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

Recruitment of inflammatory cells to the lung capillaries has been proposed as an important step in the sequence of events that lead to acute lung injury. Frequently, in the clinical setting, bacteremia and sepsis syndrome precede the acute lung failure and endotoxin priming may represent a comparable paradigm, useful for experimental pursuit. Following addition of the chemotactic tripeptide FMLP (10(-9) to 10(-6) M) to the cell-free, salt solution perfusate of isolated rat lungs, only a small degree of vasoconstriction was observed. However, in lungs isolated from rats that received 2 mg/kg intraperitoneal Salmonella enteritidis endotoxin 2 h before lung perfusion, FMLP dose dependently caused a large, transient pulmonary pressor response, edema formation, and release of large amounts of thromboxane and leukotriene B4. Since in vitro priming with endotoxin, direct vascular injury by neutrophil elastase, nor direct stimulation with FMLP of pulmonary artery rings from endotoxin-pretreated rats, mimicked the effects of in vivo endotoxin priming, we conclude that the presence of inflammatory cells in the lung capillaries accounted for the large amount of eicosanoids produced by the lungs after FMLP stimulation. In fact, by retrograde lavage of the lung circulation with a collagenase solution, previously adherent cell clumps were mobilized and identified. These cell clumps, composed of red blood cells, neutrophils, and platelets, were not seen in the vascular lavage sediment obtained from unprimed control lungs. Indomethacin, a thromboxane antagonist, AA861, a 5-lipoxygenase inhibitor, and WEB 2086, a platelet-activating factor (PAF) antagonist, reduced the thromboxane synthesis and release after FMLP (10(-7) M) in in vivo endotoxin-primed lungs. None of the inhibitors employed exclusively inhibited only one particular eicosanoid mediator but rather affected the release of several mediators, suggesting a close link between the different synthetic arachidonic acid pathways. An inhibitor of phospholipase C (2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate), NCDC, but not an inhibitor of phospholipase D (Wortmannin) or of protein kinase C (staurosporine) inhibited the FMLP-stimulated pulmonary pressure rise and eicosanoid release in endotoxin-primed lungs in vivo. Our data suggest that eicosanoids (in particular thromboxane) released from cells trapped in the lung circulation, but not from constitutive lung cells, contribute to vasoconstriction and edema formation caused by the chemoattractant FMLP in endotoxin-primed lungs.
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PMID:FMLP causes eicosanoid-dependent vasoconstriction and edema in lungs from endotoxin-primed rats. 154 53

This study investigates the in vivo glucose utilization of various immune-competent cells after an intra-arterial injection of a nonlethal dose (30 micrograms/kg body weight) of murine recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF). Injection of GM-CSF resulted in a rapid but transient reduction in the number of circulating neutrophils. After 20 min the number of neutrophils returned to normal values, and by 4 h it was about 80% greater than in time-matched saline-injected controls. One hour after the treatment, neutrophils were accumulated in the livers of GM-CSF-injected animals but not in control livers. In vivo glucose utilization by circulating neutrophils and mononuclear cells and various liver cell types was investigated by combining the 2-deoxyglucose tracer technique with cell isolation procedures. GM-CSF increased the in vivo glucose utilization of circulating and infiltrating neutrophils by more than 200%. Glucose utilization by circulating mononuclear cells was also doubled. After GM-CSF injection, glucose utilization by Kupffer cells was increased by 130% and by hepatic endothelial cells was increased by 60%. Indomethacin pretreatment blunted the hyperglycemia caused by GM-CSF injection; however, it did not inhibit the increased glucose utilization by immune-competent cells. This suggests that the effect of GM-CSF on glucose utilization by these cells is not mediated by prostanoids and is at least partially independent of the mass action of elevated glucose concentration. These findings indicate that GM-CSF may be an important member of the cytokine cascade that mediates the acute in vivo metabolic response of immune-competent cells in sepsis or endotoxemia.
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PMID:In vivo metabolic response of hepatic nonparenchymal cells and leukocytes to granulocyte-macrophage colony-stimulating factor. 156 99

Newborns are susceptible to gram-negative sepsis/septic shock, but there is no established method of its treatment. This study was performed to evaluate the adjuvant effects of dopamine and dobutamine in the indomethacin treatment of newborn endotoxic shock. Endotoxic shock was induced in newborn dogs (2 to 10 days old; 300 to 800 g) by Escherichia coli lipopolysaccharide (LPS; 1.5 mg/kg, intravenously [IV]). Indomethacin (1.5 mg/kg, IV) was injected 5 minutes after LPS injection. Dopamine (5 micrograms/kg/min) or dobutamine (5 micrograms/mg/min) infusion started 5 minutes after LPS injection immediately following indomethacin injection. Hemodynamic parameters were monitored serially for 120 minutes. LPS induced bradycardia and hypotension, decreased the cardiac output and cardiac performance, and increased the total vascular resistance. When dopamine, dobutamine, or indomethacin were used alone, they attenuated the hemodynamic deterioration by LPS. Dopamine infusion following indomethacin administration improved the hemodynamics further, although dobutamine infusion did not. Therefore, we conclude that the adjuvant therapy of dopamine in the indomethacin treatment of newborn endotoxic shock is beneficial.
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PMID:Adjuvant effects of beta-adrenergic drugs on indomethacin treatment of newborn canine endotoxic shock. 177 23

