title: A phosphodiesterase 4 inhibitor inhibits matrix protein deposition in airways in vitro.
abstract: BACKGROUND
  Airway smooth muscle (ASM) cells may contribute to airway remodeling through the release of growth factors, cytokines, and extracellular matrix (ECM) proteins. The effect of current asthma therapies on this release is not known.
  
  
  OBJECTIVE
  We examined the effect of corticosteroids, long-acting beta(2)-agonists, and a phosphodiesterase 4 (PDE4) inhibitor on ASM-released connective tissue growth factor (CTGF), collagen I, fibronectin, versican, and IL-6.
  
  
  METHODS
  Airway smooth muscle cells from individuals with and without asthma were stimulated with TGF-beta with or without the drugs and CTGF and ECM protein expression measured by real-time PCR, cell surface, or matrix-associated ELISA. IL-6 release was measured by ELISA. Bronchial rings from individuals without asthma were incubated with TGF-beta with or without the drugs.
  
  
  RESULTS
  Neither corticosteroids nor long-acting beta(2)-agonists reduced TGF-beta-induced CTGF, collagen I, or fibronectin in either cell type, whereas corticosteroids alone induced the expression of CTGF, collagen I, and fibronectin. These drugs did not prevent the accumulation of TGF-beta-induced proteins in bronchial rings, whereas the PDE4 inhibitor roflumilast inhibited TGF-beta-induced CTGF, collagen I, and fibronectin.
  
  
  CONCLUSIONS
  In our model, current asthma therapies are not able to inhibit matrix protein deposition from ASM cells. The results of this study suggest that the PDE4 inhibitor roflumilast may have a role in regulating the ECM and therefore aspects of airway remodeling in asthma.
  
  
  CONCLUSIONS
  Although current asthma therapies are effective in reducing inflammation and symptoms, reversal or prevention of structural changes contributing to remodeling may require additional therapy, which could include PDE4 inhibitors.
authors.affiliation: Department of Pharmacology, University of Sydney, NSW, Australia. janette@pharmacol.usyd.edu.au
authors.forename: Janette K
authors.initials: JK
authors.lastname: Burgess
authors.forename: Brian G G
authors.initials: BG
authors.lastname: Oliver
authors.forename: Maree H
authors.initials: MH
authors.lastname: Poniris
authors.forename: Qi
authors.initials: Q
authors.lastname: Ge
authors.forename: Sarah
authors.initials: S
authors.lastname: Boustany
authors.forename: Natalie
authors.initials: N
authors.lastname: Cox
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Moir
authors.forename: Peter R A
authors.initials: PR
authors.lastname: Johnson
authors.forename: Judith L
authors.initials: JL
authors.lastname: Black
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000328:Adult; D000631:Aminopyridines / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003521:Cyclopropanes / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D000631:Aminopyridines; D001549:Benzamides; C526317:CCN2 protein, human; D024042:Collagen Type I; D003521:Cyclopropanes; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C424423:Roflumilast; D055513:Connective Tissue Growth Factor; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4