Protective effect of substance P on permeability of airway epithelial cells in culture

Although substance P (SP) has been shown to mediate microvascular leakage in response to various stimuli, some data suggest that, in contrast, SP may play a protective role in the maintenance of airway epithelial integrity. To investigate the effect of SP on epithelial barrier function, we measured paracellular mannitol flux and the transepithelial potential difference (PD) of human bronchial epithelial (HBE) and canine bronchial epithelial (CBE) cells. Incubation of confluent cell cultures with SP had no effect on baseline flux. However, pretreatment inhibited the flux-enhancing effects of 0.5 ppm ozone by 50% in HBE cells and 40% in CBE cells and inhibited the ozone-induced decrease in PD in CBE cells by 54%. SP-afforded protection was reduced by the neurokinin (NK)-1 receptor antagonist CP- 96,345. NK₁ and NK₃ receptor agonists also inhibited ozone-induced permeability, whereas an NK₂ receptor agonist was without significant effect. These data indicate that SP exerts a protective effect on bronchial epithelial barrier function under conditions of challenge, which appears to be mediated in large part through NK₁ receptors.