Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034063 (pulmonary edema)
 10,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thromboxanes (Txs) were implicated as possible participants in the altered microvascular permeability of acute lung injury when the Tx synthase inhibitor, OKY-046, was reported to prevent pulmonary edema induced by phorbol myristate acetate (PMA). Recently, however, we found that OKY-046, at a dose just sufficient to block Tx synthesis in intact dogs, did not prevent PMA-induced pulmonary edema but rather merely reduced it modestly. The present study was designed to explore other mechanisms whereby OKY-046 might prevent PMA-induced pulmonary edema. The finding that 5-lipoxygenase (5-LO) metabolites of arachidonic acid were increased within the lung after PMA administration, coupled with the report that OKY-046 inhibited slow-reacting substance of anaphylaxis formation, permitted formulation of the hypothesis that OKY-046, at a dose in excess of that required to inhibit Tx synthesis, inhibits the formation of a product(s) of 5-LO and, thereby, prevents edema formation. In vehicle-pretreated pentobarbital-anesthetized male mongrel dogs (n = 4), PMA (20 micrograms/kg i.v.) increased pulmonary vascular resistance (PVR) from 4.4 +/- 0.3 to 26.3 +/- 8.8 mmHg.l-1 x min (P < 0.01) and extravascular lung water from 6.7 +/- 0.5 to 19.1 +/- 6.2 ml/kg body wt (P < 0.05). Concomitantly, both TxB2 and leukotriene B4 (LTB4) were significantly increased in the lung. Pretreatment with OKY-046 (100 mg/kg i.v., n = 8) prevented PMA-induced increases in TxB2, LTB4, and pulmonary edema formation but did not prevent the increase in PVR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:OKY-046 prevents increases in LTB4 and pulmonary edema in phorbol ester-induced lung injury in dogs. 133 76

Phosgene inhalation causes a severe noncardiogenic pulmonary edema characterized by an influx of neutrophils into the lung. To study the role of neutrophils in lung injury and mortality after phosgene, we investigated the effects of leukocyte depletion with cyclophosphamide, inhibiting the generation of the chemotaxin leukotriene B4 with the 5-lipoxygenase inhibitor AA861 and impairing neutrophil migration with the microtubular poison colchicine. Cyclophosphamide, AA861, and colchicine injected before exposure significantly reduced percent neutrophils, protein, and thiobarbituric acid-reactive products in bronchoalveolar lavage fluid of rats exposed to phosgene (0.5 ppm X 60 min). Cyclophosphamide, AA861, and colchicine also significantly decreased mortality from phosgene (2.0 ppm X 90 min) in mice. Colchicine significantly reduced neutrophil influx, lung injury, and mortality even when given 30 min after phosgene exposure. We conclude that lung injury and mortality after phosgene exposure are associated with an influx of neutrophils into the lung. Prevention of neutrophil migration with colchicine may hold therapeutic potential in phosgene poisoning.
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PMID:Reduction of neutrophil influx diminishes lung injury and mortality following phosgene inhalation. 165 61

Pseudomonas aeruginosa cytotoxin, a transmembrane pore-forming protein, causes an increase in pulmonary microvascular permeability with subsequent lung edema formation, possibly related to the induction of arachidonic acid (AA) lipoxygenase products. To investigate this, isolated rabbit lungs were perfused with cytotoxin-containing buffer (6.5 and 13 micrograms of toxin/ml). A severalfold increase in the capillary filtration coefficient was induced, both preceded and accompanied by a marked time- (15-60 min) and dose-dependent release of cysteinyl leukotrienes (LT), LTB4, and 5-, 12-, and 15-hydroxyeicosatetraenoic acids (HETEs) into the lung perfusate. In the bronchoalveolar lavage fluid, corresponding AA-derived products were detected; the total sum of HETEs surpassed that of cysteinyl LTs in this compartment. The lipoxygenase inhibitors AA861 (10 microM) and nordihydroguaiaretic acid (100 microM) and EGTA (5 mM) suppressed the intravascular and alveolar liberation of all 5-lipoxygenase-derived AA metabolites, paralleled by a marked reduction and retardation of microvascular permeability increase (AA861). It thus seems that Pseudomonas cytotoxin induces generation of LTs and HETEs in rabbit lungs that may contribute to the development of pulmonary microvascular injury evoked by this bacterial agent.
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PMID:Induction of vascular injury by Pseudomonas aeruginosa cytotoxin in rabbit lungs is associated with the generation of different leukotrienes and hydroxyeicosatetraenoic acids. 189 1

