title: Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs.
abstract: Cough remains a major unmet clinical need, and preclinical animal models are not predictive for new antitussive agents. We have investigated the mechanisms and pharmacological sensitivity of ozone-induced hypertussive responses in rabbits and guinea pigs. Ozone induced a significant increase in cough frequency and a decrease in time to first cough to inhaled citric acid in both conscious guinea pigs and rabbits. This response was inhibited by the established antitussive drugs codeine and levodropropizine. In contrast to the guinea pig, hypertussive responses in the rabbit were not inhibited by bronchodilator drugs (β2 agonists or muscarinic receptor antagonists), suggesting that the observed hypertussive state was not secondary to bronchoconstriction in this species. The ozone-induced hypertussive response in the rabbit was inhibited by chronic pretreatment with capsaicin, suggestive of a sensitization of airway sensory nerve fibers. However, we could find no evidence for a role of TRPA1 in this response, suggesting that ozone was not sensitizing airway sensory nerves via activation of this receptor. Whereas the ozone-induced hypertussive response was accompanied by a significant influx of neutrophils into the airway, the hypertussive response was not inhibited by the anti-inflammatory phosphodiesterase 4 inhibitor roflumilast at a dose that clearly exhibited anti-inflammatory activity. In summary, our results suggest that ozone-induced hypertussive responses to citric acid may provide a useful model for the investigation of novel drugs for the treatment of cough, but some important differences were noted between the two species with respect to sensitivity to bronchodilator drugs.
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (E.C., D.S., C.P.); Department of Corporate Drug Development (R.P.), and Department of Pharmacology (M.T.), Chiesi Farmaceutici SpA, Parma, Italy; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy (D.P.); and Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy (M.P.B.).
authors.forename: Emlyn
authors.initials: E
authors.lastname: Clay
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (E.C., D.S., C.P.); Department of Corporate Drug Development (R.P.), and Department of Pharmacology (M.T.), Chiesi Farmaceutici SpA, Parma, Italy; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy (D.P.); and Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy (M.P.B.).
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (E.C., D.S., C.P.); Department of Corporate Drug Development (R.P.), and Department of Pharmacology (M.T.), Chiesi Farmaceutici SpA, Parma, Italy; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy (D.P.); and Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy (M.P.B.).
authors.forename: Marcello
authors.initials: M
authors.lastname: Trevisani
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (E.C., D.S., C.P.); Department of Corporate Drug Development (R.P.), and Department of Pharmacology (M.T.), Chiesi Farmaceutici SpA, Parma, Italy; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy (D.P.); and Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy (M.P.B.).
authors.forename: Delia
authors.identifier: http://orcid.org/0000-0002-1075-3781
authors.initials: D
authors.lastname: Preti
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (E.C., D.S., C.P.); Department of Corporate Drug Development (R.P.), and Department of Pharmacology (M.T.), Chiesi Farmaceutici SpA, Parma, Italy; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy (D.P.); and Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy (M.P.B.).
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Branà
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (E.C., D.S., C.P.); Department of Corporate Drug Development (R.P.), and Department of Pharmacology (M.T.), Chiesi Farmaceutici SpA, Parma, Italy; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy (D.P.); and Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy (M.P.B.).
authors.forename: Domenico
authors.identifier: http://orcid.org/0000-0002-6815-1564
authors.initials: D
authors.lastname: Spina
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (E.C., D.S., C.P.); Department of Corporate Drug Development (R.P.), and Department of Pharmacology (M.T.), Chiesi Farmaceutici SpA, Parma, Italy; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy (D.P.); and Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy (M.P.B.) clive.page@kcl.ac.uk.
authors.forename: Clive
authors.initials: C
authors.lastname: Page
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000996:Antitussive Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000627:therapeutic use; D002211:Capsaicin; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced* / Q000188:drug therapy*; D003521:Cyclopropanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D010083:Oxidants, Photochemical / Q000633:toxicity*; D010126:Ozone / Q000633:toxicity*; D011409:Propylene Glycols / Q000494:pharmacology; D011817:Rabbits; D050051:Transient Receptor Potential Channels / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000996:Antitussive Agents; D001549:Benzamides; D001993:Bronchodilator Agents; D003521:Cyclopropanes; D010083:Oxidants, Photochemical; D011409:Propylene Glycols; D050051:Transient Receptor Potential Channels; C424423:Roflumilast; D019343:Citric Acid; D010126:Ozone; D002211:Capsaicin; C035916:dipropizine
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