Ozone-induced model of cough hypersensitivity for the selection of novel antitussive agents

Cough hypersensitivity syndrome is a burdensome condition characterized by a heightened cough reflex triggered by low levels of thermal, mechanical or chemical stimulus. Ozone (O3) is a very powerful oxidant and toxic pollutant able to cause important respiratory symptoms including chronic cough (CC) and known to cause hypertussive response to citric acid (CA) in experimental animals. The aim of this study was to set-up an improved preclinical model of increased cough sensitivity by exposing guinea pigs (GP) to O3 prior citric acid or capsaicin challenge. GPs were placed in a box and exposed to O3 at 1 and 2ppm or air for 20’. O3 was generated by an ozonizer (OGS-314T, OEC Italy) at a flow rate of 5L/min. After 20’ animals were put in the PWTs chambers and after 10’ of acclimatation period CA 0.15M or capsaicin 10µM was nebulized into the boxes for 10’. During this period and 5 min later, cough reflexes were counted automatically by Fine-Point interface. O3 exposure dose dependently increased the number of cough reflexes in animals challenged with CA, reaching the maximum number of cough reflexes at 2ppm (13.6 ± 4.6) compared to the control group (0.5 ± 0.5). Carcainium, a non-selective sodium channel blocker, nebulized at 3µmol/kg dose simultaneously with CA for 10’ in the PWTs, was able to reduce the number of cough reflexes (2.3 ± 1.1, p<0.01). On the contrary, capsaicin 10µM was not able to induce cough in GPs previously exposed to O3 2ppm. Overall, these results confirm that O3 may induce a hypersensitivity response to specific tussive agents such as CA and that this model may be useful for the investigation of novel mechanisms and potential new treatments for CC.