COAGULATION PATHWAY IN ACUTE LUNG INJURY

急性肺损伤的凝血途径

• 批准号: 6881266
• 负责人: CLAUDE A PIANTADOSI
• 金额: $ 35.12万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881266
• 关键词: adult respiratory distress syndrome; anticoagulants; baboons; blood coagulation; blood disorder chemotherapy; cellular pathology; coagulation factor VII; disease /disorder model; fibrin; hemodynamics; lung injury; nonhuman therapy evaluation; oxidative stress; oxygen transport; pathologic process; respiratory disorder chemotherapy; septic shock; superoxide dismutase; vascular endothelium permeability

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.

描述（改编自申请人的摘要）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，这些事件促进纤维蛋白在肺部沉积。 外源性凝血途径的组成部分，例如组织因子、凝血酶和纤维蛋白、炎症细胞交通信号改变和血管通透性增加。促凝血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受损肺的重塑。为了检验肺外源性凝血的激活和肺内纤维蛋白转换紊乱是 ARDS 中肺损伤和气体交换受损的发病机制的核心这一假设，提出用位点失活的因子 VIIa 特异性阻断外源性凝血的起始步骤(FFR-FVIIa) 或组织因子途径抑制剂 (TFPI) 将预防实验性 ARDS 中的急性肺损伤和气体交换障碍。 还提出这两种药物在阻断外源性凝血方面具有相同的效果，但 FFR-FVIIa 通过抑制组织因子-FVIIa 复合物的信号传导而具有优异的抗炎特性。 这些假设将在因脓毒症或高氧血症导致急性肺损伤的非人类灵长类动物中进行测试。 具体目标是： 1) 确定脓毒症中关键的炎症机制以及通过阻断外源性凝血途径对急性肺损伤 (ALI) 的保护程度； 2) 确定关键炎症机制以及高氧条件下阻断外源性凝血途径对 ALI 的保护程度； 3) 确定在狒狒中出现 ARDS 后实施该治疗策略时抑制外源性凝血途径的功效。