The tachykinin NK1 receptor is crucial for the development of non-atopic airway inflammation and hyperresponsiveness.
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.
van der Kleij
Hanneke P M
HP
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands. J.P.M.vanderkleij@Pharm.uu.nl
Kraneveld
Aletta D
AD
Redegeld
Frank A M
FA
Gerard
Norma P
NP
Morteau
Olivier
O
Nijkamp
Frans P
FP
D000281:Administration, Intranasal; D000402:Airway Obstruction / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001549:Benzamides; D004139:Dinitrofluorobenzene / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054833:Isoindoles; D007962:Leukocytes / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology
D001549:Benzamides; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; C073839:SR 48968; D004139:Dinitrofluorobenzene