Sheppard D, Thompson J E, Scypinski L, Dusser D, Nadel J A, Borson D B
Cardiovascular Research Institute, Lung Biology Center, San Francisco, California.
J Clin Invest. 1988 Apr;81(4):1111-5. doi: 10.1172/JCI113424.
Substance P and related tachykinins contribute to the airway hyperresponsiveness caused by toluene diisocyanate (TDI) in guinea pigs. Neutral endopeptidase (NEP) is an important modulator of substance P-induced responses. To test the hypothesis that exposure to TDI would increase responsiveness to substance P by inhibiting activity of this enzyme, we determined the dose of substance P required to increase pulmonary resistance by 200% above baseline (PD200) before and after administration of the pharmacologic inhibitor phosphoramidon in guinea pigs studied 1 h after a 1-h exposure to air or 3 ppm TDI. TDI exposure increased responsiveness to substance P significantly. However, phosphoramidon caused a significantly greater leftward shift of the substance P dose-response curve in air-exposed animals than it did in TDI-exposed animals, so that after phosphoramidon, mean values of PD200 in animals exposed to air or TDI did not differ. Tracheal NEP activity was significantly less after exposure to TDI than after exposure to air, whereas activity in the esophagus was the same in both groups. These results suggest that TDI exposure increases the bronchoconstrictor responsiveness of guinea pigs to substance P, in large part through inhibition of airway NEP.
P物质及相关速激肽会导致豚鼠因甲苯二异氰酸酯(TDI)而出现气道高反应性。中性内肽酶(NEP)是P物质诱导反应的重要调节因子。为了验证接触TDI会通过抑制该酶的活性而增加对P物质反应性的假说,我们在豚鼠暴露于空气或3 ppm TDI 1小时后1小时,测定了在给予药理抑制剂磷酰胺前后,使肺阻力比基线增加200%所需的P物质剂量(PD200)。TDI暴露显著增加了对P物质的反应性。然而,磷酰胺使空气暴露动物中P物质剂量-反应曲线向左的移动幅度明显大于TDI暴露动物,因此在给予磷酰胺后,空气暴露或TDI暴露动物的PD200平均值没有差异。暴露于TDI后气管NEP活性明显低于暴露于空气后,而两组食管中的活性相同。这些结果表明,TDI暴露在很大程度上通过抑制气道NEP增加了豚鼠对P物质的支气管收缩反应性。