UMLS:C0243026 - FACTA Search

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Query: UMLS:C0243026 (sepsis)
52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine whether arachidonic acid metabolites are mediators of regional blood flow changes during sepsis, we examined the effects of cyclooxygenase blockade on intestinal microvascular diameters and blood flow during acute bacteremia, induced in the rat by the intravenous injection of 10(9) live Escherichia coli. Mean arterial pressure, cardiac output, intestinal microvascular diameters, and blood flow were measured in the presence or absence of a topically applied selective cyclooxygenase inhibitor (mefenamate). Bacteremia caused a diffuse constriction of both arterioles and venules and a concomitant 50% decrease in blood flow. Treatment with mefenamate did not affect baseline intestinal microvascular tone or bacteremia-induced arteriolar constriction and hypoperfusion, but did reverse an intense venular constriction. Our results suggest that the small intestinal microcirculation has a differential response to cyclooxygenase products of arachidonic acid metabolism during acute bacteremia. They appear not to be mediators of the intestinal arteriolar constriction and hypoperfusion observed during acute E. coli bacteremia, but profoundly influence the mesenteric venular constriction. These observations support the concept that microvascular control mechanisms are different not only between but within organ specific vascular beds.
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PMID:Differential microvascular response to cyclooxygenase blockade in the rat small intestine during acute bacteremia. 774 70

Acute acalculous cholecystitis (AAC) is a severe inflammatory disorder of the gallbladder. It occurs primarily in patients acutely ill from other disorders and is related to sepsis and shock. We previously found that platelet-activating factor (PAF), a phospholipid autacoid purported to be a mediator of the shock response, produced AAC. This study was performed to determine the effect of intravenous lipopolysaccharide (LPS) on feline gallbladders. Anesthetized cats underwent LPS administration with and without administration of a cyclooxygenase inhibitor and PAF antagonist. Gallbladder inflammation was evaluated by quantitation of luminal water transport and tissue myeloperoxidase levels. In an attempt to understand the mechanisms of the response, gallbladder perfusate and tissue prostanoid and PAF levels were quantitated as were serum PAF levels. LPS administration resulted in alteration of the normal absorptive pattern of the gallbladder mucosa to exsorption of fluid into the gallbladder lumen, increased tissue myeloperoxidase levels and increased serum PAF levels. This was associated with increased gallbladder tissue and perfusate prostanoid levels and increased perfusate PAF levels. Indomethacin prevented the pro-inflammatory changes in the gallbladder produced by LPS. The PAF antagonist, alprazolam, increased gallbladder prostanoid production when administered alone and with LPS. The administration of LPS resulted in the production of acute changes in the gallbladder consistent with cholecystitis. These changes being prevented by a cyclooxygenase inhibitor suggests that development of AAC may be related to the release of systemic and local pro-inflammatory substances.
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PMID:The production of experimental cholecystitis by endotoxin. 801 92

Tumor necrosis factor-alpha (TNF), an inflammatory cytokine released by macrophages, may be a mediator of lung injury during septicemia. We previously reported that the cyclooxygenase inhibitor ibuprofen and histamine receptor antagonists cimetidine (H2 antagonist) and diphenhydramine (H1 antagonist) attenuate lung injury and reduce circulating TNF surges during porcine sepsis. Since pulmonary alveolar macrophages (PAM) may participate in early sepsis by producing TNF, we hypothesized that the TNF activity of PAM is reduced by ibuprofen, cimetidine, and diphenhydramine. To test this, we examined changes in PAM-derived TNF bioactivity and cell viability of freshly isolated porcine PAM during exposure to bacterial endotoxin (LPS), ibuprofen, cimetidine, and diphenhydramine. The TNF activity (% L929 cytotoxicity of PAM conditioned medium) was elevated in LPS-stimulated PAM cultures (15 to 25% increase at 1 to 6 h and 40 to 43% increase at 6 to 48 h, compared with non-LPS-stimulated cultures), and ibuprofen (150 micrograms/ml) added with LPS decreased the TNF activity for 24 h (20 to 28% reduction at 1 to 24 h). Ibuprofen added 1 h after LPS was less effective in reducing the PAM-derived TNF activity (20 to 22% reduction at 2 to 6 h). Cimetidine (112 micrograms/ml) reduced the TNF activity of LPS-stimulated PAM cultures during the first 4 h of LPS exposure (15 to 24% decrease at 1 to 4 h). Diphenhydramine (150 micrograms/ml) attenuated the PAM-derived TNF activity but also decreased viability of PAM, indicating a toxic effect of this agent on PAM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacologic reduction in tumor necrosis factor activity of pulmonary alveolar macrophages. 809 99

