Ferrets are uniquely susceptible to human influenza infections and when they are exposed to an arginine-free diet, hyperammonemia and encephalopathy develops. We developed an animal model for Reye's syndrome (RS) in young, male ferrets by infecting them with influenza B virus, treating with aspirin and feeding a small amount of arginine-free diet. We plan to continue our study of the ferret model to extend the knowledge of the pathogenesis of Reye's syndrome and to improve the diagnosis, treatment and prevention of this disorder. Our study is also designed to gain new information on the dietary, metabolic and ultrastructural features of young, adult ferrets. We plan to (1) study the role of ammonia in RS. We plan to induce hyperammonemia in young ferrets by different means and study the interactions of influenza virus with aspirin and increased serum ammonia in producing RS-like disorder in ferrets; (2) investigate vomiting as a precipitating factor in the developmet of RS; (3) identify a possible causal relationsiip between aspirin ingestion and the development of RS-like features in ferrets. We also plan to test whether influenza virus or ammonia or both either blocks or alters the metabolism and pharmacokinetics of salicylates; (4) study the nature and cause of mitochondrial injury in RS; (5) We propose that all mitochondrial enzymes that are known to decrease in the liver of RS patients may appear in blood. To test this hypothesis we plan to assay several mitochondrial enzymes in the serum or plasma of RS patients during the course of illness and study the correlation of enzyme activities with serum ammonia levels and also with the stages of disorder (severity of sickness). We also plan to test other hypotheses to explain the decrease in liver motochondrial enzymes in RS; (6) test possible alterations of polyamine metabolism in RS. We plan to measure polyamines in the serum and urine of RS patients and test whether such determinations would be useful as an additional diagnostic criteria for RS; (7) test the role of L-carnitine as a therapeutic agent in RS; (8) study virologic and immunologic features of the ferret model; (9) measure additional parameters in the ferret model to provide a complete comparison of the model with RS and to further characterize the disorder in animals; (10) test compounds that may decrease blood ammonia levels and intracranial pressure; (11) use the ferret model to guide studies designed to improve the diagnosis, treatment and prevention of RS.
