title: Differential effects of fluticasone on extracellular matrix production by airway and parenchymal fibroblasts in severe COPD.
abstract: Chronic obstructive pulmonary disease (COPD) is characterized by abnormal repair in the lung resulting in airway obstruction associated with emphysema and peripheral airway fibrosis. Because the presence and degree of airways disease and emphysema varies between COPD patients, this may explain the heterogeneity in the response to treatment. It is currently unknown whether and to what extent inhaled steroids can affect the abnormal repair process in the airways and lung parenchyma in COPD. We investigated the effects of fluticasone on transforming growth factor (TGF)-β- and cigarette smoke-induced changes in mothers against decapentaplegic homolog (Smad) signaling and extracellular matrix (ECM) production in airway and parenchymal lung fibroblasts from patients with severe COPD. We showed that TGF-β-induced ECM production by pulmonary fibroblasts, but not activation of the Smad pathway, was sensitive to the effects of fluticasone. Fluticasone induced decorin production by airway fibroblasts and partly reversed the negative effects of TGF-β treatment. Fluticasone inhibited biglycan production in both airway and parenchymal fibroblasts and procollagen 1 production only in parenchymal fibroblasts, thereby restoring the basal difference in procollagen 1 production between airway and parenchymal fibroblasts. Our findings suggest that the effects of steroids on the airway compartment may be beneficial for patients with severe COPD, i.e., restoration of decorin loss around the airways, whereas the effects of steroids on the parenchyma may be detrimental, since the tissue repair response, i.e., biglycan and procollagen production, is inhibited. More research is needed to further disentangle these differential effects of steroid treatment on the different lung compartments and its impact on tissue repair and remodeling in COPD.
authors.affiliation: Dept. of Pathology and Medical Biology, Univ. Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, the Netherlands. c.a.brandsma@umcg.nl.
authors.forename: Corry-Anke
authors.initials: CA
authors.lastname: Brandsma
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.forename: Marnix R
authors.initials: MR
authors.lastname: Jonker
authors.forename: Bea
authors.initials: B
authors.lastname: Rutgers
authors.forename: Jacobien A
authors.initials: JA
authors.lastname: Noordhoek
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
mesh_terms: D000730:Androstadienes / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D058578:Biglycan / Q000096:biosynthesis*; D002478:Cells, Cultured; D058575:Decorin / Q000096:biosynthesis*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D000068298:Fluticasone; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D011347:Procollagen / Q000096:biosynthesis*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D000730:Androstadienes; D000893:Anti-Inflammatory Agents; C546884:BGN protein, human; D058578:Biglycan; C546878:DCN protein, human; D058575:Decorin; D011347:Procollagen; D016212:Transforming Growth Factor beta; D000068298:Fluticasone
keywords: chronic obstructive pulmonary disease; tissue repair and remodeling