We evaluated the role of sulfidopeptide leukotrienes as mediators of endotoxin-induced respiratory failure in pigs. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h followed by 2 micrograms.kg-1.h-1 for 3 h in the presence and absence of LY171883, a specific leukotriene D4 (LTD4)/LTE4 receptor antagonist. Endotoxin caused hemoconcentration, granulocytopenia, decreased cardiac index, systemic hypotension, pulmonary hypertension, increased pulmonary vascular resistance, bronchoconstriction, hypoxemia, increased permeability of the alveolar-capillary membrane, pulmonary edema, and increased plasma concentrations of thromboxane B2 (TxB2), prostaglandin F2 alpha (PGF2 alpha), and 6-keto-PGF1 alpha. LY171883 did not modify endotoxin-induced cardiopulmonary and hematologic abnormalities, except for a modest attenuation of pulmonary hypertension (at 1 h) and increased pulmonary vascular resistance (at 1-2 h). Ex vivo stimulation of whole blood with calcium ionophore caused large increases in plasma concentrations of TxB2, PGF2 alpha, and LTB4. These increases were not significantly modified in blood derived from pigs treated with LY171883, indicating no inhibition of cyclooxygenase or 5-lipoxygenase. We conclude that LTD4 and LTE4 are not important mediators of endotoxin-induced lung injury in anesthetized pigs, although they may contribute modestly to pulmonary vasoconstriction.
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PMID:Effect of LY171883 on endotoxin-induced lung injury in pigs. 197 87

Leukoagglutinating antibodies have been implicated in the development of transfusion-related acute lung injury. In the present study, human neutrophil leukotriene generation was provoked by an anti-5b immunoglobulin G, isolated from a multiparous donor plasma that caused noncardiogenic lung edema during transfusion therapy. In 5b-positive polymorphonuclear neutrophils (PMNs), the antibody stimulated marked arachidonic acid metabolism, dependent on the presence of plasma as the complement source. Quantity and profile of lipid mediators (leukotriene B4 and its omega-oxidation products, 5-hydroxyeicosatetraenoic acid, and nonenzymatic hydrolysis products of leukotriene A4) corresponded to those repeatedly described after PMN in vitro stimulation with the artificial calcium ionophore A23187. Anti-5b challenge of PMNs sequestered in the microvasculature of perfused rabbit lungs did, however, induce a markedly modified metabolite profile. Nonenzymatic hydrolysis products of leukotriene A4 were not detected, and 5-hydroxyeicosatetraenoic acid was markedly reduced. In contrast, cysteinyl leukotrienes were measured as predominant compounds, with rapid appearance of leukotriene C4 and more protracted generation of leukotriene E4. Leukotriene B4 and its omega-oxidation products were released with similar kinetics, but in lower amounts, as compared with the isolated PMN stimulation. Anti-5b challenge of PMNs coincubated with pulmonary artery endothelial cells in vitro, but not stimulation of either cell type alone, provoked marked generation of cysteinyl leukotrienes. These findings suggest modulation of PMN 5-lipoxygenase metabolism in favor of leukotriene A4 transfer to adjacent acceptor cells with subsequent enzymatic conversion to cysteinyl leukotrienes under conditions of lung vascular sequestration. Endothelial cells appear to serve as predominant cooperative cells under circumstances of blood-free lung perfusion. PMN-related transcellular eicosanoid synthesis may be involved in the pathogenesis of transfusion-evoked acute lung injury.
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PMID:Human leukoagglutinating antibody evokes cooperative leukotriene synthesis in pulmonary microvasculature. Model of transfusion-related acute lung injury. 199 53

