Crocidolite Asbestos Induces Apoptosis of Pleural Mesothelial Cells: Role of Reactive Oxygen Species and Poly(ADP-Ribosyl) Polymerase

Abstract

Mesothelial cells, the progenitor cells 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. Rabbit pleural mesothelial cells were exposed to crocidolite asbestos or control particles (1-10 pg/cm2) over 24 hr 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. Induction of apoptosis was dose dependent; crocidolite (5 pg/cm2) induced apoptosis 115.0 ± 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 catalase, hypoxia (8% oxygen), deferoxamine, and 3-aminobenzamide (an inhibitor of the nuclear enzyme, poly(adenosine diphosphate-ribosyl) polymerase). 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 asbestosinduced mutations.

DNA damage in bronchial epithelial and mesothelial cells with and without associated crocidolite asbestos fibers

“…The latter could be due to iron released from the asbestos fibers or reactive oxygen species formed from iron in the fibers themselves. This explanation is supported by findings indicating that asbestos-induced apoptosis in both mesothelial [Broaddus et al, 1997] and alveolar epithelial cells [Aljandali et al, 2001] is inhibited by extracellular catalase, OH ⅐ radical scavengers, and/or iron chelators such as deferoxamine. It is also possible that the effect of reactive oxygen species is stronger when the fiber is attached or inside the cell than if further away from the cell.…”

Oxidant mechanisms in response to ambient air particles

“…Asbestos fibers constitute another example of an environmental agent thought to cause cytoxicity and carcinogenicity by a mechanism involving free radicals. This idea is supported by the observations that: (a) the toxic effects of asbestos exposure are prevented by N-acetyl cysteine (Simeonova et al, 1997) and by extracellular administration of antioxidant enzymes (Broaddus et al, 1997), and (b) exogenously administered oxidants (typically H 2 O 2 ) mimic some of the effects produced by asbestos (Gardner et al, 1997;Simeonova et al, 1997).…”

Apoptosis induced by crocidolite asbestos in human lung epithelial cells involves inactivation of Akt and MAPK pathways

“…Asbestos has been shown to induce apoptosis in a variety of different cells [2,[8][9][10][11][12][13][14]. Here, we examined whether crocidolite asbestos induced apoptosis in A549 cells.…”

“…In addition, iron has been shown to be responsible for O 2 consumption [3], DNA oxidation [4,5], lipid peroxidation [6], human lung epithelial cell apoptosis [7], and potentially cancer. Although independent studies have demonstrated asbestos-induced apoptosis in both rodent [8][9][10][11][12] and human [2,13,14] lung cells, the exact mechanism of this phenomenon is not entirely known. Kamp and coworkers [13] have proposed that asbestos-induced apoptosis in human lung epithelial cells was due to mitochondrial dysfunction resulting form reactive oxygen species (ROS) being generated within the mitochondria.…”