Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells

Am J Physiol Lung Cell Mol Physiol. 2015 Aug 1;309(3):L237-49. doi: 10.1152/ajplung.00390.2014. Epub 2015 Jun 5.


Human airway smooth muscle cells (HASMC) contribute to asthma pathophysiology through an increased smooth muscle mass and elevated cytokine/chemokine output. Little is known about how HASMC and the airway epithelium interact to regulate chronic airway inflammation and remodeling. Amphiregulin is a member of the family of epidermal growth factor receptor (EGFR) agonists with cell growth and proinflammatory roles and increased expression in the lungs of asthma patients. Here we show that bradykinin (BK) stimulation of HASMC increases amphiregulin secretion in a mechanism dependent on BK-induced COX-2 expression, increased PGE2 output, and the stimulation of HASMC EP2 and EP4 receptors. Conditioned medium from BK treated HASMC induced CXCL8, VEGF, and COX-2 mRNA and protein accumulation in airway epithelial cells, which were blocked by anti-amphiregulin antibodies and amphiregulin siRNA, suggesting a paracrine effect of HASMC-derived amphiregulin on airway epithelial cells. Consistent with this, recombinant amphiregulin induced CXCL8, VEGF, and COX-2 in airway epithelial cells. Finally, we found that conditioned media from amphiregulin-stimulated airway epithelial cells induced amphiregulin expression in HASMC and that this was dependent on airway epithelial cell COX-2 activity. Our study provides evidence of a dynamic axis of interaction between HASMC and epithelial cells that amplifies CXCL8, VEGF, COX-2, and amphiregulin production.

Keywords: COX-2; CXCL8; amphiregulin; epithelial; mesenchymal.

MeSH terms

  • Amphiregulin
  • Asthma / metabolism
  • Bradykinin / physiology
  • Cells, Cultured
  • Cyclooxygenase 2 / genetics*
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism
  • EGF Family of Proteins / metabolism*
  • Epithelial Cells / metabolism*
  • Gene Expression
  • Humans
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Myocytes, Smooth Muscle / metabolism*
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Signal Transduction
  • Transcriptional Activation
  • Vascular Endothelial Growth Factor A


  • AREG protein, human
  • Amphiregulin
  • CXCL8 protein, human
  • EGF Family of Proteins
  • Interleukin-8
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Dinoprostone
  • Bradykinin