Paul Rafferty

Primary and Secondary Effector Cells in the Pathogenesis of Bronchial Asthma

The immediate and late asthmatic reactions provoked by inhaled allergens have provided useful models enabling the dissection of individual inflammatory cells and their mediators that may contribute to the pathogenesis of asthma. The immediate reaction is considered to be mast cell-mediated on the basis that about 50% of the response is inhibitable by potent and selective H1-receptor antagonists such as terfenadine and astemizole. Additional inhibition (approximately 30%) by the potent cyclooxygenase inhibitor flurbiprofen implies an important role for prostanoids in the immediate response, the most likely mast cell-derived product being prostaglandin (PG) D2. In man, PGD2 is selectively metabolised to 9 alpha 11 beta-PGF2, a unique prostaglandin which shares with PGD2 contractile properties on guinea-pig and human airways smooth muscle. The inability of piriprost, a potent leukotriene synthesis inhibitor, to influence the allergen-provoked immediate reaction raises the possibility that sulphidopeptide leukotrienes play a minor role in this response. The late asthmatic reaction is considered to resemble clinical asthma since it is accompanied by increased responsiveness of the airways to a wide range of stimuli. The late reaction in man is inhibited by nedocromil sodium (4 mg) but only marginally attenuated by salbutamol (200 micrograms) if both drugs are administered prior to allergen challenge. Since salbutamol, in the dose administered, is a potent mast cell-stabilising agent, these findings must question the obligatory role of mast cell mediator release in the pathogenesis of the late response.(ABSTRACT TRUNCATED AT 250 WORDS)

The Bronchoconstrictor Activity of Adenosine in Asthma

Adenosine and related synthetic analogues have long been known to modify airway smooth muscle tone. In isolated guinea pig tracheal preparations these compounds produce a transient contractile, followed by a more powerful and sustained relaxant, response, which has the characteristics of A2 purinoceptor stimulation. In nonasthmatic subjects, adenosine administered by inhalation at concentrations up to 6.7 mg/ml has no significant effect on the airway, whereas in both allergic and nonallergic asthma it is a powerful bronchoconstrictor. A similar degree of bronchoconstriction in asthma is produced by adenosine 5′-monophosphate (AMP) and adenosine 5′-diphosphate, but not by the related purine nucleosides inosine and guanosine. The bronchoconstrictor effects of adenosine and AMP are selectively antagonised by inhaled and oral theophylline and are potentiated by dipyridamole, suggesting a response mediated through stimulation of cell surface purinoreceptors. The response of adenosine on asthmatic airways is unaffected by muscarinic cholinergic blockade, but is inhibited by the mast cell-stabilising drugs sodium cromoglycate and nedocromil sodium. AMP, which is rapidly converted to adenosine in vivo, provokes bronchoconstriction in the majority of atopic nonasthmatic subjects, but has little effect in nonatopic nonasthmatic subjects, suggesting involvement of an IgE-dependent mechanism in the response. The demonstration that adenosine and its nonhy-drolysable analogues potentiate ongoing IgE-dependent mediator release from isolated mast cells of man and rodents, and that this potentiation is restricted to the release of granule-associated preformed mediators, suggests a mechanism for adenosine’s bronchoconstrictor effect. The capacity of the potent and selective H1 receptor antagonists terfenadine and astemizole to almost totally inhibit AMP-induced bronchoconstriction adds support to this hypothesis. Adenosine is released upon challenge of isolated mast cell and leucocytes with appropriate activation stimuli, and increased circulating levels of the nucleoside are detected following chal-,lenge of asthmatic airways with allergen and methacholine. The capacity of aminophylline, but not enprofylline, to selectively antagonise the airways response to inahaled AMP, while both drugs have a similar effect on bronchoconstriction provoked by histamine, suggests that bronchodilatation and protection against individual endogenously released contributor mediators in asthma observed with methylxanthines does not involve adenosine antagonism. However, this finding does not preclude the potential role of endogenously released adenosine as a contributing mediator to the longer term consequences of airway inflammation characteristic of asthma.