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Background: The hepatic acute phase response(APR) is an organ-specific response to a diverse array of insults and is largely under transcriptional control. Liver-specific transcription factors, hepatic nuclear factors (HNFs)-1α and 4α play important roles in maintenance of liver phenotype and function and their binding activity changes early after injury. However, their roles in modulation of the liver's response over time are not defined., Materials and Methods: C57/BL6 mice were anesthetized and exposed to 95°C water for 10 s to create a 15% body surface area full-thickness burn. At specific time points, the mice were sacrificed. An ELISA for IL-6 was performed on serum and hepatic mRNA levels for fibrinogen-γ and serum amyloid A(SAA)-3 were obtained through polymerase chain reaction (PCR). Transcriptional factor binding activity was assessed with electrophoretic mobility shift assays., Results: Serum IL-6 levels peaked at 3 h and fibrinogen-γ and SAA mRNA levels increased more than 6-fold at 12 h before returning to control levels at 48 h. The binding activity of HNF-4α and HNF-1α rapidly declined after injury (1.5 h) but recovered to near control level at 24 and 6 h, respectively., Conclusions: Changes in HNF-4α and HNF-1α binding occurred before changes in acute phase protein mRNA levels and were preceded by the peak in IL-6 levels. The rapid suppression and reconstitution of liver-specific transcription factor binding after injury may represent a mechanism that allows the normal liver phenotype to change and an injury-response phenotype to prevail. This mechanism in the liver's adaptive response to injury suggests a central role for both HNF-4α and HNF-1α in transcriptional regulation of the hepatic APR., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Bacterial endotoxins are the principal agents causing sepsis and septic shock. Cytokine cascades produced by cellular interactions to endotoxins can cause cardiovascular failure followed by multi-organ failure and death. Endotoxin intravenously administered to mice can have fatal consequences. Previous studies have shown that the transition metals Mn2+ and Cr3+ can be protective., Methods: The effects of Mn2+, Cr3+, Zn2+, and Cu2+ on lipopolysaccharide (LPS) binding to rat Kupffer cell extracts were analyzed using dot-blots, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and Western transfer. Kupffer cells were isolated from rat livers by collagenase perfusion, differential centrifugation, and adhesion to plastic., Results: Five millimolar of Mn2+, Zn2+, Cr3+, and Cu2+ completely inhibited LPS binding. Isolated Kupffer cells were also exposed to Mn2+ and to LPS and tumor necrosis factor-alpha release measured. The presence of Mn2+ significantly (P < 0.05) reduced tumor necrosis factor-alpha production by Kupffer cells in response to LPS. Experiments to determine if these effects were mediated by binding to LPS-binding proteins showed this was not the case. More likely a complex occurs between the metal and LPS. We also showed significantly enhanced uptake of LPS into Kupffer cells in the presence of Mn2+., Conclusions: The data are consistent with the metals binding to LPS via its two phosphate groups and neutralizing their charge. These data also support the hypothesis that there is enhanced cellular uptake by non-receptor-mediated methods such as absorptive pinocytocis. At the same time receptor binding and activation of the cells is inhibited. This can explain the effects of transition metals on LPS toxicity.

Groups of 25-month-old ("old") B6C3 hybrid male mice, 6-month-old ("young") normal males, and their age-matched transgenic (TG) siblings overexpressing the bovine growth hormone gene were given an inhibitory avoidance training trial (0.20-mA electric shock, 1.0-s duration). The old B6C3 hybrids and the young TG mice displayed poorer retention (shorter latencies to enter the shock compartment) 24 h and 42 days after training than did the young normal mice. In a subsequent multiple-trial acquisition test, young TG and old normal mice required more trials to reach the criterion of complete inhibition of step-through responding for 300 s than did young normal mice. Young normal and young TG mice did not differ in trials to extinction, but TG mice met the extinction criterion sooner than did old normal mice, suggesting poorer longterm retention. In tests of T-maze appetitive learning, young normal, old normal, and young TG mice did not differ in acquisition or 24-h retention. Contrary to expectation, TG mice acquired T-maze reversal learning in fewer trials than did young normal or old normal mice. The TG and young normal mice did not differ in retention when retested 44 days after initial training, but old normal mice showed poorer retention than did the young normals. Results of locomotor activity and shock response tests suggested that learning impairments were not due to differences in locomotor activity or shock response thresholds in these animals. Tests in an elevated plus maze indicated that young TG mice were less anxious in a novel environment than their normal siblings, which may contribute to their impaired inhibitory avoidance learning. These findings suggest that 6-month-old TG mice overexpressing the bovine growth hormone gene display alterations in inhibitory avoidance (but not appetitive) learning similar to those occurring in 25-month-old normal mice. The neurobiological mechanisms mediating inhibitory avoidance and T-maze appetitive learning in these animals may be largely dissociated.