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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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Effect of dexamethasone and GW5074 on the tracheal pathology of mice exposed to passive smoke. Hematoxylin and eosin-stained tracheal tissue derived from six groups of mice: fresh air group, passive smoke-exposed group, dexamethasone (0.3 mg/kg, 1 mg/kg) plus passive smoke-exposed groups and GW5074 (0.5 mg/kg, 2 mg/kg) plus passive smoke-exposed groups. Inflammatory cells and tracheal mucous gland hypertrophy were not found in the fresh air group (A1: ×100 and A2: ×400). There were many infiltrated inflammatory cells and mucous gland hypertrophy in the tracheas of the passive smoke-exposed group (B1: ×100 and B2: ×400). The infiltration of inflammatory cells and tracheal mucous gland hypertrophy were decreased in both the 1 mg/kg (C1: ×100 and C2: ×400) and the 0.3 mg/kg (D1: ×100 and D2: ×400) dexamethasone groups and both the 2 mg/kg (E1: ×100 and E2: ×400) and the 0.5 mg/kg (F1: ×100 and F2: ×400) GW5074 groups, compared with the passive smoke-exposed group.
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Figure 4: Effect of dexamethasone and GW5074 on the tracheal pathology of mice exposed to passive smoke. Hematoxylin and eosin-stained tracheal tissue derived from six groups of mice: fresh air group, passive smoke-exposed group, dexamethasone (0.3 mg/kg, 1 mg/kg) plus passive smoke-exposed groups and GW5074 (0.5 mg/kg, 2 mg/kg) plus passive smoke-exposed groups. Inflammatory cells and tracheal mucous gland hypertrophy were not found in the fresh air group (A1: ×100 and A2: ×400). There were many infiltrated inflammatory cells and mucous gland hypertrophy in the tracheas of the passive smoke-exposed group (B1: ×100 and B2: ×400). The infiltration of inflammatory cells and tracheal mucous gland hypertrophy were decreased in both the 1 mg/kg (C1: ×100 and C2: ×400) and the 0.3 mg/kg (D1: ×100 and D2: ×400) dexamethasone groups and both the 2 mg/kg (E1: ×100 and E2: ×400) and the 0.5 mg/kg (F1: ×100 and F2: ×400) GW5074 groups, compared with the passive smoke-exposed group.

Mentions: Inflammatory cells were infiltrated into the tracheal smooth muscle layer in the sidestream smoke exposure mice and tracheal mucous gland hypertrophy could also be observed in these mice, while mice in the fresh air group had no infiltrated inflammatory cells or tracheal mucous gland hypertrophy. Compared to the mice in the fresh air group, there were significantly higher scores in the infiltration of inflammatory cells, tracheal mucous gland hypertrophy and total tracheal inflammation in the mice in the sidestream smoke exposure group. Either dose of dexamethasone (0.3 mg/kg or 1 mg/kg) significantly decreased the inflammatory cells infiltration, tracheal mucous gland hypertrophy and the total tracheal inflammation induced by sidestream smoke exposure. Similar results were obtained by treating the mice with two doses of GW5074 (0.5 mg/kg or 2 mg/kg). There were statistical differences in the total scores between the doses of dexamethasone (0.3 and 1.0 mg/kg), and between the doses of GW5074 (0.5 mg/kg and 2 mg/kg), suggesting there is a dose-dependent effect of dexamethasone and GW5074 on airway inflammatory lesions (Table 2, Figure 4).


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 and GW5074 on the tracheal pathology of mice exposed to passive smoke. Hematoxylin and eosin-stained tracheal tissue derived from six groups of mice: fresh air group, passive smoke-exposed group, dexamethasone (0.3 mg/kg, 1 mg/kg) plus passive smoke-exposed groups and GW5074 (0.5 mg/kg, 2 mg/kg) plus passive smoke-exposed groups. Inflammatory cells and tracheal mucous gland hypertrophy were not found in the fresh air group (A1: ×100 and A2: ×400). There were many infiltrated inflammatory cells and mucous gland hypertrophy in the tracheas of the passive smoke-exposed group (B1: ×100 and B2: ×400). The infiltration of inflammatory cells and tracheal mucous gland hypertrophy were decreased in both the 1 mg/kg (C1: ×100 and C2: ×400) and the 0.3 mg/kg (D1: ×100 and D2: ×400) dexamethasone groups and both the 2 mg/kg (E1: ×100 and E2: ×400) and the 0.5 mg/kg (F1: ×100 and F2: ×400) GW5074 groups, compared with the passive smoke-exposed group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Effect of dexamethasone and GW5074 on the tracheal pathology of mice exposed to passive smoke. Hematoxylin and eosin-stained tracheal tissue derived from six groups of mice: fresh air group, passive smoke-exposed group, dexamethasone (0.3 mg/kg, 1 mg/kg) plus passive smoke-exposed groups and GW5074 (0.5 mg/kg, 2 mg/kg) plus passive smoke-exposed groups. Inflammatory cells and tracheal mucous gland hypertrophy were not found in the fresh air group (A1: ×100 and A2: ×400). There were many infiltrated inflammatory cells and mucous gland hypertrophy in the tracheas of the passive smoke-exposed group (B1: ×100 and B2: ×400). The infiltration of inflammatory cells and tracheal mucous gland hypertrophy were decreased in both the 1 mg/kg (C1: ×100 and C2: ×400) and the 0.3 mg/kg (D1: ×100 and D2: ×400) dexamethasone groups and both the 2 mg/kg (E1: ×100 and E2: ×400) and the 0.5 mg/kg (F1: ×100 and F2: ×400) GW5074 groups, compared with the passive smoke-exposed group.
Mentions: Inflammatory cells were infiltrated into the tracheal smooth muscle layer in the sidestream smoke exposure mice and tracheal mucous gland hypertrophy could also be observed in these mice, while mice in the fresh air group had no infiltrated inflammatory cells or tracheal mucous gland hypertrophy. Compared to the mice in the fresh air group, there were significantly higher scores in the infiltration of inflammatory cells, tracheal mucous gland hypertrophy and total tracheal inflammation in the mice in the sidestream smoke exposure group. Either dose of dexamethasone (0.3 mg/kg or 1 mg/kg) significantly decreased the inflammatory cells infiltration, tracheal mucous gland hypertrophy and the total tracheal inflammation induced by sidestream smoke exposure. Similar results were obtained by treating the mice with two doses of GW5074 (0.5 mg/kg or 2 mg/kg). There were statistical differences in the total scores between the doses of dexamethasone (0.3 and 1.0 mg/kg), and between the doses of GW5074 (0.5 mg/kg and 2 mg/kg), suggesting there is a dose-dependent effect of dexamethasone and GW5074 on airway inflammatory lesions (Table 2, Figure 4).

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