Extracellular matrix composition is modified by β₂-agonists through cAMP in COPD

Biochem Pharmacol. 2014 Oct 1;91(3):400-8. doi: 10.1016/j.bcp.2014.07.026. Epub 2014 Aug 12.


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.

Keywords: Airway remodeling; Airway smooth muscle cells; Chronic obstructive pulmonary disease; Extracellular matrix; Long acting beta2-agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Collagen / metabolism
  • Cyclic AMP / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Ethanolamines / pharmacology
  • Extracellular Matrix / drug effects*
  • Extracellular Matrix / metabolism
  • Formoterol Fumarate
  • Humans
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Muscle, Smooth / cytology
  • Muscle, Smooth / drug effects
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • Pulmonary Disease, Chronic Obstructive / pathology*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology


  • Adrenergic beta-2 Receptor Agonists
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Ethanolamines
  • Transforming Growth Factor beta
  • Collagen
  • Cyclic AMP
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Formoterol Fumarate