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1 Asthma, Allergy, and Airway Research Center, University of Pittsburgh, Pittsburgh, PA, USA; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
2 Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: ameredesbt{at}msx.upmc.edu.
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 carbon monoxide to reverse methacholine (MCh) induced bronchoconstriction was evaluated in C57Bl6 (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% (14.5 to 7.1 cm H2O x ml-1 x sec-1), while no effect was observed in naive 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 naive A/J mice, while repeated 10-min. administrations of 500 ppm CO over a five day period decreased AR by 50%. Repeated administration of low-dose CO (250 [0.025%] and 500 ppm, 1 hour/day, 5 days)] to A/J mice with airway inflammation likewise resulted in a drop of AR by 50%, as compared to those not receiving CO. Inhibition of guanylyl cyclase/cGMP using 1H-[1,2,4] Oxydiazolo[4,3-a]quinoxalin-1-one (ODQ), or a competitive inhibitor, Rp-8Br-cGMPs, 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.
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