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)

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

It is well known that patients who undergo surgical operations have a high risk of infection and sepsis. One explanation for this high risk may be a depression of neutrophil functions at the postoperative period. In the present study, the effects of surgical stresses on neutrophil functions were studied in ten patients who underwent general anesthesia and major surgery. The neutrophil functions especially focused on were the producing capacities of 5-lipoxygenase metabolites of arachidonic acid such as Leukotriene B4 (LTB4), LTC4, LTD4, 6-trans-LTB4, and w-oxidation products of LTB4. Neutrophils were stimulated with calcium-ionophore A23187 (2x10(-5) M) in the presence of arachidonic acid (5x10(-5) M) for 5 minutes at 37 degrees C. The arachidonic acid metabolites were extracted by methanol. After centrifugation, the supernatant of the mixture was concentrated and applied to a C-18 column on reversed phase high performance liquid chromatography (RP-HPLC) system, monitoring the absorbance at 280 nm. In all cases, the LTB4 production significantly increased postoperatively with an increment of 6-trans-LTB4 and w-oxidation products of LTB4. The LTC4 production, by contrast, significantly decreased postoperatively. LTD4 production was observed at neither pre nor postoperative periods. The total amount of LTA4 metabolites at the postoperative period, including LTB4, LTC4, and 6-trans-LTB4, increased 1.2 times compared with that at preoperative period. This indicates the possibility of the alteration of the neutrophil metabolism in 5-lipoxygenase cascade, the increment of LTA4 generation and the change of LTA4 metabolism from LTC4 synthesis to LTB4 generating pathway.
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PMID:Neutrophil producing capacity of 5-lipoxygenase metabolites of arachidonic acid after major surgery. 260 90

Administration of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (5 mg/kg s.c.) provoked acute microvascular injury (assessed by the leakage of radiolabelled human serum albumin) in the rat colon within 1 h, when administered concurrently with endotoxin (Escherichia coli lipopolysaccharide, 3 mg/kg i.v.). Pretreatment with the selective inhibitor of 5-lipoxygenase, BW A137C (N-[4-benzyloxybenzyl] acetohydroxamic acid; 1-20 mg/kg s.c., 15 min before endotoxin) attenuated such damage in a dose-dependent manner. These findings suggest a balance between protective constitutive nitric oxide and the detrimental actions of 5-lipoxygenase products in the maintenance of vascular integrity in the early stage of sepsis.
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PMID:Colonic microvascular integrity in acute endotoxaemia: interactions between constitutive nitric oxide and 5-lipoxygenase products. 749 98

Ninety minutes after i.v. injection of Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) into rats, phorbol 12-myristate 13-acetate (PMA)-stimulated superoxide anion (O2-) secretion was enhanced in suspensions of in vivo LPS-treated alveolar macrophages (AM phi) when compared with saline (SAL)-treated AM phi. The purpose of this investigation was to dissect the in vitro mechanism of PMA-stimulated O2- generation in both LPS and SAL-treated rat AM phi, with a panel of inhibitors of protein kinase C (PKC), protein serine-threonine phosphatase(s) (PSP), protein tyrosine kinase(s) (PTK) and phosphatase(s) (PTP), phospholipase A2 (PLA2), cyclooxygenase (CO) and 5-lipoxygenase (5-LO). The following agents blocked PMA-stimulated O2- generation in both LPS- and SAL-treated AM phi (expressed as percentage of control): 1) PKC inhibitors: staurosporine: 100 nM, 7.0% (LPS) and 5.6% (SAL); sphingosine: 10 microM, 21% (LPS) and 10.5% (SAL); 2) PTK inhibitor: genistein: 100 microM, 44% (LPS) and 31% (SAL); 3) PTP inhibitors: phenylarsine oxide, 10 microM, 12.1% (LPS) and 18% (SAL); diamide, 1000 microM, 10.1% (LPS) and 10.5% (SAL); and 4) PLA2 inhibitors: manoalide: 1 microM, 29.3% (LPS) and 5.2% (SAL); scalaradial: 1 microM, 7.7% (LPS) and 7.1% (SAL); and WAY 125,984: 10 microM, 17.1% (LPS) and 14.5% (SAL). In addition, it was observed that exogenously added arachidonic acid (AA)-stimulated O2- generation in a time- and dose-dependent manner in both LPS and SAL-treated AM phi. The following inhibitors enhanced or did not affect PMA-stimulated O2- generation in LPS- and SAL-treated AM phi (expressed as percentage of of control): 1) PSP inhibitors: okadaic acid: 0.5 microM, 117% (LPS) and 153% (SAL); calyculin A: 1 microM, 112% (LPS) and 101% (SAL); 2) CO and 5-LO inhibitors: indomethacin: 10 microM, 107% (LPS) and 90% (SAL); WY 50, 295: 1 microM, 99% (LPS) and 103% (SAL); and 3) the PTP inhibitor orthovanadate upon prolonged preincubation. In both in vivo LPS- or SAL-primed AM phi, PMA-stimulated O2- generation appears to be modulated by PKC, PLA2, AA, PTK, PTP and PSP. No modulatory role was evident for either CO or 5-LO metabolites. These findings might bear on the design of therapeutic approaches for the modulation of O2- release by AM phi in the early stages of sepsis and adult respiratory distress syndrome.
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PMID:Modulation of superoxide generation in in vivo lipopolysaccharide-primed rat alveolar macrophages by arachidonic acid and inhibitors of protein kinase C, phospholipase A2, protein serine-threonine phosphatase(s), protein tyrosine kinase(s) and phosphatase(s). 761 27

