Interpaly of Thrombosis and Inflammation in Vasculitis

特发性炎症性脉管炎是一组多器官系统疾病，在 常见的大小不一的血管发炎，导致严重的器官和生命危险 疾病。目前的治疗方法毒性很大，并不完全有效。 血栓形成在血管炎中的重要性日益被认识到。最近，默克尔博士和 他的同事们已经证明，韦格纳肉芽肿患者的发病率增加了20倍 静脉血栓事件的发生率，这些事件与活动性脉管炎有关。的确有 越来越多的证据强烈地将血栓形成的多个方面与血管炎症和这些 区域是此应用程序的重点。在这种构造中，“血栓形成”并不限于大血管。 临床上可见血栓，但可能包括与损伤和修复周期相关的“微血栓形成”， 其中一些可能是病态的。同样，传统上被称为 “炎症”会刺激“血栓形成”。我们认为，虽然炎症可能是导致 血管炎的损害，血栓形成的每个止血成分，i)血小板依赖因子；ii) 凝血级联；和iii)纤溶，也被触发，导致血栓形成的“二次打击”和 随后出现炎症和血栓形成的恶性循环。 了解血栓形成的各个方面在血管炎中所起的作用不仅将提供重要的 深入了解这些疾病的病理生理学，但也可能解决三个关键但未得到满足的问题 脉管炎的医疗需要：i)疾病活动性生物标记物的开发；ii)发现 疾病活动性和结果的预测因素；以及三)测试新的治疗类别的理由 干预措施。 在这一应用中，我们建议评估血栓形成标志物与血栓形成的相关性。 通过实现三个相关的特定目标，脉管炎的事件、总体疾病活动性和长期结果： 1.韦格纳病血栓形成选择性标志物与疾病活动性的相关性研究 肉芽肿病；2.研究选择性血栓形成因子与慢性阻塞性肺疾病的关系 韦格纳肉芽肿患者没有临床明显的血栓形成；3.研究 血栓形成标志物对韦格纳病患者治疗反应的预测价值 肉芽肿。我们将利用来自几个大群患者的临床数据和生物标本。 患有脉管炎，并与血管生物学和血栓形成的基础科学专家合作。 这项研究与公共卫生直接相关，因为它探索了两者之间的关系 关键的生物过程：炎症和血栓形成(凝血)。这项工作可能会导致 更好地了解和治疗炎症性疾病。

The idiopathic inflammatory vasculitides are a group of multiorgan system diseases that have in common the findings of inflammation of vessels of varying sizes that results in serious, organ and lifethreatening disease. Current treatments are highly toxic and not fully effective. The importance of thrombosis in vasculitis is increasingly being recognized. Recently, Dr. Merkel and his colleagues have demonstrated that patients with Wegener's granulomatosis have a 20-fold increased incidence of venous thrombotic events and that these events are associated with active vasculitis. There is increasing evidence strongly linking multiple aspects of thrombosis with vascular inflammation and these areas are the focus of this application. In this construct, "thrombosis" is not limited to the large vessel thrombi seen clinically but may include "microthrombosis" associated with a cycle of damage and repair, some of which may be pathological. Similarly, aspects of what has traditionally been referred to as "inflammation" can stimulate "thrombosis". We propose that while inflammation may be the initial cause of damage in vasculitis, each hemostatic component of thrombosis, i) platelet-dependent factors; ii) the coagulation cascade; and iii) fibrinolysis, is also triggered, leading to a "second hit" of thrombosis and subsequently a vicious cycle of inflammation and thrombosis. Understanding the roles various aspects of thrombosis play in vasculitis will not only provide important insight into the pathophysiology of these diseases, but will also potentially address three critical but unmet medical needs in vasculitis: i) the development of biomarkers of disease activity; ii) the discovery of predictors of disease activity and outcome; and iii) a rationale for testing novel classes of therapeutic interventions. In this application we propose evaluating the association of markers of thrombosis with thrombotic events, overall disease activity, and long-term outcome in vasculitis by achieving three related specific aims: 1. Studying the association of selective markers of thrombosis with disease activity in Wegener's granulomatosis; 2. Studying the associations between selective thrombosis factors and the presence or absence of clinically evident thrombosis in patients with Wegener's granulomatosis; 3. Studying the predictive value of markers of thrombosis for response to therapy in patients with Wegener's granulomatosis. We will utilize clinical data and biological specimens from several large cohorts of patients with vasculitis and partner with experts in the basic science of vascular biology and thrombosis. This research is directly relevant to public health because it explores the relationship between two critical biological processes: inflammation and thrombosis (clotting). This work will potentially lead to a better understanding and better treatment of inflammatory diseases.