The major pore-forming exotoxin of Staphylococcus aureus, staphylococcal alpha-toxin, causes thromboxane-mediated pulmonary hypertension and prostanoid-independent protracted vascular leakage in perfused rabbit lungs. We asked whether lung responsiveness to the staphylococcal agent would be altered by a preceding period of endotoxin priming. Isolated rabbit lungs were perfused with Krebs-Henseleit buffer in the presence or absence of 100 ng/ml Salmonella abortus equii endotoxin for up to 5 h. The lipopolysaccharide exposure evoked the release of large quantities of tumor necrosis factor into the vascular and alveolar spaces but did not significantly alter pulmonary artery pressure, organ weight, or the repeatedly assessed capillary filtration coefficient (Kfc). Two and 4 h after endotoxin administration, alpha-toxin (10 to 30 ng/ml) was bolus-injected into the pulmonary artery. Toxin-evoked prostanoid generation (TxB2, 6-keto-PGF1 alpha) and pressor responses were markedly accelerated and enhanced in endotoxin-primed lungs, both for the 2 h and the 4 h priming period. No significant influence of endotoxin was noted when applied simultaneously with alpha-toxin. Cyclooxygenase inhibition suppressed the alpha-toxin-evoked pressure rise in both endotoxin-primed and nonprimed lungs. Endotoxin priming did not influence the alpha-toxin-induced protracted increase in Kfc values, assessed in the presence of cyclooxygenase inhibition. We conclude that endotoxin primes rabbit lungs for enhanced prostanoid generation and pulmonary hypertension in response to S. aureus alpha-toxin. Such cooperativity of endotoxin priming and exotoxin triggering may be relevant in critically ill patients suffering from both endotoxemia and gram-positive sepsis.
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PMID:Endotoxin primes perfused rabbit lungs for enhanced vasoconstrictor response to staphylococcal alpha-toxin. 823 51

Eicosanoids were discovered as "prostaglandins" in the mid-1930s. The discovery that eicosanoids were ubiquitous in mammalian cells and that nonsteroidal anti-inflammatory drugs worked by inhibiting enzymes that synthesized these chemicals heralded their extensive investigation in all fields of biology. Precursor fatty acids (arachidonic acids) are stored in cell phospholipids, acted on by two enzymes (cyclooxygenase and lipooxygenase) that yield prostaglandins, thromboxane, prostacyclin, and leukotrienes. Knowledge of their biochemical processes continue to unfold, but it is now believed that eicosanoids are part of a larger group of agents termed phospholipid mediators. Eicosanoids are intimately involved with cardiovascular function as well as central and peripheral vascular disease processes and ischemia. In the gastrointestinal tract, these potent lipids not only participate in many normal functions (eg, acid secretion and motility) but also in disease states (eg, inflammatory bowel disease and peptic ulcer disease). In shocklike states of sepsis and/or endotoxemia, eicosanoids have assumed a major role in many events that occur. Recently, discoveries have demonstrated that platelet-activating and tumor necrosis factors exert their effects in part through eicosanoids. The future will demonstrate these compounds to be critical not only in intracellular (molecular) events but also in the effects they produce that are far from the source of origin.
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PMID:Eicosanoids. Critical agents in the physiological process and cellular injury. 823 81

