Idiopathic pulmonary fibrosis (IPF) is a common progressive fibrotic lung disease with a dismal 50% 3-year mortality rate. Obviously, the cause of IPF is unknown;however, there are several recent publications documenting a positive correlation between Epstein-Barr virus (EBV) infection and IPF. There is virtually no literature demonstrating how herpesvirus infections contribute to the pathogenesis of lung fibrosis in animal models or in patients. Our hypothesis is that EBV enhances lung fibrogenesis through expression of either the latent or lytic EBV peptides, LMP-1 and Zta, that influence the expression and/or activity of transforming growth factor beta-1 (TGF-beta-1), metalloproteinase (MMP), and p53, molecules known to mediate fibrosis. LMP-1 is a membrane-associated peptide expressed on the surface of cells infected with EBV, and is expressed in alveolar type II (AT-II) epithelial cells in patients with IPF. LMP-1 has tumor necrosis factor alpha-like (TNF) activity, which is centrally important since TNF clearly has a role the pathobiology of lung fibrosis in humans and animal models. The replicative cycle of EBV is initiated by expression of the viral transcription factor Zta. Zta is a protein that displays sequence homology with proteins of the AP-1 family and activates the transcription of viral genes and profibrotic cellular genes such as TGF-beta-1 and MMP-9. TGF-beta-1 secretion and activation is a major focus of this proposal because it has been repeatedly implicated in lung fibrogenesis. In addition, Zta inactivates p53, which can lead to release of inflammatory and fibrogenic factors. Our data demonstrating that a transgenic mouse expressing dominant-negative p53 in AT-II cells exacerbates lung fibrosis in response to bleomycin, agrees with the possibility that Zta promotes fibrogenesis by inactivating p53. This proposal will define the pathways induced by LMP-1 and Zta, that AT-II pulmonary epithelial cells utilize to express and activate TGF-beta-1;will show how Zta-mediated inactivation of p53 enhances expression of pro-fibrotic cytokines in lung epithelial cells;and will demonstrate using a transgenic mouse model that in vivo expression of LMP-1 and Zta in type II epithelial cells recapitulates the fibrogenesis observed with murine EBV infection. There are currently no proven medicinal therapies for the treatment of IPF. Defining the mechanisms through which EBV gene products promote IPF will provide new options for the treatment of this fatal disease.
