Pulmonary fibrosis is caused by a number of insults including exposure to asbestos. An increasing amount of evidence suggests that asbestos-associated toxicity to cells of the respiratory tract involves generation of oxygen free radicals, reactive species that cause lipid peroxidation, and damage to macro-molecules. Oxygen free radicals also are implicated as causative agents in inflammation in the lung associated with other fibrogenic agents (i.e., bleomycin, TPA). During the past year, we have developed a rapid-onset inhalation model of asbestos-induced inflammation and fibrosis in Fischer 344 rats and are able to measure lung injury by asbestos using biochemical and morphologic techniques. These include determination of protein, cell content, lipid content and activity of enzymes in the lavage fluid of exposed animals, hydroxyproline content of whole lung, and a histologic grading system for inflammation and fibrosis. These markers of inflammation and disease will be used to evaluate preventive intervention with scavengers of active oxygen species when administered to asbestos-exposed animals. First we will assess whether SOD and catalase (scavengers of superoxide (O2-) and H202, respectively) are elevated in rat lung and serum after administration of scavengers coupled to polyethylene glycol (PEG) or incorporated into liposomes. These procedures will increase the half-life of enzymes and facilitate their fusion with cell membranes. Secondly, scavengers, alone and in combination, will be administered to rats to prevent asbestos-associated inflammation and fibrosis. Thirdly, isolated alveolar macrophages and rat lung fibroblasts will be used to probe mechanisms of generation of active oxygen species by asbestos.
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