Cough response to sulfur dioxide inhalation challenge is enhanced by tumor necrosis factor alpha: a primary role of vagal bronchopulmonary C‐fibers

Abstract

Tumor necrosis factor alpha (TNFα), a pro‐inflammatory cytokine, plays a significant role in the pathogenesis of asthma. We recently reported that TNFα pretreatment elevated the sensitivities of vagal bronchopulmonary C‐fibers and silent rapidly adapting rectors (RARs) to capsaicin (Front. Physiol. 2017). In this study, we investigated the effect of TNFα on cough response to sulfur dioxide (SO2), a common irritant gas, and the relative contributions of these vagal afferents. Our results showed: 1) Inhalation of SO2 (300 and 600 ppm; 8 min each) consistently elicited coughs in a concentration‐dependent manner in awake mice moving freely in a recording chamber; coughs were recorded via telemetry sensors implanted in the intrapleural space. The cough frequencies during and immediately after the SO2 inhalation challenges increased markedly in the same animals after TNFα (10 μg/ml; 0.03 ml) was administered into the lung by intratracheal instillation, and this increase in cough sensitivity sustained for >7 days after the TNFα pretreatment. In contrast, the cough response to SO2 inhalation challenges did not change after pretreatment with vehicle (0.03 ml of PBS) in a matching group of control mice. 2) In single‐fiber recording experiments in anesthetized mice, the same SO2 inhalation challenges (for 8 min) evoked a pronounced stimulatory effect on C‐fiber afferents, reaching a peak in 1–4 min. The increased fiber activity was concentration dependent and lingered for several more minutes after the termination of SO2 challenge. This stimulatory effect of SO2 was significantly elevated in the TNFα‐treated mice. 3) The same SO2 inhalation challenges, either 300 or 600 ppm, did not activate any of the silent RARs in vehicle‐treated mice, and only 600 ppm SO2 caused a very weak stimulation in 2 out of 7 of these silent RARs in TNFα‐treated mice. 4) Inhalation of SO2 (300 or 600 ppm) consistently induced an inhibitory effect on both slowly adapting receptors and phasic RARs; these afferents ceased to discharge completely in 1–5 min after the onset of SO2 (600 ppm) inhalation challenge, and a majority of them slowly returned to controls after resuming air breathing for >1 hr. No detectable difference in this inhibitory effect was found between TNFα‐ and vehicle‐treated mice. In conclusion, the cough response to SO2 inhalation challenge is enhanced by the TNFα pretreatment in wake mice, and an increase in the bronchopulmonary C‐fiber sensitivity to SO2 is primarily responsible.Support or Funding InformationNIH grant AI123832This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.