ABNORMALITIES IN HEPATIC FATTY-ACID METABOLISM IN A SURFACTANT INFLUENZA-B VIRUS MOUSE MODEL FOR ACUTE ENCEPHALOPATHY

Abnormalities in fatty-acid metabolism are believed to play a role in nonspecific acute encephalopathy (AE) with hepatomegaly, although the specific nature of these abnormalities and their temporal relationship to the pathology are not well defined. We have examined hepatic fatty -acid beta-oxidation and metabolism in a mouse model for AE in which n eonatal mice were exposed dermally to nontoxic doses of the industrial surfactant, Toximul MP8 (Tox), daily from days 1 to 12 after birth, a nd then infected with a sublethal dose (LD(30)) of mouse-adapted human influenza B (Lee) virus (FluB). The number of deaths in the group tre ated with Tox + FluB were significantly higher than those in the group infected with virus alone, Under optimal in vitro assay conditions, b eta-oxidation of [I-C-14]palmitic acid was approximate to 15% higher i n liver homogenates from mice painted with Tox for 12 days (P<0.02); c atabolism of [I-C-14]octanoic acid to C-14-labelled water-soluble prod ucts (C-14-WSP) and (CO2)-C-14 was unaltered by Tox. Infecting Tox-fre e mice with FluB inhibited beta-oxidation of both [I-C-14]palmitate an d [I-C-14]octanoate by 20-30% (P<0.001). On days 18-19, when most Tox + FluB-dependent deaths occurred, the inhibition of oxidation was incr eased to = 50% in mice given the combined treatment. Treatment of the mice with Tox/FluB also altered the pattern of incorporation of fatty acids into complex lipids. Hepatic levels of thiobarbituric acid react ive substance (TEARS), a marker for lipid peroxides, were approximate to 15% higher in Tox-painted than in control mice (P<0.01); FluB alone had no effect. In Tox + FluB-treated animals, TEARS levels were > 2-f old higher than in any other experimental group (P<0.001). These studi es demonstrated that nasally-administered FluB has profound effects on hepatic fatty-acid metabolism, particularly beta-oxidation. Exacerbat ion of this and related effects by exposing young animals to xenobioti c surfactants could be the basis of surfactant-mediated potentiation o f virus-induced mortality.