The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.
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PMID:Delayed thromboxane or tumor necrosis factor-alpha, but not leukotriene inhibition, attenuates prolonged pulmonary hypertension in endotoxemia. 766 5

Platelet-activating factor (PAF) and the interferons (IFN) are released during sepsis and the adult respiratory distress syndrome. The proinflammatory nature of PAF and anti-inflammatory property of IFN led us to investigate interactions between these two mediators in an isolated perfused lung (IPL) preparation. In the IPL, mean pulmonary arterial pressure (Ppa), lung weight gain, and peak airway pressure (Paw) were monitored continuously for 1 h in six groups of rabbits: 1) control, 2) the IFN-alpha/beta inducer polyinosinic:cytidylic acid (polyI:C) alone, 3) PAF alone, 4) polyI:C + PAF, 5) indomethacin + PAF, and 6) AA861 (a 5-lipoxygenase inhibitor) + PAF. At the end of 1 h, microvascular pressure was determined by double-occlusion technique and partition of total pulmonary vascular resistance (RT) was calculated. Serial eicosanoid concentrations in the perfusate also were measured. PAF increased Ppa, Paw, lung weight gain, and RT. These changes were associated with increased thromboxane B2 and decreased leukotriene production. PolyI:C, which induced high levels of serum IFN in rabbits, blocked the PAF-induced increase in Ppa, Paw, lung weight gain, and RT, similar to indomethacin and AA861. PolyI:C suppressed PAF-stimulated release of thromboxane B2 and increased leukotriene levels in the perfusate. The PAF-induced lung responses also were attenuated by pretreatment with human recombinant IFN. These data indicate that polyI:C protects against PAF-induced responses in the rabbit IPL, most likely via its induction of IFN. This effect is related in part to inhibition of thromboxane A2 production stimulated by PAF and leukotrienes.
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PMID:Protection against platelet-activating factor-induced injury by interferon inducer in perfused rabbit lung. 844

The sepsis syndrome is associated with increased vascular permeability. Mediators may include platelet-activating factor (PAF) and leukotrienes. We conducted experiments in the hamster cheek pouch to determine the ability of a 5-lipoxygenase (5-LO) inhibitor and a PAF antagonist to attenuate the increase in microvascular permeability that results from tissue exposure to endotoxin. Endotoxin (Escherichia coli serotype 0127:B8) or saline was administered to the surface of the cheek pouch following systemic pretreatment with either the 5-LO inhibitor (Abbott-77523; 20 mg/kg, i.v.) or PAF antagonist (Abbott-84768: 1 mg/kg, i.v.). In control hamsters, endotoxin induced a large increase in fluorescein isothiocyanate-dextran leakage into the cheek pouch interstitium. This leakage was not associated with increased leukocyte rolling or adhesion to venular endothelium. In contrast, groups pretreated with the PAF antagonist or the 5-LO inhibitor showed little or no leakage in response to endotoxin. Therefore, PAF and leukotrienes are important mediators of endotoxin-induced increases in microvascular permeability to macromolecules.
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PMID:Inhibition of endotoxin-induced microvascular leakage by a platelet-activating factor antagonist and 5-lipoxygenase inhibitor. 859 25

