The broad long-term objective of the proposed studies is to improve our understanding of the development of environmental lung disease caused by inhalation of toxic and """"""""inert"""""""" particles. The proposed studies are designed to test the hypothesis that long-term impairment of alveolar macrophage (AM) mediated particle clearance is associated with the development of chronic lung injury through the interaction of mediators released from AM with the alveolar epithelial barrier and with interstitial cells. The proposed 5-year study is directed at investigating mechanisms underlying such development. In vivo studies in rats will exmine the role of oxidants released from pulmonary inflammatory cells and of administered antioxidant enzymes in affecting fibrotic alterations in the lung. Complementary in vitro studies will fucus on mechanisms of cellular interactions between AM and fibroblasts under the influence of toxic and """"""""inert"""""""" particles. The significance of the planned studies lies in elucidating and understanding some of the basic processes linking AM dysfunction and effects of released mediators to epithelial damage and fibrotic lung injury. A multidisciplinary research team will adddress four specific aims as follows: Male Fischer 344 rats will be exposed for 12 months to CdO (50 ug/m3) and to TiO2 (30 mg/m3) and to PVC dust (30 mg/m3), 6 hours per day, 5 days per week to characterize the resulting functional and morphological damage to AM and lung tissue (Specific Aim 1). Persistence of effects after cessation of exposure will be studied in Specific Aim 2. In both series, noninvasive in vivo measurement of clearance of radioactive test particles will be performed. Other assays in serially killed rats include: mesurements of alveolar epithelial permeability, evaluation of lavaged tracheobroncheal and alveolar cells, chemotactic activity of lavage supernatants, chemotaxis of lavaged AM, determination of oxygen metabolites, lung morphology by light and electron microscopy, localization of basal laminar proteoglycans, measurement of collagen synthesis rate and fibroblast growth factor assay, and pulmonary accumulation of inhaled Cd, Ti, and PVC dust. The influence of repeated inhalation of antioxidants (SOD and catalase) and of their chronic s.c. administration on alveolar epithelial permeability and on the development of chronic lung injury will be investigated in Specific Aim 3. In the in vitro studies (Specific Aim 4), fibroblasts from exposed lung and control lungs will be cultured for measuring proliferative response and collagen biosynthesis caused by in vivo released growth mediators and by mediators from macrophage conditioned media. In vitro exposure of AM with CdO, TiO2 and PVC particles will also be performed as well as co-cultures of AM and fibroblasts.
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