Sustained increase in extracellular ATP in the lung induced by chronic inhalation exposure to nitrogen dioxide

Nitrogen dioxide (NO₂) is an environmental air pollutant and a potent oxidant. Epidemiological studies have revealed a close association between chronic cough and long-term inhalation exposure to NO₂. ATP can be released from airway/lung epithelial cells upon inhalation exposure to oxidants, and convincing evidence established in recent clinical studies indicated that extracellular ATP in the respiratory tract plays an important role in the pathogenesis of refractory chronic cough. However, whether inhalation exposure to NO₂ elevates the ATP release in the lung is not yet known. Results of this study showed: 1) in awake rats, acute and chronic inhalation exposures to NO₂ (5-10 ppm) evoked an increase in the ATP release in the bronchoalveolar lavage fluid (BALF), reaching >225% of that in the control (room air) group. 2) The NO₂-induced increase in ATP release in the lung generated by chronic exposure was substantially greater than that by acute exposure to the same concentration of NO₂. 3) Chronic but not acute exposure to NO₂ induced a mild and transient airway inflammation. 4) The elevated ATP release in the lung returned to control within 1-2 days after the acute exposure to NO₂; in sharp contrast, the increase in ATP in BALF persisted for >11-15 days following the chronic exposure when the airway inflammation had already completely recovered. These results suggest that the sustained elevation of ATP release in the lung may act as a contributing factor to the pathogenesis of chronic cough associated with long-term inhalation exposure to NO₂ in humans.NEW & NOTEWORTHY This study demonstrates that chronic inhalation exposure to NO₂, an air pollutant, induced a long-sustaining elevation of the extracellular ATP (eATP) concentration in rat lungs. This finding suggests that the elevated eATP concentration in the lungs may be an important contributing factor to the close association between chronic cough and long-term inhalation of NO₂ observed in humans. Furthermore, it presents a promising experimental animal model for future studies of the pathogenic mechanisms of chronic cough.