In the present study, we have investigated the effects of nitric oxide (NO) synthase inhibition on mortality in lipopolysaccharide (LPS)-induced sepsis in mice. Serum nitrite levels peaked at 15 h after an injection of LPS (10 mg kg-1, i.p.). Aminoguanidine, a selective inducible NO synthase (iNOS) inhibitor, at a dose of 100 mg kg-1 significantly reduced the LPS-induced increase in nitrite levels and improved mortality. Econazole, iNOS inhibitor, calmodulin antagonist, 5-lipoxygenase and a specific thromboxane synthase inhibitor, at a 1 mg kg-1 dose significantly decreased the LPS-induced increase in nitrite levels, but increased mortality 4. 9-fold when compared to the LPS group (control). Indomethacin, a putative iNOS and non-selective cyclo-oxygenase (COX) inhibitor, of 1, 10 and 100 mg kg-1, dose dependently decreased the LPS-induced increase in nitrite levels. This decrease was significantly different from the control at 10 and 100 mg kg-1 dose levels. When indomethacin (100 mg kg-1) was combined with aminoguanidine (100 mg kg-1), LPS-induced nitrite levels were significantly attenuated. NO precursor, L-arginine, was added to this combination in order to test the inhibition of iNOS activity which resulted in no change in nitrite levels. An indomethacin and aminoguanidine combination increased mortality twofold when compared to the control. The addition of L-arginine to the combination enhanced the mortality rate to 1.5-fold. These results suggest that NO appears to play a role in the LPS-induced septic shock model in mice. The improvement in sepsis-induced mortality enhanced by aminoguanidine by the inhibition of iNOS but not with the other agents or combinations should be re-evaluated in order to make an appropriate choice of the therapeutic target. In addition, it may also suggest that other mediators, such as arachidonic acid products and cytokines play a role in septic shock pathogenesis as well. (c) 1998 The Italian Pharmacological Society.
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PMID:Effects of nitric oxide synthase inhibition in lipopolysaccharide-induced sepsis in mice. 980 22

LPS from bacteria can result in the development of sepsis syndrome and acute lung injury. Although acute exposure to endotoxin primes leukocytes for enhanced synthesis of leukotrienes (LT), little is known about the effect of chronic exposure. Therefore, we determined the effect of prolonged LPS treatment on 5-lipoxygenase (5-LO) metabolism of arachidonic acid in alveolar macrophages (AM) and in peripheral blood monocytes. Pretreatment of AM with LPS caused time- and dose-dependent suppression of LT synthetic capacity. LPS pretreatment failed to inhibit arachidonic acid (AA) release. The fact that LPS inhibited LT synthesis from endogenous AA more than from exogenous AA suggested an effect on 5-LO-activating protein (FLAP). In addition, an inhibitory effect of LPS treatment on AM 5-LO activity was suggested by cell-free 5-LO enzyme assay. No effect on the expression of either 5-LO or FLAP proteins was observed. New protein synthesis was necessary for LPS-induced reduction of 5-LO metabolism in AM, and immunoblotting demonstrated marked induction of NO synthase (NOS). Inhibition by LPS was reproduced by an NO donor and was abrogated by inhibitors of constitutive and inducible NOS. Compared with AM, peripheral blood monocytes exhibited no suppression by LPS of 5-LO metabolism and no induction of inducible NOS. We conclude that prolonged exposure to LPS impairs AM 5-LO metabolism by NO-mediated suppression of both 5-LO and FLAP function. Because LT contribute to antimicrobial defense, this down-regulation of 5-LO metabolism may contribute to the increased susceptibility to pneumonia in patients following sepsis.
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PMID:Prolonged exposure to lipopolysaccharide inhibits macrophage 5-lipoxygenase metabolism via induction of nitric oxide synthesis. 1103 60

Sepsis and endotoxemia impair hypoxic pulmonary vasoconstriction (HPV), thereby reducing systemic oxygenation. To assess the role of leukotrienes (LTs) in the attenuation of HPV during endotoxemia, the increase in left lung pulmonary vascular resistance (LPVR) before and during left mainstem bronchus occlusion (LMBO) was measured in mice with and without a deletion of the gene encoding 5-lipoxygenase (5-LO). LMBO increased the LPVR equally in saline-challenged wild-type and 5-LO-deficient mice (96+/-20% and 94+/-19%, respectively). Twenty-two hours after challenge with Escherichia coli endotoxin, the ability of LMBO to increase LPVR was markedly impaired in wild-type mice (27+/-7%; P<0.05) but not in 5-LO-deficient mice (72+/-9%) or in wild-type mice pretreated with MK886, an inhibitor of 5-LO activity (76+/-10%). Compared with wild-type mice, endotoxin-induced disruption of lung structures and inflammatory cell influx in the lung were markedly attenuated in 5-LO-deficient mice. Administration of MK571, a selective cysteinyl LT(1) receptor antagonist, 1 hour before endotoxin challenge preserved HPV and attenuated pulmonary injury in wild-type mice but did not prevent the endotoxin-induced increase in pulmonary myeloperoxidase activity. Taken together, these findings demonstrate that a 5-LO product, most likely a cysteinyl LT, contributes to the attenuation of HPV and to pulmonary injury after challenge with endotoxin.
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PMID:Attenuation of hypoxic pulmonary vasoconstriction by endotoxemia requires 5-lipoxygenase in mice. 1132 76


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