Deranged Coagulation and Fibrinolytic Cascades in Idiopathic Pulmonary Fibrosis

描述(由申请人提供)：特发性肺纤维化(IPF)是一种肺部疤痕形成的疾病，尽管有最好的治疗方法，但中位生存期为3年。许多对人类的机械性和小型观察性研究表明，凝血-纤溶系统的异常与人类和实验性肺纤维化的原因有关。总而言之，他们证明了组织因子依赖的促凝血活性被诱导，而正常的纤溶活性在纤维化肺的肺泡腔中被抑制。尽管有这些概念性的知识，但关于凝血/纤溶途径中的因素是否可以预测IPF的预后或抗凝治疗反应，仍有许多需要了解。为了支持进一步研究凝血/纤溶系统的重要性，IPF患者发生动脉粥样硬化血栓相关临床事件的风险增加，一项小型试验首次证明了IPF中抗凝剂治疗的生存益处。在这里，我们的初步数据显示，IPF患者的血浆中存在凝血激活(组织因子抗原升高)和纤溶抑制(PAI-1抗原升高)。值得注意的是，组织因子抗原随着肺生理性损害的变化而变化，这与凝血激活程度可能反映预后的可能性一致。 此外，一项小型抗凝剂试验的血浆纤维蛋白D-二聚体水平在急性加重期间升高，尽管接受抗凝治疗，血浆D-二聚体水平升高的患者存活的可能性较小。我们的早期结果表明，利用基因表达谱来识别IPF的进展相关基因是可行的。根据收集的数据，我们假设凝血/纤溶系统的异常是IPF发病的基础。我们建议通过链接到NHLBI IPFnet临床研究网络华法林试验(ACE；IPF中的抗凝剂有效性)来检验这一假设。ACE是一项随机、双盲、安慰剂对照的多中心美国试验，旨在评估华法林对特发性肺纤维化患者的疗效。这项父母试验将严格确定华法林是否对IPF有改善作用。重要的是，它还提供了一个独特的机会来评估我们的假设在进展的背景下，以及抗凝剂治疗的反应，在仔细和彻底描述的IPF患者队列中。拟议的研究具有时间敏感性，因为它们将使用具有时间敏感性的处理/处理程序，在基线和之后的定时点收集和分析参加正在进行的IPFnet试验的患者的血浆样本。IPFnet指导委员会认识到这些机械性研究的价值，并完全支持这一申请。当完成后，我们将确定分子连接，并确定 凝血/纤溶状态对IPF发病的预后意义。此外，研究结果将为相关的ACE亲本临床结果试验提供抗凝剂生物学反应数据，并为试验提供华法林的作用机制(S)的信息。识别这些途径中的关键分子也将为未来开发更具靶向性的抗凝剂提供支持。公共卫生相关性：特发性肺纤维化(IPF)是一种肺部疤痕形成的疾病，尽管有最好的治疗方法，但预后很差。因此，IPF患者将从更好地了解其原因的新方法中受益匪浅。我们建议通过链接NIH赞助的一项正在进行的试验来研究IPF患者血液中的凝血和凝块溶解系统，在该试验中，IPF患者接受抗凝剂或安慰剂治疗。希望我们的结果将有助于确定IPF的原因，并提供预后和治疗上有用的信息。这些知识有望导致有效治疗剂的开发。(摘要结束)

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a scarring disorder of the lungs with a 3-yr median survival despite the best available treatment. Many mechanistic and small observational studies in humans implicate abnormalities in the coagulation-fibrinolytic systems in the causation of human and experimental pulmonary fibrosis. Collectively, they demonstrate that tissue factor-dependent pro-coagulant activity is induced, and that the normal fibrinolytic activity is suppressed in the alveolar compartment of the fibrotic lung. Despite this conceptual knowledge, there is much to be learned regarding whether factors in the coagulation/fibrinolysis pathways predict prognosis, or anticoagulant treatment response in IPF. In support of the importance of further study of the blood coagulation/fibrinolysis system, patients with IPF have an increased risk of atherothrombosis-related clinical events, and one small trial demonstrates, for the first time, a survival benefit of anticoagulant treatment in IPF. Here, we show preliminary data that there is activation of coagulation (increased tissue factor antigen), and inhibition of fibrinolysis (increased PAI-1 antigen) in plasma from patients with IPF. Strikingly, tissue factor antigen varied as a function of the pulmonary physiologic impairment, consistent with the possibility that prognosis may be reflected in the extent of coagulation activation. Furthermore, plasma fibrin D dimer levels from a small anti-coagulant trial were increased during an acute exacerbation, and those with elevated plasma D dimer levels, despite anticoagulant treatment, were less likely to survive. Our early results indicate that it is feasible to utilize gene expression profiling to identify progression related genes in IPF. Based on the collective data, we hypothesize that abnormalities in the coagulation/fibrinolytic system underlie the pathogenesis of IPF. We propose to test this hypothesis by linking to the NHLBI IPFnet clinical research network Warfarin trial (ACE; Anticoagulant Effectiveness in IPF). ACE is a randomized, double-blind placebo-controlled, multi-center US trial to evaluate the efficacy of Warfarin on outcome in patients with IPF. This parent trial will rigorously determine if Warfarin has an ameliorative effect on IPF. Importantly, it also provides a unique opportunity to evaluate our hypothesis in the context of progression, and response to anticoagulant treatment, in a carefully and thoroughly characterized cohort of IPF patients. The proposed studies are time-sensitive in that they would collect and analyze plasma samples from patients enrolled in ongoing IPFnet trials, at baseline and at timed points thereafter, using handling/processing procedures that are time-sensitive. The IPFnet steering committee recognizes the value of these mechanistic studies and fully supports this application. When completed, we will identify the molecular links, and determine the prognostic significance, of blood coagulation/fibrinolysis to the pathogenesis of IPF. Furthermore, the results will provide the anti-coagulant biological response data to support the linked ACE parent clinical outcome trial, and inform the trial as to mechanism(s) of Warfarin's effect. Identification of the critical molecules in these pathways will also support the future development of more targeted anti-coagulant agents. Public Health Relevance: Idiopathic pulmonary fibrosis (IPF) is a scarring disorder of the lungs with a poor prognosis despite the best available therapy. Thus, patients with IPF would greatly benefit from new approaches that lead to a better understanding of its cause. We propose to study the blood clotting and clot dissolving systems in blood from patients with IPF, by linking to an ongoing NIH-sponsored trial where IPF patients are treated with either an anticoagulant or placebo. It is hoped that our results will help to identify the cause of IPF, and provide prognostically and therapeutically useful information. Such knowledge will hopefully lead to the development of effective therapeutic agents. (End of Abstract)