We hypothesized that platelet-activating factor (PAF) and eicosanoids might be important mediators of endotoxin-induced respiratory failure in pigs. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h, followed by 2 micrograms.kg-1.h-1 for 3 h in the presence and absence of SRI 63-675, a specific PAF receptor antagonist. During phase I (i.e., 0-2 h), endotoxin caused pulmonary hypertension and hypoxemia, decreased cardiac index, increased pulmonary vascular resistance, and increased plasma concentrations of thromboxane B2 (TxB2), prostaglandin (PG)F2 alpha, and 6-keto-PGF1 alpha. These phase I effects were attenuated or blocked by SRI 63-675 (10 mg/kg before endotoxin + 3 mg.kg-1.h-1 during endotoxemia). During phase II endotoxemia (i.e., 2-4 h), the PAF receptor antagonist blocked endotoxin-induced pulmonary edema and hypoxemia and increased relative permeability index of the alveolar-capillary membrane. SRI 63-675 also blocked the endotoxin-induced increases in plasma and bronchoalveolar lavage fluid concentrations of leukotriene B4 (LTB4). Ex vivo stimulation of whole blood with calcium ionophore caused large increases in plasma concentrations of TxB2 and LTB4. These increases were not significantly modified in blood derived from pigs treated with SRI 63-675, indicating no inhibition of cyclooxygenase or 5-lipoxygenase and suggesting that the in vivo effects were PAF receptor mediated. We conclude that PAF plays an important role in the release of eicosanoids during endotoxemia and in mediating, either directly or indirectly, endotoxin-induced lung injury in anesthetized pigs.
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PMID:Role of platelet-activating factor and eicosanoids during endotoxin-induced lung injury in pigs. 216 17

We examined the effect of phospholipase A2 (PLA2; Naja naja) challenge on pulmonary hemodynamics, airway constriction, and fluid filtration in isolated Ringer-perfused guinea pig lungs. Intratracheal PLA2 (10-100 U) produced dose-dependent increases in pulmonary arterial pressure, intratracheal pressure, and lung weight, although intravenous PLA2 administration had no effect on monitored variables. Morphological features indicative of airway constriction and pulmonary edema were observed by light microscopy. PLA2-induced increases in intratracheal pressure and/or lung weight were attenuated to varying degrees by pretreatment with indomethacin (1 microM, a cyclooxygenase inhibitor), ICI-198,615 (1 microM, a leukotriene D4 receptor antagonist), and WEB 2086 (1 microM, a platelet-activating factor antagonist). PLA2-induced increases in pulmonary arterial pressure and intratracheal pressure were also reduced in lungs removed from animals pretreated with dexamethasone (50 mg/kg ip for 2 days; a steroidal antiinflammatory agent). Pyrilamine (1 microM, a histamine1-receptor antagonist) and Takeda AA861 (1 microM, a delta 5-lipoxygenase inhibitor) did not produce significant inhibitory effects on PLA2-induced pathophysiological changes. Intratracheal instillation of high-dose platelet-activating factor (50 micrograms) or lysophosphatidylcholine (100 micrograms) produced gradual increases in intratracheal pressure and lung weight, but these changes were not as large as those induced by PLA2. Thus these studies suggest that resident cell populations associated with airways may play an important role in PLA2-induced pathophysiological changes in the perfused guinea pig lung. These PLA2-induced effects are most likely partially mediated by generation of eicosanoids and platelet-activating factor.
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PMID:Pulmonary responses to phospholipase A2 in the perfused guinea pig lung. 260 58

