Neurohumoral Regulation of Airway Contractile Responses: Outcome
Under other circumstances, products of granulocytic infiltration and, perhaps, environmental insults (eg, ozone) elicit airway hyperreactivity that appears to be regulated at least in part by the bronchial epithelium. Neutrophilic infiltration appears to be an essential component of immune-mediated airway hyperreactivity in the rabbit. The major basic protein of eosinophils appears to augment airway contractility of airway smooth muscle when applied to the tracheal epithelium of the guinea pig.
Regional secretion of mediator long has been thought to underlie the pathogenesis of asthmatic bronchoconstriction. However, no specific pharmacologic antagonist reverses asthmatic bronchoconstriction, and all effective therapeutic agents currently used elicit bronchoconstriction by stimulating inhibitory receptors on airway smooth muscle. This finding may reflect the virtual certainty that during asthmatic bronchoconstriction—and perhaps chronically in asthmatic subjects—many mediators are secreted simultaneously. Antagonism of a single agent among the amine, peptide, and lipid mediators of airway contraction in this state would not be expected to elicit substantial inhibitory effects.
A major unsolved question is the mechanism by which morphologically normal airway smooth muscle is transformed in the asthmatic state to a hypercontractile tissue that also is more difficult to relax. Most investigations have focused on animal models of airway reactivity to agonists taken one at a time. However, several studies have shown that airway contractility to relatively weak agonists may be augmented substantially in the presence of a second agonist postsynaptically. Other studies have suggested that post-synaptic mediator-mediator interactions increase refractoriness to airway relaxing influences, such as isoproterenol. These data point to the need to consider models of airway hyperreactivity that results from complex postsynaptic interactions between regionally secreted mediators.