Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P

Neurogenic inflammation is regulated by sensory nerves and characterized by extravasation of plasma proteins and infiltration of neutrophils from post -capillary venules and arteriolar vasodilatation, Although it is well estab lished that substance P (SP) interacts with the neurokinin 1 receptor (NK1R ) to initiate neurogenic inflammation, the mechanisms that terminate inflam mation are unknown. We examined whether neutral endopeptidase (NEP), a cell -surface enzyme that degrades SP in the extracellular fluid, terminates neu rogenic inflammation in the colon. In NEP knockout mice, the SP concentrati on in the colon was approximate to 2.5-fold higher than in wild-type mice, suggesting increased bioavailability of SP, The extravasation of Evans blue -labeled plasma proteins in the colon of knockout mice under basal conditio ns was approximate to 4-fold higher than in wild-type mice. This elevated p lasma leak was attenuated by recombinant NEP or the NK1R antagonist SR14033 3, and is thus caused by diminished degradation of SP, To determine whether deletion of NEP predisposes mice to uncontrolled inflammation, we compared dinitrobenzene sulfonic acid-induced colitis in wild-type and knockout mic e. The severity of colitis, determined by macroscopic and histologic scorin g and by myeloperoxidase activity, was markedly worse in knockout than wild -type mice after 3 and 7 days. The exacerbated inflammation in knockout mic e was prevented by recombinant NEP and SR140333, Thus, NEP maintains low le vels of SP in the extracellular fluid under basal conditions and terminates its proinflammatory effects. Because we have previously shown that intesti nal inflammation results in down-regulation of NEP and diminished degradati on of SP, our present results suggest that defects in NEP expression contri bute to uncontrolled inflammation.