We analyzed differences in host regulation of tumor necrosis factor-alpha (TNF-alpha) production and pathophysiological responses in conscious rats after infection with two strains of pathogenic Candida albicans spp. (CA-1 and CA-2) compared with Escherichia coli serotype 055:B5 (EC). The hypothesis was tested that, in contrast to EC, hypotension, organ injury, and mortality after candidemia are not obligatorily dependent on TNF-alpha or TNF-alpha-induced cyclooxygenase pathway metabolites. Dose, viability, and strain-specific dependencies were established after intravenous 10(6) or 10(9) viable CA, as well as heat-killed (HK) or Formalin-inactivated (FI) CA blastospores, compared with live EC at the 24-h LD25 [10(9) colony-forming units (CFU)] and LD100 (10(10) CFU). Shock without endotoxemia developed 4-8 h after 10(9) live CA-1 or CA-2 (LD100 at 24 h) with disseminated yeast-mycelial transformation and increased microvascular permeability in multiple organs but not after HK or FI CA-1. Peak serum TNF-alpha after an LD100 of CA-1 or CA-2 was < 3% of LD25 EC values and was < 1% of peak values during lethal bacteremia. Similar pathogen-specific differences were found in liver- and lung-associated TNF. Production of functionally inactive TNF-alpha during candidemia was excluded by enzyme-linked immunosorbent assay and sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Western blotting. Passive immunization against TNF-alpha 2 h before microbial challenge was not protective against CA but prevented otherwise lethal EC sepsis. Cyclooxygenase inhibition also failed to attenuate candidemic shock. We conclude that the magnitude and kinetics of TNF-alpha production and TNF-alpha-dependent immunophysiological responses are differentially regulated after lethal fungal vs. gram-negative bacterial infection. Thus TNF-alpha is not a pivotal mediator of the acute Candida septic shock syndrome with disseminated candidiasis.
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PMID:TNF-alpha and cyclooxygenase metabolites do not modulate C. albicans septic shock with disseminated candidiasis. 833 78

Cyclooxygenase products are believed to be a major regulator of host tumor necrosis factor-alpha (TNF-alpha) production in response to trauma and sepsis. To study this relationship, Lewis rats underwent a 30% burn or sham burn. Dimethyl-prostaglandin E (dPGE, 50 micrograms/kg), ibuprofen (IFU, 2 mg/kg), or saline was administered twice daily. Rats were sacrificed at Day 7 to obtain Kupffer cells, peritoneal macrophages, splenic macrophages, and neutrophils. For in vivo studies, 10(6) cells from each group were cultured with 10 micrograms of lipopolysaccharide (LPS). For in vitro studies, cells from the burn and sham groups were cultured with LPS and dPGE (10 micrograms/ml), IBU (10 micrograms/ml), or saline. The supernatants were harvested after 2, 6, and 24 hr of culture and assayed for TNF-alpha (mu/ml) by L929 cytolysis. Burn injury resulted in a significant increase in Kupffer cell and neutrophil TNF-alpha production compared to the sham group (P < 0.001, ANOVA). The administration of IBU to burned animals led to a pronounced elevation of TNF-alpha production by Kupffer cells, peritoneal macrophages, and neutrophils compared to vehicle-treated burned animals (P < 0.001, ANOVA). With in vitro studies, IBU increased Kupffer cell, peritoneal macrophage, and neutrophil TNF-alpha release by 213, 327, and 198%, respectively (P < 0.05, ANOVA). dPGE caused a marked decrease in Kupffer cell and peritoneal macrophage TNF-alpha synthesis by 50 and 43%, respectively (P < 0.01, ANOVA). In conclusion, prostaglandins are critical for down regulating TNF-alpha production. Clinical use of cyclooxygenase inhibitors may result in adverse outcomes due to the excessive TNF-alpha production.
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PMID:Blockade of prostaglandin products augments macrophage and neutrophil tumor necrosis factor synthesis in burn injury. 836 Nov 73

