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Published ahead of print on April 29, 2004, doi:10.1164/rccm.200308-1151OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 3, August 2004, 242-251

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Submitted on September 10, 2003
Accepted on April 26, 2004

Pigment Epithelium-derived Factor in Idiopathic Pulmonary Fibrosis: A Role in Aberrant Angiogenesis

Gregory P Cosgrove1, Kevin K Brown1, William P Schiemann2, Amanda E Serls3, Jane E Parr3, Mark W Geraci4, Marvin I Schwarz4, Carlyne D Cool5, and G. Scott Worthen1*

1 Department of Medicine, Pulmonary Division, National Jewish Medical and Research Center, Denver, CO, USA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 2 Department of Pediatrics, National Jewish Medical and Research Center, The Program in Cell Biology, Denver, CO, USA, 3 Department of Pathology, University of Colorado Health Sciences Center, Denver, CO, USA, 4 Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 5 Department of Medicine, Pulmonary Division, National Jewish Medical and Research Center, Denver, CO, USA; Department of Pathology, University of Colorado Health Sciences Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: worthens{at}njc.org.

Pigment epithelium-derived factor is a 50 kD protein with angiostatic and neurotrophic activities that regulates vascular development within the eye. Pigment epithelium-derived factor expression was increased in the lungs of patients with idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis, as a result of an imbalance between pigment epithelium-derived factor and vascular endothelial growth factor. We demonstrated herein that vascular density is regionally decreased in idiopathic pulmonary fibrosis within the fibroblastic foci and that within these areas pigment epithelium-derived factor expression was increased, while that of vascular endothelial growth factor was decreased. Pigment epithelium-derived factor co-localized with the fibrogenic cytokine transforming growth factor-{beta}, particularly within the fibrotic interstitium, the fibroblastic focus, and prominently within the epithelium directly overlying the fibroblastic focus. This suggested that transforming growth factor-{beta} might regulate pigment epithelium-derived factor expression. Using 3T3-L1 fibroblasts and human lung fibroblasts, we showed that pigment epithelium-derived factor was indeed a transforming growth factor-{beta} target gene. Collectively, our findings implicate pigment epithelium-derived factor as a regulator of pulmonary angiogenesis, and an important mediator in idiopathic pulmonary fibrosis.
Key words: Vascular endothelial growth factor, Transforming growth factor-{beta} Cryptogenic organizing pneumonia




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