The mechanisms responsible for the progressive fibrotic response seen in idiopathic pulmonary fibrosis (IPF) are poorly understood despite intense investigation. IPF may represent a maladaptive response to injury with ineffective wound repair and resulting extensive extracellular matrix deposition. We hypothesize that abnormalities in vascular remodeling, due to an imbalance of angiogenic and angiostatic mediators, result in a failure of wound healing and progressive fibrosis. We describe enhanced expression of pigment epithelium-derived factor (PEDF), a 50 kD protein with potent angiostatic and neurotrophic activities, in IPF. We hypothesize that PEDF regulates vascular development within the lung. Our studies indicate that PEDF is a TGF-beta target gene and co-localizes with it in the PIF lung, further implicating it in the pathobiology of pulmonary fibrosis. We have identified TGF-beta1 response elements, as well as hypoxia response elements, within the murine and human PEDF promoters. By stabilizing HIF-1alpha, the transcription factor that regulates VEGF expression, we demonstrate that PEDF expression is suppressed while VEGF expression is enhanced. We propose to define the cellular origin of PEDF expression within the lung using in situ hybridization, the promoter response elements using in vivo footprinting, promoter reporter assays with selective truncation and site-directed mutagenesis, and the role in which mitogen-activated kinase activity regulates PEDF expression. Lastly, we will define the function significance of PEDF expression within murine models of lung fibrosis. Our proposed investigations will not only serve to define the regulation of an important angiostatic mediator, but also provide a better understanding as those mechanisms underlying the fibrotic response within the lung.
