Lipoxygenase metabolites mediate increased airways resonsiveness to histamine after acute platelet activating factor exposure in the guinea-pig

Anderson, Gary P.; Fennessy, M. R.

doi:10.1007/bf01968074

Cited by 12 publications

(9 citation statements)

References 32 publications

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“…This report also suggests that a mixture of drugs (PAF receptor antagonists, lipoxygenase pathway inhibitors and perhaps eicosanoid receptor antagonists) when they become available for clinical trials may prove to be synergistic in their actions since they may prevent several steps in a common series of events. This is supported by recent findings suggesting that PAF induced bronchial hyperreactivity in vivo in guinea pigs is inhibitable by lipoxygenase pathway inhibitors [36]. Thus, PAF may cause an activation of the lipoxygenase pathway of eicosanoid metabolism which leads to the production of eicosanoids with mucus secretagogue effects.…”

Section: Discussionsupporting

confidence: 61%

Platelet activating factor and tracheobronchial respiratory glycoconjugate release in feline and human explants: Involvement of the lipoxygenase pathway

et al. 1990

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It has been suggested that platelet activating factor (PAF) may participate in many aspects of bronchial asthma, including stimulation of mucus secretion. Feline tracheal and human bronchial explant production of respiratory glycoconjugates (RGC) in response to platelet activating factor (PAF) was investigated, in order to differentiate the actions of this putative mediator on mucus secretion. PAF caused a dose-dependent increase in RGC release in concentrations ranging from 100-0.5 microM during a 1-2 hours incubation with either feline or human explants, and the effect was inhibited by the PAF receptor antagonists Ro 19-3704. Several lines of evidence suggest that PAF enhances RGC release indirectly through stimulation of the production of lipoxygenase metabolites of arachidonic acid. 1) Incubation of 10 microM PAF together with arachidonic acid (100 micrograms/ml) enhances PAF's stimulatory effect on RGC release in cats. 2) The cyclooxygenase inhibitor ibuprofen (65 and 420 microM) either failed to effect or slightly enhanced PAF induced RGC release in both species. 3) The combined cyclooxygenase and lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) as well as the putatively specific 5-lipoxygenase inhibitor L-651,392 (both at 50 microM) inhibited the response to PAF in both species. 4) The putative LTD4 receptor antagonists (L-660,711, 100 microM) slightly reduced the PAF secretory response in human bronchi. We conclude that PAF causes specific receptor mediated RGC release. This response is indirectly mediated through the generation of lipoxygenase metabolite formation including 5-lipoxygenase pathway metabolites.

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Section: Discussionsupporting

confidence: 61%

Platelet activating factor and tracheobronchial respiratory glycoconjugate release in feline and human explants: Involvement of the lipoxygenase pathway

et al. 1990

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“…In isolated, perfused rat lungs, PAF stimulated the synthesis and release of peptidoleukotrienes, and diethylcarbamazine, a 5-lipoxygenase inhibitor, blocked PAF-induced lung edema (22,34). Various 5-lipoxygenase inhibitors or leukotriene receptor antagonists have also been shown to inhibit PAF-induced bronchoconstriction (4), bronchial hyperreactivity (35,36), and lethality (37), suggesting that many of the pulmonary and systematic effects of PAF are leukotriene-mediated.…”

Section: Discussionmentioning

confidence: 98%

Platelet-activating factor potentiates protamine-induced lung edema. Role of eicosanoids.

Chen

Voelkel²,

Chang³

1994

Am J Respir Crit Care Med

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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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“…The baseline R L was 182.6 ± 4.8 cmH 2 O/(l/s). Values are means ± SEM (n = 6 for each group) Values are means ± SEM Statistical significance was determined by Mann-Whitney U-test a P<0.01 compared with sensititzed but unchallenged guinea-pigs tized guinea pigs (Mazzoni et al 1985;Anderson and Fennesy 1988;Sanjar et al 1990). The mechanisms for these changes may vary with the mode or dose of induction (Fitzgerald 1993).…”

