Opposite effect of corticosteroids and long-acting beta(2)-agonists on serum- and TGF-beta(1)-induced extracellular matrix deposition by primary human lung fibroblasts.
Asthma and chronic obstructive pulmonary disease (COPD) are characterized by chronic airway inflammation and major structural lung tissue changes including increased extracellular matrix (ECM) deposition. Inhaled corticosteroids and long-acting beta(2)-agonists (LABA) are the basic treatment for both diseases, but their effect on airway remodeling remains unclear. In this study, we investigated the effect of corticosteroids and LABA, alone or in combination, on total ECM and collagen deposition, gene expression, cell proliferation, and IL-6, IL-8, and TGF-beta(1) levels by primary human lung fibroblasts. In our model, fibroblasts in 0.3% albumin represented a non-inflammatory condition and stimulation with 5% FCS and/or TGF-beta(1) mimicked an inflammatory environment with activation of tissue repair. FCS (5%) increased total ECM, collagen deposition, cell proliferation, and IL-6, IL-8, and TGF-beta(1) levels. In 0.3% albumin, corticosteroids reduced total ECM and collagen deposition, involving the glucocorticoid receptor (GR) and downregulation of collagen, heat shock protein 47 (Hsp47), and Fli1 mRNA expression. In 5% FCS, corticosteroids increased ECM deposition, involving upregulation of COL4A1 and CTGF mRNA expression. LABA reduced total ECM and collagen deposition under all conditions partly via the beta(2)-adrenergic receptor. In combination, the drugs had an additive effect in the presence or absence of TGF-beta(1) further decreasing ECM deposition in 0.3% albumin whereas counteracting each other in 5% FCS. These data suggest that the effect of corticosteroids, but not of LABA, on ECM deposition by fibroblasts is altered by serum. These findings imply that as soon as airway inflammation is resolved, long-term treatment with combined drugs may beneficially reduce pathological tissue remodeling.
Goulet
Stephanie
S
Department of Research, Pulmonary Cell Research, University Hospital Basel, Basel, Switzerland.
Bihl
Michel P
MP
Gambazzi
Franco
F
Tamm
Michael
M
Roth
Michael
M
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D050958:HSP47 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists; D044967:Serum / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*
D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; C526317:CCN2 protein, human; C078433:FLI1 protein, human; D050958:HSP47 Heat-Shock Proteins; C508600:IL6 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D051789:Proto-Oncogene Protein c-fli-1; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D011965:Receptors, Glucocorticoid; C494660:SERPINH1 protein, human; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D003094:Collagen