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)

In asthma a temporal association exists between the late allergic reaction (LAR), the influx of granulocytes into the airway wall, and an increase in bronchial responsiveness. We therefore tested the hypothesis that activated human granulocytes constrict isolated human airways and increase their sensitivity to cholinergic stimuli. Bronchial rings were dissected from 23 lung tissue specimens collected at thoracotomy and studied isotonically in organ baths. Airways were incubated with 1, 2, 5, 10, or 20 x 10(6) granulocytes from normal or atopic donors. Activation of the cells with serum-treated zymosan (STZ, 0.2 mg/ml), which itself did not alter baseline airway caliber, resulted in a bronchoconstriction proportional to the number of zymosan-activated granulocytes (ZAG) present (rs = 0.79, p less than 0.001). This contraction was reduced by about 70% with the leukotriene C4/D4 receptor antagonist FPL 55712 (11.5 microM; p less than 0.001) or with the lipoxygenase inhibitor nordihydroguaiaretic acid (10 microM; p less than 0.001). The scavengers of activated oxygen molecules superoxide dismutase (300 U/ml) and bovine catalase (5,000 U/ml), the cyclooxygenase inhibitor indomethacin (10 microM), or the histamine (H1) receptor antagonist mepyramine (2.8 microM) had no effect. Granulocyte suspensions from atopic donors contained more eosinophils (p less than 0.001), and the magnitude of the contraction to 10 x 10(6) ZAG was related to the proportion of eosinophils (rs = 0.66, p less than 0.01). The sensitivity of the airways to methacholine was unchanged in the presence of 1, 2, or 5 x 10(6) ZAG and decreased with 10 or 20 x 10(6) ZAG (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of zymosan-activated human granulocytes on isolated human airways. 200 Oct 66

Pulmonary hypertension and foreign body granulomas are recognized sequelae of chronic intravenous drug abuse. We have recently described the development of transient pulmonary hypertension and increased permeability pulmonary edema after the intravenous injection of crushed, suspended pentazocine tablets in both humans and dogs. To determine the role of vasoactive substances in the development of this transient pulmonary hypertension, we measured pulmonary hemodynamics and accumulation of arachidonic acid metabolites in dogs during the infusion of indomethacin, a cyclooxygenase inhibitor, diethylcarbamazine (DEC), a lipoxygenase inhibitor, and FPL 55712, a receptor antagonist for leukotriene C4/D4 (LTC4/D4). Following the intravenous administration of crushed, suspended pentazocine tablets (3-4 mg/kg of body weight), mean pulmonary artery pressure increased from 14 +/- 2 mmHg to 30 +/- 6 mmHg (p less than 0.05) at 60 secs with a concomitant increase in plasma concentrations of 6-keto-PGF1 alpha from 187 +/- 92 pg/ml to 732 +/- 104 pg/ml and thromboxane B2 from 206 +/- 83 pg/ml to 1362 +/- 117 pg/ml (both p less than 0.05). Indomethacin prevented the increase in both cyclooxygenase metabolites, but had no effect on the pulmonary hypertension. In contrast, DEC had no effect on the increase in cyclooxygenase products, but blocked the pulmonary hypertension. FPL 55712 did not effect either the increase in cyclooxygenase metabolites or the pulmonary hypertension. We conclude that the transient pulmonary hypertension, induced by the intravenous injection of crushed, suspended pentazocine tablets, is not mediated by cyclooxygenase products but may be mediated by lipoxygenase product(s) other than LTC4/D4.
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PMID:Pulmonary hypertensive response to foreign body microemboli. 211 55

We have previously shown that phosgene markedly increases lung weight gain and pulmonary vascular permeability in rabbits. The current experiments were designed to determine whether cyclooxygenase- and lipoxygenase-derived mediators contribute to the phosgene induced lung injury. We exposed rabbits to phosgene (1,500 ppm/min), killed the animals 30 min later, and then perfused the lungs with a saline buffer for 90 min. Phosgene markedly increased lung weight gain, did not appear to increase the synthesis of cyclooxygenase metabolites, but increased 10-fold the synthesis of lipoxygenase products. Pre- or posttreatment with indomethacin decreased thromboxane and prostacyclin levels without affecting leukotriene synthesis and partially reduced the lung weight gain caused by phosgene. Methylprednisolone pretreatment completely blocked the increase in leukotriene synthesis and lung weight gain. Posttreatment with 5,8,11,14-eicosatetraynoic acid (ETYA), a nonmetabolized competitive inhibitor of arachidonic acid metabolism, or the leukotriene receptor blockers, FPL 55712 and LY 171883, also dramatically reduced the lung weight gain caused by phosgene. These results suggest that lipoxygenase products contribute to the phosgene-induced lung damage. Because phosgene exposure did not increase cyclooxygenase synthesis or pulmonary arterial pressure, we tested whether phosgene affects the lung's ability to generate or to react to thromboxane. Infusing arachidonic acid increased thromboxane synthesis to the same extent in phosgene-exposed lungs as in control lungs; however, phosgene exposure significantly reduced pulmonary vascular reactivity to thromboxane but not to angiotension II and KCl.
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PMID:Mechanism of phosgene-induced lung toxicity: role of arachidonate mediators. 212 93

