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Updated: Jun 1, 2026
Injections of Lipopolysaccharide into Mice to Mimic Entrance of Microbial-derived Products After Intestinal Barrier Breach
Published on: May 2, 2018
Prolonged hepatomegaly in mice that cannot inactivate bacterial endotoxin
Baomei Shao1, Richard L Kitchens, Robert S Munford
1Infectious Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA.
Unlabelled:
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.
Insights
A host enzyme, acyloxyacyl hydrolase (AOAH), is crucial for resolving liver enlargement caused by bacterial lipopolysaccharide (LPS). Mice lacking AOAH show prolonged hepatomegaly, highlighting AOAH
Area of Science:
- Immunology
- Hepatology
- Microbiology
Background:
- Transient hepatomegaly is common in bacterial infections and can be induced by bacterial lipopolysaccharide (LPS).
- The enzyme acyloxyacyl hydrolase (AOAH) is known to inactivate LPS.
Purpose of the Study:
- To investigate the role of AOAH in the resolution of LPS-induced hepatomegaly.
- To elucidate the cellular and molecular mechanisms underlying prolonged liver enlargement in the absence of AOAH.
Main Methods:
- Comparison of LPS-induced hepatomegaly in wild-type (Aoah(+/+)) and AOAH-deficient (Aoah(-/-)) mice.
- Analysis of liver histology, including Kupffer cells, leukocytes, and sinusoidal endothelial cells.
- Measurement of cytokine and mRNA expression (TNF, IL-10, IRAK-M).
- Depletion studies of specific immune cell populations (Kupffer cells, neutrophils, etc.).
- Pharmacological interventions including dexamethasone, TNF neutralization, IL-1β neutralization, and IL-10 receptor antagonism.
Main Results:
- Aoah(-/-) mice exhibited significantly prolonged and severe hepatomegaly upon challenge with LPS or gram-negative bacteria.
- Livers of Aoah(-/-) mice showed increased Kupffer cells, leukocyte aggregates, activated sinusoidal endothelial cells, and sustained IL-10 and inflammatory mRNA production.
- Kupffer cell depletion partially reduced liver enlargement in Aoah(-/-) mice; other immune cell depletions had no effect.
- Dexamethasone prevented prolonged hepatomegaly, while TNF or IL-1β neutralization had partial effects; IL-10 receptor antagonism exacerbated it.
Conclusions:
- Persistent LPS stimulation in AOAH-deficient mice leads to Kupffer cell activation and leukocyte accumulation, promoting sustained liver enlargement.
- Elevated IL-10 and other mediators do not prevent prolonged hepatomegaly in the absence of LPS inactivation by AOAH.
- These findings underscore the critical role of AOAH in liver physiology and suggest its involvement in human liver diseases.
