Dibutyryl cAMP attenuates asbestos-induced pulmonary epithelial cell cytotoxicity and decline in ATP levels.
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.
Department of Medicine, Northwestern University Medical School, Chicago, Illinois.
V A
VA
Israbian
S A
SA
Weitzman
D W
DW
Kamp
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000628:Aminophylline / Q000494:pharmacology; D001194:Asbestos / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis; D013726:Terbutaline / Q000494:pharmacology
D001194:Asbestos; D000628:Aminophylline; D017665:Hydroxyl Radical; D003994:Bucladesine; D000255:Adenosine Triphosphate; D005978:Glutathione; D013726:Terbutaline