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

Lei Y, Cao YX, Xu CB, Zhang Y - Respir. Res. (2008)

Bottom Line: Sidestream smoke is closely associated with airway inflammation and hyperreactivity.Intraperitoneal administration of GW5074 or dexamethasone significantly suppressed the enhanced airway contractile responses, while airway epithelium-dependent relaxation was not affected.Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi Province 710061, PR China. joanna2022@163.com

ABSTRACT

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.

Conclusion: Sidestream smoke induces airway contractile hyperresponsiveness. Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.

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Related in: MedlinePlus

Effect of dexamethasone (A and C) and GW5074 (B and D) on the concentration-contractile curves of the trachea segments isolated from the sidestream smoke exposed mice induced by sarafotoxin 6c and by endothelin-1. Results are expressed as the mean ± SEM, n = six or seven animals/group.
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Figure 2: Effect of dexamethasone (A and C) and GW5074 (B and D) on the concentration-contractile curves of the trachea segments isolated from the sidestream smoke exposed mice induced by sarafotoxin 6c and by endothelin-1. Results are expressed as the mean ± SEM, n = six or seven animals/group.

Mentions: Sarafotoxin 6c, a specific agonist of the endothelin ETB receptor, caused concentration-dependent contractile responses in all of the mouse tracheal segments from the sidestream smoke exposure group, fresh air group, dexamethasone (0.3 mg/kg, 1 mg/kg) plus sidestream smoke exposure groups and GW5074 (0.5 mg/kg, 2 mg/kg) plus sidestream smoke exposure groups. However, the airway contraction in response to sarafotoxin 6c showed no significant differences among these groups (Figure 2A, 2B). Although at the 1 × 10-7 M dose of sarafotoxin 6c could get a maximal contractive effect in the control group (fresh air exposure), its curve in the smoke-exposed group was incomplete (Figure 2A, 2B). This suggests an enhanced potency of sarofotoxin in the airway after sidestream smoke exposure.


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

Lei Y, Cao YX, Xu CB, Zhang Y - Respir. Res. (2008)

Effect of dexamethasone (A and C) and GW5074 (B and D) on the concentration-contractile curves of the trachea segments isolated from the sidestream smoke exposed mice induced by sarafotoxin 6c and by endothelin-1. Results are expressed as the mean ± SEM, n = six or seven animals/group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2599896&req=5

Figure 2: Effect of dexamethasone (A and C) and GW5074 (B and D) on the concentration-contractile curves of the trachea segments isolated from the sidestream smoke exposed mice induced by sarafotoxin 6c and by endothelin-1. Results are expressed as the mean ± SEM, n = six or seven animals/group.
Mentions: Sarafotoxin 6c, a specific agonist of the endothelin ETB receptor, caused concentration-dependent contractile responses in all of the mouse tracheal segments from the sidestream smoke exposure group, fresh air group, dexamethasone (0.3 mg/kg, 1 mg/kg) plus sidestream smoke exposure groups and GW5074 (0.5 mg/kg, 2 mg/kg) plus sidestream smoke exposure groups. However, the airway contraction in response to sarafotoxin 6c showed no significant differences among these groups (Figure 2A, 2B). Although at the 1 × 10-7 M dose of sarafotoxin 6c could get a maximal contractive effect in the control group (fresh air exposure), its curve in the smoke-exposed group was incomplete (Figure 2A, 2B). This suggests an enhanced potency of sarofotoxin in the airway after sidestream smoke exposure.

Bottom Line: Sidestream smoke is closely associated with airway inflammation and hyperreactivity.Intraperitoneal administration of GW5074 or dexamethasone significantly suppressed the enhanced airway contractile responses, while airway epithelium-dependent relaxation was not affected.Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi Province 710061, PR China. joanna2022@163.com

ABSTRACT

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.

Conclusion: Sidestream smoke induces airway contractile hyperresponsiveness. Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.

Show MeSH
Related in: MedlinePlus