Cough is a major symptom of chronic airway diseases (eg COPD & IPF) but remains an unmet medical need. Cough is assessed clinically by ambulatory cough monitoring; current best preclinical methodology involves challenging naïve guinea pigs (GP) with a tussive agent to measure evoked coughs. This mirrors a clinical method to assess cough reflex sensitivity which can demonstrate target engagement, but is not predictive of how effective interventions may be.  This study aimed to characterise the development of ?spontaneous? cough in GP models of COPD&IPF using 24h video monitoring.

Videos were manually reviewed to count coughs in GP which were instilled (i.t) with saline or bleomycin (BM) (IPF model), or exposed to air or cigarette smoke (CS) daily for 30 days (COPD model).  At an appropriate timepoint, tussive challenge responses were assessed in vivo [established cough challenge method], and functional isolated vagus nerve responses in vitro.

Spontaneous cough developed over time in both disease models, with a peak in coughs observed 16 days after BM (BM 23±7.8, SAL 0.1±0.1 coughs/24h) and 30 days after CS exposure (CS 8±3.7, air 0±0 coughs/24h). BM-treated GP had an enhanced cough response to the TRPA1 agonist acrolein, but no change in vagal nerve responses. Similar to observations after 8 days CS exposure¹, the TRPV1 agonist capsaicin evoked more cough in CS than air-exposed GP, and an altered neurophenotype of enhanced capsaicin & reduced PGE2 responses was seen in isolated vagus nerves.

We have demonstrated spontaneous cough occurs in two preclinical models of chronic lung disease, and moreover, have shown them both to be underpinned by two distinct airway neurophenotypes.

¹Belvisi(2016)AMJRCCM 193(12)