Lipopolysaccharide augments the in vivo lethal action of doxorubicin against mice via hepatic damage

The effect of lipopolysaccharide (LPS) on the in vivo lethal action of doxorubicin (DOX) against mice was studied. DOX killed LPS-pretreated mice much earlier than untreated mice, and exhibited a stronger toxic action against LPS-pretreated mice. DOX-induced lethality in LPS-pretreated mice was due to severe hepatic damage, but there were no significant lesions in the heart, kidney and lung. Hepatic lesions were accompanied by caspase 3-positive cells and fragmented DNA-positive cells, suggesting the involvement of apoptosis. DOX induced the production of a high level of interferon (IFN)-γ and tumour necrosis factor (TNF)-α in LPS-pretreated mice, but not in non-treated mice. The DOX-induced lethality was prevented significantly by anti-IFN-γ antibody, but not anti-TNF-α antibody. Administration of recombinant IFN-γ in place of LPS augmented definitively the DOX-induced lethality. LPS augmented the DOX-induced lethality in TNF-α-deficient mice. Taken together, LPS was suggested to enhance DOX-induced IFN-γ production and augment the in vivo lethal action via hepatic damage.