Oxidant stress responses in human pleural mesothelial cells exposed to asbestos.

Abstract

The generation of oxidants is a proposed mechanism of cell injury by asbestos fibers. To determine whether human pleural mesothelial cells (HMC) respond to asbestos and active oxygen species (AOS) by induction of antioxidant enzymes, cells obtained from pleural effusion were exposed to crocidolite or chrysotile asbestos or xanthine/xanthine oxidase (X/XO), a chemical-generating system of AOS. Gene expression of manganese-containing superoxide dismutase (MnSOD) and heme oxygenase (HO), endogenous enzymes involved in cell defense against oxidant stresses, was then determined. Dosage-dependent increases in steady-state mRNA levels of MnSOD and HO were observed in HMC exposed to asbestos or X/XO. However, increases in gene expression of MnSOD or HO did not occur in HMC after exposure to particulates such as polystyrene beads or riebeckite, the nonfibrous analog of crocidolite asbestos. Comparative experiments with human adult lung fibroblasts (HAL) showed less striking increases in mRNA levels of MnSOD and HO in response to asbestos, but steady-state mRNA levels for HO were increased more than fivefold in response to X/XO. To determine whether increases in mRNA levels of MnSOD were translated into protein, Western blot analyses were performed on HMC and HAL cells exposed to asbestos or X/XO. Slight increases in MnSOD immunoreactive protein were observed in HMC in response to both agents. In contrast, X/XO caused striking elevations in MnSOD protein levels in HAL cells. These results suggest that certain antioxidant enzymes are inducible in HMC after exposure to asbestos and other oxidants.

Gene Expression Profiles Reveal Increased mClca3 (Gob5) Expression and Mucin Production in a Murine Model of Asbestos-Induced Fibrogenesis

“…This observation corresponds to earlier work in human cells showing that heme oxygenase was inducible by crocidolite asbestos. 31 In contrast, the radical scavenger superoxide dismutase 3 (extracellular superoxide dismutase) was down-regulated by asbestos, an observation noted in rabbit mesothelial cells exposed to chrysotile asbestos. 32 We also observed increases in levels of arginase II, a mitochondrial enzyme that has been recently implicated in repair processes by altering the inflammation-mediated production of nitric oxide.…”

Oxygen Radicals and Asbestos-Mediated Disease

“…Studies in our laboratory have focused on the regulation of the enzymes in response to oxidant stress and have elucidated that these enzymes are differentially regulated in vitro when lung cells are exposed to a variety of oxidant generators (20,22,23). In other words, which antioxidant enzymes are induced is dependent upon both the cell type exposed and which oxidant stress is used in the experiment.…”

“…Human pleural mesothelial cells (HMCs), the progenitor cells of mesothelioma, exposed to either chrysotile or crocidolite asbestos, or X/XO, also show dose-dependent increases in Mn-SOD and heme oxygenase (HO) mRNA expression (23). No induction of gene expression was seen in HMCs exposed to polystyrene beads or riebeckite, a nonfibrous analog of crocidolite.…”

The Inhibitory Effect of Phytochemicals on the Oxidative DNA Damage in Lymphocytes by Chrysotile

“…Previous studies have yielded conflicting data on the cytotoxic effects of asbestos on mesothelial cells. For example, increase in intracellular oxidation have not been found in studies of asbestos-exposed mesothelial cells (Gabrielson et al, 1986;Ollikainen et al, 1999), although upregulation of antioxidant enzymes and oxidative changes in DNA suggest a role for oxidative damage to the cell and to cellular DNA (Janssen et al, 1994). In addition, DNA strand breakage, an expected toxic effect of oxidative damage to DNA, has not been found in previous studies of asbestos-exposed mesothelial cells (Gabrielson et al, 1986;Kinnula et al, 1994), although other DNA lesions an indirect measures of DNA damage have been reported (Renier et al, 1990;Liu et al, 2000).…”