The density of sensory nerves in the respiratory epithelium is increased in people with chronic cough, suggesting that neuroplasticity contributes to cough hypersensitivity.
Up to 12% of the general population suffers from chronic cough. Most are due to smoking and chronic respiratory disease, but a relevant proportion have a chronic refractory cough (CRC) or unexplained cough. This is typically dry or minimally productive and characterised by frequent coughing (sometimes hundreds of times a day), which significantly affects quality of life. Patients often describe increased sensitivity to inhaled irritants (perfumes, detergents) or innocuous stimuli (such as temperature changes or use of the voice). However, the underlying mechanisms are still poorly understood.
Sensory nerves in the respiratory tract trigger coughing. Researchers at Oregon Health & Science University (Portland, USA) therefore took a closer look at them: they performed bronchoscopies and biopsies on a small sample of people with and without a chronic cough and measured airway nerve density (axonal length) and complexity (nerve branching, neuropeptide expression).1,2
Nerve length and number of branch points were significantly increased in epithelium, but not in subepithelium, in people with chronic cough, which may contribute to excessive and persistent cough. Substance-P expression was comparably sparse in both groups (chronic cough versus healthy airways). Nerve length and branching were not associated with eosinophil peroxidase or demographic characteristics such as age and gender in either group.
The study thus provides further evidence that changes in airway innervation play a role. In recent years, there has been increasing recognition that hyperexcitability of the neural pathways controlling cough may be a fundamental component of the pathophysiology in question.
The accompanying editorial2 to the study published in the American Journal of Respiratory and Critical Care Medicine rates the finding as important food for thought, even though the present study was small and fraught with methodological limitations.
The factors involved in increased neuronal branching are best studied in the brain, but the editorial cites other examples: increased neuronal sprouting also occurs in peripheral tissues, including diseased skin in atopic dermatitis or colonic mucosa in irritable bowel syndrome. An increase in nerve density has also been described in animal models of cystitis/irritable bladder, painful arthritic joints and breast cancer-induced bone pain.
Branching is stimulated by extracellular factors (such as axon guidance molecules, neurotrophic factors and cell-adhesive ligands), but also by the position of intracellular organelles and gene expression. Branching may be activity-dependent, but may also occur as a compensatory mechanism following neuronal damage.
The increased density of epithelial fibres reported in the study may therefore be a consequence of many processes, the editorial’s authors suggest: "These include not only the direct effects of cough-generated shear stress and pressures, but also the resulting release of inflammatory mediators (e.g. ATP)." The location and morphological characteristics of the fibres studied indicate that they are most likely vagal C-fibres, which respond predominantly to chemical stimuli and temperature changes. This would match the sensitivities described by patients with chronic cough. "Remodelling of these fibres in patients with chronic cough may contribute to the increased airway sensitivity via increased density of fibre endings in the epithelium and/or enlargement of the fibres' receptive fields" the authors added.
References:
1. Shapiro, C. O. et al. Airway Sensory Nerve Density Is Increased in Chronic Cough. Am J Respir Crit Care Med 203, 348–355 (2020).
2. Smith, J. A. & West, P. W. Branching Out in Chronic Cough: Evidence for Increased Airway Nerve Density. Am J Respir Crit Care Med 203, 283–284 (2020).