(30) SURFACTANT POTENTIATION OF VIRUS-INDUCED MITOCHONDRIAL DISEASE IN ACUTE HEPATIC ENCEPHALOPATHY

M.G. Murphy¹, J.F.S. Crocker², S.H. Lee³ and P. Acott^2
1Department of Physiology & Biophysics
²Department of Pediatrics
³Department of Microbiology and Immunology, Dalhousie University and the IWK~Grace Health Centre for Children, Women and Families, Halifax, Nova Scotia   Canada   B3H 4H7

Disruption of hepatic mitochondrial structure and function is a hallmark feature of acute hepatic encephalopathy (AHE), including Reye’s Syndrome.  Our mouse model of AHE dermally exposes neonatal mice to subclinical doses of an industrial surfactant (IS), followed by infection with sublethal doses (LD20) of mouse-adapted human influenza B (Lee) virus (FluB).  Mortality in the combined treatment group (IS+FluB) is significantly greater than deaths with FluB alone.  Hepatic mitochondria in the IS+FluB group are increased in number and size, and exhibit focal rarefaction of their matrices.  Cristae breakdown, flocculation, and occasional formation of intramitochondrial vesicular structures are greatest in combined treatment. Only the combined treatment group exhibit extreme biochemical changes.  Ornithine transcarbamylase activity is depressed ~40% and serum ammonia increased ~60% without carbamylphosphate synthetase changes, isolating the effect to mitochondria.  Recently, the role of hepatic energy metabolism in the development of AHE in the mice has been investigated.  Hepatic fatty-acid beta-oxidation in mice treated with IS+FluB is inhibited to a significantly greater extent than is beta-oxidation in mice treated with either IS alone or FluB alone (>80%, 20% and 30% inhibition, respectively). Recently, we determined that carbohydrate metabolism also is severely compromised in the mice.  Mice painted dermally for each of 12 days had significantly lower hepatic glycogen than did any of the other treatment groups.  Importantly, the animals have adequate ingestion of food judged by gastric content at autopsy.  We propose that reduced availability of both endogenous major sources of energy substrates could be directly linked to the mitochondrial damage that is characteristic of AHE. 

Supported by the Natural Sciences and Engineering Research Council of Canada.

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