Neurohumoral Regulation of Airway Contractile Responses: Conclusion
Similar consideration has been applied to bronchoconstriction elicited by mediators secreted from respiratory mast cells and circulating blood elements. Mast cell secretion is a dynamic process, which itself is regulated by endogenous secretory influences. Beta-adrenergic stimulation may substantially downregulate mast cell secretion of preformed mediators such as histamine13 and de novo synthesis of bronchoactive products of the lipoxygenase and cycloxyge-nase pathways. Parasympathetic influences may augment mast cell secretion of mediator to antigenic stimulation.
Considerable recent attention has focused on the role of platelet activating factor (PAF), a lipid secreted from numerous cells, including mast cells, during immune activation. The complex interactions of this mediator in eliciting bronchoconstriction typifies the multieffector action of some mediators in eliciting bronchoconstriction. In the dog, PAF causes hypotension comparable to that in anaphylaxis. This appears to result from a direct effect of PAF on vascular smooth muscle. PAF also is an extremely potent contractile agent in canine airways; however, this does not appear to result from any direct action of PAF on an airway smooth muscle receptor. PAF causes release of serotonin from platelets, and its actions in causing airway smooth muscle contraction in vitro are blocked completely by serotonin or by pretreatment of platelets with receptor specific PAF-antagonist. In vivo, contractility elicited by PAF is blocked partially, but not completely, by atropine but is unaffected by ganglion blockade with hexamethonium.15 This indicates a second mode of action, where contraction results from postganglionic stimulation of efferent parasympathetic nerves. A similarly complex mode of action has been suggested for substance ? which also acts at least in part through parasympathetic activation.1718 Future investigations are likely to uncover even more complex actions of single mediators, further compounded, of course, by subsequent mediator-mediator interactions.
The complexity of these interactions is confounding, and research continues to be focused clarifying the relevant mechanisms that underlie airway hyperreactivity. The innovations of cellular and molecular biological investigations now in progress will serve to elucidate these mechanisms in the next generation.