Mechanisms Underlying the Stimulatory Effect of Inhaled Sulfur Dioxide on Rat Vagal Bronchopulmonary Sensory Nerves

Abstract

Chronic exposure to sulfur dioxide (SO2), an air pollutant, can cause airway injury and lung diseases. Acute exposure to SO2 triggers cough and reflex bronchoconstriction, indicating a stimulatory effect of SO2 on airway sensory nerves. Indeed, a recent study in our lab has demonstrated that vagal bronchopulmonary C‐fibers are the primary target of inhaled SO2. This study was carried out to investigate the underlying mechanism of this stimulatory effect of SO2 on bronchopulmonary C‐fibers. Our results showed: 1) Inhalation of SO2 (1,000–2,000 ppm, 10 breaths) evoked a pronounced and reproducible stimulatory effect on pulmonary C‐fibers in anesthetized rats. 2) Pretreatment with an intravenous infusion of sodium bicarbonate (120 μmol/kg) raised the baseline arterial pH by 0.08 units, which profoundly diminished the stimulatory effect of SO2 on pulmonary C‐fibers by 83.9%. 3) This stimulatory effect of SO2 was also significantly attenuated by a pretreatment with amiloride (a blocker of acid‐sensing ion channels, ASICs; 11 μmol/kg) alone (Δ = 70.7%); AMG9810 (an antagonist of transient receptor potential vanilloid type‐1, TRPV1; 10 μmol/kg) alone (Δ = 76.7%); and by a combination of amiloride and AMG9810 (Δ = 91.4%). 4) To further investigate if this stimulatory effect is generated by a direct action of SO2 on sensory nerves, the change in intracellular Ca2+ concentration, [Ca2+]i, was measured in isolated rat vagal pulmonary sensory neurons. Perfusion with extracellular fluid saturated with SO2 (1,000 and 2,000 ppm) evoked a significant increase in [Ca2+]i in a concentration‐dependent manner in these neurons, and these responses to SO2 were markedly suppressed by a combined pretreatment with amiloride and AMG9810. 5) In addition, inhalation of SO2 (300 and 600 ppm for 5 min) evoked cough reflex responses consistently in awake mice in a concentration‐dependent manner; the cough responses were almost completely prevented by a pretreatment with amiloride aerosol inhalation (5 mM for 4 min) in TRPV1‐knockout mice. In conclusion, this study suggested that inhalation of SO2 lowered the pH in airway/lung tissues, which exerted a stimulatory effect on vagal bronchopulmonary C‐fibers by activating both ASICs and TRPV1 channels.Support or Funding InformationNIH grants AI123832 & UL1TR001998This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.