Skip to main content
NCBI home page
International Journal of Experimental Pathology logoLink to International Journal of Experimental Pathology
. 1993 Jun;74(3):251–258.

The influenza B virus mouse model of Reye's syndrome: pathogenesis of the hypoglycaemia.

L E Davis 1, B M Woodfin 1, T Q Tran 1, L S Caskey 1, J M Wallace 1, O U Scremin 1, K S Blisard 1
PMCID: PMC2002166  PMID: 8392860

Abstract

Up to 40% of children with Reye's syndrome have hypoglycaemia that could contribute to the patient's encephalopathy. We developed a mouse model in which intravenous inoculation of influenza B/Lee virus produced a non-permissive infection of hepatocytes and cerebral endothelial cells and caused many clinical, biochemical and pathologic features of Reye's syndrome. We used this model to study the pathogenesis of the hypoglycaemia. Beginning 6 hours after virus inoculation and persisting to death 18-30 hours later, blood glucose levels fell by 40% and glycogen disappeared from the liver. Gluconeogenesis in liver slices from a pyruvate substrate was significantly impaired. Pyruvate carboxylase, normally present in hepatocyte mitochondria, was largely displaced into the cytosol, rendering that enzyme fraction relatively useless in the gluconeogenesis pathway. Brain glucose levels fell proportionately to the depressed blood glucose level to a mean of 44 mg/100 g compared to 108 mg/100 g in control brains. We conclude that hypoglycaemia in the mouse model developed largely as a result of a non-permissive influenza viral infection of hepatocytes which impaired the mitochondrial phase of gluconeogenesis. The hypoglycaemia may have contributed to, but did not solely account for, the encephalopathy. A similar non-permissive influenza B infection may cause hypoglycaemia in Reye's syndrome.

