Increased alveolar soluble annexin V promotes lung inflammation and fibrosis

Eur Respir J. 2015 Nov;46(5):1417-29. doi: 10.1183/09031936.00002115. Epub 2015 Jul 9.


The causes underlying the self-perpetuating nature of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal disease, remain unknown. We hypothesised that alveolar soluble annexin V contributes to lung fibrosis, based on the observation that human IPF bronchoalveolar lavage fluid (BALF) containing high annexin V levels promoted fibroblast involvement in alveolar epithelial wound healing that was reduced when annexin V was depleted from the BALF. Conditioned medium from annexin V-treated alveolar epithelial type 2 cells (AEC2), but not annexin V per se, induced proliferation of human fibroblasts and contained pro-fibrotic, IPF-associated proteins, as well as pro-inflammatory cytokines that were found to correlate tightly (r>0.95) with annexin V levels in human BALF. ErbB2 receptor tyrosine kinase in AECs was activated by annexin V, and blockade reduced the fibrotic potential of annexin V-treated AEC-conditioned medium. In vivo, aerosol delivery of annexin V to mouse lung induced inflammation, fibrosis and increased hydroxyproline, with activation of Wnt, transforming growth factor-β, mitogen-activated protein kinase and nuclear factor-κB signalling pathways, as seen in IPF. Chronically increased alveolar annexin V levels, as reflected in increased IPF BALF levels, may contribute to the progression of IPF by inducing the release of pro-fibrotic mediators.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A5 / analysis*
  • Bronchoalveolar Lavage Fluid / chemistry
  • Cells, Cultured
  • Epithelial Cells / metabolism*
  • Fibroblasts / metabolism*
  • Humans
  • Idiopathic Pulmonary Fibrosis / metabolism*
  • Male
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Pulmonary Alveoli / cytology
  • Rats
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Recombinant Proteins / pharmacology
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism


  • Annexin A5
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • ERBB2 protein, human
  • Erbb2 protein, mouse
  • Receptor, ErbB-2
  • Mitogen-Activated Protein Kinases