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.

Low-dose carbon monoxide treatment attenuates early pulmonary neutrophil recruitment after acid aspiration

“…We did examine two different CO exposure times (3 or 6 h) and demonstrated similar decreases in neutrophil recruitment at 6 h postaspiration with both treatments. It is possible that intermittent administration of CO over short exposure times would be beneficial, and this strategy has proven effective for reducing airway hyperresponsiveness in an asthma model (1). It is also likely that the degree of injury would dictate the relative efficacy of CO treatment.…”

CCAAT/Enhancer-Binding Protein Mediates Carbon Monoxide–Induced Suppression of Cyclooxygenase-2

“…CO, one of the byproducts of the HO-1 pathway, has been shown to be anti-inflammatory and cytoprotective in various models of inflammation and tissue injury, including sepsis (4-6), asthma (17,18), chronic graft rejection (19), and ventilator-induced lung injury (20). The signaling pathways and transcription factors involved in CO-mediated anti-inflammatory and cytoprotective effects remain elusive.…”

Enhanced nitric oxide production associated with airway hyporesponsiveness in the absence of IL-10

“…AR was measured in unanesthetized mice as previously described (1). In brief, mice were placed within smallvolume (ϳ600 ml) Plexiglas chambers that allowed for free movement.…”

“…Likewise, in animal models, MCh administration can establish links between experimental manipulations of airway inflammation and the consequent airway smooth muscle responses. Furthermore, a reduction in AR to MCh can be indicative of the effectiveness of an exogenous experimental or clinical treatment that reduces airway smooth muscle contractility (1) or the induction of an endogenous agent that reduces contractility (5).…”