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Inhaled PAF fails to induce airway hyperresponsiveness to methacholine in normal human subjects
C K Lai1, J R Jenkins, R Polosa
1Immunopharmacology Group, Southampton General Hospital, United Kingdom.
Abstract:
The effects of three increasing doses of platelet-activating factor (PAF) on airway caliber and methacholine bronchial responsiveness were studied. On separate occasions nine normal subjects inhaled a single cumulative provocation concentration of methacholine (control) causing a 40% fall (PC40 Vp30) in maximum expiratory flow rate at 70% of base-line vital capacity below total lung capacity during a partial forced expiratory maneuver or 100 or 200 micrograms PAF, and seven subjects inhaled a further dose of 400 micrograms PAF. Methacholine responsiveness was measured before, at 3 and 7 h, then on days 1, 2, 3, 4, 7, 10, and 14 after each challenge. The maximum falls in Vp30 appeared dose dependent, but a significant difference between the magnitude of the responses was only observed between the 400- and 100-micrograms PAF dose (P less than 0.05). During the control period repeated methacholine challenges resulted in a progressive increase in cumulative provocation concentration of an agonist causing a 20% fall in forced expiratory volume in 1 s from base line, reaching significance on days 1 and 2 (2.44- and 2.4-fold of base line, respectively, P less than 0.01) before returning to base line on day 7. No difference was seen in methacholine responsiveness after any of the three doses of PAF compared with that after the control. We conclude that PAF causes dose-dependent bronchoconstriction but does not change airways responsiveness to methacholine and that repeated high-dose methacholine challenge leads to loss of responsiveness to this agonist.
Insights
Platelet-activating factor (PAF) causes dose-dependent bronchoconstriction in normal subjects. However, PAF does not alter airway responsiveness to methacholine, while repeated methacholine challenges reduce responsiveness.
Area of Science:
- Pulmonary Medicine
- Respiratory Physiology
- Pharmacology
Background:
- Platelet-activating factor (PAF) is a potent mediator implicated in airway inflammation and bronchoconstriction.
- Understanding PAF's effects on airway caliber and responsiveness to other agonists is crucial for respiratory disease research.
Purpose of the Study:
- To investigate the dose-dependent effects of inhaled platelet-activating factor (PAF) on airway caliber.
- To assess the impact of PAF on bronchial responsiveness to methacholine in normal subjects.
- To evaluate the effect of repeated methacholine challenges on airway responsiveness.
Main Methods:
- Nine healthy subjects inhaled increasing doses of PAF (100, 200, 400 micrograms) or a control methacholine concentration.
- Airway caliber (Vp30) and methacholine responsiveness (PC40 FEV1) were measured at multiple time points post-inhalation.
- Statistical analysis compared dose-dependent responses and changes in responsiveness over time.
Main Results:
- Inhaled PAF caused a dose-dependent decrease in airway caliber, with a significant difference between 400 and 100 micrograms (P<0.05).
- No significant changes in methacholine responsiveness were observed after any PAF dose compared to the control.
- Repeated methacholine challenges significantly increased airway responsiveness on days 1 and 2 (2.4-fold increase, P<0.01) before returning to baseline.
Conclusions:
- Platelet-activating factor (PAF) induces dose-dependent bronchoconstriction in humans.
- PAF does not alter subsequent airway responsiveness to methacholine.
- Repeated high-dose methacholine challenges result in a transient loss of bronchial responsiveness.