Abstract
Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of allergic asthma. Inhalation of TNFα also induces airway hyperresponsiveness in healthy human subjects, and the underlying mechanism is not fully understood. A recent study reported that TNFα caused airway inflammation and a sustained elevation of pulmonary chemoreflex responses in mice, suggesting a possible involvement of heightened sensitivity of vagal pulmonary C-fibers. To investigate this possibility, the present study aimed to investigate the effect of a pretreatment with TNFα on the sensitivity of vagal pulmonary afferents in anesthetized mice. After TNFα (10 μg/ml, 0.03 ml) and vehicle (Veh; phosphate buffered saline (PBS), 0.03 ml) were administered by intra-tracheal instillation in each mouse of treated (TNF) and control (Veh) groups, respectively, the peak activity of pulmonary C-fibers in response to an intravenous bolus injection of a low dose of capsaicin (Cap; 0.5 μg/kg) was significantly elevated in TNF group (6.5 ± 1.3 impulses/s, n = 12) 24–48 h later, compared to that in Veh group (2.2 ± 0.5 impulses/s, n = 11; P < 0.05). Interestingly, the same low dose of Cap injection also evoked a distinct burst of discharge (2.4 ± 0.7 impulses/s) in 75% of the silent rapidly adapting receptors (RARs), a subtype of RARs exhibiting no phasic activity, in TNF group, but did not stimulate any of the silent RARs in Veh group. To further determine if this sensitizing effect involves a direct action of TNFα on these sensory nerves, the change in intracellular Ca2+ concentration in response to Cap challenge was measured in isolated mouse vagal pulmonary sensory neurons. The Cap-evoked Ca2+ influx was markedly enhanced in the neurons incubated with TNFα (50 ng/ml) for ~24 h, and this sensitizing effect was attenuated in the neurons isolated from the TNF-receptor double homozygous mutant mice. In conclusion, the TNFα pretreatment enhanced the Cap sensitivity in both pulmonary C-fibers and silent RARs, and the action was mediated through TNF receptors. These sensitizing effects of TNFα may contribute, at least in part, to the pathogenesis of airway hyperresponsiveness induced by this cytokine.
Highlights
It is well-documented that tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of chronic airway inflammatory diseases such as allergic asthma (Thomas, 2001; Howarth et al, 2005; Berry et al, 2006; Heffler et al, 2007; Brightling et al, 2008)
A total of 125 vagal bronchopulmonary afferents were studied in 40 anesthetized, open-chest mice: 17 C-fibers, 37 rapidly adapting receptors (RARs) (24 silent and 13 phasic) and slowly adapting receptors (SARs) in the Veh group (23 mice pre-treated with phosphate buffered saline (PBS)); and C-fibers, 32 RARs (22 silent and 10 phasic) and 12 SARs in the TNF group (17 mice pretreated with TNFα)
In TNFα-treated mice, the pulmonary C-fiber responses to both low and high doses of Cap were significantly higher than that in Veh-treated mice: the fiber activity (FA) evoked by the low dose of Cap (0.5 μg/kg) was 2.2 ± 0.5 impulses/s in the Veh group, and 6.5 ± 1.3 imp/s (n = 12; P < 0.05) in the TNF group; the FA evoked by the high dose of Cap (1.0 μg/kg) was 8.1 ± 1.4 imp/s (n = 17) in the Veh group, and 17.8 ± 2.8 imp/s (n = 14; P < 0.01) in the TNF group
Summary
It is well-documented that tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of chronic airway inflammatory diseases such as allergic asthma (Thomas, 2001; Howarth et al, 2005; Berry et al, 2006; Heffler et al, 2007; Brightling et al, 2008). Inhalation of aerosolized TNFα can induce bronchial hyperresponsiveness. Hypersensitivity of Pulmonary Afferents Induced by TNFα accompanied by airway inflammation in healthy human subjects (Thomas et al, 1995), but the underlying mechanism is not fully understood. One of the prominent pathophysiological features of inflammation-induced bronchial hyperresponsiveness is a heightened sensitivity of airway sensory nerves (Lee and Yu, 2014; Mazzone and Undem, 2016). A recent study carried out in our laboratory has demonstrated that intra-tracheal instillation of TNFα 24 h earlier caused airway inflammation and a sustained (>48 h) elevation of pulmonary chemoreflex sensitivity in mice (Lin et al, 2013). Whether the sensitivity of these afferents is elevated following the TNFα treatment in intact animals remains to be determined
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