Prolonged hepatomegaly in mice that cannot inactivate bacterial endotoxin

Baomei Shao, Richard L. Kitchens, Robert S. Munford, Thomas E. Rogers, Don C. Rockey, Alan W. Varley

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Transient hepatomegaly often accompanies acute bacterial infections. Reversible, dose-dependent hepatomegaly also occurs when animals are given intravenous infusions of bacterial lipopolysaccharide (LPS). We found that recovery from LPS-induced hepatomegaly requires a host enzyme, acyloxyacyl hydrolase (AOAH), that inactivates LPS. When we challenged Aoah -/- mice with low doses of LPS or Gram-negative bacteria, their livers remained enlarged (as much as 80% above normal) many weeks longer than did the livers of Aoah +/+ animals. When compared with livers from LPS-primed Aoah +/+ mice, LPS-primed Aoah -/- livers had (1) more numerous and larger Kupffer cells, (2) intrasinusoidal leukocyte aggregates and activated sinusoidal endothelial cells, and (3) sustained production of interleukin (IL)-10 and messenger RNAs (mRNAs) for tumor necrosis factor (TNF), IL-10, and IRAK-M. Depleting Kupffer cells decreased the liver enlargement by ≈40%, whereas depletion of neutrophils, dendritic cells, natural killer (NK) cells, NK-T cells, or B cells had no effect. Pretreatment with dexamethasone almost completely prevented prolonged hepatomegaly in Aoah -/- mice, whereas neutralizing TNF or interleukin-1β was only partially effective. In contrast, an antagonistic antibody to the IL-10 receptor increased LPS-induced hepatomegaly by as much as 50%. Conclusion: our findings suggest that persistently active LPS induces Kupffer cells to elaborate mediators that promote the accumulation of leukocytes within enlarged sinusoids. Large increases in IL-10 and several other modulatory molecules are unable to prevent prolonged hepatomegaly in mice that cannot inactivate LPS. The striking findings in this mouse model should encourage studies to find out how AOAH contributes to human liver physiology and disease.

Original languageEnglish (US)
Pages (from-to)1051-1062
Number of pages12
JournalHepatology
Volume54
Issue number3
DOIs
StatePublished - Sep 2 2011

ASJC Scopus subject areas

  • Hepatology

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    Shao, B., Kitchens, R. L., Munford, R. S., Rogers, T. E., Rockey, D. C., & Varley, A. W. (2011). Prolonged hepatomegaly in mice that cannot inactivate bacterial endotoxin. Hepatology, 54(3), 1051-1062. https://doi.org/10.1002/hep.24488