Full text

PDF
251

Images in this article

255Figure 1
on p.255

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blisard K. S., Davis L. E. The sequence of changes in liver and brain in the influenza B virus mouse model of Reye's syndrome. J Neuropathol Exp Neurol. 1990 Sep;49(5):498–508. doi: 10.1097/00005072-199009000-00005. [DOI] [PubMed] [Google Scholar]
  2. Davis L. E., Cole L. L., Lockwood S. J., Kornfeld M. Experimental influenza B virus toxicity in mice. A possible model for Reye's syndrome. Lab Invest. 1983 Feb;48(2):140–147. [PubMed] [Google Scholar]
  3. Davis L. E., Green C. L., Wallace J. M. Influenza B virus model of Reye's syndrome in mice: the effect of aspirin. Ann Neurol. 1985 Nov;18(5):556–559. doi: 10.1002/ana.410180508. [DOI] [PubMed] [Google Scholar]
  4. Davis L. E. Influenza B virus model of Reye's syndrome. Evidence for a nonpermissive infection of liver and brain. Lab Invest. 1987 Jan;56(1):32–36. [PubMed] [Google Scholar]
  5. Glasgow A. M., Cotton R. B., Dhiensiri K. Reye syndrome. 3. The hypoglycemia. Am J Dis Child. 1973 Jun;125(6):809–811. doi: 10.1001/archpedi.1973.04160060021004. [DOI] [PubMed] [Google Scholar]
  6. Griffith A. D., Cyr D. M., Egan S. G., Tremblay G. C. Inhibition of pyruvate carboxylase by sequestration of coenzyme A with sodium benzoate. Arch Biochem Biophys. 1989 Feb 15;269(1):201–207. doi: 10.1016/0003-9861(89)90101-x. [DOI] [PubMed] [Google Scholar]
  7. Hurwitz E. S., Barrett M. J., Bregman D., Gunn W. J., Pinsky P., Schonberger L. B., Drage J. S., Kaslow R. A., Burlington D. B., Quinnan G. V. Public Health Service study of Reye's syndrome and medications. Report of the main study. JAMA. 1987 Apr 10;257(14):1905–1911. [PubMed] [Google Scholar]
  8. Huttenlocher P. R., Trauner D. A. Reye's syndrome in infancy. Pediatrics. 1978 Jul;62(1):84–90. [PubMed] [Google Scholar]
  9. Lewis L. D., Ljunggren B., Ratcheson R. A., Siesjö B. K. Cerebral energy state in insulin-induced hypoglycemia, related to blood glucose and to EEG. J Neurochem. 1974 Oct;23(4):673–679. doi: 10.1111/j.1471-4159.1974.tb04390.x. [DOI] [PubMed] [Google Scholar]
  10. Medina M. A., Jones D. J., Stavinoha W. B., Ross D. H. The levels of labile intermediary metabolites in mouse brain following rapid tissue fixation with microwave irradiation. J Neurochem. 1975 Feb;24(2):223–227. doi: 10.1111/j.1471-4159.1975.tb11868.x. [DOI] [PubMed] [Google Scholar]
  11. Pardridge W. M., Crane P. D., Mietus L. J., Oldendorf W. H. Nomogram for 2-deoxyglucose lumped constant for rat brain cortex. J Cereb Blood Flow Metab. 1982;2(2):197–202. doi: 10.1038/jcbfm.1982.19. [DOI] [PubMed] [Google Scholar]
  12. RAABO E., TERKILDSEN T. C. On the enzymatic determination of blood glucose. Scand J Clin Lab Invest. 1960;12(4):402–407. doi: 10.3109/00365516009065404. [DOI] [PubMed] [Google Scholar]
  13. REYE R. D., MORGAN G., BARAL J. ENCEPHALOPATHY AND FATTY DEGENERATION OF THE VISCERA. A DISEASE ENTITY IN CHILDHOOD. Lancet. 1963 Oct 12;2(7311):749–752. doi: 10.1016/s0140-6736(63)90554-3. [DOI] [PubMed] [Google Scholar]
  14. Robinson B. H., Taylor J., Cutz E., Gall D. G. Reye's syndrome: preservation of mitochondrial enzymes in brain and muscle compared with liver. Pediatr Res. 1978 Nov;12(11):1045–1047. doi: 10.1203/00006450-197811000-00003. [DOI] [PubMed] [Google Scholar]
  15. Siesjö B. K. Hypoglycemia, brain metabolism, and brain damage. Diabetes Metab Rev. 1988 Mar;4(2):113–144. doi: 10.1002/dmr.5610040203. [DOI] [PubMed] [Google Scholar]
  16. Srere P. A. Citric acid cycle redux. Trends Biochem Sci. 1990 Nov;15(11):411–412. doi: 10.1016/0968-0004(90)90273-e. [DOI] [PubMed] [Google Scholar]
  17. Trauner D. A., Horvath E., Davis L. E. Inhibition of fatty acid beta oxidation by influenza B virus and salicylic acid in mice: implications for Reye's syndrome. Neurology. 1988 Feb;38(2):239–241. doi: 10.1212/wnl.38.2.239. [DOI] [PubMed] [Google Scholar]
  18. Van Coster R. N., De Vivo D. C., Blake D., Lombes A., Barrett R., DiMauro S. Adult Reye's syndrome: a review with new evidence for a generalized defect in intramitochondrial enzyme processing. Neurology. 1991 Nov;41(11):1815–1821. doi: 10.1212/wnl.41.11.1815. [DOI] [PubMed] [Google Scholar]
  19. Woodfin B. M., Davis L. E. Altered OCTase location in the influenza B/Lee virus model for Reye's syndrome. Biochem Med. 1982 Aug;28(1):109–114. doi: 10.1016/0006-2944(82)90060-6. [DOI] [PubMed] [Google Scholar]
  20. Woodfin B. M., Davis L. E. Liver autophagy in the influenza B virus model of Reye's syndrome in mice. J Cell Biochem. 1986;31(4):271–275. doi: 10.1002/jcb.240310404. [DOI] [PubMed] [Google Scholar]

Articles from International Journal of Experimental Pathology are provided here courtesy of Wiley

RESOURCES