The cellular and molecular events involved in the pathogenesis of asbestos- induced pulmonary diseases have not been resolved; although it is evident that asbestos directly affects various pulmonary cells as fibers migrate into and through the interstitium. Further, the clarification of whether it is the chemical composition or the physical characteristics of an asbestos fiber responsible for its damaging potential remains unclear. In models of pulmonary fibrosis, it has been demonstrated that vascular endothelial cells contribute to the development and expansion of a fibrotic lesion through angiogenic activation and alteration in endothelial cell phenotype. Endothelial cells are known to elaborate growth factors such as basic fibroblast growth factor (bFGF), transforming growth factor beta1 (TGF-beta1), and proteases such as basic fibroblast growth factor (bFGF), transforming growth factor beta1 (TGF)-beta1), and proteases such as urokinase-like plasminogen activator (u-PA) when assuming an angiogenic phenotype. in preliminary studies, we have demonstrated that endothelial cell cultures exposed to non-cytotoxic doses of chrysotile asbestos assume altered phenotype and function in areas of fiber deposition. Characteristic """"""""cobble-stone"""""""" endothelial cells are present in sites distant from the location of the asbestos fiber. A """"""""spindled"""""""" endothelial cell phenotype is evident at the site of fiber deposition, with these cells increasing adhesion to neutrophils potentially through increased expression of intercellular adhesion molecule (ICAM-1). A third, """"""""flattend"""""""" endothelial cell phenotype can be seen between these two extremes. We propose to use in situ techniques to investigate the hypothesis that asbestos, upon contact with the endothelium, induces an active cell phenotype, resulting in increased expression of growth factors and proteases, which are relevant to tissue remodeling and the development of pulmonary fibrosis. Cultured endothelial cells will be exposed to asbestos fibers, and then evaluated by in situ and immunocytochemical techniques for alteration in bFGF, u-PA, and TGFbeta1 steady state mRNA and protein levels. Following exposure to various fibers, active protein levels will be measured by enzymatic activity assays for u-PA and by bioassay for the growth factors. This novel approach to demonstrating the localized effects of fibers on cells in culture should increase the understanding of the endothelial cell component in the pathogenesis of pneumoconiosis and allow rational development of in vitro models for fiber toxicity. These models will provide data for accurate assessment of the risks of environmental exposure to asbestos and non-asbestos fibers in the occupational setting.
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