Enhanced cough reflex in a model of bleomycin-induced lung fibrosis in guinea pigs.
Fibrotic lung diseases, such as idiopathic pulmonary fibrosis, are associated with spontaneous dry cough and hypersensitivity to tussive agents. Understanding the pathophysiology driving enhanced cough may help us to define better therapies for patients. We hypothesized that lung fibrosis induced by intratracheal bleomycin would exacerbate the cough reflex induced by tussive agents in guinea pigs. Disease progression in the lungs was characterized at days 1, 7, 14, 21 and 28 after bleomycin administration. Inflammatory and fibrotic markers, as well as neurotrophin levels, were assessed in bronchoalveolar lavage fluid and/or lung tissue. Cough sensitivity to citric acid, capsaicin and allylisothiocyanate was evaluated in conscious animals at days 14 and 21 after bleomycin administration. Pulmonary lesions evolved from an early inflammatory phase (from day 1 to day 7) to a fibrotic stage (between days 14 and 28). Fibrosis was related to increased levels of matrix metalloproteinase-2 in bronchoalveolar lavage fluid (day 21: saline, 0.26 ng/ml; bleomycin, 0.49 ng/ml). At day 14, we also observed increased cough reflexes to citric acid (163%), capsaicin (125%) and allylisothiocyanate (178%). Cough exacerbation persisted, but at a lower extent, by day 21 for capsaicin (100%) and allylisothiocyanate (54%). Moreover, bronchoalveolar lavage fluid concentrations of brain-derived neurotrophic factor, suggested to induce nerve remodelling in chronic cough, were also enhanced (day 1: saline, 14.21 pg/ml; bleomycin, 30.09 pg/ml). In summary, our model of bleomycin-induced cough exacerbation may be a valuable tool to investigate cough hypersensitivity and develop antitussive therapies for fibrotic lung diseases.
Respiratory Therapeutic Area - Discovery, Almirall, R&D Centre, Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Joan Antoni
JA
Fernández-Blanco
Respiratory Therapeutic Area - Discovery, Almirall, R&D Centre, Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Mònica
M
Aguilera
Pathology and Predictive Toxicology, Almirall, R&D Centre, Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Anna
A
Domènech
Respiratory Therapeutic Area - Discovery, Almirall, R&D Centre, Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Gema
G
Tarrasón
Pathology and Predictive Toxicology, Almirall, R&D Centre, Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Neus
N
Prats
Respiratory Therapeutic Area - Discovery, Almirall, R&D Centre, Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Montse
M
Miralpeix
Respiratory Therapeutic Area - Discovery, Almirall, R&D Centre, Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain jorgedealba@hotmail.com.
Jorge
J
De Alba
D000818:Animals; D001761:Bleomycin; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002211:Capsaicin; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D006168:Guinea Pigs; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D017879:Isothiocyanates; D008168:Lung / Q000294:innervation* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D012021:Reflex, Abnormal; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D007473:Ion Channels; D017879:Isothiocyanates; D001761:Bleomycin; D019343:Citric Acid; C004471:allyl isothiocyanate; D020778:Matrix Metalloproteinase 2; D002211:Capsaicin
bleomycin; brain-derived neurotrophic factor; capsaicin; citric acid; cough; matrix metalloproteinase-2; pulmonary fibrosis.