Tissue Factor Mediated Fibrin Deposition in Acute Lung Injury

描述（由申请人提供）：本提案的目的是培养Julie Bastarache博士的科学和专业发展，使其成为一名独立的研究者。她目前正在范德比尔特大学医学中心的肺部研究中心发展她的研究事业。在Lorraine Ware和Timothy Blackwell博士的指导下，Bastarache博士将设计和执行实验，以提高她在急性肺损伤和急性呼吸窘迫综合征（ALI/ARDS）病理生物学方面的知识和研究技能。通过实验室经验，正式的课程，和同行评审过程中，她将获得在实验设计和执行，实验室技术，数据分析和手稿准备的专业知识。这些技能将为Bastarache博士在肺部研究中追求独立的职业生涯奠定基础。尽管在理解ALI/ARDS的基本致病机制方面取得了进展，但基本问题仍未得到解答，并且缺乏疾病特异性治疗。实验研究已经确定，作为促凝血剂肺泡内环境的结果，肺泡内凝血酶形成和纤维蛋白沉积是有害的，然而，调节纤维蛋白沉积在气隙中并将肺部炎症和凝血联系起来的具体机制尚不清楚。我们的初步数据确定肺泡上皮细胞作为组织因子（TF）的一个潜在来源，在肺泡隔室的主要促凝刺激。因此，我们已经形成了以下假设：响应促炎刺激的空域中的组织因子的局部产生使炎症持续并导致肺损伤。肺中TF的抑制将减少纤维蛋白形成，减少细胞因子产生并限制肺损伤。为了验证这一假设，我们将：1）确定急性损伤肺中调节TF活性、凝血酶形成和纤维蛋白沉积的因素。2)明确减弱肺泡内TF活性对急性损伤肺中持续炎症和损伤的影响。3)确定肺泡上皮中TF上调和活化的机制。这些研究的完成将提供关于ARDS发病机制的关键信息，可能导致新的治疗策略。相关性（参见说明）：急性呼吸窘迫综合征（ARDS）是一种常见病，死亡率高，无特效药物治疗。新的数据表明，肺损伤中涉及的两个重要途径之间存在关键联系：炎症和凝血。该提案将使用独特的动物模型来定义连接这两个独立途径的特定机制，并将有助于确定新疗法的关键靶点。

DESCRIPTION (provided by applicant): The purpose of this proposal is to cultivate the scientific and professional development of Dr. Julie Bastarache so that she may become an independent investigator. She is currently developing her research career in the Center for Lung Research at Vanderbilt University Medical Center. Under the guidance of Drs. Lorraine Ware and Timothy Blackwell, Dr. Bastarache will design and perform experiments that will enhance her knowledge and research skills in the pathobiology of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). Through laboratory experience, formal coursework, and the peer review process she will gain expertise in experimental design and execution, laboratory techniques, data analysis, and manuscript preparation. These skills will provide the foundation for Dr. Bastarache to pursue an independent career in lung research. Despite progress in understanding the basic pathogenic mechanisms of ALI/ARDS, fundamental questions remain unanswered and disease specific treatments are lacking. Experimental studies have established that intra-alveolar thrombin formation and fibrin deposition as a consequence of a pro-coagulant intra-alveolar environment are detrimental however, the specific mechanisms that regulate fibrin deposition in the airspaces and link lung inflammation and coagulation are unknown. Our preliminary data identifies the alveolar epithelium as a potential source of tissue factor (TF), the major pro-coagulant stimulus in the alveolar compartment. As a result we have formed the following hypothesis: Local production of tissue factor in the airspace in response to pro-inflammatory stimuli perpetuates inflammation and leads to lung injury. Inhibition of TF in the lungs will reduce fibrin formation, decrease cytokine production and limit lung injury. To test this hypothesis we will:1) determine the factors that regulate TF activity, thrombin formation, and fibrin deposition in the acutely injured lung. 2) define the impact of attenuating intra-alveolar TF activity on ongoing inflammation and injury in the acutely injured lung. 3) determine the mechanisms of TF upregulation and activation in the alveolar epithelium. Completion of these studies will provide critical information about the pathogenesis of ARDS that could lead to novel therapeutic strategies. RELEVANCE (See instructions): The Acute Respiratory Distress Syndrome (ARDS) is a common disorder with a high mortality rate with no specific drug treatments. New data suggests critical links between two important pathways involved in lung injury: inflammation and coagulation. This proposal will use unique animal models to define the specific mechanisms that link these two independent pathways and will help to identify key targets for new therapies.