Mechanical stress triggers selective release of fibrotic mediators from bronchial epithelium

Daniel J. Tschumperlin, Jonathan D. Shively, Tadashi Kikuchi, Jeffrey M. Drazen

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) and endothelin (ET) are found in elevated amounts in the airways of individuals with asthma. The cellular source of these peptides and their role in mediating the airway fibrosis of chronic asthma are unknown. In response to mechanical stresses similar to those occurring in vivo during airway constriction, bronchial epithelial cells increase the steady-state level of mRNA for both ET-1 and ET-2, followed by increased release of ET protein. Mechanical stress also enhances release of TGF-β2 from a preformed cell-associated pool. TGF-β2 and ET act individually and, more importantly, synergistically to promote fibrotic protein synthesis in reporter fibroblasts. To confirm the role of these intermediates in stress-induced fibrosis, conditioned medium from mechanically stressed bronchial epithelial cells was shown to elicit fibrotic protein synthesis in reporter fibroblasts; this effect was significantly inhibited by combined treatment with ET receptor antagonists and a neutralizing antibody to TGF-β2. These data are consistent with a primary pathogenic role for mechanical stress-induced release of both TGF-β2 and ET in the subepithelial fibrosis that characterizes chronic asthma.

Original languageEnglish (US)
Pages (from-to)142-149
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume28
Issue number2
DOIs
StatePublished - Feb 1 2003

ASJC Scopus subject areas

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

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