Intravenous injection of oleic acid (OA) induces acute, edematous lung injury resembling some of the features of adult respiratory distress syndrome. One class of inflammatory agents speculated to be mediators of acute lung injury are eicosanoids. We tested the hypothesis that 5-lipoxygenase and cyclooxygenase metabolites of arachidonic acid mediate the pulmonary injury induced by OA. OA (0.1 ml), injected as a bolus into the pulmonary artery (PA) of isolated, Krebs-perfused rabbit lungs, resulted in significant (P less than .05) increases in lung weight (an index of pulmonary edema), maximum airway pressure, perfusate immunoreactive (i) 6-keto PGF1a, and a significant, though minimal, increase in perfusate i-thromboxane B2. No measurable increases were recorded in PA pressure or perfusate i-leukotriene (LT) C4/D4. Neither pretreatment with the LTD4/E4 antagonist, LY171883 (10 microM), nor the 5-lipoxygenase/cyclooxygenase inhibitor, BW755C (100 microM), attenuated the pulmonary edema. However, BW755C abrogated the increase in i6-keto PGF1a. Additionally, administration of exogenous LTD4 (100 nM) into the perfusate produced only a minimal increase in lung weight in the isolated rabbit lungs (n = 4). These results demonstrate that 5-lipoxygenase and cyclooxygenase metabolites do not appear to mediate OA-induced injury in the isolated, Krebs-perfused rabbit lung.
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PMID:Oleic acid induces pulmonary injury independent of eicosanoids in the isolated, perfused rabbit lung. 311 57

It is known that reactive oxygen species cause lung injury in association with activation of arachidonate metabolism. Because metabolites of the cyclooxygenase pathway do not appear to mediate the injury, we considered that the 5-lipoxygenase pathway might be activated and that inhibition of the pathway could interfere with the development of the injury. Thus, we sought to induce an oxidant lung injury and to prevent such injury by inhibiting lipoxygenase pathway or by blocking leukotriene action. In isolated rat lungs, glucose oxidase added to a glucose-containing, cell-free perfusate was used to produce the injurious oxygen species. Lung edema occurred and increased with increasing oxygen tension in the inspired air. Light microscopy of the lung showed perivascular fluid cuffs, and electron microscopy showed endothelial cell damage. Measurements in the lung effluent showed that concentrations of 5-hydroxyeicosatetraenoic acid (5-HETE) and of cyclooxygenase metabolites increased after glucose oxidase administration; BW 755C, U60,257, and FPL 55712 inhibited the glucose-oxidase-induced lung edema. And U60,257 also inhibited the glucose-oxidase-induced increase in 5-HETE without concomitant inhibition of cyclooxygenase metabolites. Thus, glucose oxidase via generation of active oxygen species stimulated the lung 5-lipoxygenase pathway, and inhibitors of 5-lipoxygenase protected against the oxidant lung injury. Further, in these experiments, the injury occurred in the absence of circulating blood cells and was augmented by increasing the inspired oxygen concentration.
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PMID:Leukotriene inhibitors attenuate rat lung injury induced by hydrogen peroxide. 392 81

Platelet-activating factor (PAF) is a cell membrane-derived ether lipid that plays an important role in acute lung vascular injury. We recently reported that PAF potentiates protamine-induced lung edema by enhancing pulmonary venoconstriction. As PAF is known to stimulate lung eicosanoid synthesis, we investigated the role of peptidoleukotrienes and other eicosanoids in this priming effect of PAF. Addition of PAF (1.6 nM), followed 10 min later by protamine (50 micrograms/ml), to perfusate of salt solution-perfused rat lungs resulted in marked arterial and venous constrictions and severe lung edema. Lung tissue thromboxane B2, 6-ketoprostaglandin F1 alpha and leukotriene C4 (LTC4) were markedly elevated 20 min after PAF/protamine. Pretreatment of the lungs with AA-861, a specific 5-lipoxygenase inhibitor, blocked PAF/protamine-induced leukotriene synthesis, arterial and venous constrictions, and lung edema. In addition, injection of LTC4 (1 microgram) markedly potentiated protamine-induced arterial and venous constrictions and caused lung edema similar to PAF/protamine. Indomethacin, a specific cyclooxygenase inhibitor, also reduced the vasoconstrictive and edemagenic responses to PAF/protamine. However, the pulmonary edema after LTC4/protamine was not blocked by indomethacin. In separate experiments, infusion of this "priming" dose of PAF into isolated perfused lungs induced LTC4 synthesis and augmented lung thromboxane A2 synthesis after arachidonic acid infusion. We conclude that both cyclooxygenase and lipoxygenase products of arachidonic acid metabolism are involved in PAF-induced potentiation of protamine lung edema.
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PMID:Platelet-activating factor potentiates protamine-induced lung edema. Role of eicosanoids. 811 95


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