of septic and traumatic shock. It ranges from slight pulmonary dysfunction to forms so severe as to be incompatible with life. There seem to be initial pathogenic differences between sepsis-induced and trauma-induced ARDS, in that activation of granulocytes is primarily involved in the former and activation of the clotting system during a fibrinolysis-inhibition phase in the latter. In the later course the granulocyte-mediated and the coagulation-mediated injury can potentially amplify each other's effects in several positive feedback systems. In the end stage the two forms involve similar pathogenic mechanisms which may include production of oxygen radicals. Therapy aims primarily to eradicate the initiating event. Firm data support shock treatment with dextran-70 and early or prophylactic ventilator treatment using positive end-expiratory pressure. Despite lack of conclusive evidence, high-dose corticosteroids in one or two doses should be given very early, at least in sepsis-induced ARDS. Other agents which may be tried early in the course of ARDS include prostaglandin E1, cyclooxygenase inhibitors and oxygen radical scavengers.
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PMID:Adult respiratory distress syndrome. Pathogenesis and treatment. 242 88

TNF is a small protein secreted by activated monocytes and macrophages that mediates the in vivo effects of endotoxin. When injected into experimental animals, TNF reproduces the picture of septic or endotoxin shock. In addition, antibodies to TNF protect animals against the deleterious effects of IV injections of either LPS or live bacteria. Specifically, the available evidence suggests that TNF may be necessary for the organ injury and failure seen in sepsis. However, TNF probably is not the final common pathway to shock and tissue injury. Inhibition of cyclooxygenase is protective from the lethal effects of both LPS and TNF infusion, suggesting that prostanoids play an important, and perhaps more proximal role in the generation of tissue injury. In addition, TNF is produced and cleared from the blood-stream within a short period of time after an LPS stimulus, suggesting that TNF sets into motion a chain of events that may be self-perpetuating even in the absence of further TNF stimulus. In the near future, the treatment of sepsis may involve the administration of antibodies both to TNF and to LPS. Cyclooxygenase inhibitors should also begin to play a role in the therapy of sepsis. In the more distant future it is likely that we will be able to manipulate the state of activation of genes that code for TNF to exert some control over its production and secretion. It is perhaps within our grasp to finally reduce the morbidity and mortality of this lethal condition.
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PMID:Role of tumor necrosis factor in sepsis and acute lung injury. 264 25

Patients suffering severe trauma, including thermal injuries, demonstrate both a hypermetabolic response and an immunosuppressed state following the injury. Biochemically, these patients produce extremely large amounts of cyclooxygenase products, including prostaglandin E. We have investigated the effect of a drug, ibuprofen, which blocks the synthesis of prostaglandins in a burned rat model. Ibuprofen at high doses was found to significantly diminish the hypermetabolic response to burn injury and sepsis. The same dosage of ibuprofen increased the mortality rate in the same burn sepsis model. Prostaglandin E may therefore exert some beneficial effects in traumatized patients by altering their metabolism.
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PMID:The effect of ibuprofen on postburn metabolic and immunologic function. 278 85

In order to evaluate the role of leukotrienes in group B streptococcal (GBS) sepsis we studied the effect of a leukotriene receptor antagonist, FPL 57231, on the late hemodynamic changes occurring secondary to an infusion of live GBS. Paralyzed, mechanically ventilated piglets received a continuous intravenous infusion of bacteria (5 x 10(7) org/kg/min) while systemic arterial (Psa) and pulmonary artery pressures (Ppa) were measured. To separate the effects of the lipoxygenase products of arachidonic acid from those of the cyclooxygenase by-products, animals in control and treatment groups received indomethacin, a cyclooxygenase blocking agent, 15 min after the infusion of GBS was begun. In addition to GBS and indomethacin, treatment animals received a 30 min infusion of FPL 57231 starting 120 min after the bacterial infusion was begun. All study animals responded to bacteria within 15 min with marked elevation in pulmonary artery pressure (X +/- SD) (12 +/- 3 to 49 +/- 5 mmHg; p less than .01), and a decline in PaO2 (84 +/- 9 to 49 +/- 5 mmHg; p less than .01) and cardiac output (0.29 +/- 0.04 to 0.18 +/- .07 liter/min/kg; p less than .01). These changes were reversed by indomethacin. Subsequent values remained relatively stable until approximately 90 min when a gradual decrease in cardiac output (CO) and PaO2, and an increase in Ppa, and calculated systemic (SVR) and pulmonary (PVR) vascular resistances occurred. After the initial increase in TxB2 and 6-keto-PGF1 alpha, indomethacin treatment resulted in return of these values to baseline with no further increase throughout the study period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of leukotrienes in the late hemodynamic manifestations of group B streptococcal sepsis in piglets. 305 37

In pathological states associated with hypermetabolism, such as acute sepsis, there is marked negative N balance. It has been suggested that the pathway for this response is via leukocyte pyrogen (interleukin I) acting on cyclooxygenase to stimulate prostaglandin release, which then stimulates proteolysis via the lysosomal pathway. In vitro, cyclooxygenase inhibitors decrease proteolysis in muscle tissue from septic rats. We tested this hypothesis in vivo in severely septic patients by using aspirin as the test cyclooxygenase inhibitor. Septic patients (n = 4) were given a primed, constant infusion (183 mg prime, then 37 mg/hr) of 15N-labeled urea for 6 hr to obtain a blood [15N]urea plateau. Blood samples were taken every 30 min. At 180 min 1500 mg of aspirin was given po. If aspirin inhibited protein breakdown, the plateau level should rise, since less cold urea derived from protein breakdown will enter the urea pool. Aspirin did not cause any change in either the BUN concentration, its 15N enrichment, or any of the plasma amino acids. In conclusion, cyclooxygenase inhibition by aspirin in vivo does not decrease protein breakdown in hypercatabolic septic patients.
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PMID:The effect of aspirin on protein breakdown in septic man. 309 51

Previous studies have indicated that various arachidonic acid metabolites are involved in the cardiovascular dysfunction seen during endotoxemia and sepsis. However, the possible role of these metabolites in mediating the metabolic alterations under similar conditions remains to be elucidated. Thus, the purpose of the present study was to determine if cyclooxygenase and lipoxygenase blockade could prevent the elevated rates of glucose appearance (Ra), glucose recycling, and hyperlactacidemia seen during hypermetabolic sepsis. Sepsis was induced in chronically catheterized conscious rats by multiple injections of live Escherichia coli via a subcutaneous catheter. Septic animals received intravenous (i.v.) injections of BW755C every 6-8 h to block both the cyclooxygenase and lipoxygenase pathways. Glucose kinetics were assessed in 24-h fasted rats by using a constant i.v. infusion of [6-3H] and [U-14C]-glucose. Treatment with BW755C prevented the 1-2 degrees C increase in body temperature induced by sepsis in the vehicle-treated animals. Septic rats receiving saline instead of BW755C exhibited an elevated plasma lactate concentration and increased rates of glucose appearance, recycling, and metabolic clearance. The sepsis-induced alterations in these variables were not attenuated by BW755C. These results suggest that neither arachidonic acid metabolites nor elevated body temperature are responsible for increasing glucose production and utilization in hypermetabolic septic rats.
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PMID:Inhibition of eicosanoid production by BW755C does not attenuate sepsis-induced alterations in glucose kinetics. 310 59

Previous studies have suggested that alterations in the classical neuroendocrine system may not be responsible for the increased glucose metabolism observed during hypermetabolic sepsis. The purpose of the present study was to determine whether inhibition of the cyclooxygenase pathway with indomethacin, which prevents the production of arachidonic acid metabolites by this pathway and the sepsis-induced increase in body temperature, would abolish the increases in glucose appearance (Ra), recycling, and hyperlactacidemia. Sepsis was induced in chronically catheterized conscious rats by multiple injections of live Escherichia coli via a subcutaneous catheter. Septic animals received iv injections of indomethacin (5 mg/kg) every 6-8 hr to block the cyclooxygenase pathway. Glucose kinetics were assessed in 24-hr fasted rats using a constant iv infusion of [6-3H]- and [U-14C]glucose. Treatment with indomethacin prevented the 1-2 degrees C increase in body temperature observed in septic animals. Septic rats exhibited an elevated plasma lactate concentration and increased rates of glucose appearance and recycling. The sepsis-induced alterations in these variables were not attenuated by indomethacin. These results suggest that neither elevated body temperature nor the generation of arachidonic acid metabolites of the cyclooxygenase pathway is responsible for increasing glucose production in hypermetabolic septic rats.
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PMID:Fever is not responsible for the elevated glucose kinetics in sepsis. 311 80

Group B beta hemolytic streptococcal sepsis has many of the characteristics of gram negative sepsis (Hellerqvist, et al., 1981). This is further shown in the model developed for this study. The newborn piglet septic model developed for this study appears to be an adequate model for group B, beta-streptococcal sepsis characterized by the development of significant hypotension by six hours. As with human sepsis, this model develops hypoglycemia, hemoconcentration as noted by the increased hematocrit, thrombocytopenia and a significant drop in WBC with an increase in immature forms (Wilson, 1986). The only finding not correlated to the septic newborn is the development of DIC as characterized by an increased PT/PTT and increased FSP. As with other animal models for both gram positive and negative sepsis, the cyclooxygenase inhibitor, indomethacin significantly increased survival out to 72 hours. Previous studies with thromboxane synthetase inhibitors have not shown increased survival, but shunting into the prostacyclin pathway has occurred and the effect of this on survival could not be ruled out (Short, et al., 1983). The use of a thromboxane receptor site antagonist should not cause this shunt, and thus may help to evaluate the effect of thromboxane blockade. In this model no effect of the receptor site antagonist was noted, but due to the short half-life of this compound, a different dosing schedule may be needed before its efficacy can be determined. In summary, the cyclooxygenase inhibitors do appear to have a protective effect in gram positive sepsis, but the mechanisms of action are still to be determined.
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PMID:Group B streptococcal (GBSS) newborn septic shock model: the role of prostaglandins. 313 20


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