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Mast cell activation, bronchoconstriction, inflammation and airway hyperreactivity are prominent features of non-atopic hypersensitivity reactions in mouse airways. We studied the role of tachykinin receptors in mice that were skin-sensitized with dinitrofluorobenzene (or vehicle) and challenged intranasally with dinitrobenzene sulfonic acid. Tachykinin NK1 receptor blockade, by treatment with the antagonist RP67580, or absence of the tachykinin NK1 receptor resulted in a strong reduction in the accumulation of neutrophils in the bronchoalveolar lavage fluid, and in the development of tracheal hyperreactivity in mice 48 h after challenge. In contrast, treatment with the tachykinin NK2 receptor antagonist SR48968 did not affect the dinitrofluorobenzene-induced hypersensitivity reaction. We have previously shown that mast cells play a crucial role in the development of non-atopic asthma. However, we did not observe an inhibitory effect of the tachykinin receptor antagonists or the genetic absence of tachykinin NK1 receptors on mast cell protease release. In conclusion, distal from mast cell activation, the tachykinin NK1 receptor is crucial for the infiltration of pulmonary neutrophils and the development of tracheal hyperreactivity in non-atopic asthma. [Copyright &y& Elsevier]

Abstract: The gastro-intestinal tract is highly innervated by both intrinsic and extrinsic sensory nerves and this neuronal component is thought to play a role in local inflammatory responses. This in vivo study was designed to determine the function of substance P and the tachykinin NK1 receptor in the pathogenesis of inflammatory bowel disease by the use of the specific antagonist RP 67580. The dinitrofluorobenzene (DNFB)-induced colonic hypersensitivity model is associated with increased levels of substance P in the colon. The tachykinin NK1 receptor antagonist RP 67580 was used to investigate the role of substance P on the development of diarrhea, mast cell infiltration and activation, colonic tissue damage, hypertrophy of colonic lymphoid structures and leukocyte infiltration. The formation of watery diarrhea could completely be abrogated by treatment with RP 67580 in DNFB-sensitized animals 72 h after challenge. Antagonizing the tachykinin NK1 receptor in these animals also resulted in significantly reduced colonic patch hypertrophy, leukocyte recruitment and tissue damage. Total levels of substance P in the colon of DNFB-sensitized mice treated with the inactive enantiomer of the tachykinin NK1 receptor antagonist were significantly higher compared to DNFB-sensitized mice treated with RP 67580 72 h after challenge. Although RP 67580 was capable of reducing the total number of mast cells present in the colon, mast cell activation was not affected by this treatment. In conclusion, in this chemically-induced immunological model for inflammatory bowel disease we demonstrated an important role for tachykinin NK1 receptors, and its ligand substance P, in the development of colitis downstream from mast cell activation. [Copyright &y& Elsevier]