The role of prostaglandins in the regulation of muscle protein breakdown is controversial. We examined the influence of arachidonic acid (5 microM), prostaglandin E2 (PGE2) (2.8 microM) and the prostaglandin-synthesis inhibitor indomethacin (3 microM) on total and myofibrillar protein breakdown in rat extensor digitorum longus and soleus muscles incubated under different conditions in vitro. In other experiments, the effects of indomethacin, administered in vivo to septic rats (3 mg/kg, injected subcutaneously twice after induction of sepsis by caecal ligation and puncture) on plasma levels and muscle release of PGE2 and on total and myofibrillar protein breakdown rates were determined. Total and myofibrillar proteolysis was assessed by measuring production by incubated muscles of tyrosine and 3-methylhistidine respectively. Arachidonic acid or PGE2 added during incubation of muscles from normal rats did not affect total or myofibrillar protein degradation under a variety of different conditions in vitro. Indomethacin inhibited muscle PGE2 production by incubated muscles from septic rats, but did not lower proteolytic rates. Administration in vivo of indomethacin did not affect total or myofibrillar muscle protein breakdown, despite effective plasma levels of indomethacin with decreased plasma PGE2 levels and inhibition of muscle PGE2 release. The present results suggest that protein breakdown in skeletal muscle of normal or septic rats is not regulated by PGE2 or other prostaglandins.
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PMID:Prostaglandin E2 does not regulate total or myofibrillar protein breakdown in incubated skeletal muscle from normal or septic rats. 211 60

Interleukin 1 has been implicated as a mediator of both systemic and local responses to infection and injury. Since systemic and local vasodilatation are hallmarks of sepsis and infection, we studied the direct effect of IL-1 on vascular contractility. We report here that human recombinant IL-1-beta potently inhibits the response of rat thoracic aorta to vasoconstrictor agents. Exposure of isolated rat aortic rings to IL-1 (20 ng/ml) for 1 h did not affect phenylephrine-induced contractions during the exposure period. However, when rings were retested 150-200 min after initiation of IL-1 exposure, contractions were markedly decreased. The cytokine had a similar effect in rings from which the endothelium was removed. Contractions caused by potassium depolarization also were depressed, indicating the effect of IL-1 is not specific to the alpha-adrenoceptor agonist. The inhibitory effect of IL-1 was concentration-dependent (0.2 to 20 ng/ml), and eliminated by pretreatment with cycloheximide (20 micrograms/ml). Indomethacin (10(-5) M) did not prevent the inhibition caused by IL-1. These studies identify IL-1 as a potent inhibitor of vascular contraction, via an endothelium-independent mechanism. Studies with inhibitors suggest that the action of IL-1 is independent of prostanoid synthesis, and may involve synthesis of protein.
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PMID:Interleukin 1 inhibits contraction of vascular smooth muscle. 278 26

Evidence suggests that part of the pathophysiologic response seen in group B streptococcal (GBS) sepsis may be due to polymorphonuclear leukocyte (PMN) activation. Indomethacin (INDO), which inhibits eicosanoid metabolism, attenuates the pathophysiologic response stimulated by GBS, possibly due to inhibition of PMN aggregation. We examined the capability of two eicosanoid metabolism inhibitors, INDO and nordihydroguaiaretic acid (NDGA), to inhibit PMN aggregation induced by heat-inactivated opsonized GBS and GBS-activated plasma. Opsonized GBS-induced PMN aggregation was inhibited by INDO (50-500 microM) and NDGA (1-100 microM). Over similar concentration ranges, INDO and NDGA had no significant effect on PMN aggregation induced by GBS-activated plasma. PMNs in plasma aggregate in response to unopsonized GBS. The stimuli for aggregation are opsonized GBS and GBS-activated plasma. INDO (50-500 microM) was unable to inhibit aggregation under this condition. Over the same concentration range in which INDO inhibited opsonized GBS-induced PMN aggregation, INDO was unable to inhibit opsonized GBS-induced superoxide production in PMNs. NDGA was examined but was found to interfere with the assay. The above evidence suggests PMN aggregation via eicosanoid metabolism may play a role in GBS-induced sepsis, which may be attenuated by agents such as INDO and NDGA.
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PMID:In vitro inhibition of group B streptococcus-induced polymorphonuclear leukocyte aggregation. 303 92

