BIOMAT INDUCED PATHOPHYSIOLOGICAL CHANGES IN LEUKOCYTES

BIOMAT 引起白细胞的病理生理变化

• 批准号: 2415579
• 负责人: STUART L COOPER
• 金额: $ 16.27万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2415579
• 关键词: CD antigens; biomaterial interface interaction; blood coagulation; cell cell interaction; complement pathway; fibrinolysis; glass; host organism interaction; human tissue; inflammation; kallikreins; kininogens; leukocyte activation /transformation; leukocyte adhesion molecules; leukocytes; phagocytosis; platelet aggregation; polyethylenes; polymers; polyurethanes; silicone rubber; surface property; thrombosis; video microscopy

DESCRIPTION: (Adapted from the applicant's abstract) In recent years the increasing use of therapies involving both acute and chronic contact of materials and blood have brought a keen awareness of biomaterial induced morbidity and mortality. Our understanding of contributory factors to such pathophysiological changes involving alterations to various biochemical systems remains imperfect. It is proposed to investigate specifically the role of leukocytes and postulate that leukocyte involvement is a significant factor in the acute and chronic reactions to an artificial surface in contact with blood. Specifically we hypothesize that (a) studying the interactions of leukocytes with cellular elements will broaden our understanding of thrombus formation on biomaterials and (b) induction of complement activation and impairment of leukocyte function consequent to material contact has major implications for subsequent inflammation responses as well as device related infections. Leukocyte responses to artificial surfaces are complex and varied and include adhesion, aggregation, granule release, expression of cell surface markers and procoagulant activity, fibrinolysis and phagocytosis. It is proposed to investigate these responses using a combination of novel and well-established techniques on a series of well-characterized materials. Polyethylene, silicone rubber, glass and a polyurethane will be used as the test surfaces in all studies. Modified polyurethanes with specific properties may be selectively introduced to extend the study. To determine the relationship between leukocytes and cellular elements particularly platelets the investigators propose to investigate at a fundamental level, the receptor-ligand pair involved in platelet- leukocyte interactions using blocking peptides, divalent cation depletion and antibodies. Further, the investigators propose to determine if platelet-leukocyte interactions result in CD11/CD18 upregulation, tissue factor upregulation and L selectin down-regulation by quantitative and functional assays. The interactions of leukocytes and the contact and complement system will be evaluated by determining the formation of kallikrein-inhibitor complexes, decreases in kininogen coagulant activity and cleavage of kininogen. Activation of the classical complement pathway will be evaluated by measuring C1-C1 inhibitor complexes, C4d and the final pathway by measuring iC3b and C5b-9. In addition to being involved in the blood contacting response to biomaterial surfaces, leukocyte adhesion and activation are also relevant for the pathogenesis of device related infections, a significant source of mortality. We hypothesize that the chemical properties of an artificial surface may affect leukocyte responses either directly or through the modulation of blood components such as complement or coagulation factors. Concomitantly or subsequently bacteria colonization may be affected. The investigators propose to investigate the complex interactions involving bacteria, leukocytes and biomaterials using video microscopy. It is expected that the proposed study will significantly enhance our understanding of the role of leukocytes in pathophysiological changes induces by biomaterials and will ultimately lead to the design of better materials for clinical use.

描述：（根据申请人的摘要改编）近年来 涉及急性和慢性接触的疗法的使用增加 材料和血液使生物材料引起的敏锐认识 发病率和死亡率。 我们对促成因素的理解 这种病理生理的变化涉及各种改变 生化系统仍然不完美。 提议调查 特别是白细胞的作用，并假设白细胞 参与是急性和慢性反应的重要因素 与血液接触的人造表面。 特别是我们 假设（a）研究白细胞与 细胞元素将扩大我们对血栓形成的理解 关于生物材料和（b）诱导补体激活和 材料接触造成的白细胞功能的损害很重要 对随后的炎症反应和设备的影响 相关感染。 白细胞对人造表面的反应是复杂而多样的，并且 包括粘附，聚集，颗粒释放，细胞表达 表面标记和凝聚活性，纤维蛋白溶解和 吞噬作用。 建议使用 一系列新颖和公认的技术的结合 特征良好的材料。 聚乙烯，有机硅橡胶，玻璃和 在所有研究中，聚氨酯将用作测试表面。 具有特定特性的修饰聚氨酯可以选择性地 介绍以扩展研究。 确定白细胞与细胞元素之间的关系 特别是血小板调查人员建议在 基本水平，与血小板有关的受体配体对 白细胞相互作用使用阻断肽，二价阳离子 消耗和抗体。 此外，调查人员建议 确定血小板 - 白细胞相互作用是否导致CD11/CD18 上调，组织因子上调和L选择素下调 通过定量和功能测定。 白细胞的相互作用 接触和补充系统将通过确定来评估 kallikrein抑制剂复合物的形成，降低了差异 促促凝蛋白活性和裂解。 激活 经典补体途径将通过测量C1-C1进行评估 通过测量IC3B和 C5B-9。 除了参与血液接触的反应 生物材料表面，白细胞粘附和激活也是 与设备相关感染的发病机理相关，这是显着的 死亡率来源。 我们假设 人造表面可能直接影响白细胞反应或 通过调节血液​​成分，例如补体或 凝血因子。 同时或随后的细菌 殖民可能会受到影响。 调查人员建议调查 涉及细菌，白细胞和生物材料的复杂相互作用 使用视频显微镜。 预计拟议的研究将 显着增强我们对白细胞在 病理生理变化是由生物材料引起的，最终将 导致设计更好的临床材料。