Abstract
The chronic progressive decline in lung function observed in idiopathic pulmonary fibrosis (IPF) appears to result from persistent nonresolving injury to the epithelium, impaired restitution of the epithelial barrier in the lung, and enhanced fibroblast activation. Thus, understanding these key mechanisms and pathways modulating both is essential to greater understanding of IPF pathogenesis. We examined the association of VEGF with the IPF disease state and preclinical models in vivo and in vitro. Tissue and circulating levels of VEGF were significantly reduced in patients with IPF, particularly in those with a rapidly progressive phenotype, compared with healthy controls. Lung-specific overexpression of VEGF significantly protected mice following intratracheal bleomycin challenge, with a decrease in fibrosis and bleomycin-induced cell death observed in the VEGF transgenic mice. In vitro, apoptotic endothelial cell–derived mediators enhanced epithelial cell injury and reduced epithelial wound closure. This process was rescued by VEGF pretreatment of the endothelial cells via a mechanism involving thrombospondin-1 (TSP1). Taken together, these data indicate beneficial roles for VEGF during lung fibrosis via modulating epithelial homeostasis through a previously unrecognized mechanism involving the endothelium.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the subacute and permanent accumulation of scar tissue in the lung in the absence of an identifiable cause
In order to begin to characterize the relationship between VEGF and idiopathic pulmonary fibrosis (IPF), we evaluated VEGF expression in a gene expression dataset of 219 lung biopsy samples derived from IPF patients (n = 123) and normal lung histology samples from control subjects (n = 96)
This dataset was previously generated by members of our group [18] and is publicly available both in Gene Expression Omnibus (GEO) under accession number GSE47460 and in the Lung Genomics Research Consortium (LGRC) website
Summary
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the subacute and permanent accumulation of scar tissue in the lung in the absence of an identifiable cause. Some patients exhibit only a gradual decline in forced vital capacity (FVC) and may live for many years following diagnosis [2], while others suffer a more progressive clinical course characterized by rapid physiologic decline and death. The current pathogenic model of IPF suggests that the progressive decline in lung function is mediated in part by chronic epithelial injury. We and others have reported that IPF fibroblasts exhibit an altered and activated phenotype, compared with fibroblasts isolated from normal lung tissue [4]. Understanding the driving forces of epithelial injury and repair, in coordination with aberrant fibroblast activation, is essential to determining the significance of these cellular interactions
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