Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.13.11.12 (lipoxygenase)
 8,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aerosolized doses of the ionophore, A23187, and arachidonic acid individually resulted in no airway response in rhesus monkeys. When these two agents were given simultaneously, by aerosol, an airway response occurred. The pulmonary function abnormalities that occurred qualitatively simulated those of an antigen-induced airway response. This is the first demonstration in our laboratory of two agents which singly will not produce a response but which are reactive when delivered in combination. Other fatty acids did not produce a similar response. The response to A23187 and arachidonic acid occurred only in rhesus monkeys from our colony which had been demonstrated to have airway responses to aerosolized antigen challenge, a response shown previously to be associated with hyperreactive airways to pharmacologic stimuli. The A23187 and arachidonic acid response was inhibited by aerosolized 5,8,11,14-eicosatetraynoic acid, an inhibitor of the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism. Further, indomethacin, a prostaglandin synthetase inhibitor of the cyclooxygenase pathway, inhibited the response, although previous studies showed that this drug will potentiate an antigen-induced response in this animal model of asthma. The slow-reacting substance of anaphylaxis antagonist, FPL 55712, did not inhibit the A23187-arachidonic acid response under the conditions of these experiments. The mechanism of the A23187-arachidonic acid airway response in rhesus monkeys may or may not be the same as the antigen-induced response.
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PMID:Ionophore and arachidonic acid stimulation of airway responses in rhesus monkeys. 10 72

Acid aspiration leads to thromboxane-dependent lung neutrophil sequestration associated with microvascular permeability increase. Leukotriene B4 (LTB4) is postulated to be a cofactor in the thromboxane-induced inflammatory response. This study tests the interaction between LTB4 and thromboxane, focusing on LTB4 induction of thromboxane-dependent lung neutrophil sequestration after acid aspiration. Anesthetized rats underwent tracheostomy and insertion of a cannula in a left lung segment. This was followed by instillation of either 0.1 ml 0.1N hydrochloric acid (n = 18) or 0.1 ml saline in control rats (n = 18). When assayed at 3 hours, acid aspiration led to increased plasma levels of LTB4 and thromboxane B2 (TxB2), higher than control values (p less than 0.05). The rise in plasma LTB4 was correlated (p less than 0.05; r = 0.83) with sequestration of neutrophils in the nonaspirated lung. The entrapment of thromboxane-dependent lung neutrophil was associated with an increase in protein concentration in bronchoalveolar lavage of the aspirated and nonaspirated sides and an increase in lung wet to dry weight ratio. Pretreatment of other rats (n = 18) with the lipoxygenase inhibitor diethylcarbamazine IV prevented an aspiration-induced rise in plasma LTB4 and TxB2. Further, there was an attenuation of lung leukosequestration and protein leak in bronchoalveolar lavage and lung edema (all p less than 0.05). Pretreatment of other rats (n = 12) with the leukotriene receptor antagonist FPL 55712 IV did not prevent the aspiration-induced rise in LTB4 or TxB2, but otherwise was as effective as diethylcarbamazine in preventing injury. Finally, other hydrochloric acid-aspirated rats (n = 8) were pretreated intravenously with the thromboxane synthetase inhibitor OKY 046 or the thromboxane receptor antagonist SQ 29548. Both agents limited the aspiration-induced rise in plasma LTB4 (p less than 0.05). The data indicate that localized acid aspiration induces synthesis of LTB4 and thromboxane A2. Inhibition of either leukotriene or thromboxane will limit PMN adhesion and increased lung permeability.
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PMID:Synergism between leukotriene B4 and thromboxane A2 in mediating acid-aspiration injury. 130 2

