The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice

Ying Lei,Yaping Zhang,Cang-Bao Xu,Yong-Xiao Cao

doi:10.1186/1465-9921-9-71

Ying Lei, Yaping Zhang + Show 2 more

Open Access

https://doi.org/10.1186/1465-9921-9-71

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Abstract

BackgroundSidestream 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.MethodsMice 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.ResultsFour 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.ConclusionSidestream smoke induces airway contractile hyperresponsiveness. Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.

Highlights

Sidestream smoke is closely associated with airway inflammation and hyperreactivity
The Raf-1 inhibitor GW5074 was used in the present investigation to determine if the Raf/mitogen-activated protein kinase (MAPK) signaling pathway is involved in sidestream smoke-induced airway inflammation and hyperreactivity
Tracheal segment hyperresponsiveness to potassium The viability and general contractility of the trachea ring segments from the sidestream smoke exposure group, the fresh air group, dexamethasone plus sidestream smoke exposure groups and GW5074 plus sidestream smoke exposure groups were examined by their contractile responses to a cumulative concentration of potassium chloride

Summary

Introduction

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. Inhibition of airway inflammatory signaling may improve smoking-associated airway inflammation and hyperresponsiveness. Activation of intracellular mitogen-activated protein kinase (MAPK) inflammatory signal transduction pathways are responsible for the upregulation of GPCRs in the airway [5,6]. As one of the three members in the Raf family, Raf-1 (C-Raf) is the most widely expressed It is the initial and key protein kinase in the MAPK signal transduction cascade [7]. The Raf-1 inhibitor GW5074 was used in the present investigation to determine if the Raf/MAPK signaling pathway is involved in sidestream smoke-induced airway inflammation and hyperreactivity

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