Oxidative stress as activators of sensory nerves for cough
Introduction
The cough reflex serves to protect the airways of mammals from noxious substances/events. Guinea pigs and larger mammals have been shown to cough in response to multiple airway stimuli, including mechanical perturbation, acid, water and irritants [1]. Electrophysiological recordings have demonstrated that the cough reflex is dependent on the activation of sensory afferent nerves innervating the airways, and that these nerves are specifically stimulated by tussive stimuli [2], [3]. Although mice and rats do not cough, they also have similar afferent innervation of the airways.
Despite the fact that the cough reflex is in general protective, chronic cough or cough hypersensitivity is a major clinical issue. It is thought that excessive activity in cough afferents contributes to an excessive cough reflex and there has been considerable effort made in elucidating the underlying mechanisms. In particular we have focused on oxidative stress as a likely contributor to cough hypersensitivity. As we shall discuss in more detail below, the lung is exposed to many oxidative and/or electrophilic agents and, furthermore, the afferents themselves may even be the source of oxidative stress during inflammation.
Section snippets
Afferents involved in cough
The afferent innervation of the airways is almost exclusively derived from vagal sensory nerves [2], [4], [5]. Sensory afferents are heterogeneous with respect to protein expression, structure, conduction velocity and function. At the most basic level, sensory afferents are either (1) low threshold mechanosensors involved in the homeostatic control of breathing or (2) afferents activated by noxious stimuli (termed ‘nociceptors’) involved in defense of the airways [6]. However, further
Oxidative stress is a noxious stimulus
Oxidative stress is a term that defines an aberrant redox state in which phospholipids, proteins and nucleic acids are oxidized by reactive oxygen species (ROS) causing major cellular dysfunction [18]. Oxidation and autooxidation of phospholipids can also lead to further damage via the actions of electrophilic products of peroxidation and nitration (e.g. alpha-beta-unsaturated carbonyl groups such as 4-hydroxynonenal) [19].
Oxidative stress in the airways can arise from 2 distinct sources:
Activation of airway C fibers by oxidative stress and electrophilic irritants
The activation of sensory nerve terminals (i.e. action potential discharge) by irritants is dependent on ion fluxes through specific irritant-sensitive ion channels in the plasma membrane. Extensive efforts have been made to understand the ion channels involved in the activation of airway C fibers by noxious stimuli. For example, the canonical noxious stimulus capsaicin [24], the pungent ingredient in chili peppers, activates airway C fibers through the gating of transient receptor potential
Afferent terminal mitochondria as a potential source of ROS
The peripheral nerve terminals of vagal airway sensory fibers are densely packed with mitochondria [51], [52], [53]. Mitochondria can also be observed in axonal terminals of vagal neurons in long-term culture [54]. In order to further understand the functional effect of increased mitochondrial ROS on airway afferent, we have used specific inhibitors of the mitochondrial electron transfer chain. Antimycin A selectively inhibits the Qi site on complex III, resulting in superoxide formation and
Mitochondrial ROS activate airway nociceptors via TRP channels
Antimycin A (20 μM), which evokes ROS from mitochondrial complex III, evoked action potential discharge from nociceptive C fiber terminals innervating the mouse airways (Fig. 1) [36]. Antimycin A-induced nociceptive C fiber activation was significantly greater in nociceptors that expressed TRPA1 compared to nociceptors that did not express TRPA1. Antimycin A failed to activate non-nociceptive fibers. Consistent with the sensitivity of TRPA1 to ROS, the antimycin A-induced action potential
Mitochondrial ROS increase airway nociceptor excitability via PKC
Antimycin A (20 μM) had a profound effect on the excitability of nociceptive C fibers innervating the mouse airways (Fig. 2) [49]. Antimycin A decreased the threshold sensitivity for mechanical punctate stimulation by 50% and increased the action potential firing elicited by a P2X2/3 agonist (α,β methylene ATP, 30 μM) to 270% of control. Antimycin A had no effect on the excitability of non-nociceptive airway afferents. Antimycin A-induced nociceptor hyperexcitability was independent of TRPA1
Conclusions
Oxidative stress, either in the form of ROS or electrophilic lipid product of peroxidation, causes significant increases in the activity of nociceptive neurons. Oxidative stress causes the activation of nociceptors via TRPA1 and increases the excitability of nociceptors via PKC. Nerve terminals of afferents innervating the airways are densely packed with mitochondria. ATP production from nerve terminal mitochondria is not required for continued electrical excitability. Given that multiple
Acknowledgments
This work was supported by the National Heart, Lung & Blood Institute (R01HL119802, Bethesda, USA).
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