MODULATION OF NEUROGENIC INFLAMMATION BY NEUTRAL ENDOPEPTIDASE

The enzyme neutral endopeptidase (NEP) is bound to the membranes of selected cells in the airways that have receptors for tachykinins. The location of the enzyme, along with its selectivity of substrates (tachykinins are a preferred substrate), allows the enzyme to cleave tachykinins that come close to the cell-surface receptors. By cleaving and thus inactivating tachykinins released during stimulation of the sensory nerves, NEP limits the degree of neurogenic inflammation. Neutral endopeptidase exists in the basal cells of the airway epithelium, nerves, smooth muscle, glands, blood vessels, and perhaps other cells. Thus, the enzyme modulates smooth muscle contraction, gland secretion, cough, vascular permeability, and neutrophil adhesion. Decreased NEP activity occurs with epithelial removal, during respiratory viral infections, and during exposure to irritants (e.g., cigarette smoke and toluene dilsocyanate). Delivery of recombinant NEP (rNEP) by aerosol suppressed cough responses during neurogenic inflammation. We suggest that decreased NEP activity will result in exaggerated neurogenic inflammation and may play an important role in inflammatory diseases in airways. Furthermore, drugs that cause up-regulation of NEP may play a therapeutic role by suppressing neurogenic responses. Replacement therapy with rNEP may be useful in diseases where inflammatory peptides (e.g., tachykinins, bradykinin) play a role in pathogenesis.