title: Extracellular matrix composition is modified by β₂-agonists through cAMP in COPD.
abstract: Long acting β₂-agonists (LABA) have been reported to modify the extracellular matrix (ECM) composition in the airway wall. Based on our earlier studies we here investigated the mechanism underlying the control of ECM modification by LABA in primary human airway smooth muscle cells. Cells were treated with formoterol or salmeterol (30 min) before TGF-β₁ stimulation (2-3 days) Using RT-PCT, immuno-blotting and ELISA the de novo synthesis and deposition of collagen type-I, -III, -IV and fibronectin were determined. Matrix metalloproteinases (MMP)-2 and -9 were analyzed by zymography. Both LABA activated cAMP and its corresponding transcription factor CREB within 60 min and thus partly reduced TGF-β₁-induced gene transcription of collagen type-I, -III, fibronectin and connective tissue growth factor (CTGF). The inhibitory effect of both LABA on collagen type-I and -III deposition involved a cAMP dependent mechanism, while the inhibitory effect of the two drugs on TGF-β1-induced fibronectin deposition and on CTGF secretion was independent of cAMP. Interestingly, none of the two LABA reduced CTGF-induced synthesis of collagen type-I or type-III deposition. In addition, none of the two LABA modified collagen type-IV deposition or the expression and activity of MMP-2 or MMP-9. Our results show that LABA can prevent de novo deposition of specific ECM components through cAMP dependent and independent signaling. However, they do not reduce all ECM components by the same mechanism and they do not reduce existing collagen deposits. This might explain some of the controversial reports on the anti-remodeling effect of LABA in chronic inflammatory lung diseases.
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine II, Medical University of Vienna, A-1090 Vienna, Austria. Electronic address: christopher.lambers@meduniwien.ac.at.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lambers
authors.affiliation: Pulmonary Cell Research, Dept Biomedicine and Pneumology, Department of Internal Medicine, University Hospital and University of Basel CH-4031 Basel, Switzerland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Pharmacology, School of Medicine, University of Thessaloniki, GR-54621 Thessaloniki, Greece.
authors.forename: Papakonstantinou
authors.initials: P
authors.lastname: Eleni
authors.affiliation: Pulmonary Cell Research, Dept Biomedicine and Pneumology, Department of Internal Medicine, University Hospital and University of Basel CH-4031 Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Costa
authors.affiliation: Pulmonary Cell Research, Dept Biomedicine and Pneumology, Department of Internal Medicine, University Hospital and University of Basel CH-4031 Basel, Switzerland.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Pulmonary Cell Research, Dept Biomedicine and Pneumology, Department of Internal Medicine, University Hospital and University of Basel CH-4031 Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine II, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Lutz-Henning
authors.initials: LH
authors.lastname: Block
authors.affiliation: Pulmonary Cell Research, Dept Biomedicine and Pneumology, Department of Internal Medicine, University Hospital and University of Basel CH-4031 Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D000068759:Formoterol Fumarate; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004983:Ethanolamines; D016212:Transforming Growth Factor beta; D003094:Collagen; D000242:Cyclic AMP; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000068759:Formoterol Fumarate
keywords: Airway remodeling; Airway smooth muscle cells; Chronic obstructive pulmonary disease; Extracellular matrix; Long acting beta2-agonists