CRYSTAL-MEMBRANE INTERACTIONS IN SILICOSIS

矽肺等纤维性尘肺患者的肺损害似乎是 由吸入的晶体与细胞的直接相互作用引发 膜，随后的吞噬体膜溶解，细胞死亡， 炎症和纤维化的发展。它的作用机制 晶体诱导的膜溶解和随后的特定细胞事件 晶体吞噬作用的定义并不明确，以前的研究已经 产生了相互矛盾的数据。我们建议用一种 多学科研究方案。 我们将确定与晶膜结合有关的原子力。 并对晶体诱导膜溶解的机制进行了探讨。这些 研究将表明是否有特定的结构和/或化学物质 膜的参数或磷脂成分，允许一些 晶体结合到膜上，然后裂解。这些问题将被研究。 通过测量一些不同分子的膜溶解电位 二氧化硅和二氧化钛与人红细胞孵育后的结构形态 合成脂质体。此外，二氧化硅的裂解电位将是 使用由各种特定电荷制备的脂质体进行测量 头部团体。溶血电位也将用石英测量， 化学变化的表面。 我们还将分析细胞和亚细胞事件，这些事件作为 颗粒与细胞相互作用的结果。我们将确定是否 不同的晶体在潜在炎症的数量上有所不同 细胞摄取后释放出来的物质。离体 实验将评估细胞和二氧化硅晶体之间的相互作用 中性粒细胞活化、细胞活力、溶酶体释放的测定 酶、有毒氧代谢产物的释放和晶体诱导 细胞毒性。

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.