AJP - Lung Cellular and Molecular Physiology, Vol 267, Issue 5 518-L525, Copyright © 1994 by American Physiological Society
Dibutyryl cAMP attenuates asbestos-induced pulmonary epithelial cell cytotoxicity and decline in ATP levels
V. A. Israbian, S. A. Weitzman and D. W. Kamp
Department of Medicine, Northwestern University Medical School, Chicago, Illinois.
Adenosine 3',5'-cyclic monophosphate (cAMP) analogues prevent lung injury
in various models by mechanisms that remain unknown. We speculated that
cAMP attenuates asbestos-induced pulmonary epithelial cell injury by
limiting the effects of an oxidant stress. Agents that increase
intracellular cAMP [dibutyryl cAMP (DBcAMP), terbutaline, or aminophylline]
but not guanosine 3',5'-cyclic monophosphate (cGMP) attenuated WI-26
cell-specific 51Cr release caused by asbestos. The protective effects of
DBcAMP were associated with negligible alterations in asbestos-induced .OH
formation or decline in WI-26 cell glutathione levels. Cycloheximide, an
inhibitor of protein synthesis, failed to diminish the effects of DBcAMP.
ATP levels were measured to determine whether the effects of DBcAMP are due
to preservation of cellular ATP. Asbestos caused dose-dependent reductions
in cellular ATP and DB-cAMP attenuated these effects. To determine whether
the protective effects of DBcAMP related to alterations in WI-26 cell
growth, we assessed the effects of DBcAMP on WI-26 cell number over time.
DBcAMP diminished WI-26 cell replication and increased the doubling time.
These results demonstrate that DBcAMP diminishes asbestos-induced
cytotoxicity to cultured WI-26 cells in part by maintaining intracellular
ATP levels and inhibiting cellular replication. The reduction in
asbestos-induced WI-26 cell injury occurs despite a persistent oxidant
stress. The data suggest a novel strategy to limit pulmonary toxicity from
asbestos that warrants further investigation.
