Capsaicin-sensitive C-fiber-mediated protective responses in ozone inhalation in rats

Abstract

To assess the role of lung sensory C fibers during and after inhalation of 1 part/million ozone for 8 h, we compared breathing pattern responses and epithelial injury-inflammation-repair in rats depleted of C fibers by systemic administration of capsaicin as neonates and in vehicle-treated control animals. Capsaicin-treated rats did not develop ozone-induced rapid, shallow breathing. Capsaicin-treated rats showed more severe necrosis in the nasal cavity and greater inflammation throughout the respiratory tract than did control rats exposed to ozone. Incorporation of 5-bromo-2'-deoxyuridine (a marker of DNA synthesis associated with proliferation) into terminal bronchiolar epithelial cells was not significantly affected by capsaicin treatment in rats exposed to ozone. However, when normalized to the degree of epithelial necrosis present in each rat studied, there was less 5-bromo-2'-deoxyuridine labeling in the terminal bronchioles of capsaicin-treated rats. These observations suggest that the ozone-induced release of neuropeptides does not measurably contribute to airway inflammation but may play a role in modulating basal and reparative airway epithelial cell proliferation.

Activation of Neurokinin-1 Receptors during Ozone Inhalation Contributes to Epithelial Injury and Repair

“…Vesely and colleagues found less BrdU incorporation in terminal bronchiolar epithelium of capsaicin-treated rats exposed to filtered air and ozone, suggesting that neuropeptides released by C fibers may modulate basal and reparative airway epithelial cell proliferation (27). Our observations, that the NK-1 antagonist, SR140333, decreases airway cell proliferation after ozone exposure, confirms the previous findings of Vesely and colleagues (27), and extends them to the large conducting airways examined in this study. This implies that the release of substance P from lung C fibers acts to orchestrate the proliferation of basal cells, nonciliated Clara cells, and type II pneumocytes to replace the ciliated cells and type I pneumocytes lost during and after the acute inhalation of ozone.…”

“…Substance P stimulates proliferation and migration of guinea pig tracheal epithelial cells (19), and works synergistically with insulin-like growth factor-1 to stimulate corneal epithelial wound healing (20,44). Vesely and colleagues found less BrdU incorporation in terminal bronchiolar epithelium of capsaicin-treated rats exposed to filtered air and ozone, suggesting that neuropeptides released by C fibers may modulate basal and reparative airway epithelial cell proliferation (27). Our observations, that the NK-1 antagonist, SR140333, decreases airway cell proliferation after ozone exposure, confirms the previous findings of Vesely and colleagues (27), and extends them to the large conducting airways examined in this study.…”

“…In a series of experiments, we found that rats depleted of C fibers with neonatal capsaicin treatment did not develop reflex rapid, shallow breathing, epithelial injury of terminal bronchioles was greater, and there was an uncoupling of neutrophil accumulation and other inflammatory responses from repair after ozone exposure. That is, for a given amount of epithelial necrosis, C fiber ablation had no influence on the degree of inflammation, but did modulate epithelial cell turnover and proliferative repair (26,27). Although clearly implicating airway C fibers and the neuropeptides they release in ozoneinduced epithelial injury and repair, interpretation of these observations are complicated by the fact that we do not know how the neonatal ablation of airway C fibers with capsaicin affects the ontogeny of the distal airway epithelium and its response to oxidant stress.…”

TRPA1 is a major oxidant sensor in murine airway sensory neurons

“…Chemosensory respiratory reflexes triggered in the upper airways are thought to limit exposure of the lower airways to potentially damaging chemicals (15,(24)(25)(26). Neuronal activation also triggers airway pain, possibly to induce avoidance behavior, as well as mucus secretion, to buffer or inactivate oxidants.…”

Ozone-Induced Release of Neuropeptides from Human Nasal Mucosa Cells

“…Several animal studies and trials examining the effect of a number of pharmacological agents on the respiratory responses to ozone support the concept that the effects of ozone are mediated, at least in part, by neural mechanisms [13, 14, 15, 16, 17, 18]. This leads to the hypothesis that neuropeptides may also be involved.…”