Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species.
Mesothelial cells, the progenitor cell of the asbestos-induced tumor mesothelioma, are particularly sensitive to the toxic effects of asbestos, 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 were important. Pleural mesothelial cells (rabbit or human) were exposed to asbestos (crocidolite, amosite, or chrysotile) or control particles at moderate doses (1-10 microg/cm2) over 24 h and evaluated for oligonucleosomal DNA fragmentation, loss of membrane phospholipid asymmetry, and nuclear condensation. Asbestos fibers, not control particles, induced apoptosis in mesothelial cells by all assays and induction of apoptosis was dose dependent for all types of asbestos, with crocidolite (5 microg/cm2) inducing 15.0+/-1.1% (mean+/-SE; n = 12) apoptosis versus control particles < 4%. Apoptosis induced by asbestos, but not by actinomycin D, was inhibited by extracellular catalase, superoxide dismutase in the presence of catalase, hypoxia (8% oxygen), deferoxamine, 3-aminobenzamide [an inhibitor of poly(ADP-ribosyl) polymerase], and cytochalasin B. Only catalase and cytochalasin B decreased fiber uptake. 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.
Department of Medicine and Lung Biology Center, San Francisco General Hospital, California 94143, USA. sfcourt@itsa.ucsf.edu
V C
VC
Broaddus
L
L
Yang
L M
LM
Scavo
J D
JD
Ernst
A M
AM
Boylan
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D001194:Asbestos / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000737:chemistry; D053938:DNA Fragmentation; D003676:Deferoxamine / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D010994:Pleura / Q000166:cytology / Q000187:drug effects*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011485:Protein Binding; D011817:Rabbits; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism
D017304:Annexin A5; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D001194:Asbestos; D002374:Catalase; D013482:Superoxide Dismutase; D003676:Deferoxamine