Alpha-1-acid glycoprotein reduces hepatic leukocyte recruitment in early sepsis

Background

Alpha-1-acid glycoprotein (AGP) is a positive acute-phase circulating colloid reported to have anti-inflammatory properties. We have previously shown that hepatic leukocyte recruitment at 6 hours of sepsis varies with the choice of fluid used for resuscitation. Our objective in this study was to compare the ability of AGP versus normal saline (SAL) or albumin (ALB) to reduce the systemic inflammation associated with early sepsis.

Methods

Human AGP and ALB were isolated and purified under pyrogen-free conditions from plasma. Sepsis was induced in male C57Bl/6 mice by cecal ligation and perforation (CLP) with an 18-gauge needle. Sham-operated (SHAM) and CLP mice received 2 ml subcutaneous saline before surgery. Mice received either 20 ml/kg SAL or 5 ml/kg of 3% AGP or 5% ALB in saline (matched for molar weight) as an intravenous bolus after inducing sepsis. The hepatic microcirculation was examined by intravital microscopy 4 hours later. Pulmonary inflammation was assessed by myeloperoxidase assay.

Results

We have previously published that bolus SAL induces an increase in leukocyte rolling within the hepatic microcirculation. A similar finding was noted in the animals receiving saline in this study. Surprisingly, in the colloid-resuscitated CLP mice this rolling was reduced by 50%. In the central venules SHAM surgery did not induce significant leukocyte adhesion. CLP mice receiving SAL had a 30-fold increase in leukocyte adhesion, which was reduced by 30% when mice were treated with ALB and by 60% in those mice receiving AGP. Both colloids maintained sinusoidal perfusion during sepsis but there was a 20% reduction in perfusion in the SAL-treated CLP mice. Only treatment with AGP, however, was able to reduce the sepsis-induced increase in sinusoidal leukocyte adhesion to SHAM levels. At this early time point there was no evidence of neutrophil sequestration within the lungs as measured by myeloperoxidase assay.

Conclusions

At 4 hours of sepsis there is evidence of hepatic but not pulmonary inflammation. In this model of early sepsis, treatment with a colloid significantly reduced the hepatic leukocyte–endothelial cell interactions compared with saline resuscitation. The presence of a glycosylated protein in the circulation appears to be more beneficial than albumin in limiting the systemic inflammatory response.