Reye's syndrome (RS) is a childhood disease of unknown cause and high morbidity and mortality characterized by an antecedent viral infection (particularly influenza or varicella), followed by hepatic dysfunction and neurologic deterioration. The lipid peroxidation hypothesis states that RS develops in certain susceptible children during the course of a viral infection, because the infection induces excesssive peroxidation of polyunsaturated fatty acids in mitochondrial and microsomal membranes. The children are susceptible because of an imbalance between oxidant stresses and endogenous antioxidants. The consequence is widespread structural and functional damage to mitochondria. In this proposal, the validity of that hypothesis will be examined in two ways: 1) Erythrocytes or children with RS will be studied for evidence of lipid peroxidation (malondialdehyde), oxidant stress (polyunsaturated fatty acids), and antioxidant deficiency (vitamin E and selenium). Values will be compared to three pediatric control groups: intensive care unit patients, RS siblings and children with an easily diagnosed viral infection, varicella; 2) two different animal models will be used to investigate the effect of influenza virus on lipid peroxidation (as measured by diene conjugation), in hepatic microsomes and mitochondria. To determine the importance of the route of virus administration, experimental Balb/c mice will be given virus intranasally or intravenously, and hepatic lipid peroxidation will be compared to controls given vehicle, alone. This model (Balb/c mice given intravenous virus) has previously been used as an animal model by Davis, et al.(1) The ferret was selected to investigate the role of host susceptibility to virally-induced lipid peroxidation because it is the mammal in which influenza infection most closely simulates the human disease. At weaning, groups of ferrets will be given diets with various polyunsaturated fatty acid: vitamin E ratios; some will also be chronically exposed to ozone, (an environmental oxidant). Several weeks later, animals will be infected and subsequently lipid peroxidation will be measured in hepatic microsomes and mitochondria (diene conjugation).
| Schwarz, K B; Larroya, S; Vogler, C et al. (1991) Role of influenza B virus in hepatic steatosis and mitochondrial abnormalities in a mouse model of Reye syndrome. Hepatology 13:96-103 |
| Schwarz, K B; Arey, B J; Tolman, K et al. (1988) Iron chelation as a possible mechanism for aspirin-induced malondialdehyde production by mouse liver microsomes and mitochondria. J Clin Invest 81:165-70 |
| Schwarz, K B; Larroya, S; Kohlman, L et al. (1987) Erythrocyte lipid abnormalities in Reye's syndrome. Pediatr Res 21:352-6 |
