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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 potassium chloride (KCl) and by carbachol. Results 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 1: 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 potassium chloride (KCl) and by carbachol. Results 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: 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. The potassium induced a concentration-dependent contraction of the tracheal ring segments isolated from the fresh air group (Figure 1). The sidestream smoke exposure caused a significant increase in the contraction and shifted the concentration-contraction curves to the left with an increased Emax of 5.51 ± 0.46 mN (Figure 1, Table 1), compared with the fresh air group. Treatment of mice with either dose of dexamethasone (0.3 mg/kg or 1 mg/kg) attenuated the potassium-induced contraction of tracheal ring segments in sidestream smoke exposed mice and shifted the concentration-contraction curves to the right with a decreased Emax of 3.50 ± 0.45 mN and 3.94 ± 0.52 mN, respectively (Table 1, Figure 1A). The contraction induced by potassium was also significantly decreased by treatment with either dose of GW5074 (0.5 mg/kg or 2 mg/kg) compared with the sidestream smoke exposure group, which had a decreased Emax (Table 1, Figure 1B).


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 potassium chloride (KCl) and by carbachol. Results 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 1: 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 potassium chloride (KCl) and by carbachol. Results 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: 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. The potassium induced a concentration-dependent contraction of the tracheal ring segments isolated from the fresh air group (Figure 1). The sidestream smoke exposure caused a significant increase in the contraction and shifted the concentration-contraction curves to the left with an increased Emax of 5.51 ± 0.46 mN (Figure 1, Table 1), compared with the fresh air group. Treatment of mice with either dose of dexamethasone (0.3 mg/kg or 1 mg/kg) attenuated the potassium-induced contraction of tracheal ring segments in sidestream smoke exposed mice and shifted the concentration-contraction curves to the right with a decreased Emax of 3.50 ± 0.45 mN and 3.94 ± 0.52 mN, respectively (Table 1, Figure 1A). The contraction induced by potassium was also significantly decreased by treatment with either dose of GW5074 (0.5 mg/kg or 2 mg/kg) compared with the sidestream smoke exposure group, which had a decreased Emax (Table 1, Figure 1B).

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