Chronic intermittent mechanical stress increases MUC5AC protein expression

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Increased abundance of mucin secretory cells is a characteristic feature of the epithelium in asthma and other chronic airway diseases. We showed previously that the mechanical stresses of airway constriction, both in the intact mouse lung and a cell culture model, activate the epidermal growth factor receptor (EGFR), a known modulator of mucin expression in airway epithelial cells. Here we tested whether chronic, intermittent, short-duration compressive stress (30 cmH2O) is sufficient to increase the abundance of MUC5AC-positive cells and intracellular mucin levels in human bronchial epithelial cells cultured at an air-liquid interface. Compressive stress applied for 1 hour per day for 14 days significantly increased the percentage of cells staining positively for MUC5AC protein (22.0 ± 3.8%, mean ± SD) relative to unstimulated controls (8.6 ± 2.6%), and similarly changed intracellular MUC5AC protein levels measured by Western and slot blotting. The effect of compressive stress was gradual, with significant changes in MUC5AC-positive cell numbers evident by Day 7, but required as little as 10 minutes of compressive stress daily. Daily treatment of cells with an EGFR kinase inhibitor (AG1478, 1 μM) significantly but incompletely attenuated the response to compressive stress. Complete attenuation could be accomplished by simultaneous treatment with the combination of AG1478 and a transforming growth factor (TGF)-β2 (1 μg/ml)-neutralizing antibody, or with anti-TGF-β2 alone. Our findings demonstrate that short duration episodes of mechanical stress, representative of those occurring during bronchoconstriction, are sufficient to increase goblet cell number and MUC5AC protein expression in bronchial epithelial cells in vitro. We propose that the mechanical environment present in asthma may fundamentally bias the composition of airway epithelial lining in favor of mucin secretory cells.

Original languageEnglish (US)
Pages (from-to)459-466
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume41
Issue number4
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

Fingerprint

Mechanical Stress
Compressive stress
Mucins
Epithelial Cells
Cells
Transforming Growth Factors
Proteins
Epidermal Growth Factor Receptor
Asthma
Cell Count
Goblet Cells
Bronchoconstriction
Neutralizing Antibodies
Linings
Cell culture
Constriction
Modulators
Chronic Disease
Epithelium
Cell Culture Techniques

Keywords

  • Asthma
  • Bronchial epithelium
  • EGFR
  • Mechanotransduction
  • TGF-β

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Chronic intermittent mechanical stress increases MUC5AC protein expression. / Park, Jin Ah; Tschumperlin, Daniel J.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 41, No. 4, 01.10.2009, p. 459-466.

Research output: Contribution to journalArticle

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abstract = "Increased abundance of mucin secretory cells is a characteristic feature of the epithelium in asthma and other chronic airway diseases. We showed previously that the mechanical stresses of airway constriction, both in the intact mouse lung and a cell culture model, activate the epidermal growth factor receptor (EGFR), a known modulator of mucin expression in airway epithelial cells. Here we tested whether chronic, intermittent, short-duration compressive stress (30 cmH2O) is sufficient to increase the abundance of MUC5AC-positive cells and intracellular mucin levels in human bronchial epithelial cells cultured at an air-liquid interface. Compressive stress applied for 1 hour per day for 14 days significantly increased the percentage of cells staining positively for MUC5AC protein (22.0 ± 3.8{\%}, mean ± SD) relative to unstimulated controls (8.6 ± 2.6{\%}), and similarly changed intracellular MUC5AC protein levels measured by Western and slot blotting. The effect of compressive stress was gradual, with significant changes in MUC5AC-positive cell numbers evident by Day 7, but required as little as 10 minutes of compressive stress daily. Daily treatment of cells with an EGFR kinase inhibitor (AG1478, 1 μM) significantly but incompletely attenuated the response to compressive stress. Complete attenuation could be accomplished by simultaneous treatment with the combination of AG1478 and a transforming growth factor (TGF)-β2 (1 μg/ml)-neutralizing antibody, or with anti-TGF-β2 alone. Our findings demonstrate that short duration episodes of mechanical stress, representative of those occurring during bronchoconstriction, are sufficient to increase goblet cell number and MUC5AC protein expression in bronchial epithelial cells in vitro. We propose that the mechanical environment present in asthma may fundamentally bias the composition of airway epithelial lining in favor of mucin secretory cells.",
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