Mechanisms of allergen-induced late phase asthmatic responses and increased bronchial responsiveness

Twentyman, Orion P (1992) Mechanisms of allergen-induced late phase asthmatic responses and increased bronchial responsiveness. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Allergen bronchoprovocation of the airways in sensitised asthmatic subjects provokes changes similar to many features of asthma. I studied this model demonstrating repeatable mean late phase responses may be observed (coefficient of repeatability for the % fall in FEV1 at 7.5 h was 35% ) and thus powerful studies can be performed (when n= 10, predicted power to detect a difference of 20% between the falls in FEV1 at 7.5 h was 94% ). Repeated individual responses were highly varible due to random factors.

The late asthmatic response and increase in bronchial responsiveness increased progressively over several hours peaking between 7.5 and 11.5 after allergen challenge before resolving slowly over days. Bronchial responsiveness increased before the onset of the late asthmatic response, a mean 0.5 doubling dilutions increases occurred at 1.5H (p< 0.05). The late asthmatic response was reversed by β2-agonists, compatible with an aetiology of bronchial smooth muscle contraction. The most important predictors of both the early and late asthmatic responses were allergen sensitivity and the prevailing level of bronchial responsiveness. The factors predicting the increase in bronchial responsiveness could not be identified, possibly due to a lack of power in the study design. Studies with β2-agonists were undertaken to identify mechanisms mediating late responses and the activity of this class of drug. Salbutamol (200μg) inhibited the late asthmatic response (p< 0.01).

Salbutamol (2500μg) inhibited the late asthmatic response (p> 0.05) and allergen-induced increase in bronchial responsiveness (p< 0.001) and allergen-induced increase in bronchial responsiveness (p< 0.001). These β2-agonist anti-asthma actions were not due to bronchodilatation or functional antagonism of bronchoconstriction. The prolonged duration of action of salmeterol may explain how this β2 agonist could translate the anti-asthma activity seen in the late phase response asthma model into a clinical benefit not identified with earlier β2-agonists. With carefully designed studies this asthma model is valid and useful.

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