PATHOLOGICAL CONSEQUENCES OF THE PLASMINOGEN SYSTEM

这项建议的长期目标是利用基因敲除小鼠在明确的生理和病理过程中测试纤溶酶原系统的假想功能，并确定该系统以前未被认识的功能。纤溶酶原系统通过纤溶酶直接降解纤维蛋白的能力在止血中的作用已被广泛分析并被广泛接受。一些细胞表面纤溶酶原系统成分的受体的鉴定表明，纤溶酶在细胞迁移事件中发挥作用，如炎症反应。这种反应和其他细胞迁移事件最重要的是细胞外基质的降解。纤溶酶被认为在这一过程中直接或通过激活其他基质降解蛋白，即金属蛋白酶发挥主要作用。炎症反应与许多病理的早期阶段有关，如肺纤维化和动脉粥样硬化，对这些早期事件的调节可能决定这些疾病的临床结果。基因敲除小鼠可用于纤溶酶原系统的所有组件，这为在体内以机械方式分析其在这些病理中的作用提供了独特的机会。在这项研究中，缺乏纤溶酶原系统成分的小鼠将受到两种炎症性疾病模型的挑战，即肺纤维化和动脉粥样硬化。纤溶酶原系统的成分对与这些疾病的早期炎症反应和后期相关事件的影响将被调查。利用这些基因敲除小鼠，这项建议将专门：(1)通过评估早期炎症事件、毛细血管/肺泡壁完整性的改变、病变发展和金属蛋白酶参与来研究博莱霉素诱导的肺纤维化。(2)应用一系列组织学和免疫组织学技术，通过测定血管壁和管腔的定性和定量变化来研究铜套致动脉粥样硬化。

The long-term goal of this proposal is to test hypothesized functions of the plasminogen system in defined physiological and pathological processes utilizing gene knock-out mice and to identify previously unrecognized functions of this system. The contribution of the plasminogen system in hemostasis, through plasmin's ability to directly degrade fibrin, has been extensively analyzed and is well accepted. The identification of receptors for components of the plasminogen system on a number of cell surfaces implicates plasmin in playing a role in cell migratory events such as the inflammatory response. Paramount to this response and other cell migratory events is the degradation of extracellular matrix. Plasmin is believed to play a major role in this process either directly or through activation of other matrix degrading proteins, i.e., metalloproteases. The inflammatory response is associated with the early stages of a number of pathologies, such as pulmonary fibrosis and atheroscelerosis and regulation of these early events may dictate the clinical outcome of these diseases. The availability of gene knock-out mice to all components of the plasminogen system offers an unique opportunity to analyze, in vivo, in a mechanistic fashion its function in these pathologies. In this study mice deficient for components of the plasminogen system will be challenged utilizing two models of inflammatory diseases, pulmonary fibrosis and atherosclerosis. The effect components of the plasminogen system has on events associated with both early inflammatory response and later stages of these diseases will be investigated. Utilizing these gene knock-out mice, this proposal will specifically: (1) study bleomycin induced pulmonary fibrosis by assessing early inflammatory events; alterations in the integrity of the capillary/alveolar wall integrity; lesion development; and metalloprotease involvement. (2) study copper cuff induced atherosclerosis by determine qualitative and quantitative changes in the vessel wall and lumen utilizing a battery of histological and immunohistological techniques.