Vagal Afferent Innervation of the Airways in Health and Disease

Abstract

Vagal sensory neurons constitute the major afferent supply to the airways and lungs. Subsets of afferents are defined by their embryological origin, molecular profile, neurochemistry, functionality, and anatomical organization, and collectively these nerves are essential for the regulation of respiratory physiology and pulmonary defense through local responses and centrally mediated neural pathways. Mechanical and chemical activation of airway afferents depends on a myriad of ionic and receptor-mediated signaling, much of which has yet to be fully explored. Alterations in the sensitivity and neurochemical phenotype of vagal afferent nerves and/or the neural pathways that they innervate occur in a wide variety of pulmonary diseases, and as such, understanding the mechanisms of vagal sensory function and dysfunction may reveal novel therapeutic targets. In this comprehensive review we discuss historical and state-of-the-art concepts in airway sensory neurobiology and explore mechanisms underlying how vagal sensory pathways become dysfunctional in pathological conditions.

Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves

“…Alterations in both the sensory and parasympathetic nervous systems most likely contribute to airway pathologies such as asthma and COPD (reviewed in Undem and Potenzieri, 2012;Mazzone and Undem, 2016). That NaV1.7 is the dominant controller of neurotransmission in human and guinea pig airway parasympathetic neurons provides for a strategy of limiting parasympathetic tone in the respiratory tract via selective NaV1.7 blockade.…”

Brainstem mechanisms underlying the cough reflex and its regulation

“…However, although the central pathways have not been investigated in detail, they are probably similar to those displayed by tracheobronchial cough afferents (Kalia and Mesulam, 1980;Nomura and Mizuno, 1983;Mifflin, 1993). In addition, "irritant" receptors may evoke many other airway protective reflexes such as glottal closure, apnea, bronchoconstriction, mucus secretion, the expiration reflex, the swallowing reflex and cardiovascular reflexes (Korpáš and Tomori, 1979;Widdicombe, 1986;Mutolo et al, 1995;Sant'Ambrogio and Widdicombe, 2001;Jean, 2001;Nishino et al, 2004;Mazzone and Undem, 2016). The expiration reflex closely resembles cough responses, but it consists of a pure expiratory effort evoked by the mechanical stimulation of the vocal fold mucosa in the absence of a preparatory inspiratory phase (Korpáš and Tomori, 1979;Korpas and Jakus, 2000;Sant'Ambrogio and Widdicombe, 2001).…”

“…In addition, functional evidence has been provided that local interneurons release substance P in response to glutamatergic inputs (Colin et al, 2002; see also Sekizawa et al, 2003 for further Refs.). For a recent interesting, comprehensive review on vagal afferent innervation of the airways, its functional characteristics, and related central pathways under healthy or pathological conditions see Mazzone and Undem (2016).…”

“…In fact, the cough afferent pathway extends beyond a simple pontomedullary reflex to impinge on neuronal networks widely distributed throughout subcortical and cortical brain areas (Mazzone et al, 2011;Ando et al, 2014;Driessen et al, 2016). For further details on the central mechanisms subserving generation or modulation of the cough reflex see also Mazzone and Undem (2016). Fig.…”

Mechanisms of Mycobacterial Transmission: How does Mycobacterium Tuberculosis enter and Escape from the Human Host

“…Cough may be a natural consequence of lung inflammation and host production of prostaglandins, bradykinin and other inflammatory mediators that activate afferent neuronal C-fibers in the lung mucosa [18]. In addition, cavity or cyst formation itself might induce mechanical activation of either rapidly adapting receptors or slowly adapting stretch receptors that can sensitize the lungs to cough triggers [19,20]. Conversely, cough itself, perhaps triggered by secreted mycobacterial factors, could lead to Mtb aerosolization and/or cavity formation.…”