C. K. W. Lai

Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma.

Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV, by 20% of baseline (PC20) from 0.7 to > 22.9 mg/ml for histamine (P < 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P < 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin. geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P < 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin‐induced bronchoconstriction, they are unlikely to account for the majority of the response.

The effect of an increase in inhaled allergen dose after terfenadine on the occurrence and magnitude of the late asthmatic response

We have attempted to use a potent and selective histamine H1‐receptor antagonist terfenadine to allow a larger dose of allergen to be administered to previous single early responders to investigate if an increased dose of allergen could induce a late asthmatic response. Pre‐treatment with 180 mg of terfenadine enabled a geometric mean increase in allergen dose of 412‐fold to be inhaled by eight atopic subjects with mild asthma, who initially were classified as single early responders, with maximal fall in FEV1 3–8 hr after allergen challenge (Lmax) of < 15 % from baseline value. The magnitude of early asthmatic response was similar to that obtained on the control day when allergen challenge was performed in the absence of terfenadine. Two subjects were converted to dual responders with Lmax of 23.1 and 24.3%, which occurred with a 32‐ and 65‐fold increase in allergen dose respectively, and a 6‐ and 4.9‐fold decrease in non‐specific airways responsiveness measured as the cumulative provocative concentration of methacholine that caused a 20% fall in FEV1 from baseline. The remaining six subjects failed to achieve an Lmax of > 10% even with a 1.29–2.66‐fold increase in allergen dose. For the group as a whole an increase in allergen dose was associated with an increase in overall bronchoconstrictor response 3–8 hr after challenge. These results indicate that it is possible to induce a late asthmatic response in a subject who previously demonstrated only an early response by increasing the dose of allergen inhaled.

Effect of azelastine and ketotifen on the bronchial and skin responses to platelet-activating factor in humans.

In a randomized, double‐blind placebo‐controlled study we investigated the effect of single oral doses of 8 mg azelastine and 2 mg ketotifen on the immediate response to platelet‐activating factor (PAF) inhalation and to increasing doses of PAF injected intradermally. Bronchial provocation with 100 μg of PAF resulted in marked bronchoconstrictor responses, but neither azelastine nor ketotifen had any significant effect on these responses. Intradermal injection of PAF (100, 200 and 400 ng) resulted in a dose‐related weal and flare response. Azelastine and ketotifen both caused significant reductions in this response (P < 0.002‐ P < 0.01). There was no significant difference between the effect of the two drugs.

Effect of inhaled platelet-activating factor on bronchial inflammation in atopic non-asthmatic subjects

We have investigated the effect of inhaled platelet-activating factor (PAF) on bronchial mucosal inflammation in 6 atopic non-asthmatic subjects in a double-blind, placebo-controlled, randomised and crossover study. On 2 study periods at least 4 weeks apart, fiberoptic bronchoscopy was performed 24 h after inhalation of either 200 micrograms PAF or methacholine (control) to obtain endobronchial biopsies. Immunocytochemistry using antibodies for trypase (AA1) and eosinophil cationic protein (EG2) was performed to enumerate mast cells and eosinophils, respectively, in the bronchial submucosa. Median values of AA1+ cells and EG2+ cells did not differ significantly after inhalation of PAF or control (23.8 vs. 39 and 6 vs. 8/mm2, respectively, PAF vs. control, non-significant). Our findings suggest that within 24 h of inhaling a bronchoconstrictor dose of PAF, this agonist does not induce bronchial hyperresponsiveness or mucosal inflammation in atopic non-asthmatic subjects. However, because of the small number of subjects studied, these preliminary data should be interpreted with caution.

The mediator and cellular basis of the allergic response

Allergen provocation of extrinsic allergic subjects initiates a complex series of mediator and cellular events which, for the purpose of pharmacological and pathological examination, may be sub-divided into three phases, namely the early asthmatic response (EAR), the late asthmatic response (LAR) and bronchial hyperresponsiveness (BHR). We have developed a number of clinical, animal and in vitro models in order to gain an understanding of the pathophysiological mechanisms underlying these responses and the relationships between them.