Inhaling carbon dioxide (CO2) in humans is known to cause inconsistent effects on airway function. These could be due to direct effects of CO2 on airway smooth muscle or to changes in minute ventilation (V̇e). To address this issue, we examined the responses of the respiratory system to inhaled methacholine in healthy subjects and subjects with mild asthma while breathing air or gas mixtures containing 2% or 4% CO2. Respiratory mechanics were measured by a forced oscillation technique at 5 Hz during tidal breathing. At baseline, respiratory resistance (R5) was significantly higher in subjects with asthma (2.53 ± 0.38 cmH2O·L-1·s) than healthy subjects (2.11 ± 0.42 cmH2O·L-1·s) (P = 0.008) with room air. Similar values were observed with CO2 2% or 4% in the two groups. V̇e, tidal volume (VT), and breathing frequency (BF) significantly increased with CO2-containing mixtures (P < 0.001) with insignificant differences between groups. After methacholine, the increase in R5 and the decrease in respiratory reactance (X5) were significantly attenuated up to about 50% with CO2-containing mixtures instead of room air in both asthmatic (P < 0.001) and controls (P < 0.001). Mediation analysis showed that the attenuation of methacholine-induced changes in respiratory mechanics by CO2 was due to the increase in V̇e (P = 0.006 for R5 and P = 0.014 for X5) independently of the increase in VT or BF, rather than a direct effect of CO2. These findings suggest that the increased stretching of airway smooth muscle by the CO2-induced increase in V̇e is a mechanism through which hypercapnia can attenuate bronchoconstrictor responses in healthy subjects and subjects with mild asthma.NEW & NOTEWORTHY The main results of the present study are as follows: 1) breathing gas mixtures containing 2% or 4% CO2 significantly attenuated bronchoconstrictor responses to methacholine, not differently in healthy subjects and subjects with mild asthma, and 2) the causal inhibitory effect of CO2 was significantly mediated via an indirect effect of the increment of V̇e in response to intrapulmonary hypercapnia.
Keywords: CO2 breathing; airway responsiveness; forced oscillation technique; methacholine challenge; ventilation.