Histamine release from guinea pig heart treated with compound 48/80 was potentiated by the cyclooxygenase inhibitors indomethacin and piroxicam but not by aspirin or phenylbutazone. This differential effect suggests that the potentiation is not merely due to an inhibition of prostaglandin synthesis. Piroxicam potentiated the histamine release induced by cardiac anaphylaxis whereas indomethacin reduced this effect. The SRS-A antagonist FPL 55712 inhibited histamine release induced by cardiac anaphylaxis, but not that evoked by compound 48/80, and also prevented the potentiation due to indomethacin and piroxicam. In total, these data suggest that the potentiation of histamine release by piroxicam and indomethacin is probably due to a diversion of arachidonic acid metabolism from the cyclooxygenase to the lipoxygenase pathways. The resulting lipoxygenase products may then regulate histamine release, with the secretion due to antigen being more sensitive to such modulation than that evoked by compound 48/80.
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PMID:Effect of non-steroidal anti-inflammatory drugs (NSAID) on the histamine release induced by compound 48/80 and cardiac anaphylaxis in guinea-pig isolated heart. 242 82

The effects of mediator antagonists and synthesis inhibitors on anaphylactic responses of lung parenchymal strips from ovalbumin-sensitized guinea-pigs have been investigated. The dependence of the responses on the concentration of the antigen has been studied using a cumulative concentration-response technique. Anaphylactic contraction and histamine release were similar in response to cumulative and single additions of ovalbumin. Contractile responses to high doses of antigen (1 and 10 micrograms/ml) were slightly inhibited by mepyramine, whereas those to low doses (0.01 microgram/ml) were inhibited by leukotriene antagonist FPL 55712 and the lipoxygenase inhibitors nordihydroguaiaretic acid and BW 755C. Indomethacin potentiated both histamine release and contraction induced by ovalbumin. It is concluded that leukotrienes play a major role in anaphylactic responses to low antigen concentrations. Such responses may more closely resemble allergic bronchoconstriction in man. Histamine has a minor role in responses to higher antigen concentrations, where the major mediator of the responses may also be leukotrienes. This possibility cannot be proved with currently available leukotriene antagonists and synthesis inhibitors.
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PMID:Anaphylactic responses of guinea-pig lung parenchymal strips: antigen concentration dependence and pharmacological modification. 242 24

Indomethacin potentiates antigen-induced contraction and histamine release in lung parenchymal strips from ovalbumin-sensitized guinea-pigs. Mepyramine and the leukotriene antagonist FPL 55712 did not affect the potentiating effect of indomethacin on anaphylactic contraction, but two lipoxygenase inhibitors, BW 755C and nordihydroguaiaretic acid, abolished it. FPL 55712 inhibited contractile responses to leukotriene D4, but not those to leukotriene C4. The potentiation of histamine release by indomethacin was unaffected by the lipoxygenase inhibitors. It is concluded that a lipoxygenase product, possibly leukotriene C4, mediates the potentiation of contraction by indomethacin; the enhancement of histamine release, however, involves a different mechanism, possibly inhibition of the production of inhibitory prostaglandins.
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PMID:The effect of indomethacin on anaphylactic contraction and histamine release in guinea-pig lung parenchymal strips. 242 25

In vivo and in vitro studies with a water-soluble extract of cotton bracts (CBE) suggest that CBE may be responsible for some of the clinical manifestations of byssinosis. Since chronic bronchitis has been repeatedly documented as a major feature of byssinosis, we studied the effect of CBE on respiratory glycoconjugate (RGC) release from human airways (HAs) in vitro. HAs were incubated with [3H]glucosamine to label RGC molecules. CBE in increasing concentrations was added to radiolabeled HAs, and the release of 3H-RGC, histamine, and other mediators was measured. CBE in concentrations of 1 to 7 mg/ml caused a dose-related increase in RGC, as well as histamine release (RGC, 14% to 45% increase above control; histamine, 12 to 70 ng/ml released concurrently). Additionally, CBE in a dose of 5 mg/ml caused a more than threefold increase in peptidoleukotriene production above baseline. The effect of histamine H1 and H2 (pyrilamine and cimetidine), cyclooxygenase pathway inhibitor (indomethacin), leukotriene (LY 171883 and FPL 55712), and lipoxygenase pathway (BW nordihydroguaiarectic acid) blocking agents on CBE-induced RCG secretion was studied. In addition to histamine-H1 blockers, lipoxygenase inhibitors (nordihydroguaiarectic acid and BW 755C) and leukotriene blockers (FPL 55712 and LY 171883) are also potent inhibitors of CBE-induced RGC secretion. This suggests that CBE may act via the release of several mediators (histamine and leukotrienes), possibly from airway cells, such as mast cells, macrophages, or epithelial cells, to stimulate RGC secretion.
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PMID:The effect of cotton bract extract on respiratory glycoconjugate secretion from human airways in vitro. 247 5