1. In patients with sepsis syndrome, plasma levels of ET-LI and NA were elevated. In the porcine endotoxin shock model, plasma ET-1-L1 levels were also elevated and increased plasma levels of NA, A and NPY-LI indicated enhanced sympatho-adrenal activation. 2. ET-1 infusion in healthy human subjects to arterial plasma levels of ET-1-LI below or similar to those seen in patients with sepsis syndrome, induced a fall in splanchnic and renal blood flow, indicating that circulating ET-1-LI at levels seen in sepsis syndrome, have vasoactive effects. 3. In man, ET-1-LI was extracted in the pulmonary, splanchnic, renal and skeletal muscle vascular beds, but not in the cerebral circulation. The pulmonary circulation eliminated almost half of the administered ET-1. Apart from an initial short half-life of plasma ET-1-LI (1-2 min) after infusion, a prolonged presence of slightly elevated plasma ET-1-LI may have contributed to the long-lasting vasoconstrictor effect of the peptide in lung, splanchnic and renal circulations. In contrast, signs of vasodilation were present in the cerebral and skeletal muscle circulations, indicating net ETB receptor activation in these vascular beds. In the pig, upon infusion of similar doses of ET-1, the vascular response was slightly smaller than that in man while the pulmonary fractional extraction of ET-1-LI was similar in both species. At high levels of ET-1-LI the extraction capacity in the pig lung was saturated. Pretreatment with diclofenac did not significantly change the cardiovascular response to ET-1 nor plasma levels of ET-1-LI or the disappearance rate of ET-1-LI after infusion. 4. In the pig, pretreatment with diclofenac led to a more stable haemodynamic course during endotoxin infusion. Further, it abolished the first peak in the biphasic increase in PAP and PVR seen in endotoxin controls, indicating participation of products from the cyclooxygenase pathway in both the pulmonary hypertension and systemic hypotension seen in endotoxin shock. The increase in arterial plasma levels of ET-1-LI was delayed but not reduced by diclofenac whereas the activation of the sympathetic nervous system was attenuated. 5. A low dose of inhaled NO (10 ppm) markedly reduced the second, more prolonged phase of pulmonary hypertension during endotoxaemia. No signs of tachyphylaxis was seen during 2.5 h of NO inhalation, and upon cessation a rapid (within 15 min) elevation of PAP and PVR was seen. The effect was selective to the lung circulation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Circulatory responses to endothelin-1 and nitric oxide with special reference to endotoxin shock and nitric oxide inhalation. 837 40

The present studies evaluated the role cyclooxygenase products play in bacterial sepsis induced pulmonary injury in the rat. Lung injury was assessed by determining the pulmonary capillary filtration coefficient (Kf) and the lung lavage protein concentration four and 18 hours after cecal ligation and puncture. Four hours after cecal ligation, the Kf was unchanged from control, however, by 18 hours, the Kf was increased 171% (p < .05). Similarly, lung lavage protein levels were unchanged four hours after cecal ligation but were significantly (p < .05) elevated at 18 hours. On the other hand, pulmonary lavage immunoreactive thromboxane B2 (iTXB2) levels were increased both four and 18 hours after the initiation of sepsis. In order to determine if cyclooxygenase products played a role in the sepsis associated lung injury, ibuprofen was administered prior to cecal ligation. Ibuprofen pretreatment prevented the sepsis associated increase in both Kf and lung lavage protein concentration. These studies suggest that bacterial sepsis in the rat is associated with pulmonary injury and that early administration of ibuprofen ameliorates this damage.
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PMID:Cecal ligation and puncture is associated with pulmonary injury in the rat: role of cyclooxygenase pathway products. 849 58

The production of tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 and their pharmacomodulation were evaluated in a model of polymicrobial sepsis induced in mice by cecal ligation and puncture (CLP) and were compared with the effects of endotoxin (lipopolysaccharide [LPS]) treatment. LPS levels rose as early as 1 h after CLP and increased further after 2 and 21 h. TNF-alpha was detectable in serum, spleen, liver, and lungs during the first 4 h, with a peak 2 h after CLP. IL-1 beta was measurable in serum after 24 h, and levels increased significantly in spleen and liver 4 and 8 h after CLP. IL-6 levels increased significantly in serum throughout the first 16 h after CLP. These cytokines were detectable after LPS injection, with kinetics similar to those after CLP but at a significantly higher level. To cast more light on the differences between these two animal models of septic shock, we studied the effects of different reference drugs. Pretreatment with dexamethasone (DEX); ibuprofen (IBU), an inhibitor of cyclooxygenase; and NG-nitro-L-arginine, an inhibitor of nitric oxide synthase, significantly reduced survival, while chlorpromazine (CPZ) and TNF did not affect it. Only the antibiotics and pentoxifylline significantly increased survival in mice with CLP. However, CPZ and DEX protected the mice from LPS mortality. On inhibiting TNF-alpha with DEX, CPZ, or pentoxifylline, survival was reduced, unchanged, and increased, respectively, and on increasing TNF-alpha with IBU and TNF, survival was decreased or unchanged, respectively, suggesting that the modulation of this cytokine does not play a significant role in sepsis induced by CLP, unlike treatment with LPS. The negative effects of IBU and N(G)-nitro-L-arginine suggest a protective role by prostaglandins and nitric oxide in sepsis induced by CLP.
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PMID:Pattern of cytokines and pharmacomodulation in sepsis induced by cecal ligation and puncture compared with that induced by endotoxin. 854 33

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