Exposure of rats to ozone (O3) produces an increase in airway permeability and a concomitant influx of polymorphonuclear leukocytes in the lung. These observations raise the possibility that the inflammatory cells play a role in the cellular injury and increased airway permeability after O3 exposure. This study was therefore designed to determine if the inflammatory cells or their products are essential for the O3 effect. In a series of experiments, rats were rendered leukopenic with cyclophosphamide, treated with leukotriene B4 (LTB4), or with the inhibitors of lipoxygenase or cyclooxygenase products of arachidonic acid, followed by exposure to O3. A 2-h exposure to 0.8 ppm O3 caused a significant increase in the flux of proteins and albumin in bronchoalveolar lavage (BAL) and elevated the transport of 99mTc-diethylenetriaminepentaacetate (99mTc-DTPA) from trachea to blood. The treatment with cyclophosphamide caused a significant reduction in the circulating and pulmonary leukocytes and prevented an increase in tracheal mucosal permeability to 99mTc-DTPA and the protein and albumin flux in BAL. While the intratracheal instillation of LTB4 did not affect the permeability, tracheal permeability and albumin levels in BAL in rats treated with LTD4 antagonist FPL 55712 and exposed to O3 were lower than in the untreated O3-exposed rats. Pretreatment with indomethacin also prevented the O3 effects, as reflected by the decreased protein and albumin flux in BAL and 99mTc-DTPA transport from trachea to blood. These data show a reduction in the effect of O3 by agents that affect leukocytes or their products. The results support a mechanism of increased permeability that is dependent upon inflammatory cells and their products.
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PMID:Attenuation of ozone-induced airway permeability in rats by pretreatment with cyclophosphamide, FPL 55712, and indomethacin. 132 Sep 4

The objective of this study was to determine whether the metabolism of arachidonic acid via the cyclooxygenase pathway, the lipoxygenase pathway, or both has a pivotal role in the human sperm acrosome reaction. To do so, the stimulatory effect of arachidonic acid and a number of its metabolites, as well as the inhibitory effect of cyclooxygenase and lipoxygenase inhibitors on the acrosome reaction, was evaluated. Arachidonic acid, prostaglandin E2, and prostacyclin (PGI2) induced the acrosome reaction when added to 3-hour preincubated (capacitated) spermatozoa. The arachidonic acid-induced acrosome reaction was dependent upon extracellular calcium. Leukotriene B4 and 15-HPETE only induced the acrosome reaction when present throughout the preincubation period, indicating that they may enhance the capacitation process rather than the acrosome reaction. Thromboxane did not affect the acrosome reaction under any of the conditions tested. Inhibitors of cyclooxygenase (indomethacin, phenylbutazone) and lipoxygenase (phenidone, nordihydroguiaretic acid) or FPL 55712 (a leukotriene antagonist) did not prevent the arachidonic acid-stimulated acrosome reaction. Furthermore, 5, 8, 11, 14-eicosatetraynoic acid (ETYA), the acetylenic analog of arachidonic acid that inhibits arachidonic acid metabolism, induced an acrosome reaction equivalent to that of arachidonic acid. These results strongly suggest that the acrosome reaction induced by exogenous arachidonic acid is not mediated via either the cyclooxygenase pathway or the lipoxygenase pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The human sperm acrosome reaction does not depend on arachidonic acid metabolism via the cyclooxygenase and lipoxygenase pathways. 133 69

To clarify the mechanism of hypoxic pulmonary vasoconstriction in man, human pulmonary artery segments (2 mm O.D.) were suspended and changes in isometric force were measured. The arteries were contracted by hypoxia (PO2 43 +/- 2 Torr) developing a tension of 127 +/- 36 mg over the course of 15 min. This contraction was completely blocked by 10(-6) M L-isoproterenol, 10(-6) M nitroglycerin, partially blocked by 10(-8)-10(-6) M verapamil, unchanged by 10(-6) M phentolamine, 10(-6) M L-propranolol, 10(-6) M diphenhydramine, 10(-6) M guanethidine, 10(-7) M FPL 55712 and enhanced by 10(-6) M BAY K 8644, 10(-3) M procaine, 3 x 10(-6) M quinacrine, 10(-6) M indomethacin or 10(-6) M methylene blue. Removal of the endothelium significantly enhanced the magnitude of hypoxia-induced contraction. These results suggest that the human pulmonary artery constricts in response to hypoxia, at least in part, through activation of the voltage-dependent Ca2+ channels and that neither alpha, beta, H1 receptors, the lipoxygenase pathway nor neural reflexes are involved. They also show that the endothelium is not required for hypoxic contraction and that its presence reduces sensitivity to hypoxia.
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PMID:Hypoxic contraction of pre-stretched human pulmonary artery. 137 51

