Role of neutral endopeptidase in endotoxin-induced bronchial hyperresponsiveness to substance P in guinea pigs

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Abstract
To investigate effects of endotoxin on allergic airway diseases, we studied bronchial responsiveness to histamine (HI) and substance P (SP) in actively sensitized and non-sensitized guinea pigs 24 h after exposure to endotoxin (75 (μg/mL; 40 min) and its vehicle, saline. Bronchial responsiveness to HI and SP was assessed by calculation of-log PC250 HI and -log PC250 SP, respectively, where the PC250 is the provocative concentration producing a 250% increase in lung resistance. Endotoxin increased bronchial responsiveness to SP but not to HI and caused airway inflammation characterized by accumulation of neutrophils in bronchoalveolar lavage fluid (BALF) without increasing SP-induced airway microvascular leakage assessed by the extravasation of Evans blue dye. The actively sensitized animals showed a tendency to increase the value of -logPC250 SP (P < 0.1) compared with that of non-sensitized control animals. To elucidate the mechanisms underlying preferential bronchial hyperresponsiveness to SP, neutral endopeptidase (NEP) activities in the airways were measured. Neutral endopeptidase activities were significantly decreased in actively sensitized animals and were further decreased in endotoxin-exposed animals. There was a significant inverse correlation between NEP activity and bronchial responsiveness to SP (r = −0.55; P < 0.001), while no such relationship was observed for HI. These data suggest that NEP mediates endotoxin-induced bronchial hyperresponsiveness to SP and that active sensitization may affect bronchial responsiveness to SP in guinea pigs