LUNG LAVAGE PROCOAGULANTS IN LUNG INJURY AND REPAIR

纤维蛋白沉积通常伴随炎症，并可能参与 组织修复。凝血功能异常，血管内和血管外 肺纤维蛋白沉积与肺纤维化的早期发展 常见于成人呼吸窘迫综合征(ARDS)。阿兹 每年影响15万名患者，其中一半是致命的。这个 凝血机制在ARDS发病机制中的作用 特别是关于肺修复和纤维化的定义不是很好。 一种激活促凝血剂活性的因子X已在 ARDS患者的肺泡灌洗(BAL)。类似 在处理后的绒猴的BAL中发现了活性 博莱霉素，一种导致急性肺损伤的药物，随后是肺 纤维化症。这项研究的目的是确定它们的起源和特征 BAL促凝血活性的性质及其与 BAL促凝剂治疗急性肺损伤。这将在人体上进行研究，并 一种很有特色的肺损伤动物模型。此外，我们将研究 促凝血剂在肺纤维化发生发展中的作用 在急性肺损伤后。本提案涉及以下几个方面 问题： 1.肺泡灌洗液中X因子激活的机制是什么 炎症性肺病？ 2.凝血因子X的激活是ARDS BAL的主要促凝活性吗 以及其他形式的肺部炎症？ 3.BAL促凝剂在体内的产生是否与 ARDS和博莱霉素诱导的生理性损害或肺纤维化 肺损伤？ 4.BAL中哪些细胞产生促凝剂？ 促凝血因子激活物的免疫化学和功能测定 X；特别是第VII因子和组织因子，将被用于研究 凝血因子X激活机制的研究进展 实验动物将有助于确定生理学重要性 促凝血因子X激活剂。培养中的肺细胞将被用于 研究BAL促凝剂的来源和表达机制。 来自这些研究的信息将有助于理解 凝血机制在急性肺损伤修复中的作用。

Fibrin deposition commonly accompanies inflammation and may be involved in tissue repair. Coagulation abnormalities, intravascular and extravascular pulmonary fibrin deposition and the early development of pulmonary fibrosis are commonly found in the Adult Respiratory Distress Syndrome (ARDS). ARDS affects 150,000 patients annually and is lethal in half these cases. The participation of coagulation mechanisms in the pathogenesis of ARDS particularly with respect to lung repair and fibrosis is not well defined. A factor X activating procoagulant activity has been found in bronchoalveolar lavage (BAL) from the lungs of patients with ARDS. Similar activity has been found in BAL of marmosets following treatment with bleomycin, an agent which causes acute lung injury followed by pulmonary fibrosis. The purpose of this study is to characterize the origins and properties of BAL procoagulant activity and to define the relationship of BAL procoagulants to acute lung injury. This will be studied in humans and a well characterized animal model of lung injury. Further, we will examine the role of these procoagulants in the development of pulmonary fibrosis following acute lung injury. This proposal addresses the following questions: 1. What are the mechanisms of the activation of factor X in BAL in inflammatory lung disease? 2. Is the factor X activation the major procoagulant activity in ARDS BAL and in other forms of pulmonary inflammation? 3. Is the generation of BAL procoagulant correlated in vivo with physiologic impairment or pulmonary fibrosis in ARDS and bleomycin induced lung injury? 4. Which cells produce the procoagulants in BAL? Immunochemical and functional assays of procoagulant activators of factor X; in particular factor VII and tissue factor, will be used to investigate the mechanism of activation of factor X. Serial studies of patients and experimental animals will help to determine the physiologic importance of the procoagulant factor X activator. Lung cells in culture will be used to study the origins and mechanisms of expression of BAL procoagulants. Information from these studies will contribute to an understanding of the role of coagulation mechanisms in acute lung injury and repair.