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.
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