Peroxynitrite induces airway hyperresponsiveness in guinea pigs in vitro and in vivo.
Peroxynitrite (ONOO-) is a cytotoxic product of the rapid reaction between nitric oxide and superoxide that may initiate inflammation. Isolated perfused tracheas from guinea pigs were incubated from the mucosal side for 15 min with peroxynitrite (1 to 100 muM). Thereafter, concentration-response curves to histamine and methacholine were constructed on the preparations. Peroxynitrite (10 muM) caused a significant hyperresponsiveness; the maximal contractions in response to histamine and methacholine were enhanced by 30% and 40%, respectively. In the peroxynitrite-treated group, clear epithelial damage as well as eosinophil destruction were detected. Moreover, 3, 5, and 10 days after intratracheal instillation of peroxynitrite (100 nmol), a significant rise in pulmonary resistance to histamine of anesthetized animals was observed. It is suggested that the generation of peroxynitrite from nitric oxide superoxide radicals during inflammatory processes induces epithelial damage, mediator release, and hence airway hyperresponsiveness. These findings may have clinical implications, because airway inflammation, epithelial damage, and hyperresponsiveness are characteristic features in patients suffering from asthma.
Sadeghi-Hashjin
G
G
Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands.
Folkerts
G
G
Henricks
P A
PA
Verheyen
A K
AK
van der Linde
H J
HJ
van Ark
I
I
Coene
A
A
Nijkamp
F P
FP
D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004357:Drug Synergism; D004804:Eosinophils / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects; D005856:Germ-Free Life; D006168:Guinea Pigs; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000494:pharmacology; D009092:Mucous Membrane / Q000187:drug effects; D009566:Nitrates / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors; D014132:Trachea / Q000187:drug effects
D016085:Bronchoconstrictor Agents; D018836:Inflammation Mediators; D009566:Nitrates; D016210:Methacholine Chloride; C039642:peroxynitric acid; D006632:Histamine