Intra-luminal exposure of murine airways to peroxynitrite causes inflammation but not hyperresponsiveness.
OBJECTIVE
There is increasing evidence for the involvement of reactive nitrogen species like peroxynitrite (ONOO-) in airway pathology, for example during allergic airway inflammation. Therefore, the effect of peroxynitrite exposure on airway responsiveness and inflammation was studied.


METHODS
Male BALB/c mice were treated intra-tracheally with authentic peroxynitrite and the peroxynitrite donor 3-morpholinosydnonimine (SIN-1). Control animals received decomposed solutions of peroxynitrite and SIN- 1.


METHODS
Airway inflammation was monitored by bronchoalveolar lavage, three and seven days after administration. Airway responsiveness to methacholine and acetylcholine was measured on day 1, 2, 3 and 7 post administration using whole body plethysmography.


RESULTS
Intra-tracheal administration of peroxynitrite 200 microM in 50 microl phosphate buffered saline (PBS) induced a significant increase in macrophages (>35%, p < 0.05) in the airway lumen three days after administration. In contrast, neither intra-tracheal administration of authentic peroxynitrite (up to 5 mM) nor the peroxynitrite donor SIN-1 (1 mM, both intra-tracheal and nebulized) changed airway responsiveness to methacholine. Moreover, peroxynitrite (5 mM) did not alter responsiveness to acetylcholine.


CONCLUSIONS
Administration of peroxynitrite directly into the airways of BALB/c mice, induces airway inflammation, but not airway hyperresponsiveness. It is suggested that antioxidants in the epithelial lining fluid and/or the epithelium itself form an efficient barrier, which prevents peroxynitrite from reaching putative targets in the airway interstitium.
Muijsers
R B R
RB
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
van der Veeken
A
A
Habernickel
J
J
Folkerts
G
G
Postma
D S
DS
Nijkamp
F P
FP
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced*; D007249:Inflammation / Q000139:chemically induced*; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000633:toxicity*; D014132:Trachea / Q000187:drug effects*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis
D016210:Methacholine Chloride; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; C002385:linsidomine; D008981:Molsidomine; D000109:Acetylcholine