title: Low-dose carbon monoxide reduces airway hyperresponsiveness in mice.
abstract: Carbon monoxide (CO) in expired gas has been shown to be elevated with asthma; however, its function is not known, and there is some potential that it may serve a bronchoprotective role to decrease airway hyperresponsiveness (AHR). Thus the ability of CO to reverse methacholine (MCh)-induced bronchoconstriction was evaluated in C57BL/6 (C57) and A/J mice with and without airway inflammation produced by ovalbumin (OVA). Acutely administered CO (1% in air, 10 min) reduced MCh-driven increases in lung resistance in OVA-challenged C57 mice by an average of 50% (from 14.5 to 7.1 cmH2O.ml-1.s-1), whereas no effect was observed in naïve C57 mice or OVA-challenged C57 mice inhaling air alone. Acutely inhaled CO (500 ppm = 0.05%, for 10 min) reduced MCh-induced airway reactivity (AR) by 20-60% in airway hyperresponsive naïve A/J mice, whereas repeated 10-min administrations of 500 ppm CO over a 5-day period decreased AR by 50%. Repeated administration of low-dose CO [250 (0.025%) and (0.05%) 500 ppm, 1 h/day, 5 days] to A/J mice with airway inflammation likewise resulted in a drop of AR by 50%, compared with those not receiving CO. Inhibition of guanylyl cyclase/guanosine 3',5'-cyclic monophosphothioate (cGMP) using 1H-[1,2,4] oxydiazolo[4,3-a]quinoxalin-1-one or a competitive inhibitor, Rp diastereomers of 8-bromo-cGMP, resulted in inhibition of the effect of CO on AHR, suggesting that the effects of CO were mediated through this mechanism. These results indicate that low-dose CO can effectively reverse AHR in the presence and absence of airway inflammation in mice and suggest a potential role for CO in the modulation of AHR.
authors.affiliation: Asthma, Allergy, and Airway Research Center, and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 628NW Montefiore University Hospital, Pittsburgh, PA 15213, USA. ameredesbt@msx.upmc.edu
authors.forename: Bill T
authors.initials: BT
authors.lastname: Ameredes
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: Lauryn K
authors.initials: LK
authors.lastname: Kohut
authors.forename: Amber L
authors.initials: AL
authors.lastname: Gligonic
authors.forename: William J
authors.initials: WJ
authors.lastname: Calhoun
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D002248:Carbon Monoxide / Q000494:pharmacology*; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000502:physiology; D011014:Pneumonia / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D002248:Carbon Monoxide; D006152:Cyclic GMP