Herpesvirus infection/injury govern fibrocyte recruitment and activation

项目总结/摘要 肺纤维化可能是由于对连续性肺损伤的创伤愈合反应失调所致。 循环骨髓来源的间充质前体细胞（纤维细胞）的募集对于一个人的健康至关重要。 损伤后纤维增生宿主反应。纤维细胞有助于细胞外基质（ECM）的产生， 通过分泌促纤维化/促炎因子促进纤维化。局灶性肺泡上皮细胞 (AEC)损伤被认为是纤维化过程的起始事件。肺损伤的病因是 未知但潜伏的病毒感染，特别是疱疹病毒亚科成员的感染， 特发性肺纤维化（IPF）。病毒感染可能通过溶解 实质肺细胞或通过诱导驻留或募集的细胞的功能改变。感染 感染MHV-68（一种鼠γ疱疹病毒）的小鼠导致AEC和模拟物的溶解性和潜伏性感染 人类感染EB病毒（EBV）。我们的初步数据表明：1）MHV-68感染 增强异硫氰酸荧光素（FITC）诱导的肺纤维化时，给予之前或之后的纤维化 侮辱。2)纤维细胞响应于MHV-68感染被募集到肺。3)MHV-68感染导致 半胱氨酰白三烯（cys LTs）的产生可诱导纤维细胞的迁移和活化。 4)MHV-68可感染纤维细胞并促进其增殖。5)致额外肺泡损伤 FITC诱导有利于纤维细胞增殖的失调的细胞因子和类花生酸应答， 分化和ECM沉积。我们假设MHV-68后纤维化增加 感染/FITC损伤是增强的募集、增殖和分化的结果， 纤维细胞由于cys LT和CC趋化因子的释放，募集和增殖增加 由肺部的常驻细胞引起。通过改变纤维细胞的比例， 实质和募集细胞的刺激和保护分子。完成以下 具体目标将提供新的信息，说明导致产生或加剧 肺纤维化目的1）确定肺泡MHV-68感染的动力学和作用， FITC诱导的肺纤维化;目的2）确定MHV-68感染是否改变了前 或AEC、肺泡巨噬细胞（AM）、间质巨噬细胞（IM）和B细胞的抗纤维化介质， 目的3）确定MHV-68是否与EB病毒感染有关， 无论是MHV-68还是EBV感染改变了纤维细胞和成纤维细胞， 并确定cys LT在MHV-68诱导的纤维细胞募集和纤维化增强中的作用。项目叙述/相关性 在本申请中提出的实验将提供对病毒感染的作用的机制性见解， 可能会使人们容易患上纤维化。研究还将探讨病毒在 感染在已确定的纤维化患者中加重疾病中起作用。最后，这项工作将探讨 抗白三烯策略限制病毒诱导的纤维化恶化的治疗潜力。

Project Summary/Abstract Pulmonary fibrosis may result from dysregulated wound healing responses to sequential lung injuries. Recruitment of circulating bone-marrow-derived mesenchymal precursors (fibrocytes) is crucial for a fibroproliferative host response post-injury. Fibrocytes contribute to extracellular matrix (ECM) generation and promote fibrosis through the secretion of profibrotic/proinflammatory factors. A focal alveolar epithelial cell (AEC) injury is believed to be the initiating event of the fibrotic process. The etiologic agents of lung injury are unknown but latent viral infections, especially by members of the herpesvirinae have been associated with idiopathic pulmonary fibrosis (IPF). Viral infection might influence fibroproliferative responses via lysis of parenchymal lung cells or by inducing alterations in the function(s) of resident or recruited cells. Infection of mice with MHV-68 (a murine gammaherpesvirus) results in both lytic and latent infection of AECs and mimics human infection with Epstein-Barr virus (EBV). Our preliminary data demonstrate 1) MHV-68 infection augments fluorescein isothiocyanate (FITC)-induced lung fibrosis when given both prior to or after the fibrotic insult. 2) Fibrocytes are recruited to the lung in response to MHV-68 infection. 3) MHV-68 infection results in the generation of cysteinyl leukotrienes (cys LTs) which can induce migration and activation of fibrocytes. 4) MHV-68 can infect fibrocytes and enhance their proliferation. 5) The additional alveolar injury induced by FITC, induces a dysregulated cytokine and eicosanoid response which favors fibrocyte proliferation, differentiation and ECM deposition. We hypothesize that increased fibrosis following MHV-68 infection/FITC injury is the result of enhanced recruitment, proliferation and differentiation of fibrocytes. Recruitment and proliferation are increased due to releases of cys LTs and CC chemokines by resident cells of the lung. Differentiation is enhanced by production of altered ratios of fibrocyte stimulatory and protective molecules by parenchymal and recruited cells. Completion of the following specific aims will provide new information regarding mechanisms that lead to generation of or exacerbation of pulmonary fibrosis. Aim 1) To determine the kinetics and role of alveolar MHV-68 infection in augmentation of FITC-induced pulmonary fibrosis; Aim 2) To determine whether MHV-68 infection alters the secretion of pro- or anti-fibrotic mediators by AECs, alveolar macrophages (AMs), interstitial macrophages (IMs) and B cells and to perform correlative studies in human AMs infected with EBV; Aim 3) To determine whether MHV-68 infection recruits more fibrocytes to the lung, whether MHV-68 or EBV infection alters fibrocytes and fibroblasts and to determine the role of cys LTs in MHV-68-induced recruitment of fibrocytes and augmentation of fibrosis. Project Narrative/Relevance The experiments proposed in this application will provide mechanistic insight into the role that viral infections may play in predisposing people to the development of fibrosis. Research will also address the role that viral infections play in exacerbating disease in patients with established fibrosis. Finally, this work will explore the therapeutic potential of anti-leukotriene strategies to limit viral-induced exacerbations of fibrosis.