Spencer, David Anthony;
(1992)
The actions and interactions of inhaled platelet-activating factor in man.
Doctoral thesis (M.D), UCL (University College London).
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Abstract
The effects and mechanism of action of inhaled platelet activating factor (PAF) were investigated in normal man. A cumulative dose-response PAF challenge performed on two separate occasions in six normal subjects resulted in a variable degree of bronchoconstriction and transient fall in circulating neutrophil count. There was no significant increase in bronchial responsiveness to methacholine in any subject at any time when measured on five occasions in the two weeks following each PAF challenge. The potential involvement of platelets in mediating the effects of PAF in man was investigated by measuring changes in the plasma levels of BTG and PF4 following PAF inhalation. There were no increases in BTG or PF4 levels shortly after PAF inhalation to suggest platelet activation. The effects of pre-treatment with the cysteinyl-leukotriene receptor antagonist SKF 104353-Z2 and the 5-lipoxygenase inhibitor BW A4C in modifying the acute responses to inhaled PAF were examined in two placebo-controlled double-blind crossover studies. SKF IO4353-Z2 caused a significant reduction in PAF-induced bronchoconstriction, but with no effects on the PAF-induced fall in circulating neutrophil count. BW A4C caused a small, statistically insignificant, reduction in PAF-induced bronchoconstriction and a significant reduction in the transient fall in circulating neutrophils. Measurement of ionophore-stimulated whole blood LTB4 generation ex vivo revealed incomplete 5-lipoxygenase inhibition at the time of PAF challenge. There were positive correlations between the degree of 5-lipoxygenase inhibition and the reduction in PAF-induced falls in sGaw, Vmax30 and circulating neutrophil count obtained with BW A4C. The reproducibility of acute changes in pulmonary function and circulating neutrophils following the cumulative dose- response challenges was very poor due to tachyphylaxis. In subsequent studies tachyphylaxis was avoided, and the reproducibility improved, by the use of a single high dose PAF challenge.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | M.D |
| Title: | The actions and interactions of inhaled platelet-activating factor in man |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10123998 |
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