title: TGF-β enhances deposition of perlecan from COPD airway smooth muscle.
abstract: Chronic obstructive pulmonary disease (COPD) and asthma are characterized by irreversible remodeling of the airway walls, including thickening of the airway smooth muscle layer. Perlecan is a large, multidomain, proteoglycan that is expressed in the lungs, and in other organ systems, and has been described to have a role in cell adhesion, angiogenesis, and proliferation. This study aimed to investigate functional properties of the different perlecan domains in relation to airway smooth muscle cells (ASMC). Primary human ASMC obtained from donors with asthma (n = 13), COPD (n = 12), or other lung disease (n = 20) were stimulated in vitro with 1 ng/ml transforming growth factor-β(1) (TGF-β(1)) before perlecan deposition and cytokine release were analyzed. In some experiments, inhibitors of signaling molecules were added. Perlecan domains I-V were seeded on tissue culture plates at 10 μg/ml with 1 μg/ml collagen I as a control. ASM was incubated on top of the peptides before being analyzed for attachment, proliferation, and wound healing. TGF-β(1) upregulated deposition of perlecan by ASMC from COPD subjects only. TGF-β(1) upregulated release of IL-6 into the supernatant of ASMC from all subjects. Inhibitors of SMAD and JNK signaling molecules decreased TGF-β(1)-induced perlecan deposition by COPD ASMC. Attachment of COPD ASMC was upregulated by collagen I and perlecan domains IV and V, while perlecan domain II upregulated attachment only of asthmatic ASMC. Seeding on perlecan domains did not increase proliferation of any ASMC type. TGF-β(1)-induced perlecan deposition may enhance attachment of migrating ASMC in vivo and thus may be a mechanism for ASMC layer hypertrophy in COPD.
authors: Cell Biology group, Woolcock Institute of Medical Research, NSW, Australia.
authors: Yukikazu
authors: Y
authors: Ichimaru
authors: David I
authors: DI
authors: Krimmer
authors: Janette K
authors: JK
authors: Burgess
authors: Judith L
authors: JL
authors: Black
authors: Brian G G
authors: BG
authors: Oliver
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D055767:Immobilized Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology*; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology*; D055815:Young Adult
chemical_list: D019812:Heparan Sulfate Proteoglycans; D055767:Immobilized Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C071927:perlecan; D048670:MAP Kinase Kinase 4