Platelet-activating factor (PAF) is a naturally occurring phospholipid that acts as a potent mediator of inflammation and bronchoconstriction. Since mucus secretion accompanies many pulmonary-allergic reactions, we examined the effect of PAF on respiratory glycoconjugate (RGC) release from human airways in vitro. PAF, in concentrations of 5 to 100 ng/ml, induced a specific, dose-dependent release of [3H]RGC from human airways in vitro (range of 15% to 120% increase above control, p less than 0.001; n = 8). Time-course studies revealed that RGC release reached its peak level by 60 minutes, and by the end of 4 hours, decreased almost to the baseline level, suggesting a stimulatory effect on secretion rather than synthesis. PAF analog, RO 19-3704, which is a PAF-receptor antagonist, inhibited RGC secretion mediated by PAF in a dose-dependent manner with an inhibitory concentration of 50% of 70 ng/ml. BW 755C and nordihydroguaiaretic acid, but not indomethacin, inhibited RGC release by PAF. LY 171883, a specific leukotriene D4-receptor antagonist, totally inhibited the release of RGC by PAF. Similar results were observed with FPL 55712. PAF-treated airways generated peptidoleukotrienes significantly above control airways in association with enhanced RGC secretion. This enhanced effect on RGC secretion was specifically and significantly blocked by LY 171883. Atropine (10(-5) mol/L) augmented the secretagogue activity of PAF, whereas dexamethasone (10(-5) mol/L) inhibited it. These data indicate that PAF is a significant RGC secretagogue that affects the RGC-secreting cells via the lipoxygenase pathway of arachidonic acid metabolism and the generation of leukotrienes in the airways, but not through the cholinergic receptors on the secretory cells.
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PMID:Platelet-activating factor stimulates secretion of respiratory glycoconjugate from human airways in culture. 247 7

1. The injection of platelet activating factor (Paf; 250 ng), leukotriene B4 (LTB4; 50 ng) and leukotriene D4 (LTD4; 10 ng) elicited contractions of strips of guinea-pig trachea, bronchus and lung parenchyma. 2. When the effluent of perfused guinea-pig lungs was superfused over strips of guinea-pig trachea, bronchus and parenchyma, the intra-arterial injection of Paf (250 ng) caused the release of spasmogen(s) which contracted all three tissues. 3. The infusion of indomethacin (10 micrograms ml-1) into the pulmonary artery and over the assay tissues inhibited the responses of the tissues to the effluent of the lungs stimulated by Paf (250 ng) and LTB4 (50 ng). However, treating only the assay tissues with indomethacin (10 micrograms ml-1) did not block the contractile responses to the effluent of the lungs stimulated with LTB4 or Paf. stimulated with Paf. 4. Pretreatment of the lungs with indomethacin (10 micrograms ml-1) or aspirin (30 micrograms ml-1) for 30 min, washing them out and suspending them over the assay tissues did not block the release of spasmogens elicited by Paf but appeared to inhibit the release of cyclo-oxygenase products. 5. The infusion of two lipoxygenase inhibitors, nordihydroguaiaretic acid (NDGA; 1 microgram ml-1) and L-655,240 (1 microgram ml-1), into the pulmonary artery completely blocked the release of spasmogen(s) from the perfused lungs. 6. The slow reacting substance of anaphylaxis (SRS-A) antagonist, FPL-55712 (10 ng ml-1), did not block the responses of the tissues to the spasmogen(s) release by Paf. 7. The infusion of the Paf antagonist BN-52021 (30 micrograms ml-1) into the pulmonary artery completely abolished the release of spasmogen(s) induced by Paf. 8. These data suggest that a lipoxygenase product, possibly LTB4, could be responsible for the spasmogenic activity released by the lungs following Paf stimulation. Cyclo-oxygenase products released following Paf stimulation appear to result from the initial LTB4 generation.
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PMID:Paf-induced release of spasmogens from guinea-pig lungs. 253 79

We studied the effect of airway epithelium on mucus secretion by use of an isolated tracheal submucosal gland preparation reported previously (J. Appl. Physiol. 60: 1237-1247, 1986). Mucus glycoconjugate release from submucosal glands of feline trachea was examined using [3H]glucosamine as a mucus precursor. Isolated glands showed significantly higher secretory responses to cholinergic, alpha-, and beta-adrenergic agonists and dibutyryladenosine 3',5'-cyclic monophosphate (average 400% of control) than the conventional tracheal mucosal explants, which contained epithelium and submucosal tissues in addition to submucosal glands (average 160% of control). The addition of isolated epithelium depressed the secretory response of isolated glands to the same level as that of tracheal explants. However, the supernatant from isolated epithelium failed to inhibit secretory responses to methacholine in isolated glands, suggesting that the epithelium-derived inhibitory factor to secretion may be short-lived. Leukotriene D4 antagonist (FPL 55712), cyclooxygenase and/or lipoxygenase inhibitors (indomethacin or BW 755C) caused no significant change in the inhibitory action of epithelium, suggesting that the inhibition is not due to arachidonic acid metabolites. The newly found secretory inhibitory action of epithelium is of particular interest in the pathogenesis of hypersecretion associated with epithelial damage.
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PMID:Effect of epithelium on mucus secretion from feline tracheal submucosal glands. 254 Jan 40


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