Abstract
Asbestos causes asbestosis and malignancies by mechanisms that are not fully understood. Alveolar epithelial cell (AEC) injury by iron-derived reactive oxygen species (ROS) is one important mechanism implicated. We previously showed that iron-catalyzed ROS in part mediate asbestos-induced AEC DNA damage and apoptosis. Mitochondria have a critical role in regulating apoptosis after exposure to agents causing DNA damage but their role in regulating asbestos-induced apoptosis is unknown. To determine whether asbestos causes AEC mitochondrial dysfunction, we exposed A549 cells to amosite asbestos and assessed mitochondrial membrane potential changes (ΔΨm) using a fluorometric technique involving tetremethylrhodamine ethyl ester (TMRE) and mitotracker green. We show that amosite asbestos, but not an inert particulate, titanium dioxide, reduces AR after a 4 h exposure period. Further, the AT after 4 h was inversely proportional to the levels of apoptosis noted at 24 h as assessed by nuclear morphology as well as by DNA nucleosome formation. A role for iron-derived ROS was suggested by the finding that phytic acid, an iron chelator, blocked asbestos-induced reductions in A549 cell ΔΨmand attenuated apoptosis. Finally, overexpression of Bcl-xl, an anti-apoptotic protein that localizes to the mitochondria, prevented asbestos-induced decreases in A549 cell ΔΨmafter 4 h and diminished apoptosis. We conclude that asbestos alters AEC mitochondrial function in part by generating iron-derived ROS, which in turn can result in apoptosis. This suggests that the mitochondrial death pathway is important in regulating pulmonary toxicity from asbestos. (Mol Cell Biochem 234/235: 153–160, 2002)
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Mossman BT, Churg A: Mechanisms in the pathogenesis of asbestos and silicosis. Am J Resp Crit Care Med 157: 1666–1680, 1998
Kamp DW, Weitzman SA: The molecular basis of asbestos induced lung injury. Thorax 54: 638–652, 1999
Uhal BD: Cell cycle kinetics in the alveolar epithelium. Am J Physiol (Lung Cell Mol Physiol 16) 272: L1031–L1045, 1997
Kamp DW, Israbian VA, Preusen SE, Zhang CX, Weitzman SA: Asbestos causes DNA strand breaks in cultured pulmonary epithelial cells: role of iron-catalyzed free radicals. Am J Physiol (Lung Cell Mol Physiol 12) 268: L471–L480, 1995
Aljandali A, Pollack N, Li Y, Yeldandi A, Weitzman SA, Kamp DW: Asbestos-induced alveolar epithelial cell apoptosis: Role of iron-induced free radicals. J Lab Clin Med 137: 330–339, 2001
Kamp DW, Graceffa P, Pryor WA, Weitzman SA: The role of free radicals in asbestos induced diseases. Free Rad Biol Med 12: 293–312, 1992
Hardy JA, Aust AE: Iron in asbestos chemistry and carcinogenicity. Chem Rev 95: 97–118, 1995
Weitzman SA, Graceffa P: Asbestos catalyzes hydroxyl and superoxide radical generation from hydrogen peroxide. Arch Biochem Biophys 228: 373–376, 1984
Jaurand M-C: Mechanisms of fiber-induced genotoxicity. Environ Health Persp 105(suppl 5): 1073–1084, 1997
Kamp DW, Pollack N, Yeldandi A, Chu R, Weitzman S: Catalase reduces asbestos-induced DNA damage in pulmonary epithelial cells. Am J Resp Crit Care Med 155: 687A, 1997
Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD: The release of cytochromecfrom mitochondria: A primary site for Bc1–2 regulation of apoptosis. Science 275: 1–2, 1997
VanderHeiden MG, Chandel NS, Williamson EK, Schumaker PT, Thompson CB: Bel-xi regulates the membrane potential and volume homeostasis of mitochondria. Cell 91: 627–637, 1997
Green DR, Reed JC: Mitochondria and apoptosis. Science 281: 1309–1312, 1998
Ranger AM, Malynn BA, Korsmeyer SJ: Mouse models of cell death. Nature Gen 28: 113–118, 2001
Chandel NS, Schumaker PT: Cells depleted of mitochondrial DNA (p0) yield insights into physiologic mechanisms. FEBS Lett 454: 173–176, 1999
Gross A, McDonnell JM, Korsmeyer SJ: Bcl-2 family members and the mitochondria in apoptosis. Genes Dev 13: 1899–1911, 1999
