Effects of antipyretics on mortality due to influenza B virus in a mouse model of Reye's syndrome.

OBJECTIVES: To determine the effects of acetylsalicylic acid (ASA) and acetaminophen on mortality due to influenza B infection in neonatal and weanling mice, as well as any synergistic, antagonistic or indifferent effects of the combined antipyretic and virus on mortality in mice pretreated with low doses of an industrial surfactant, Toximul MP8, which has been shown to reproduce many of the features of Reye's syndrome. In vitro studies were done to determine whether ASA or acetaminophen altered the normal, interferon-mediated antiviral responses of mammalian cells. The involvement of ASA or other commonly used xenobiotics in the induction of Reye's syndrome following virus illness has not been resolved; to do so, and to elucidate the underlying metabolic mechanism, requires these studies in an animal model. DESIGN: Prospective animal study. ANIMALS: Newborn (945) and weanling (840) Swiss white mice, divided into 12 subgroups. INTERVENTIONS: Some groups received Toximul MP8 before inoculation with a dose of mouse-adapted human influenza B that produces 30% mortality (LD30); after infection, each subgroup received either placebo, ASA or acetaminophen. Mortality counts were taken daily. The in vitro effects of the antipyretics on interferon response were determined using standard virology techniques. OUTCOME MEASURE: Mortality, analyzed by survival curves (log rank test) or cumulative daily mortality (chi 2 analysis). Plaque-reducing dose (PRD50) was used to determine the outcome of the in vitro analyses. RESULTS: In neonatal mice, only subgroups given combined treatment with acetaminophen and Toximul MP8 had a statistically significant higher mortality rate than with the mice given influenza B alone. In weanling mice, it appeared that ASA shortened the time until death; however, this difference was not statistically significant. In vitro studies demonstrated that both ASA and acetaminophen decreased the interferon-induced antiviral responses of cultured mammalian cells. CONCLUSION: Antipyretics have the potential to exacerbate the consequences of a viral infection, although the specific effects are subtle and appear to be age-related.

Glucocorticoid-induced polycystic kidney disease--a threshold trait.

Administration of hydrocortisone acetate (250 mg/kg) to newborn mice caused polycystic kidney disease (PKD) of varying proportions in each of 18 different inbred strains; none of the injected controls were affected. All kidneys were histologically examined and scored for degree of cyst formation using a semi-continuous (0 to 4+) grading scheme. Results suggested that this condition is a multifactorial threshold trait. For each strain, estimates of the mean and standard deviation of normally distributed liability were determined by maximum likelihood methods. Concomitant analyses showed: 1) a significant environmental effect related to drug source; 2) a variation in thresholds ranging from 0.94 (N = 46) for the B10.M strain to -0.71 (N = 297) for the C57B1/6J strain; and 3) three groups of strains with different susceptibility to PKD. These results are consistent with a multifactorial basis for susceptibility to PKD. Quantitative analysis of thresholds and liability distributions reveals that genetic, environmental and random elements all contribute to the expression and extent of the cystic trait.

Hepatic lipid abnormalities in a chemical/viral mouse model for Reye's syndrome.

We have examined hepatic lipid profiles in a mouse model for Reye's Syndrome (RS) in which young animals are exposed to nontoxic doses of an industrial pesticide emulsifier and subsequently are infected with sublethal doses of mouse-adapted human Influenza B (Lee) virus (FluB). The purpose of this study was to determine whether liver lipid content was altered in the mice, the time course of any changes, and whether lipid changes were consistent with liver pathology. Neonatal mice exposed dermally to the emulsifier, Toximul MP8 (Tox), had significantly elevated levels of hepatic cholesterol, with otherwise normal lipid composition. Subsequent inoculation of the mice with FluB significantly increased mortality rate. The combined Tox + FluB treatment had several significant effects on liver lipids, including a transient increase in phospholipid (PL) content, a reduction in neutral glycerides and persistently high cholesterol levels. Abnormalities in fatty acid profiles included an apparent elevation in medium chain fatty acids and increased ratios of PL arachidonic to docosahexaenoic acids. Histologically, there was no evidence of fat accumulation in the liver; however, hepatic mitochondria had severe structural abnormalities characteristic of RS. These studies demonstrate that chemical-dependent enhancement of viral virulence is associated with significant alterations of hepatic lipids. We believe that these abnormalities are related to mitochondrial structural damage in RS despite the absence of hepatic steatosis.

Biochemical and morphological characteristics of a mouse model of Reye's syndrome induced by the interaction of influenza B virus and a chemical emulsifier.

One theory of the etiology of Reye's syndrome is that environmental toxins predispose the child to react abnormally to virus infection. Influenza B is the most commonly implicated virus. Suckling mice were exposed to a surfactant, Toximul MP8, either by a single intraperitoneal injection or by repeated applications to the skin. At various times after exposure, the mice were infected intranasally with influenza B virus. Mice exposed to a combination of chemical and virus had a higher mortality rate than that of the control groups. Serum ammonia levels were elevated and the mitochondrial urea cycle enzyme, ornithine transcarbamylase, had reduced activity in the livers of mice exposed to Toximul and infected with virus. The hepatocyte cytoplasmic urea cycle enzyme concentrations were variable. Livers of the animals with "chronic" skin application of Toximul followed by virus infection showed mitochondrial swelling and breakdown of cristae. Those animals who received one intraperitoneal injection of Toximul and those infected with virus alone showed either negative or mild morphologic changes in the liver. We conclude that young mice exposed to a chemical emulsifier and subsequently to influenza B develop histomorphic and urea cycle changes, as well as hyperammonemia analogous to human Reye's syndrome.

Lethal interaction of ubiquitous insecticide carriers with virus.

Large quantities of presumably nontoxic petroleum oil by-products are introduced into the environment as pesticide dispersal agents and emulsifiers. An increase in viral lethality with a concomitant influence on the liver and central nervous system occurs in young mice previously primed with such chemicals.