Increased alveolar soluble annexin v promotes lung inflammation and fibrosis

Susan Buckley, Wei Shi, Wei Xu, Mark R. Frey, Rex Moats, Annie Pardo, Moises Selman, David Warburton

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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-κβ 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.

Original languageEnglish (US)
Pages (from-to)1417-1429
Number of pages13
JournalEuropean Respiratory Journal
Volume46
Issue number5
DOIs
StatePublished - Nov 1 2015

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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