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Pigment Epithelium–derived Factor in Idiopathic Pulmonary Fibrosis

A Role in Aberrant Angiogenesis

Pulmonary Division, Department of Medicine, National Jewish Medical and Research Center; Program in Cell Biology, Department of Pediatrics and Division of Pulmonary Sciences and Critical Care Medicine; and the Departments of Medicine and Pathology, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to G. Scott Worthen, M.D., National Jewish Medical and Research Center, D403, 1400 Jackson Street, Denver, CO 80206. E-mail: worthens{at}njc.org

Pigment epithelium-derived factor (PEDF) is a 50-kD protein with angiostatic and neurotrophic activities that regulates vascular development within the eye. PEDF expression was increased in the lungs of patients with idiopathic pulmonary fibrosis (IPF) based on microarray analyses. Angiogenesis has been implicated in the pathogenesis of fibrotic lung diseases, we therefore hypothesized that regional abnormalities in vascularization occur in IPF as a result of an imbalance between PEDF and vascular endothelial growth factor. We demonstrated that vascular density is regionally decreased in IPF within the fibroblastic foci, and that within these areas PEDF was increased, whereas vascular endothelial growth factor was decreased. PEDF colocalized with the fibrogenic cytokine, transforming growth factor (TGF)-ß1, particularly within the fibrotic interstitium and the fibroblastic focus, and prominently within the epithelium directly overlying the fibroblastic focus. This suggested that TGF-ß1 might regulate PEDF expression. Using 3T3-L1 fibroblasts and human lung fibroblasts, we showed that PEDF was indeed a TGF-ß1 target gene. Collectively, our findings implicate PEDF as a regulator of pulmonary angiogenesis and an important mediator in IPF.

Key Words: cryptogenic organizing pneumonia • pigment epithelium–derived factor • transforming growth factor-ß1 • vascular endothelial growth factor

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