Inhalation of toxic mineral particles causes acute injury to alveolar macrophages and several types of chronic lung disease including pulmonary fibrosis, increased susceptibility to tuberculosis, and an increased incidence of cancer. The objectives of this research are first, to determine the mechanisms of acute mineral particle toxicity and second, to describe the pathogenesis of the chronic complications resulting from exposure to toxic mineral particles. To explore the first objective, a model system using the mouse macrophage cell line P388D1 in vitro has been developed. Experiments are proposed to identify biochemical and structural changes in P388D1 cells injured by asbestos. The following changes will be evaluated as necessary or sufficient conditions responsible for irreversible injury in this model system: 1) oxidative damage to membrane proteins and lipids, 2) depletion of cellular antioxidants, 3) direct changes in membrane structure produced by toxic mineral particles, and 4) altered cytoskeletal organization. The extent of oxidative damage and antioxidant depletion resulting from asbestos exposure will be determined by biochemical assays. Changes in membrane structure and cytoskeletal organization will be detected by high resolution electron microscopy combined with freeze-drying, deep-etching with rotary replication, and critical point drying techniques. To explore the second objective, an in vitromodel system will be developed using co-cultures of primary mouse mesothelial cells and peritoneal macrophages exposed to asbestos. The extent of mesothelial injury will be assessed by the biochemical and structural procedures described in the first model. These experiments should determine whether asbestos fibers directly damage mesothelial cells or whether mediators released from injured macrophages are indirectly responsible for mesothelial reactions to asbestos fibers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003189-05
Application #
3250347
Study Section
Safety and Occupational Health Study Section (SOH)
Project Start
1982-11-01
Project End
1988-12-31
Budget Start
1987-01-01
Budget End
1987-12-31
Support Year
5
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Brown University
Department
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Cordier Kellerman, Laurence; Valeyrie, Laurence; Fernandez, Nadine et al. (2003) Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma. Cancer Gene Ther 10:481-90
Goodglick, L A; Vaslet, C A; Messier, N J et al. (1997) Growth factor responses and protooncogene expression of murine mesothelial cell lines derived from asbestos-induced mesotheliomas. Toxicol Pathol 25:565-73
Kane, A B (1992) Animal models of mesothelioma induced by mineral fibers: implications for human risk assessment. Prog Clin Biol Res 374:37-50
Gleva, G F; Goodglick, L A; Kane, A B (1990) Altered calcium homeostasis in irreversibly injured P388D1 macrophages. Am J Pathol 137:43-57
Goodglick, L A; Kane, A B (1990) Cytotoxicity of long and short crocidolite asbestos fibers in vitro and in vivo. Cancer Res 50:5153-63
Goodglick, L A; Pietras, L A; Kane, A B (1989) Evaluation of the causal relationship between crocidolite asbestos-induced lipid peroxidation and toxicity to macrophages. Am Rev Respir Dis 139:1265-73
Dobson, M E; Stern, R O; Kane, A B (1988) Selective purine release from P388D1 macrophages injured by silica. J Cell Physiol 135:244-52
Moalli, P A; MacDonald, J L; Goodglick, L A et al. (1987) Acute injury and regeneration of the mesothelium in response to asbestos fibers. Am J Pathol 128:426-45
Goodglick, L A; Kane, A B (1986) Role of reactive oxygen metabolites in crocidolite asbestos toxicity to mouse macrophages. Cancer Res 46:5558-66
Macdonald, J L; Kane, A B (1986) Identification of asbestos fibers within single cells. Lab Invest 55:177-85

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