Effects of macrolides on antigen-induced increases in cough reflex sensitivity in guinea pigs.
BACKGROUND
Macrolides are antibiotics that have anti-inflammatory activities. Hence, they are used for both acute and chronic inflammatory airway diseases. However, the effects of these agents on allergic airway disorders presenting with an isolated chronic cough, such as non-asthmatic eosinophilic bronchitis and eosinophilic tracheobronchitis with cough hypersensitivity (atopic cough), still remain to be elucidated.


OBJECTIVE
To determine if macrolides are effective in the management of chronic cough caused by eosinophilic airway inflammation.


METHODS
The cough reflex sensitivity to inhaled capsaicin was measured at 48h after challenge with an aerosolized antigen in actively sensitized guinea pigs. The 14-, 15- or 16-membered macrolides (erythromycin, azythromycin, or josamycin, respectively) were given intraperitoneally every 12h after the antigen challenge. Bronchoalveolar lavage and the resection of the tracheal tissue were performed immediately after the measurement of the cough response to capsaicin.


RESULTS
The antigen-induced increase in the number of coughs elicited by capsaicin inhalation was significantly reduced by treatments with erythromycin and azythromycin, but not with josamycin. Erythromycin dose-dependently inhibited the increases in the substance P, prostaglandin E(2) and leukotriene B(4) levels, but not the histamine levels, in the bronchoalveolar lavage fluid. However, erythromycin did not influence the antigen-induced decrease in the neutral endopeptidase (NEP) activity in the tracheal tissue.


CONCLUSIONS
Both 14- and 15-membered, but not 16-membered, macrolides could reduce the antigen-induced cough reflex hypersensitivity by inhibiting the antigen-induced release of the afferent sensory nerve sensitizers. These macrolides may be therapeutically useful for the treatment of isolated chronic cough based on cough reflex hypersensitivity in allergic airway diseases such as non-asthmatic eosinophilic bronchitis and atopic cough.
Tokuda
Akira
A
Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa-city, Ishikawa 920-8641, Japan. tokuda@med3.m.kanazawa-u.ac.jp
Ohkura
Noriyuki
N
Fujimura
Masaki
M
Furusho
Shiho
S
Abo
Miki
M
Katayama
Nobuyuki
N
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000941:Antigens / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003371:Cough / Q000188:drug therapy* / Q000503:physiopathology; D015232:Dinoprostone / Q000032:analysis; D004917:Erythromycin / Q000627:therapeutic use; D006168:Guinea Pigs; D007975:Leukotriene B4 / Q000032:analysis; D018942:Macrolides / Q000627:therapeutic use*; D008297:Male; D012018:Reflex / Q000187:drug effects*; D013373:Substance P / Q000032:analysis
D000900:Anti-Bacterial Agents; D000941:Antigens; D018942:Macrolides; D007975:Leukotriene B4; D013373:Substance P; D004917:Erythromycin; D015232:Dinoprostone