Timbrell V: In: H.A. Shapiro (ed). Characteristics of International Union Against Cancer Standard Reference Samples of Asbestos. Oxford University Press, Cape Town, South Africa, 1970, pp 28–36
Bernardi P, Scorrano L, Colonna R: Mitochondria and cell death: Mechanistic aspects and methodologic issues. Eur J Biochem 264: 687–701, 1999
Brody AR, Hill LH, Adkins B, O’Connor RW: Chrysotile asbestos inhalation in rats: deposition pattern and reaction of alveolar epithelium and pulmonary macrophages. Am Rev Resp Dis 123: 670–679, 1981
Kamp DW, Dunne M, Anderson JA, Weitzman SA, Dunn MM: Serum promotes asbestos-induced injury to human pulmonary epithelial cells. J Lab Clin Med 116: 289–297, 1990
Sawyer DE, Van Houten B: Repair of DNA damage in mitochondria. Mutat Res 434: 161–176, 1999
Richter C: Oxidative damage to mitochondrial DNA and its relationship to aging. Int J Biochem Cell Biol 27: 647–653, 1995
Fliss MS, Usadel H, Cabellero OL: Facile detection of mitochondrial DNA mutation in tumors and bodily fluids. Science 287: 2017–2019, 2000
Graf E, Eaton JW: Antioxidant functions of phytic acid. Free Rad Biol Med 8: 61–69, 1990
Broaddus VC, Yang L, Scavo LM, Ernst JD, Boylan AM: Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species. J Clin Invest 98: 2050–2059, 1996
Itoh H, Shioda T, Matsura T: Iron ion induces mitochondrial DNA damage in HTC rat hepatoma cell culture: Role of antioxidants in mitochondrial DNA protection from oxidative stresses. Arch Biochem Biophys 313: 120–125, 1994
Robb SJ, Robb-Gaspers LD, Scaduto RC, Thomas AP, Connor JR: Influence of calcium and iron on cell death and mitochondrial function in oxidatively stressed astrocytes. J Neurosci Res 55: 674–686, 1999
VanderHeiden MG, Li XX, Gottleib E, Hill RB, Thompson CB, Colombini M: Bc1-xl promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem 276: 19414–19419, 2001
Schapira RM, Ghio AJ, Effros RM, Morrisey J, Dawson CA, Hacker AD: Hydroxyl radicals are formed in the rat lung after asbestos instillationin vivo.Am J Resp Cell Mol Biol 10: 573–579, 1994
Mossman BT, Marsh JP, Sesko A: Inhibition of lung injury, inflammation, and interstitial pulmonary fibrosis by polyethylene glycol-conjugated catalase in a rapid inhalation model of asbestosis. Am Rev Resp Dis 141: 1266–1271, 1990
Goodglick LA, Kane AB: Cytotoxicity of long and short crocidolite asbestos fibersin vitroandin vivo.Cancer Res 50: 5153–5163, 1990
Hobson J, Wright JL, Churg A: Active oxygen species mediate asbestos fiber uptake by tracheal epithelial cells. FASEB J 4: 3135–3139, 1990
Brody AR, Overby LH: Incorporation of tritiated thymidine by epithelial and interstitial cells in bronchiolar-alveolar regions of asbestos-exposed rats. Am J Pathol 134: 133–140,1989
Kamp DW, Israbian VA, Yeldandi A, Panos RJ, Graceffa P, Weitzman SA: Phytic acid, an iron chelator, attenuates pulmonary inflammation and fibrosis in rats after intratracheal instillation of asbestos. Toxicol Patho123: 689–695,1995
Kuwano K, Kunitake R, Kawasaki M, Nomoto Y, Hagimoto N, Nakanishi Y, Hara N: P21 (WAF1, CIP1, sdil) and P53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis. Am J Resp Crit Care Med 154: 477–483, 1996
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Springer Science+Business Media New York
About this chapter
Cite this chapter
Kamp, D.W., Panduri, V., Weitzman, S.A., Chandel, N. (2002). Asbestos-induced alveolar epithelial cell apoptosis:Role of mitochondrial dysfunction caused by iron-derived free radicals. In: Vallyathan, V., Shi, X., Castranova, V. (eds) Oxygen/Nitrogen Radicals: Cell Injury and Disease. Developments in Molecular and Cellular Biochemistry, vol 37. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1087-1_17
Download citation
DOI: https://doi.org/10.1007/978-1-4615-1087-1_17
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-5388-1
Online ISBN: 978-1-4615-1087-1
eBook Packages: Springer Book Archive