COAGULATION PATHWAY IN ACUTE LUNG INJURY

急性呼吸窘迫综合征（ARDS）的关键病理生理学特征是外源性凝血的局部激活和纤维蛋白溶解的抑制。 随着损伤的发展，这些事件促进肺中纤维蛋白的沉积。 外源性凝血途径的组分，例如组织因子、凝血酶和纤维蛋白，在炎症细胞运输中发出信号改变并增加血管通透性。促凝剂和纤维蛋白还促进损伤中的其他关键事件，包括补体激活、促炎细胞因子的产生、纤维蛋白溶解的抑制和损伤肺的重塑。为了检验肺中外源性凝血的激活和纤维蛋白周转紊乱是ARDS中肺损伤和气体交换受损的发病机制的核心的假设，提出用位点失活的因子VIIa（FFR-FVIIa）或组织因子途径抑制剂（TFPI）特异性阻断外源性凝血的起始步骤将预防实验性ARDS中的急性肺损伤和气体交换受损。 还提出这两种药物对外源性凝血的阻断具有等效作用，但FFR-FVIIa通过抑制组织因子-FVIIa复合物的信号传导而具有上级抗炎特性。 将在患有脓毒症或高氧所致急性肺损伤的非人灵长类动物中检验这些假设。 具体目标是：1）探讨脓毒症时外源性凝血途径的主要炎症机制及阻断外源性凝血途径对急性肺损伤的保护作用; 2）探讨高氧时外源性凝血途径的主要炎症机制及阻断外源性凝血途径对急性肺损伤的保护作用;和3）确定当在狒狒中建立ARDS后实施该治疗策略时抑制外源性凝血途径的功效。

Description (Adapted from Applicant's Abstract) A critical pathophysiological feature of the acute respiratory distress syndrome (ARDS) is local activation of extrinsic coagulation and inhibition of fibrinolysis. These events promote deposition of fibrin in the lung as the injury evolves. Components of the extrinsic coagulation pathway, e.g. tissue factor, thrombin and fibrin, signal alterations in inflammatory cell traffic and increases in vascular permeability. Procoagulants and fibrin also promote other key events in the injury including complement activation, production of pro-inflammatory cytokines, inhibition of fibrinolysis and remodeling of the injured lung. To test the hypotheses that activation of extrinsic coagulation and disordered fibrin turnover in the lung are central to the pathogenesis of lung injury and impaired gas exchange in ARDS, it is proposed that specific blockade of the initiating steps of extrinsic coagulation with site- inactivated factor VIIa (FFR-FVIIa) or tissue factor pathway inhibitor (TFPI) will prevent acute lung injury and gas exchange impairment in experimental ARDS. It is also proposed that the two agents will have equivalent effects on blockade of extrinsic coagulation but FFR-FVIIa will have superior anti-inflammatory properties by inhibiting signaling by tissue factor-FVIIa complex. The hypotheses will be tested in non-human primates with acute lung injury from either sepsis or hyperoxia. The Specific Aims are: 1) To determine the key inflammatory mechanisms and the extent of protection from acute lung injury (ALI) effected by blockade of the extrinsic coagulation pathway in sepsis; 2) To determine the key inflammatory mechanisms and the extent of protection from ALI effected by blockade of the extrinsic coagulation pathway in hyperoxia; and 3) To determine the efficacy of inhibition of the extrinsic coagulation pathway when this treatment strategy is implemented after ARDS is established in baboons.