1. Intravenous administration of substance P (SP) or of the NK1 selective agonist [beta-Ala4, Sar9, Met (O2)11] SP-(4-11) increased vascular permeability in the urinary bladder of urethane-anaesthetized rats, providing evidence for an NK1 receptor-mediated inflammatory response. 2. BW 755C, a dual inhibitor of arachidonate cyclo-oxygenase and lipoxygenase, significantly reduced the plasma extravasation induced by SP, but did not modify the effect of [beta-Ala4, Sar9, Met (O2)11] SP-(4-11). 3. SP-induced microvascular leakage was also inhibited by systemic pretreatment with indomethacin or with the prostaglandin receptor antagonist SC-19220, while it was unaffected by the selective 5-lipoxygenase inhibitor BW A4C or the leukotriene antagonist FPL 55712. 4. Pretreatment of rats with the mast cell degranulating agent compound 48/80 significantly attenuated the inflammatory effect of SP. Indomethacin administration to 48/80-pretreated animals failed to produce further inhibition. 5. These findings indicate that intravascular SP promotes plasma exudation in rat urinary bladder through an NK1-mediated effect on venular permeability and the release of cyclo-oxygenase metabolites of arachidonic acid. The latter effect largely derives from the interaction of the neuropeptide with mast cells.
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PMID:Microvascular leakage induced by substance P in rat urinary bladder: involvement of cyclo-oxygenase metabolites of arachidonic acid. 138 Sep 64

Rat hind-paw swelling was induced dose-dependently by subplantar injection of acidic phospholipase A2 (NNAVPLA2) from Naja naja atra venom. Diphenhydramine and methysergide pretreatment greatly reduced the swelling effect caused by NNAVPLA2. Several doses of compound 48/80 given to deplete the histamine content of rat hind paw, also greatly suppressed NNAVPLA2-induced paw swelling. The paw swelling caused by NNAVPLA2 was reduced following pretreatment with BW 755C, a dual inhibitor of cyclooxygenase/lipoxygenase, or subplantar co-injection with FPL 55712, a SRS-A antagonist, while pretreatment with acetylsalicylic acid had no effect. Captopril significantly potentiated the NNAVPLA2-induced paw swelling. The recovered myeloperoxidase activity was increased within 1 h and still elevated in the rat paw 3 to 6 h after subplantar injection of NNAVPLA2. In isolated peripheral PMN leukocyte suspension, NNAVPLA2 caused a release of superoxide radical. Subplantar co-injection with superoxide dismutase/catalase significantly inhibited NNAVPLA2-induced paw swelling. NNAVPLA2 did not trigger platelet aggregation either in platelet-rich plasma or in washed platelet suspension. NNAVPLA2-induced hind-paw swelling was also suppressed by the pretreatment with isoprenaline or terbutaline, while this response was not affected by co-injection with BN 52021, a PAF antagonist, into the paw. It is concluded that the hind-paw swelling caused by NNAVPLA2 is mainly due to histamine and serotonin released from mast cells and partly due to the formed kinins and SRS-A in the inflammatory area, and superoxide radical from PMN leukocytes.
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PMID:Effects of anti-inflammatory drugs on rat hind-paw swelling caused by phospholipase A2 from Naja naja atra venom. 168 89

