Abnormal intraepithelial airway nerves in persistent unexplained cough?

Abstract

Idiopathic persistent nonproductive cough (PNPC) is characterized by enhanced cough sensitivity to inhaled capsaicin, suggesting that capsaicin-sensitive afferent airway nerves are either present in increased numbers or functionally upregulated. In 16 patients with idiopathic PNPC and eight healthy control subjects, we measured cough sensitivity to inhaled capsaicin and the anatomic density in bronchial epithelium of nerves immunoreactive for the general nerve-marker protein gene product (PGP)-9.5 and the sensory neuropeptides calcitonin-gene-related-peptide (CGRP) and substance-P (SP). The log concentrations of capsaicin required to elicit at least two (C2) and five (C5) coughs were significantly lower in patients (P) than in control subjects (C) (median [range] log C2, P = 0.3 [-0.3 to 1.2] microM; C = 1.5 [0.9 to 2.1], p < 0.0005; log C5, P = 0.8 [-0.3 to 2.1]; C = 2.6 [1.8 to 3.0], p < 0.0005). In bronchial epithelium taken from the carina of the right upper lobe (RUL) and a subsegmental carina of the right lower lobe (RLL), total nerve density (PGP-9.5 immunoreactivity) was greater in P than C, although this was not significant. CGRP-immunoreactive nerve density was significantly higher in P than in C in the RUL (median [range] P = 1.05% [0.13 to 5.08]; C = 0.02% [0 to 0.24], p = 0.001) and RLL (P = 0.59% [0.04 to 3.14]; C = 0% [0 to 0.50], p < 0.02). SP-immunoreactive nerves were not significantly different in the two groups. Abnormal intraepithelial airway nerves containing increased quantities of CGRP are present in patients with idiopathic PNPC.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitonin gene-related peptide relates to cough sensitivity in children with chronic cough

“…Neurogenic inflammatory mediators, particularly CGRP, have been implicated in the pathogenesis of chronic cough [12,18]. The present finding of CGRP in the BAL also being related to cough sensitivity in coughers but not in noncoughers is perhaps not surprising.…”

“…The present finding of CGRP in the BAL also being related to cough sensitivity in coughers but not in noncoughers is perhaps not surprising. In biopsy specimens, CGRP immunoreactivity has been found to be related to cough sensitivity in adults with chronic cough [18]. This is likely to relate to the plasticity of the peripheral nervous system, with neurotrophins altering the pattern of innervation changes in inflammatory disease, as SP-and CGRP-immunoreactive nerves are sparse in normal human airways [27].…”

“…In particular, CGRP has been shown to be important in the mechanism of chronic cough [16,17]. In human studies, increased CGRP but not SP immunoreactive nerves were found in biopsies of adults with chronic cough [18]. These adults also had significantly increased cough sensitivity to capsaicin (i.e.…”

“…These adults also had significantly increased cough sensitivity to capsaicin (i.e. a reduced threshold to elicit a cough response) [18]. In animal models, gastrooesophageal reflux (GOR) is associated with sensory nerve stimulation [19].…”

“…Prior studies have used selected populations of adults presenting with cough [13,18], and this may select individuals with an abnormal airway response. In order to avoid this potential bias in the present study, children have been studied presenting for upper gastrointestinal endoscopy where there was no selection bias for coughing [20,21].…”