CROCIDOLITE ASBESTOS INDUCES APOPTOSIS OF PLEURAL MESOTHELIAL CELLS -ROLE OF REACTIVE OXYGEN SPECIES AND POLY(ADP-RIBOSYL) POLYMERASE

Mesothelial cells, the progenitor cells of the asbestos-induced tumor mesothelioma, are particularly sensitive to the toxic effects of asbes tos, although the molecular mechanisms jy which asbestos induces injur y in mesothelial cells are not known. We asked whether asbestos induce d apoptosis in mesothelial cells and whether reactive oxygen species w ere important. Rabbit pleural mesothelial cells were exposed to crocid olite asbestos or control particles (1 - 10 mu g/cm(2)) over 24 hr and evaluated for oligonucleosomal DNA fragmentation, loss of membrane ph ospholipid asymmetry, and nuclear condensation. Asbestos fibers, not c ontrol particles, induced apoptosis in mesothelial cells by all assays . Induction of apoptosis was dose dependent, crocidolite (5 mu g/cm(2) ) induced apoptosis (15.0 +/- 1.1%, mean +/- SE; n = 12)versus control particles (< 4%), as measured by appearance of nuclear condensation. Apoptosis induced by asbestos, but not by actinomycin D, was inhibited by extracellular catalase, superoxide dismutase in the presence of ca talase, hypoxia 18% oxygen), deferoxamine, and 3-aminoibenzamide (an i nhibitor of the nuclear enzyme, poly(adenosine diphosphate-ribosyl) po lymerase). We conclude that asbestos induces apoptosis in mesothelial cells via reactive oxygen species. We speculate that escape from this pathway could allow the abnormal survival of mesothelial cells with as bestos-induced mutations.