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), a ct through NK-1 and NK-2 receptors. There is considerable evidence of inter action between the neurogenic and the immune systems, and NKs are candidate s for mediating such interactions. We hypothesized that selective inhibitio n of pulmonary NK-1 or NK-2 receptors may modulate immune responses so as t o prevent the development of allergic airway responses in the atopic BN rat sensitized to ovalbumin (OA). To address this hypothesis, we have validate d 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 alle rgen challenge failed to reduce the allergic early airway responses. In con trast, both neurokinin antagonists decreased allergen-induced late airway r esponses in OA-challenged animals. However, only the NK-2 antagonist decrea sed the eosinophil numbers in the bronchoalveolar lavage (BAL), Likewise, t he NK-2, but not NK-1, antagonist decreased both Th1 (INF-gamma) and Th2 (I L-4 and -5) cytokine expression in BAL cells by in situ hybridization. Thes e results provide initial in vivo evidence linking neurokinins to the regul ation of cytokine expression in cells without discrimination as to their ph enotype. We conclude that there is a dichotomy between NK receptors in the modulation of the allergic airway inflammation, which has important implica tions for future therapeutic strategies for asthma using the NK antagonists .