Maintaining nitric oxide-induced airway relaxation with superoxide dismutase.
BACKGROUND
We have previously shown that the protective effect of inhaled nitric oxide (iNO) against methacholine-induced bronchoconstriction is negated in airways subjected to hyperosmotic stress. In this study, hypothesizing that the impaired efficiency of iNO was caused by release of reactive oxygen radicals, we examined the effect of the radical scavenging enzyme superoxide dismutase (SOD).


METHODS
Hemodynamic and respiratory measurements were performed on anesthetized rabbits after (1) inhalation of methacholine (MCh), (2) iNO (80ppm), followed by MCh, (3) inhalation of hypertonic saline (HS), followed by iNO and MCh and (4) pre-treatment with inhalation of SOD, followed by HS, iNO and MCh. We analyzed plasma for a marker of oxidative stress, 8-iso-prostaglandin (PG)F(2alpha) and for a marker of activation of COX-mediated inflammatory cascades, PGF(2alpha) metabolite.


RESULTS
Pre-treatment with SOD restored the bronchoprotective response to iNO in hyperosmotic airways. No direct effect was seen by SOD treatment on levels of 8-iso-PGF(2alpha), but this marker of oxidative stress correlated positively with increased bronchoconstriction. Hyperosmotic challenge elevated levels of PGF(2alpha) metabolite, and pre-treatment with SOD protected against this activation of the inflammatory cascade.


CONCLUSIONS
SOD pre-treatment restores the relaxant effects of iNO in hyperosmotically challenged airways by attenuating oxidative stress and activation of COX-mediated inflammatory cascades.
Krenn
Claus G
CG
Department of Medical Sciences, Clinical Physiology, Uppsala University, SE-751 85 Uppsala, Sweden.
Hedenstierna
Göran
G
Basu
Samar
S
Marklund
Stefan L
SL
Hjoberg
Josephine
J
D000280:Administration, Inhalation; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D016210:Methacholine Chloride / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000097:blood / Q000494:pharmacology*
D015415:Biomarkers; D001993:Bronchodilator Agents; D016210:Methacholine Chloride; C008228:15-keto-13,14-dihydroprostaglandin F2alpha; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D015237:Dinoprost; D013482:Superoxide Dismutase