Neutral endopeptidase modulation of neurogenic inflammation in airways

Abstract

Tachykinins, including substance P, are contained in sensory nerves of airways. Sensory nerve stimulation causes release of the tachykinins, thus producing a pattern of responses (smooth muscle contraction, submucosal gland secretion, increased vascular permeability, neutrophil adhesion, and cough) collectively referred to as "neurogenic inflammation". The responses to either exogenously or endogenously-released tachykinins are modulated selectively by neutral endopeptidase (NEP), an enzyme that exists on the membranes of cells that contain tachykinin receptors (e.g. submucosal glands, smooth muscle, postcapillary venous endothelium). By cleaving and thus inactivating the tachykinins, NEP limits their action on receptors. The reduced NEP activity associated with respiratory viral infections and inhaled irritants (e.g. toluene diisocyanate, cigarette smoke) potentiates neurogenic inflammatory responses. Exogenously delivered human recombinant NEP reduces responses to tachykinins. Thus, reduced NEP activity in tissues, by exaggerating inflammatory responses resulting from sensory nerve stimulation, may play an important role in the pathogenesis of inflammatory diseases in airways and in other tissues.