The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice.
BACKGROUND
Sidestream smoke is closely associated with airway inflammation and hyperreactivity. The present study was designed to investigate if the Raf-1 inhibitor GW5074 and the anti-inflammatory drug dexamethasone suppress airway hyperreactivity in a mouse model of sidestream smoke exposure.


METHODS
Mice were repeatedly exposed to smoke from four cigarettes each day for four weeks. After the first week of the smoke exposure, the mice received either dexamethasone intraperitoneally every other day or GW5074 intraperitoneally every day for three weeks. The tone of the tracheal ring segments was recorded with a myograph system and concentration-response curves were obtained by cumulative administration of agonists. Histopathology was examined by light microscopy.


RESULTS
Four weeks of exposure to cigarette smoke significantly increased the mouse airway contractile response to carbachol, endothelin-1 and potassium. Intraperitoneal administration of GW5074 or dexamethasone significantly suppressed the enhanced airway contractile responses, while airway epithelium-dependent relaxation was not affected. In addition, the smoke-induced infiltration of inflammatory cells and mucous gland hypertrophy were attenuated by the administration of GW5074 or dexamethasone.


CONCLUSIONS
Sidestream smoke induces airway contractile hyperresponsiveness. Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.
Lei
Ying
Y
Department of Pharmacology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi Province 710061, PR China. joanna2022@163.com
Cao
Yong-Xiao
YX
Xu
Cang-Bao
CB
Zhang
Yaping
Y
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D003907:Dexamethasone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010636:Phenols / Q000008:administration & dosage*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors*; D012906:Smoke; D014026:Nicotiana / Q000633:toxicity*
D007211:Indoles; D010636:Phenols; D012906:Smoke; D003907:Dexamethasone; D019908:Proto-Oncogene Proteins c-raf; C489251:5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone