title: Increased alveolar soluble annexin V promotes lung inflammation and fibrosis.
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.
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Buckley
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Frey
authors.affiliation: Imaging Core Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Rex
authors.initials: R
authors.lastname: Moats
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, México DF, México.
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas", México DF, México.
authors.forename: Moises
authors.initials: M
authors.lastname: Selman
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA dwarburton@chla.usc.edu.
authors.forename: David
authors.initials: D
authors.lastname: Warburton
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000032:analysis*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D017304:Annexin A5; D020928:Mitogen-Activated Protein Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse