Abstract
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.
Abstract
Soluble annexin V, found at increased levels in BALF from IPF patients, promotes inflammation and fibrosis in mouse lung http://ow.ly/MHobz
Footnotes
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Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
Support statement: This study was funded by the United States Department of Health and Human Services, National Institutes of Health (NIH) (RO1 HL44060 to D. Warburton; HL068597 and HL109932 to W. Shi; R01 DK095004 to M.R. Frey; and UO1 HL122681 to W. Shi, R. Moats and D. Warburton), the American Cancer Society (Research Scholar Grant 124678 to M.R. Frey), the Pasadena Guild of Children's Hospital Los Angeles Endowment and the Garland Foundation and the Webb foundation (to D. Warburton). Funding information for this article has been deposited with FundRef.
- Received January 7, 2015.
- Accepted April 25, 2015.
- Copyright ©ERS 2015