Functional implications of the multiple afferent pathways regulating cough☆
Introduction
Coughing protects and clears the airways of inhaled irritants, particulates, accumulated secretions and aspirated gastric contents. An inability to cough or an impaired cough reflex greatly increases susceptibility to pneumonia. Cough can thus be considered an essential homeostatic reflex, preserving airway patency and thus lung capacity for gas exchange. Cough can also be problematic. Chronic cough, afflicting as much as 10% of the general population, and nonproductive post-infectious cough are thought to be pathophysiologic and subserving no protective functions [1], [2], [3].
Vagal afferent nerves regulate the cough reflex. Multiple vagal afferent nerve subtypes have been identified and their roles in regulating cough have been reviewed in detail elsewhere [3]. The existence of multiple pathways for cough and the presentation of cough as either homeostatic or pathophysiologic leads to speculation about the utility of these multiple pathways and their role in regulating different types of cough. The physiological and morphological attributes of the vagal afferent nerves regulating cough are briefly reviewed. Also reviewed is the evidence against the notion that different vagal afferent nerve subtypes uniquely and separately regulate homeostatic and pathophysiologic coughing.
Section snippets
Capsaicin-sensitive and insensitive afferent pathways regulating cough
Work carried out in multiple species including humans has identified at least 2 vagal afferent pathways that initiate coughing upon activation: C-fibers and cough receptors [3]. Bronchopulmonary C-fibers are activated selectively by stimuli such as capsaicin, bradykinin, protons and activators of the cation channel TRPA1. These stimuli reliably evoke coughing in humans and in awake guinea pigs [3], [4], [5], [6], [7], [8], [9], [10]. C-fibers terminate in the airway mucosa, submucosa, lung
Is there good cough and bad cough?
The identification of anatomically and functionally distinct vagal afferent pathways known to regulate cough might suggest the existence of 2 types of cough [3], [29]. In this scheme, the acid-sensitive mechanoreceptors innervating the extrapulmonary airways subserve an all-important homeostatic function, producing a “good” cough that protects the airways and lungs from aspirated particulates and gastric contents. Evidence in favor of this function includes the termination sites of these
Afferent interactions regulating cough
Coughing regardless of the tussive stimulus, disease state or the specific vagal afferent nerves activated ultimately utilizes the same efferent signaling pathways and cough pattern generators to produce the forceful expiratory reflexes so readily defined as cough. Implicit in this shared efferent limb is that cough reflex pathways ultimately converge through a single medullary pathway controlling respiratory muscle activity [50]. Afferent pathways regulating cough may also converge more
Conclusions
Two vagal afferent nerve subtypes initiate coughing upon activation, the bronchopulmonary C-fibers and the cough receptors. These afferent pathways produce at least 2 types of cough, one a robust cough that persists even under general anesthesia and produces few, powerful cough efforts in response to chemical and mechanical stimuli in the large airways, the second a cough that is prevented by general anesthesia, can be paroxysmal in patterning and most resembles the dry, nonproductive cough
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2022, NeuronCitation Excerpt :Early models hypothesized that a single, broadly tuned sensory population may sense diverse airway threats and engage different protective reflexes depending on discharge frequency (Storey, 1968). However, at least two types of cough afferents with different airway distributions have been proposed, including capsaicin- and anesthetic-sensitive C fibers and anesthetic-insensitive A fibers (Canning, 2011), and more recent studies have indicated an even more substantial division of labor among primary afferent neurons (Mazzone et al., 2020; Prescott et al., 2020). We are only beginning to understand the diversity of vagal sensory neurons that guard the upper airways and how they detect threats, such as irritants, pathogens, force, and aspirated food and water.
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2022, Respiratory Physiology and NeurobiologyCitation Excerpt :Lung transplant patients have their lower airways denervated, and in these patients, laryngeal cough could be evoked 6 weeks to 36 months after surgery (Higenbottam et al., 1989), and in patients 1.5–12 weeks after surgery, cough responses were elicited from all sites except distal to the airway anastomosis (Duarte et al., 2008). Canning (2011) observed that the intrathoracic capsaicin-induced cough is extinguished with anesthesia in the guinea pig (Canning, 2011), and another group reported similar observations in the dog (Palecek et al., 1989). We have observed that cough remains present during anesthesia in the cat when capsaicin is administered into the trachea.
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2017, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :Inflammatory cells are capable of producing reactive oxygen species, potent stimulators and sensitizers of bronchopulmonary C-fibres [17]. C-fibres respond to capsaicin, bradykinin, citric acid, ATP, thrombin, adenosine and mechanical stimulation [18], although and it has been suggested that cough caused by capsaicin is due to secondary activation of RARs following odema and/or bronchoconstriction [4]. The activation of C-fibres in the intrapulmonary airways in guinea pigs can augment cough reflex responses, presumably by acting synergistically with Aδ fibre stimulation at the level of the brain stem [4].
Role of reactive oxygen species and TRP channels in the cough reflex
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