title: Bronchoconstriction Induces TGF-β Release and Airway Remodelling in Guinea Pig Lung Slices.
abstract: 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.
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, The Netherlands ; Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.
authors.forename: Tjitske A
authors.initials: TA
authors.lastname: Oenema
authors.forename: Harm
authors.initials: H
authors.lastname: Maarsingh
authors.forename: Marieke
authors.initials: M
authors.lastname: Smit
authors.forename: Geny M M
authors.initials: GM
authors.lastname: Groothuis
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D014022:Tissue Survival / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1