ASBESTOS INDUCES APOPTOSIS OF HUMAN AND RABBIT PLEURAL MESOTHELIAL CELLS VIA REACTIVE OXYGEN SPECIES

Mesothelial cells, the progenitor cell of the asbestos-induced tumor m esothelioma, are particularly sensitive to the toxic effects of asbest os, although the molecular mechanisms by which asbestos induces injury in mesothelial cells are not known, We asked whether asbestos induced apoptosis in mesothelial cells and whether reactive oxygen species we re important. Pleural mesothelial cells (rabbit or human) were exposed to asbestos (crocidolite, amosite, or chrysotile) or control particle s at moderate doses (1-10 mu g/cm(2)) over 24 h and evaluated for olig onucleosomal DNA fragmentation, loss of membrane phospholipid asymmetr y, and nuclear condensation, Asbestos fibers, not control particles, i nduced apoptosis in mesothelial cells by all assays and induction of a poptosis was dose dependent for all types of asbestos, with crocidolit e (5 mu g/cm(2)) inducing 15.0+/-1.1% (mean+/-SE; n = 12) apoptosis ve rsus control particles < 4%. Apoptosis induced by asbestos, but not by actinomycin D, was inhibited by extracellular catalase, superoxide di smutase in the presence of catalase, hypoxia (8% oxygen.), deferoxamin e, 3-aminobenzamide [an inhibitor of poly(ADP-ribosyl) polymerase], an d cytochalasin B. Only catalase and cytochalasin B decreased fiber upt ake, We conclude that asbestos induces apoptosis in mesothelial cells via reactive oxygen species, Escape from this pathway could allow the abnormal survival of mesothelial cells with asbestos-induced mutations .