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Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
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[Mechanism of p38 mitogen-activated protein kinase inhibitor SB203580 to glucocorticoid sensitivity]

Wen Li1, Jiang-tao Lin, Li-chao Sun

  • 1Chinese Academy of Medical Sciences, Beijing, China.

Zhonghua Yi Xue Za Zhi
|November 20, 2012
PubMed
Abstract

Insights

This study demonstrates that SB203580 enhances corticosteroid sensitivity in asthma models by improving glucocorticoid receptor (GR) nuclear translocation. This finding offers a potential therapeutic mechanism for glucocorticoid resistance in asthma.

Area of Science:

  • Pulmonary Medicine
  • Cell Biology
  • Pharmacology

Background:

  • Asthma is a chronic respiratory disease often associated with inflammation and airway hyperresponsiveness.
  • Glucocorticoid resistance is a significant clinical challenge in managing severe asthma.
  • Cigarette smoke exposure can exacerbate asthma symptoms and contribute to glucocorticoid resistance.

Purpose of the Study:

  • To develop a rat model of asthma induced by cigarette smoke exposure.
  • To investigate nicotine-induced glucocorticoid resistance in A549 alveolar epithelial cells.
  • To elucidate the mechanism by which the p38 MAPK inhibitor SB203580 affects glucocorticoid sensitivity.

Main Methods:

  • Establishment of a rat model involving asthma and cigarette smoke exposure.
  • In vivo analysis of glucocorticoid receptor (GR), HSP90, and p38 MAPK mRNA and protein expression using RT-PCR and Western blot.
  • In vitro study using A549 cells treated with dexamethasone, nicotine, and SB203580.
  • Immunofluorescence staining to assess GR nuclear translocation in A549 cells.

Main Results:

  • Cigarette smoke exposure significantly altered the expression of GR, HSP90, and p38 MAPK in asthmatic rats.
  • Nicotine treatment in A549 cells induced glucocorticoid resistance.
  • SB203580 treatment significantly increased the nuclear translocation of GR in A549 cells compared to nicotine-treated cells.
  • SB203580 treatment reversed nicotine-induced changes in HSP90 and p38 MAPK expression.

Conclusions:

  • The p38 MAPK pathway plays a crucial role in mediating glucocorticoid resistance in asthma.
  • SB203580 enhances corticosteroid sensitivity by promoting the nuclear translocation of the glucocorticoid receptor (GR).
  • Targeting the p38 MAPK pathway may represent a novel therapeutic strategy for overcoming glucocorticoid resistance in asthma.

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