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肺纤维化，3年死亡率为50%。显然，IPF的原因尚不清楚；然而，最近有几篇文献记录了EB病毒(EBV)感染与IPF之间的正相关关系。几乎没有文献表明疱疹病毒感染如何在动物模型或患者中促进肺纤维化的发病机制。我们的假设是，EBV通过表达潜伏或溶解的EBV多肽LMP-1和Zta来促进肺纤维化的发生，这些多肽影响转化生长因子β-1(TGF-β-1)、金属蛋白酶(MMPs)和p53的表达和/或活性，这些分子是已知的介导纤维化的分子。LMP-1是一种表达于EBV感染细胞表面的膜相关多肽，表达于IPF患者肺泡II型上皮细胞。LMP-1具有肿瘤坏死因子α样活性，这是非常重要的，因为肿瘤坏死因子在人类和动物模型肺纤维化的病理生物学中具有明显的作用。EBV的复制周期是由病毒转录因子Zta的表达启动的。Zta是一种与AP-1家族蛋白显示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的转录，如转化生长因子-β-1和基质金属蛋白酶-9。转化生长因子-β1的分泌和激活是这一提议的主要焦点，因为它已多次被认为与肺纤维化有关。此外，Zta还会使P53失活，从而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的转基因小鼠对博莱霉素的反应加剧了肺纤维化，这与Zta通过灭活P53促进纤维化形成的可能性一致。这项建议将确定LMP-1和Zta诱导AT-II肺上皮细胞表达和激活转化生长因子-β1的途径；将展示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，在体内表达LMP-1和Zta在II型上皮细胞中重演了小鼠EBV感染所观察到的纤维化形成。目前还没有被证实的治疗IPF的药物疗法。确定EBV基因产品促进IPF的机制将为这种致命疾病的治疗提供新的选择。

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.