Asbestos-induced Endothelial Cell Activation and Injury: Demonstration of Fiber Phagocytosis and Oxidant-dependent Toxicity

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Abstract
Vascular endothelial cell injury is important in the development of a variety of chronic interstitial lung disorders. However, the involvement of such injury in the inflammatory response associated with the inhalation of asbestos fibers is unclear and the mechanism of asbestos fiber cytotoxicity remains unknown. In the present study, human umbilical vein endothelial cells were challenged with amosite asbestos and several parameters of cellular function were examined. Electron microscopic examination revealed that endothelial cell exposure to asbestos resulted in active phagocytosis of these particulates. Biochemical evidence of dose-dependent asbestos-mediated endothelial cell activation was indicated by increased metabolism of arachidonic acid. For example, amosite asbestos (500 .mu.g/ml) produced a ninefold increase in prostacyclin (PGI2) levels over those in non-exposed cells. Incubation of human endothelial cells with asbestos fibers induced specific 51Cr release in both a dose- and time-dependent fashion indicative of cellular injury. Injury induced by amosite asbestos was not significantly attenuated by treatment of the endothelial cell monolayer with either the iron chelator deferoxamine, which prevents hydroxyl radical (OH) formation, or by the superoxide anion (O2-) scavenger, superoxide dismutase. However, significant dose-dependent protection was observed with the hydrogen peroxide (H2O2) scavenger, catalase. Chelation of elemental iron present within amosite asbestos fibers by deferoxamine produced a 33% reduction in asbestos cytotoxicity, suggesting a potential role for hydroxyl radical-mediated injury via the iron-catalyzed Haber-Weiss reaction. Maximal endothelial cell protection against fiber cytotoxicity was found with the combination of catalase (3,000 U/ml) and deferoxamine-treated amosite asbestos, which reduced asbestos-induced 51Cr-release by 87 .+-. 3%. In addition, the asbestos-stimulated release of PGI2 was significantly attenuated by both the concomitant treatment of endothelial monolayers with catalase, as well as the use of deferoxamine-treated asbestos. Thus, asbestos-induced endothelial cell injury and alterations in cell function would appear to be mediated via oxidant-dependent mechanisms. These studies suggest that asbestos activates endothelial cells and that these target cells may be important participants in the inflammatory response associated with in vivo asbestos exposure.