NR8383 ALVEOLAR MACROPHAGE TOXIC GROWTH ARREST BY HYDROGEN-PEROXIDE IS ASSOCIATED WITH INDUCTION OF GROWTH-ARREST AND DNA DAMAGE-INDUCIBLE GENES GADD45 AND GADD153
Gw. Patton et al., NR8383 ALVEOLAR MACROPHAGE TOXIC GROWTH ARREST BY HYDROGEN-PEROXIDE IS ASSOCIATED WITH INDUCTION OF GROWTH-ARREST AND DNA DAMAGE-INDUCIBLE GENES GADD45 AND GADD153, Toxicology and applied pharmacology, 147(1), 1997, pp. 126-134
Breathing air exposes humans and other mammals to various toxic agents
including oxidative contaminants associated with fine particles of le
ss than 2.5 mu m which may be deposited in the deep lung and have been
implicated in the increased morbidity and mortality correlated with a
ir pollution. Oxidative damage from inhaled particles may include dama
ge to DNA, thereby adversely affecting the immunosurveillance provided
by alveolar macrophages. Using the rat alveolar macrophage cell line
NR8383, we demonstrated that cell proliferation was inhibited by exoge
nous hydrogen peroxide, an oxidant naturally produced in cellular resp
iration and phagocytosis. Mercaptosuccinate, a specific inhibitor of t
he antioxidant enzyme glutathione peroxidase, also inhibited cell grow
th. Genes known to be coordinatively regulated in response to growth a
rrest and DNA damage, GADD45 and GADD153, were induced compared to the
housekeeping gene beta-ACTIN by equitoxic doses of hydrogen peroxide
and mercaptosuccinate. Hydrogen peroxide treatment of cells in which g
lutathione peroxidase was inhibited by mercaptosuccinate resulted in e
ven greater induction of both GADD genes. This approach using the NR83
83 alveolar macrophage cell line provides a model for studying genotox
icity at the mechanistic level at which stress-responsive genes involv
ed in growth arrest and DNA-damage response are modulated. (C) 1997 Ac
ademic Press.