title: Abnormalities in hepatic fatty-acid metabolism in a surfactant/influenza B virus mouse model for acute encephalopathy.
abstract: 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 neonatal mice were exposed dermally to nontoxic doses of the industrial surfactant, Toximul MP8 (Tox), daily from days 1 to 12 after birth, and then infected with a sublethal dose (LD30) of mouse-adapted human influenza B (Lee) virus (FluB). The number of deaths in the group treated with Tox + FluB were significantly higher than those in the group infected with virus alone. Under optimal in vitro assay conditions, beta-oxidation of [1-14C]palmitic acid was approximately 15% higher in liver homogenates from mice painted with Tox for 12 days (P < 0.02); catabolism of [1-14C]octanoic acid to 14C-labelled water-soluble products (14C-WSP) and 14CO2 was unaltered by Tox. Infecting Tox-free mice with FluB inhibited beta-oxidation of both [1-14C]palmitate and [1-14C]octanoate by 20-30% (P < 0.001). On days 18-19, when most Tox + FluB-dependent deaths occurred, the inhibition of oxidation was increased to approximately 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 reactive substance (TBARS), a marker for lipid peroxides, were approximately 15% higher in Tox-painted than in control mice (P < 0.01); FluB alone had no effect. In Tox + FluB-treated animals, TBARS levels were > 2-fold higher than in any other experimental group (P < 0.001). These studies demonstrated that nasally-administered FluB has profound effects on hepatic fatty-acid metabolism, particularly beta-oxidation. Exacerbation of this and related effects by exposing young animals to xenobiotic surfactants could be the basis of surfactant-mediated potentiation of virus-induced mortality.
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada. Mary.Murphy@dal.ca.
authors.forename: M G
authors.initials: MG
authors.lastname: Murphy
authors.forename: J F
authors.initials: JF
authors.lastname: Crocker
authors.forename: H
authors.initials: H
authors.lastname: Her
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000279:Administration, Cutaneous; D000818:Animals; D002210:Caprylates / Q000378:metabolism; D004195:Disease Models, Animal; D004655:Emulsions / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism* / Q000821:virology; D006801:Humans; D009981:Influenza B virus / Q000502:physiology; D007251:Influenza, Human / Q000150:complications*; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009930:Organic Chemicals; D010084:Oxidation-Reduction; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000378:metabolism; D012202:Reye Syndrome / Q000150:complications; D013501:Surface-Active Agents / Q000633:toxicity*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: D002210:Caprylates; D004655:Emulsions; D005227:Fatty Acids; D009930:Organic Chemicals; D010169:Palmitic Acids; D013501:Surface-Active Agents; D017392:Thiobarbituric Acid Reactive Substances; D019308:Palmitic Acid; C019116:Toximul MP8; D000255:Adenosine Triphosphate; C031492:octanoic acid