Stimulatory effect of CO 2 on vagal bronchopulmonary C-fiber afferents during airway inflammation. J Appl Physiol 99: 1704 -1711, 2005. First published June 30, 2005; doi:10.1152/japplphysiol.00532.2005.-This study investigated 1) whether pulmonary C fibers are activated by a transient increase in the CO 2 concentration of alveolar gas; and 2) if the CO 2 sensitivity of these afferents is altered during airway inflammation. Single-unit pulmonary C-fiber activity was recorded in anesthetized, open-chest rats. Transient alveolar hypercapnia (HPC) was induced by administering a CO 2-enriched gas mixture (25-30% CO2, 21% O2, balance N 2) for five to eight breaths, which increased alveolar CO2 concentration progressively to near or above 13% for 3-5 s and lowered the arterial pH transiently to 7.10 Ϯ 0.05. Our results showed the following. 1) HPC evoked only a mild stimulation in a small fraction (4/47) of pulmonary C fibers, and there was no significant change in fiber activity (change in fiber activity ϭ 0.22 Ϯ 0.16 imp/s; P Ͼ 0.1, n ϭ 47).2) In sharp contrast, after airway exposure to poly-L-lysine, a cationic protein known to induce mucosal injury, the same challenge of transient HPC activated 87.5% of the pulmonary C fibers tested and evoked a distinct stimulatory effect on these afferents (change in fiber activity ϭ 6.59 Ϯ 1.78 imp/s; P Ͻ 0. 01, n ϭ 8). 3) Similar potentiation of the C-fiber response to HPC was also observed after acute exposure to ozone (n ϭ 6) and during a constant infusion of inflammatory mediators such as adenosine (n ϭ 15) or prostaglandin E 2 (n ϭ 12). 4) The enhanced C-fiber sensitivity to CO 2 after poly-L-lysine was completely abrogated by infusion of NaHCO 3 (1.82 mmol⅐kg Ϫ1 ⅐min Ϫ1) that prevented the reduction in pH during HPC (n ϭ 6). In conclusion, only a small percentage (Ͻ10%) of the bronchopulmonary C fibers exhibit CO 2 sensitivity under control conditions, but alveolar HPC exerts a consistent and pronounced stimulatory effect on the C-fiber endings during airway inflammation. This effect of CO 2 is probably mediated through the action of hydrogen ions. hydrogen ion; airway mucosal injury; airway hyperreactivity; hypercapnia PREVIOUS INVESTIGATORS HAVE suggested the existence of sensory receptors that can detect an increase in CO 2 in the lung (32). However, no direct and definitive evidence has been established in identifying the presence of "CO 2 sensors" in the lung structures. Experiments employing various techniques to block the conduction of myelinated fibers in the vagus have yielded compelling evidence suggesting the involvement of bronchopulmonary C fibers in the hyperpneic response to CO 2 (26, 28). One possibility is that the increase in alveolar CO 2 concentration in those experiments led to a decrease in the pulmonary interstitial pH, which then activated the pulmonary C fibers. This hypothesis is supported by a recent study demonstrating that pulmonary C fibers are consistently activated when pH in the arterial blood (pH a ) (pulmonary venous blood) is lowered to...