Bronchoconstriction Induces TGF-β Release and Airway Remodelling in Guinea Pig Lung Slices

PLoS One. 2013 Jun 26;8(6):e65580. doi: 10.1371/journal.pone.0065580. Print 2013.


Airway remodelling, including smooth muscle remodelling, is a primary cause of airflow limitation in asthma. Recent evidence links bronchoconstriction to airway remodelling in asthma. The mechanisms involved are poorly understood. A possible player is the multifunctional cytokine TGF-β, which plays an important role in airway remodelling. Guinea pig lung slices were used as an in vitro model to investigate mechanisms involved in bronchoconstriction-induced airway remodelling. To address this aim, mechanical effects of bronchoconstricting stimuli on contractile protein expression and TGF-β release were investigated. Lung slices were viable for at least 48 h. Both methacholine and TGF-β1 augmented the expression of contractile proteins (sm-α-actin, sm-myosin, calponin) after 48 h. Confocal fluorescence microscopy showed that increased sm-myosin expression was enhanced in the peripheral airways and the central airways. Mechanistic studies demonstrated that methacholine-induced bronchoconstriction mediated the release of biologically active TGF-β, which caused the increased contractile protein expression, as inhibition of actin polymerization (latrunculin A) or TGF-β receptor kinase (SB431542) prevented the methacholine effects, whereas other bronchoconstricting agents (histamine and KCl) mimicked the effects of methacholine. Collectively, bronchoconstriction promotes the release of TGF-β, which induces airway smooth muscle remodelling. This study shows that lung slices are a useful in vitro model to study mechanisms involved in airway remodelling.

MeSH terms

  • Airway Remodeling* / drug effects
  • Animals
  • Biomechanical Phenomena / drug effects
  • Bronchoconstriction* / drug effects
  • Gene Expression Regulation / drug effects
  • Guinea Pigs
  • Lung / drug effects
  • Lung / metabolism*
  • Lung / pathology*
  • Male
  • Tissue Survival / drug effects
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta1 / pharmacology


  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1

Grants and funding

This work was supported by the Groningen Center for Drug Research and the University of Groningen. Part of the work has been performed at the University Medical Center Groningen Imaging and Microscopy Center (UMIC), which is sponsored by NWO-grants 40-00506-98-9021 and 175-010-2009-023. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.