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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 GW5074 (B) on the concentration-relaxation curves induced by isoprenaline in the trachea segments isolated from the sidestream smoke exposed mice, which were pre-contracted with carbachol (Cch) 2 × 10-7 M. Results are the percent of relaxation induced by isoprenaline after pre-contraction with carbachol and are expressed as the mean ± SEM. n = six or seven animals/group, *p < 0.05 and **p < 0.01 vs. sidestream smoke exposure group.
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Figure 3: Effect of dexamethasone (A) and GW5074 (B) on the concentration-relaxation curves induced by isoprenaline in the trachea segments isolated from the sidestream smoke exposed mice, which were pre-contracted with carbachol (Cch) 2 × 10-7 M. Results are the percent of relaxation induced by isoprenaline after pre-contraction with carbachol and are expressed as the mean ± SEM. n = six or seven animals/group, *p < 0.05 and **p < 0.01 vs. sidestream smoke exposure group.

Mentions: Airway hyperresponsiveness can be manifested as a response to both increases in the receptors that mediate airway constriction and decreases in the receptors that mediate airway dilatation. β-adrenoceptor is the most important receptor that mediates airway dilatation. In the present study, we investigated the effect of sidestream smoke on the dilatation function of β-adrenoceptor and the effect of GW5074 and dexamethasone. A sustained contraction of the tracheal segments was obtained by carbachol 2 × 10-7 M. Subsequently, cumulative administration of the β-adrenoceptor agonist, isoprenaline, induced a concentration-dependent relaxation of all of the segments of the mouse trachea isolated from the sidestream smoke exposure group, fresh air group, dexamethasone (0.3 mg/kg, 1 mg/kg) plus sidestream smoke exposure group and GW5074 (0.5 mg/kg, 2 mg/kg) plus sidestream smoke exposure group. A significant difference in the concentration-relaxation curves was not observed among these groups (Figure 3).


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 GW5074 (B) on the concentration-relaxation curves induced by isoprenaline in the trachea segments isolated from the sidestream smoke exposed mice, which were pre-contracted with carbachol (Cch) 2 × 10-7 M. Results are the percent of relaxation induced by isoprenaline after pre-contraction with carbachol and are expressed as the mean ± SEM. n = six or seven animals/group, *p < 0.05 and **p < 0.01 vs. sidestream smoke exposure group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Effect of dexamethasone (A) and GW5074 (B) on the concentration-relaxation curves induced by isoprenaline in the trachea segments isolated from the sidestream smoke exposed mice, which were pre-contracted with carbachol (Cch) 2 × 10-7 M. Results are the percent of relaxation induced by isoprenaline after pre-contraction with carbachol and are expressed as the mean ± SEM. n = six or seven animals/group, *p < 0.05 and **p < 0.01 vs. sidestream smoke exposure group.
Mentions: Airway hyperresponsiveness can be manifested as a response to both increases in the receptors that mediate airway constriction and decreases in the receptors that mediate airway dilatation. β-adrenoceptor is the most important receptor that mediates airway dilatation. In the present study, we investigated the effect of sidestream smoke on the dilatation function of β-adrenoceptor and the effect of GW5074 and dexamethasone. A sustained contraction of the tracheal segments was obtained by carbachol 2 × 10-7 M. Subsequently, cumulative administration of the β-adrenoceptor agonist, isoprenaline, induced a concentration-dependent relaxation of all of the segments of the mouse trachea isolated from the sidestream smoke exposure group, fresh air group, dexamethasone (0.3 mg/kg, 1 mg/kg) plus sidestream smoke exposure group and GW5074 (0.5 mg/kg, 2 mg/kg) plus sidestream smoke exposure group. A significant difference in the concentration-relaxation curves was not observed among these groups (Figure 3).

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