Herpesvirus in Idiopathic Pulmonary Fibrosis

描述(申请人提供)：特发性肺纤维化(IPF)是一种进行性的、纤维化的肺部疾病，没有被证明有效的治疗方法。自发性缓解不会发生，通常在确诊后3至5年内死亡。IPF的发病机制复杂，尚未完全阐明。然而，IPF发展过程中的一个关键致病事件是持续的肺上皮损伤。这种损伤的原因尚不清楚，尽管肺部的慢性病毒感染，特别是疱疹病毒感染，作为一种潜在的损伤原因引起了越来越多的关注。我们和其他使用IPF患者肺组织的研究表明，IPF患者的肺中存在一种或多种疱疹病毒。此外，我们还发现，接种小鼠疱疹病毒的T辅助分子(Th)-2表型的小鼠会发生慢性肺上皮感染，许多组织学特征使人联想到IPF。基于这些数据，我们的概念是疱疹病毒通常不会感染肺部，但在易感宿主中，疱疹病毒感染肺上皮细胞，感染的上皮细胞表达细胞因子和生长因子，这些细胞因子和生长因子指导纤维化反应，导致IPF的发生。我们的长期目标是证明肺部疱疹病毒感染与IPF的发生之间存在因果联系。实现这一目标的关键一步是制定策略，根除肺部疱疹病毒感染，然后显示IPF的改善。当前提案的目的有两个。首先，为疱疹病毒在IPF发病机制中的潜在作用提供充分的证据，以证明在IPF中进行抗病毒治疗试验是合理的。第二是收集有关IPF肺内病毒复制周期的信息，以便为此类试验设计最有效的抗病毒策略。因此，我们提出以下具体目标。 在IPF患者的肺组织中： I.用聚合酶链式反应鉴定肺部存在哪些疱疹病毒； 二、用免疫组织化学和免疫荧光分析确定疱疹病毒感染的细胞部位，以检测病毒蛋白； 三、确定疱疹病毒是否主要潜伏在受感染的细胞中，或者是否正在发生裂解复制；以及 四、确定感染疱疹病毒的细胞或邻近未感染的细胞是否表达已知参与IPF发病机制的宿主蛋白。 将检查与进行性纤维化无关的慢性肺部疾病患者的对照肺组织。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic, pulmonary disease with no proven effective treatment. Spontaneous remissions do not occur and death usually ensues within 3 to 5 years of diagnosis. The pathogenesis of IPF is complex and not fully delineated. However, a critical pathogenic event in the development of IPF is ongoing injury of lung epithelium. The cause of this injury remains unknown although chronic viral infection of the lungs, particularly with herpesvirus, is garnering increasing interest as a potential cause of the in jury. Studies from us and others that use lung tissue from humans with IPF show the presence of one or more herpesviruses in the lungs of IPF patients. In addition, we found that mice with a T helper(Th)-2 phenotype inoculated with murine herpesvirus develop chronic lung epithelial infection and many histologic features reminiscent of IPF. Based on these data, our concept is that herpesvirus does not normally infect the lung but in a susceptible host, herpesvirus infects lung epithelium and the infected epithelium expresses cytokines and growth factors which directs the fibrogenic response leading to the development of IPF. Our long term goal is to prove that there is a causal link between herpesvirus infection of the lung and the development of IPF. A critical step in reaching that goal is to develop strategies to eradicate herpesvirus infection in the lung and then show amelioration of IPF. The purpose of the current proposal is two-fold. First is to provide sufficient evidence for a potential role of herpesvirus in the pathogenesis of IPF to justify an antiviral therapeutic trial in IPF. Second is to gather information on the viral replication cycle in the IPF lung in order to design the most effective antiviral strategy for such a trial. Therefore, we propose the following specific aim. In lung tissue from patients with IPF: i. Identify which herpesviruses are present in the lung using PCR; ii. Identify cellular sites of herpesvirus infection using immunohistochemical and immunofluorescent analysis for detection of viral proteins; iii. Determine whether herpesviruses are primarily latent in the infected cells or whether lytic replication is occurring; and iv. Determine whether cells infected with herpesvirus, or neighboring uninfected cells, express host proteins known to be involved in the pathogenesis of IPF. Control lung tissue from patients with chronic lung diseases not associated with progressive fibrosis will be examined.