CRYSTAL-MEMBRANE INTERACTIONS IN SILICOSIS

硅肺病中的晶膜相互作用

• 批准号: 3340944
• 负责人: NEIL S. MANDEL
• 金额: $ 7.72万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-12-01 至 1988-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3340944
• 关键词: X ray crystallography; chemical binding; crystallization; cytotoxicity; erythrocyte membrane; hemolysis; human tissue; liposomes; membrane lipids; membrane structure; occupational disease /disorder; particle; phagocytosis; phospholipids; pneumoconiosis; pulmonary fibrosis /granuloma; radiotracer; superoxides; tissue /cell culture

Pulmonary damage in fibrotic pneumoconioses such as silicosis appears to be initiated by the direct interaction of the inhaled crystals with cellular membranes, subsequent phagolysosomal membranolysis, cell death, inflammation, and the development of fibrosis. The mechanism of crystal-induced membranolysis and the specific cellular events following crystal phagocytosis are not well-defined, and previous investigations have yielded conflicting data. We propose to study these questions employing a multidisciplinary research protocol. We will determine the atomic forces involved in crystal-membrane binding and delineate the mechanism of crystal-induced membranolysis. These studies will indicate if there are specific structural and/or chemical parameters or phospholipid components of membranes which allow some crystals to bind to and then lyse membranes. These issues will be studied by measuring the membranolytic potentials of some of the different structural forms of Si02 and Ti02 incubated with human erythrocytes and synthetic liposomes. In addition, the lytic potentials of silica will be measured using liposomes prepared with a variety of specifically charged head groups. Hemolytic potentials will also be measured using quartz with chemically altered surfaces. We will also analyze the cellular and subcelluar events which occur as a result of particulate-cell interactions. We will determine whether different crystals vary in the quantity of potentially inflammatory substances released from cells following their ingestion. In vitro experiments will evaluate the interaction of cells and silica crystals with assays for neutrophil activation, cell viability, release of lysosomal enzymes, release of toxic oxygen metabolites, and crystal-induced cytotoxicity.

纤维化尘肺（如硅肺）的肺损伤似乎是 由吸入的晶体与细胞的直接相互作用引发， 膜，随后的吞噬溶酶体膜溶解，细胞死亡， 炎症和纤维化的发展。 的机理 晶体诱导的膜溶解和随后的特定细胞事件 晶体吞噬作用没有很好地定义，以前的研究 产生了相互矛盾的数据。 我们建议采用一种 多学科研究协议。 我们将确定晶体-膜结合所涉及的原子力 并阐明晶体诱导的膜溶解机制。 这些 研究将表明是否有特定的结构和/或化学 参数或磷脂成分的膜，允许一些 晶体结合并溶解细胞膜。 将研究这些问题 通过测量一些不同的细胞的膜溶解电位， 与人红细胞孵育的SiO2和TiO 2的结构形式， 合成脂质体。 此外，二氧化硅的溶解潜力将是 使用用各种特异性电荷的 领导小组。 还将使用石英测量溶血电位， 化学改变的表面 我们还将分析细胞和亚细胞的事件，发生作为一个 这是颗粒细胞相互作用的结果。 我们将决定 不同的晶体在潜在炎症的量上不同， 从细胞中释放出来的物质。 体外 实验将评估细胞和二氧化硅晶体与 中性粒细胞活化、细胞活力、溶酶体释放的测定 酶，释放有毒的氧代谢产物，晶体诱导 细胞毒