Transforming growth factor-beta1 drives airway remodeling in cigarette smoke-exposed tracheal explants

Am J Respir Cell Mol Biol. 2005 Oct;33(4):387-93. doi: 10.1165/rcmb.2005-0203OC. Epub 2005 Jun 30.


Small airway remodeling (SAR) is an important cause of airflow obstruction in cigarette smokers, but whether SAR represents a response to smoke-evoked inflammation or is directly mediated by smoke-induced growth factor production is disputed. To examine this process, we exposed rat tracheal explants, a model free of exogenous inflammatory cells, to cigarette smoke in vitro. Cigarette smoke caused release of active transforming growth factor (TGF)-beta1, and this was prevented by the oxidant scavenger tetramethythiourea. Nuclear immunostaining for phospho-Smad2, a TGF-beta downstream signaling molecule, was present in epithelial and interstitial cells within 1 h after exposure. Smoke caused upregulation of gene expression of connective tissue growth factor (CTGF), a mediator of TGF-beta fibrogenic effects, within 2 h, and upregulation of procollagen gene expression at 24 h; both changes could be prevented by the TGF-beta antagonist fetuin (alpha2-HS-glycoprotein). In a cell-free system, recombinant human TGF-beta latency-associated peptide was oxidized by cigarette smoke, and smoke released active TGF-beta1 from recombinant latent TGF-beta1 via an oxidant mechanism. These experiments suggest that SAR in cigarette smokers may be caused by direct, smoke-mediated, oxidant-driven induction of growth factor signaling in the airway wall, and that SAR does not necessarily require exogenous inflammatory cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Connective Tissue Growth Factor
  • Culture Media, Conditioned
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • In Vitro Techniques
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Macrophages / metabolism
  • Procollagen / genetics
  • Procollagen / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Smad2 Protein
  • Smoking*
  • Thiourea / analogs & derivatives
  • Thiourea / metabolism
  • Trachea / anatomy & histology*
  • Trachea / pathology
  • Trachea / physiology*
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta1


  • CCN2 protein, human
  • CCN2 protein, rat
  • Collagen Type I
  • Culture Media, Conditioned
  • DNA-Binding Proteins
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Procollagen
  • SMAD2 protein, human
  • Smad2 Protein
  • Smad2 protein, rat
  • TGFB1 protein, human
  • Tgfb1 protein, rat
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor
  • Thiourea
  • tetramethylthiourea