We investigated the roles of eicosanoid mediators in acute systemic anaphylaxis in anesthetized sheep. Sheep were sensitized with dinitrophenylated Ascaris suum extract and were challenged with an intravenous injection of dinitrophenylated bovine serum albumin. During anaphylaxis, cyclooxygenase inhibitors eliminated the elevation of arterial plasma levels of thromboxane B2 and 6-ketoprostaglandin F 1 alpha but markedly elevated the levels of leukotriene E4 in lung lymph without significantly eliminating elevation of plasma levels of histamine. Most of the measured physiological abnormalities accompanying anaphylaxis were aggravated by cyclooxygenase blockade. Enhancement of this anaphylactic mediator response was associated with an accentuated and prolonged increase of airway pressure (P less than 0.05, compared with sensitized, antigen-challenged but otherwise untreated sheep), a more intense hypoxemia (P less than 0.0001), and leukopenia (P less than 0.001), changes that were largely eliminated by pretreating with the sulfidopeptide leukotriene (SPLT) antagonist FPL 55712, suggesting that the SPLTs were important mediators of these responses. In contrast, the prolonged, but less severe, systemic vascular collapse and the reduced pulmonary hypertension induced by cyclooxygenase inhibitors were not influenced by the SPLT antagonist. These results demonstrate that in sheep cyclooxygenase metabolites are mainly involved in the acute, but transient, systemic and pulmonary vascular response of systemic anaphylaxis, whereas SPLTs are primarily implicated in the airway and secondary cardiovascular response. SPLT may act either directly or by potentiating the release of and reactivity to histamine and other mediators. Our data therefore suggest that a combination of cyclooxygenase and lipoxygenase inhibition will be necessary to more effectively protect against the consequences of an anaphylactic reaction.
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PMID:Leukotrienes, thromboxane A2, and prostaglandins during systemic anaphylaxis in sheep. 171 64

1. Parameters of isolated hearts from rats which were actively sensitized to ovalbumin were found to be impaired on ovalbumin challenge: the heart rate increased whereas the contractility force and coronary flow decreased significantly. 2. Treatment in vivo or in vitro with histamine receptor antagonists (promethacine and cimetidine), the leukotriene antagonist FPL 55712, the PAF antagonist BN 52021, the combined prostaglandin endoperoxide receptor antagonist/thromboxane A2 synthesis inhibitor R 68070, the thromboxane synthetase inhibitor HOE 944, the lipoxygenase inhibitor ZIMET 47/79, the antioxidant sodium hyposulfite or with dexamethasone caused a different improvement of the parameters to a different degree. 3. Consequently, histamine, leukotrienes, PAF, activated oxygen, thomboxane A2 and possibly further autacoids might be involved in mediating the described anaphylactic reaction.
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PMID:Rat heart anaphylaxis: influence of mediator antagonists. 193

The effects of endogenous arachidonic acid (AA) metabolites on inherent tone and histamine-induced constriction were studied in guinea pig tracheal smooth muscle. Inhibitors of either cyclooxygenase (indomethacin) or lipoxygenase (AA 861) significantly diminished the inherent tone of the muscle. Antagonists of prostaglandins (SC 19220) or leukotrienes (FPL 55712) also diminished the inherent tone, whereas an inhibitor of thromboxane synthase (OKY 046) had no significant effect. These results show that the metabolites of the lipoxygenase pathway as well as prostaglandins also participate in the maintenance of inherent tone. To reexamine the previously reported augmentation of histamine constriction induced by the inhibitors and the antagonists, we compared the active tension of the muscle measured from the maximum relaxed level as the base line to eliminate the fluctuation of inherent tone. Such comparison revealed that the inhibitors and the antagonists have no augmentative effect on either the maximum response to histamine or the concentration required to produce 50% of maximum active tension and that there is functional synergism between the exogenously added histamine and the endogenously produced AA metabolites. Therefore the zero active tension is useful as a base line to compare the contractile response of a drug-treated preparation with that of a nontreated preparation.
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PMID:Endogenous AA metabolites and their possible role in tracheal smooth muscle tone in guinea pigs. 197 76


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