DIBUTYRYL-CAMP ATTENUATES ASBESTOS-INDUCED PULMONARY EPITHELIAL-CELL CYTOTOXICITY AND DECLINE IN ATP LEVELS

Adenosine 3',5'-cyclic monophosphate (cAMP) analogues prevent lung inj ury in various models by mechanisms that remain unknown. We speculated that cAMP attenuates asbestos-induced pulmonary epithelial cell injur y by limiting the effects of an oxidant stress. Agents that increase i ntracellular cAMP [dibutyryl cAMP (DBcAMP), terbutaline, or aminophyll ine] but not guanosine 3',5'-cyclic monophosphate (cGMP) attenuated WI -26 cell-specific Cr-51 release caused by asbestos. The protective eff ects of DBcAMP were associated with negligible alterations in asbestos -induced.OH formation or decline in WI-26 cell glutathione levels. Cyc loheximide, an inhibitor of protein synthesis, failed to diminish the effects of DBcAMP. ATP levels were measured to determine whether the e ffects of DBcAMP are due to preservation of cellular ATP. Asbestos cau sed dose-dependent reductions in cellular ATP and DBcAMP attenuated th ese effects. To determine whether the protective effects of DBcAMP rel ated to alterations in WI-26 cell growth, we assessed the effects of D BcAMP on WI-26 cell number over time. DBcAMP diminished WI-26 cell rep lication and increased the doubling time. These results demonstrate th at DBcAMP diminishes asbestos-induced cytotoxicity to cultured WI-26 c ells in part by maintaining intracellular ATP levels and inhibiting ce llular replication. The reduction in asbestos-induced WI-26 cell injur y occurs despite a persistent oxidant stress. The data suggest a novel strategy to limit pulmonary toxicity from asbestos that warrants furt her investigation.