Mechanisms underlying the stimulatory effect of inhaled sulfur dioxide on vagal bronchopulmonary C‐fibres

Abstract

Key points Brief inhalation of SO2 of concentration >500 p.p.m. triggered a pronounced stimulatory effect on vagal bronchopulmonary C‐fibres in anaesthetized rats. This stimulatory effect was drastically diminished by a pretreatment with NaHCO3 that raised the baseline arterial pH, suggesting a possible involvement of acidification of airway fluid and/or tissue generated by inhaled SO2. The stimulation was completely abolished by pretreatment with antagonists of both acid‐sensing ion channels and transient receptor potential vanilloid type‐1 receptors, indicating that this effect was caused by acid activation of these cation channels expressed in airway sensory nerves. This conclusion was further supported by the results obtained from studies in isolated rat vagal bronchopulmonary sensory neurones and also in the cough response to SO2 inhalation challenge in awake mice. These results provide new insight into the underlying mechanism of harmful irritant effects in the respiratory tract caused by accidental exposure to a high concentration of SO2. Abstract Inhalation of sulfur dioxide (SO2) triggers coughs and reflex bronchoconstriction, and stimulation of vagal bronchopulmonary C‐fibres is primarily responsible. However, the mechanism underlying this stimulatory effect is not yet fully understood. In this study, we tested the hypothesis that the C‐fibre stimulation was caused by SO2‐induced local tissue acidosis in the lung and airways. Single‐unit activities of bronchopulmonary C‐fibres in response to inhalation challenges of SO2 (500–1500 p.p.m., 10 breaths) were measured in anaesthetized rats. Inhalation of SO2 reproducibly induced a pronounced and sustained stimulation (lasting for 15–60 s) of pulmonary C‐fibres in a concentration‐dependent manner. This stimulatory effect was significantly attenuated by an increase in arterial pH generated by infusion of sodium bicarbonate (NaHCO3), and completely abrogated by a combined pretreatment with amiloride (an antagonist of acid‐sensing ion channels, ASICs) and AMG8910 (a selective antagonist of the transient receptor potential vanilloid type‐1 receptor, TRPV1). Furthermore, in isolated rat vagal pulmonary sensory neurones, perfusion of an aqueous solution of SO2 evoked a transient increase in the intracellular Ca2+ concentration; this response was also markedly diminished by a pretreatment with amiloride and AMG8910. In addition, inhalation of SO2 consistently evoked coughs in awake mice; responses were significantly smaller in TRPV1−/− mice than in wild‐type mice, and almost completely abolished after a pretreatment with amiloride in TRPV1−/− mice. These results suggested that the stimulatory effect of inhaled SO2 on bronchopulmonary C‐fibres was generated by acidification of fluid and/or tissue in the lung and airways, which activated both ASICs and TRPV1 expressed in these sensory nerves.

Influence of intrathoracic vagotomy on the cough reflex in the anesthetized cat

“…The role of SARs in cough production has been questioned recently based, in part, on the nonspecificity of sulfur dioxide ( Canning et al, 2006 ), which was employed in these previous studies to block SARs in the rabbit ( Hanáček et al, 1984 ; Sant’Ambrogio et al, 1984 ); sulfur dioxide can excite airway C-fibers ( Atzori et al, 1992 ; Lin et al, 2020 ; Wang et al, 1996 ). However, recent work by Poliacek and coworkers (2016) ( Poliacek et al, 2016 ) has shown that the cough motor pattern can be altered by out-of-phase inflations delivered by a custom mechanical ventilator in animals with intact chest walls.…”

Air pollution and long-term risk of hospital admission due to chronic obstructive pulmonary disease exacerbations in Poland: a time-stratified, case-crossover study

“…In our study, the lag pattern between exposure and the risk of COPD admission was different for particulate and gaseous pollutants: gaseous pollutants increased the risk immediately after exposure, whereas particulate pollutants increased the risk gradually up to day 10. Gaseous pollutants, such as NO2 and SO2, might directly cause bronchoconstriction resulting in a COPD exacerbation [40,41]. The effects of PM on the airways may take longer to develop; they might include increased production of mucus in the airways, downregulation of expression of antimicrobial peptides leading to infectious exacerbations, and a proinflammatory environment induced by alveolar macrophages that clear PM [42].…”

EAACI guidelines on environmental science for allergy and asthma: The impact of short‐term exposure to outdoor air pollutants on asthma‐related outcomes and recommendations for mitigation measures

“…Short-term exposures to SO 2 induce coughing and mucus secretion, acting mainly through afferent neurones and reflex bronchoconstriction, upregulation of vanilloid receptors and down-regulation of tight junctions. 89,90 High concentrations of SO 2 can cause inflammation of the respiratory tract, increase the risk of respiratory tract infections and increase all-cause mortality. [90][91][92][93][94][95]…”