Rabbit Anti-Human AOAH Polyclonal antibody

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 approximate to 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-1 beta 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. (HEPATOLOGY 2011;54:1051-1062)

Introduction:Lipopolysaccharide (LPS) is a systemic response-triggering endotoxin, which has the kidney as one of its first targets, thus causing acute injuries to this organ. Physical exercise is capable of promoting physiological alterations and modulating inflammatory responses in the infectious process through multiple parameters, including the toll-like receptor (TLR)-4 pathway, which is the main LPS signaling in sepsis. Additionally, previous studies have shown that physical exercise can be both a protector factor and an aggravating factor for some kidney diseases. This study aims at analyzing whether physical exercise before the induction of LPS endotoxemia can protect kidneys from acute kidney injury. Methods:C57BL/6J male mice, 12 weeks old, were distributed into four groups: (1) sedentary (control,N= 7); (2) sedentary + LPS (N= 7); (3) trained (N= 7); and (4) trained + LPS (N= 7). In the training groups, the animals exercised 5x/week in a treadmill, 60 min/day, for 4 weeks (60% of max. velocity). Sepsis was induced in the training group by the application of a single dose of LPS (5 mg/kg i.p.). Sedentary animals received LPS on the same day, and the non-LPS groups received a saline solution instead. All animals were euthanized 24 h after the administration of LPS or saline. Results:The groups receiving LPS presented a significant increase in serum urea (p< 0.0001) and creatinine (p< 0.001) concentration and renal gene expression of inflammatory markers, such as tumor necrosis factor alpha and interleukin-6, as well as TLRs. In addition, LPS promoted a decrease in reduced glutathione. Compared to the sedentary + LPS group, trained + LPS showed overexpression of a gene related to kidney injury (NGAL,p< 0.01) and the protein levels of LPS receptor TLR-4 (p< 0.01). Trained + LPS animals showed an expansion of the tubulointerstitial space in the kidney (p< 0.05) and a decrease in the gene expression of hepatic AOAH (p< 0.01), an enzyme involved in LPS clearance. Conclusion:In contrast to our hypothesis, training was unable to mitigate the renal inflammatory response caused by LPS. On the contrary, it seems to enhance injury by accentuating endotoxin-induced TLR-4 signaling. This effect could be partly due to the modulation of a hepatic enzyme that detoxifies LPS.