Role of EBV gene products in lung fibrogenesis

描述（由申请人提供）： 特发性肺纤维化（IPF）是一种常见的进行性纤维化肺病，3年死亡率高达50%。显然，IPF的病因尚不清楚;然而，最近有几篇出版物记录了EB病毒（EBV）感染与IPF之间的正相关性。几乎没有文献证明疱疹病毒感染如何在动物模型或患者中导致肺纤维化的发病机制。我们的假设是EBV通过表达潜伏性或裂解性EBV肽LMP-1和Zta增强肺纤维化，LMP-1和Zta影响转化生长因子β-1（TGF-β-1）、金属蛋白酶（MMP）和p53（已知介导纤维化的分子）的表达和/或活性。LMP-1是一种膜相关肽，在EBV感染的细胞表面表达，并在IPF患者的肺泡II型（AT-II）上皮细胞中表达。LMP-1具有肿瘤坏死因子α样（TNF）活性，这是重要的，因为TNF在人类和动物模型中明显具有肺纤维化的病理生物学作用。EBV的复制周期由病毒转录因子Zta的表达启动。Zta是一种与AP-1家族的蛋白质具有序列同源性的蛋白质，并激活病毒基因和促纤维化细胞基因如TGF-β-1和MMP-9的转录。TGF-β-1的分泌和激活是该建议的主要焦点，因为它已被反复牵连在肺纤维化。此外，Zta使p53失活，这可能导致炎症和纤维化因子的释放。我们的数据表明，在AT-II细胞中表达显性阴性p53的转基因小鼠加重了博莱霉素引起的肺纤维化，这与Zta通过灭活p53促进纤维化的可能性一致。该提议将定义由LMP-1和Zta诱导的途径，AT-II肺上皮细胞利用该途径来表达和激活TGF-β-1;将显示Zta介导的p53失活如何增强肺上皮细胞中促纤维化细胞因子的表达;并将使用转基因小鼠模型证明LMP-1的体内表达，1和Zta在II型上皮细胞中的表达再现了在鼠EBV感染中观察到的纤维化。目前尚无经证实的治疗IPF的药物疗法。明确EBV基因产物促进IPF的机制将为治疗这种致命疾病提供新的选择。

DESCRIPTION (provided by applicant): 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.