Dichotomy between neurokinin receptor actions in modulating allergic airway responses in an animal model of helper T cell type 2 cytokine-associated inflammation.

Neurokinins (NKs), which include substance P (SP) and neurokinin A (NKA), act through NK-1 and NK-2 receptors. There is considerable evidence of interaction between the neurogenic and the immune systems, and NKs are candidates for mediating such interactions. We hypothesized that selective inhibition of pulmonary NK-1 or NK-2 receptors may modulate immune responses so as to prevent the development of allergic airway responses in the atopic BN rat sensitized to ovalbumin (OA). To address this hypothesis, we have validated our animal model by showing that NK-1 and NK-2 receptors are expressed in the lungs, and that SP is released in the airways after allergen challenge. The selective NK-1 (CP-99,994) or NK-2 (SR-48968) antagonists before allergen challenge failed to reduce the allergic early airway responses. In contrast, both neurokinin antagonists decreased allergen-induced late airway responses in OA-challenged animals. However, only the NK-2 antagonist decreased the eosinophil numbers in the bronchoalveolar lavage (BAL). Likewise, the NK-2, but not NK-1, antagonist decreased both Th1 (INF-gamma) and Th2 (IL-4 and -5) cytokine expression in BAL cells by in situ hybridization. These results provide initial in vivo evidence linking neurokinins to the regulation of cytokine expression in cells without discrimination as to their phenotype. We conclude that there is a dichotomy between NK receptors in the modulation of the allergic airway inflammation, which has important implications for future therapeutic strategies for asthma using the NK antagonists.