Despite elevated plasma concentrations of norepinephrine (NE), septic patients generally have normal or low mean arterial pressure (MAP) and systemic vascular resistance. We tested the hypothesis that sustained sepsis in rats results in relative hyporesponsiveness to the pressor actions of NE and angiotensin II (AII). Sprague-Dawley rats were studied 48 hr after sepsis was induced by cecal ligation. Sham-operated rats served as controls. Carotid artery and jugular venous catheters were placed under halothane anesthesia and the rats were allowed to waken fully in restraining cages. Peak increments in MAP were measured after bolus iv doses of NE (0.125-8.0 micrograms/kg) or AII (0.0125-0.5 microgram/kg). Some rats were pretreated with indomethacin (5 mg/kg, iv) 30 min prior to the dose-response study. Data were fitted to a two-parameter hyperbolic function and the resulting curves were compared by analysis of variance. Compared with controls, sepsis decreased the pressor response to both NE (P less than 0.0001) and AII (P less than 0.0001). Indomethacin restored responsiveness toward normal for both pressor agents (P less than 0.0001). It is concluded that sepsis is associated with hyporesponsiveness to two chemically dissimilar vasopressors and that this phenomenon may be mediated by prostaglandins.
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PMID:Diminished pressor response to exogenous norepinephrine and angiotensin II in septic, unanesthetized rats: evidence for a prostaglandin-mediated effect. 388

Hypoimmunity after major trauma and thermal injury appears to predispose to septicemia. An increase of immune suppressive T cells and the inhibitory monocytes product PGE2 has been demonstrated postburn and are suggested as contributing to postburn hypoimmunity. TP5, the biologically active part of thymopoientin, has an immunomodulating effect on T cells. Indomethacin, an irreversible blocker of the prostaglandin synthesis has been suggested to reduce the inhibitory monocytes-mediated immunosuppression. In this study strains 2 and 13 guinea pigs received 20-30% TBSA scald burn and were subsequently injected with either TP5 or indomethacin or a combination of both on the 3 following days postburn. The ability of splenocytes to produce a secondary immune response to SRBC was measured in the in vitro AFC assay. The animals who had received TP5 and indomethacin showed significant improvement in their ability to mount an immune response in the AFC assay.
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PMID:The immunomodulating effect of TP5 and indomethacin in burn-induced hypoimmunity. 623 2

Seventeen piglets were infected with a continuous intravenous infusion of live group B beta-hemolytic streptococci (GBS). Hemodynamic changes were recorded, and blood samples were drawn for measurement of thromboxane B2 (TxB2) (stable metabolite of thromboxane A2) and 6-keto-PGF1 alpha (stable metabolite of prostacyclin). Control animals (n = 9) received only bacteria, while treatment animals (n = 8) received indomethacin, 3 mg/kg IV, 15 min after the start of the bacterial infusion. Control animals responded to the bacteria within 15 min with marked elevation in mean pulmonary artery pressure (Ppa) from 15 +/- 8 to 39 +/- 6 mm Hg and decline in PaO2 from 80 +/- 11 to 51 +/- 6 mm Hg and cardiac output (CO) from 0.24 +/- 0.07 to 0.13 +/- 0.07 liters/min/kg. Mean arterial blood pressure (AoP) significantly decreased from baseline value of 95 +/- 13 to 51 +/- 32 mm Hg by 180 min. In animals treated with indomethacin, these changes were reversed or significantly attenuated. The hemodynamic changes were associated temporally with elevations in plasma concentrations of TxB2 or 6-keto-PGF1 alpha. In the first 60 min, TxB2 levels in both groups correlated with Ppa (r = 0.72, p less than 0.001) and PaO2 (r = -0.60, p less than 0.001). A strong negative correlation between TxB2 and CO was observed over the first 180 min (r = -0.73, p less than 0.001). There was a statistically significant correlation between AoP and 6-keto-PGF1 alpha concentration between 60 and 180 min (r = -0.54, p less than 0.002). Indomethacin improved the hemodynamic function in this model of GBS sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardiovascular changes in group B streptococcal sepsis in the piglet: response to indomethacin and relationship to prostacyclin and thromboxane A2. 638 9

Systemic infection with Streptococcus pneumoniae produced atrophy, decreased twitch and tetanic tension, and altered intracellular electrolyte composition in rat skeletal muscle. Cathepsin B activity was selectively elevated early in the course of illness. Luepeptin, a cathepsin B inhibitor, and indomethacin, a prostaglandin synthesis inhibitor, prevented muscle atrophy and impaired contractility. Indomethacin, but not leupeptin, prevented the intracellular electrolyte changes. Acetaminophen reduced fever but did not prevent muscle atrophy, impaired contractility, or altered intracellular electrolytes. Muscle wasting and impaired contractility associated with sepsis may involve selective prostaglandin stimulation of cathepsin B activity. Intracellular electrolyte changes may involve prostaglandin synthesis but do not require cathepsin B activation.
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PMID:Inhibitors of prostaglandin synthesis or cathepsin B prevent muscle wasting due to sepsis in the rat. 671 47


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