The causes underlying the self-perpetuating nature of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal disease, remain unknown. We hypothesized that alveolar soluble Annexin V contributes to lung fibrosis, based on the observation that human IPF 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 (CM) from AEC2 treated with Annexin V, but not Annexin V per se, induced proliferation of adult human fibroblasts, and contained pro-fibrotic proteins that are also highly expressed in human IPF BALF or lung, 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 (RTK) in AEC was activated by Annexin V, and blockade reduced the fibrotic potential of Annexin-treated AEC CM.
In vivo, aerosol delivery of Annexin V to mouse lung induced inflammation, fibrosis and increased hydroxyproline, with activation of Wnt, TGF-β, MAPK and NFκB signaling pathways, as seen in IPF.
Increased alveolar Annexin V, as reflected in increased IPF BAL levels, may play an active role in the progression of IPF by inducing the release of pro-fibrotic mediators from AEC.