Pulmonary fibrosis is a progressive, debilitating lung disease caused by a number of chemical, environmental and occupational insults including exposure to asbestos. An increasing amount of evidence reported by this laboratory 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 macromolecules. Oxygen free radicals also are implicated as causative agents in inflammation in the lung associated with other fibrotic agents including bleomycin and 12-0-tetradecanoyl-phorbol-13-acetate (TPA). During the past year, we have developed a rapid-onset inhalation model of crocidolite asbestos-induced inflammation and fibrosis in Fischer 344 rats and are able to measure lung injury by asbestos using quantitative biochemical and morphologic techniques. These include determination of protein, cell content and activity of enzymes in the lavage fluid of exposed animals and hydroxyproline content of whole lung. In addition, fibrosis is scored using a histologic grading system. These markers of inflammation and fibrosis in lung will be used in the proposed studies 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 (02) and H202, respectively] are elevated in rat lung and serum after admininstration 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 using mini-pumps and aerosolization to assess their effects on prevention of asbestos-associated inflammation and fibrosis. Thirdly, isolated alveolar macrophages and rat lung fibroblasts in vitro will be used to probe mechanisms of generation of active oxygen species by asbestos and other silicates. These studies will provide new insights into prevention and treatment of fibrosis in man.
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