Section: Discussionmentioning

confidence: 99%

“…PAF-induced pulmonary platelet accumulation was suggested responsible for this responses (Mazzoni et al 1985). In the present study, we adopted bolus injections of low dose of PAF to induce an acute, short-lived increase in reactivity which was shown to be sustained for at least 20 min in the present study, and was reported previously to subside within 30 min (Anderson and Fennesy 1988). This effect was reported to be partly dependent on lipoxygenase products and partly on a vagal reflex (Anderson and Fennesy 1988).…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we adopted bolus injections of low dose of PAF to induce an acute, short-lived increase in reactivity which was shown to be sustained for at least 20 min in the present study, and was reported previously to subside within 30 min (Anderson and Fennesy 1988). This effect was reported to be partly dependent on lipoxygenase products and partly on a vagal reflex (Anderson and Fennesy 1988). Since thromboxane A2 generation has also been demonstrated to mediate PAF-induced microvascular leakage (Tokuyama et al 1991) and enhanced O 2 -generation (Kato et al 1993), an inhibition of PAF-induced thromboxane A2 generation may be contributory to the inhibitory effects of CIS-19 on PAF-induced bronchial hyperreactivity as well as microvascular leakage shown in this study.…”

Section: Discussionmentioning

confidence: 99%

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The effect of the selective PAF antagonist CIS-19 on PAF- and antigen-induced bronchoconstriction, microvascular leakage and bronchial hyperreactivity in guinea-pigs

Lin

Ishii

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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We investigated the effects of a novel platelet-activating factor (PAF) receptor antagonist, CIS-19 [cis-2-(3, 4-dimethoxyphenyl)-6-isopropoxy-7-methoxy-1-(N-methyl-formamido)-1, 2, 3, 4-tetrahydronaphthalene], on PAF-, histamine-, substance P- and antigen-induced bronchoconstriction and microvascular leakage, as well as PAF- and antigen-induced bronchial hyperreactivity to methacholine in urethane-anesthetized guinea-pigs. Administration of CIS-19 (0.5-5 mg/kg, i.v.) inhibited the increase in lung resistance induced by PAF (30 ng/kg, i.v.) in a dose-dependent manner, but failed to inhibit the increase induced by histamine (30 micrograms/kg, i.v.) or substance P (6.5 micrograms/kg, i.v.). CIS-19 (5 mg/kg, i.v.) did not inhibit the increase in lung resistance induced by ovalbumin (2 mg/kg, i.v.) in actively sensitized guinea-pigs. PAF (30 ng/kg, i.v.)-induced microvascular leakage, measured by the extravasation of Evans blue dye, was dose-dependently inhibited by CIS-19 (0.5-5 mg/kg, i.v.) in the trachea, main bronchi and intrapulmonary airways, but it did not affect histamine (30 micrograms/kg, i.v.)- or substance P (6.5 micrograms/kg, i.v.)-induced microvascular leakage at all airway levels. CIS-19 (2.5 and 5 mg/kg) did not affect ovalbumin (2 mg/kg, i.v.)-induced microvascular leakage in all airway levels in actively sensitized guinea-pigs, CIS-19 (2.5 and 5 mg/kg, i.v.) significantly inhibited PAF-induced enhancement of the bronchial response to methacholine, but had no effect on ovalbumin (0.05 mg/kg, i.v.)-induced bronchial hyperreactivity in actively sensitized guinea-pigs. It is concluded that CIS-19 is a potent PAF receptor antagonist which inhibits PAF- but not antigen-induced bronchoconstriction, microvascular leakage and bronchial hyperreactivity. These results suggest that PAF plays little or no role in early airway responses following antigen challenge.

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Lipoxygenase metabolites mediate increased airways resonsiveness to histamine after acute platelet activating factor exposure in the guinea-pig

Cited by 12 publications

References 32 publications

Platelet activating factor and tracheobronchial respiratory glycoconjugate release in feline and human explants: Involvement of the lipoxygenase pathway

Platelet activating factor and tracheobronchial respiratory glycoconjugate release in feline and human explants: Involvement of the lipoxygenase pathway

Platelet-activating factor potentiates protamine-induced lung edema. Role of eicosanoids.

The effect of the selective PAF antagonist CIS-19 on PAF- and antigen-induced bronchoconstriction, microvascular leakage and bronchial hyperreactivity in guinea-pigs

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