Inhaled PAF stimulates leukotriene and thromboxane A2 production in humans.
Platelet-activating factor (PAF) is a potent bronchoconstrictor in humans and has been implicated as an inflammatory mediator in asthma. This study was performed to evaluate whether PAF-induced bronchoconstriction in vivo could be mediated through the release of the bronchoconstrictor eicosanoids, thromboxane (Tx) A2 and the cysteinyl leukotrienes. Ten asthmatic subjects were studied on three occasions after bronchial challenges with aerosolized PAF, methacholine, or isotonic saline. PAF caused bronchoconstriction in all 10 subjects (mean maximal percent fall in specific airway conductance 48.2 +/- 4.6) and was matched by methacholine challenge. Saline caused no changes in specific airway conductance. Urinary leukotriene E4 was significantly elevated after inhaled PAF (366.0 +/- 66.9 ng/mmol creatinine, P less than 0.01) compared with methacholine (41.6 +/- 13.3) and saline (33.6 +/- 4.6). The major urinary TxA2 metabolite 2,3-dinor TxB2 was elevated after inhaled PAF (41.3 +/- 7.1 ng/mmol creatinine, P less than 0.01) compared with methacholine (14.0 +/- 2.7) and saline (17.1 +/- 3.9). Urinary 2,3-dinor 6-oxo-prostaglandin F1 alpha after PAF (22.2 +/- 1.4) was raised with respect to the methacholine challenge (13.9 +/- 1.8, P less than 0.02), although no significant increase was observed compared with the saline control (18.6 +/- 3.3). Inhaled PAF leads to the secondary generation of cysteinyl leukotrienes and TxA2, and it is possible that these mediate some of the acute effects of inhaled PAF in vivo.
Taylor
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IK
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, United Kingdom.
Ward
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PS
Taylor
G W
GW
Dollery
C T
CT
Fuller
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RW
D000280:Administration, Inhalation; D000328:Adult; D000403:Airway Resistance / Q000187:drug effects; D001249:Asthma / Q000503:physiopathology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D015777:Eicosanoids / Q000652:urine; D004730:Endothelium, Vascular / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D006801:Humans; D017999:Leukotriene E4; D015289:Leukotrienes / Q000096:biosynthesis*; D008297:Male; D008688:Methacholine Compounds / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D011453:Prostaglandins / Q000652:urine; D013189:SRS-A / Q000031:analogs & derivatives / Q000652:urine; D013268:Stimulation, Chemical; D013928:Thromboxane A2 / Q000096:biosynthesis*
D016085:Bronchoconstrictor Agents; D015777:Eicosanoids; D015289:Leukotrienes; D008688:Methacholine Compounds; D010972:Platelet Activating Factor; D011453:Prostaglandins; D013189:SRS-A; D013928:Thromboxane A2; D017999:Leukotriene E4; D011464:Epoprostenol