We first compared the clearance profile of radiolabeled AGP delivered by intravenous or intraperitoneal injection. As shown in Figure 3A, significantly less AGP reached the circulation following intraperitoneal injection, particularly in the first few hours after administration; for instance, at three hours post-injection, 39 ± 3% of the radioactive dose delivered intravenously

remained in the circulation as it declined from peak values, versus 18 ± 6% of that delivered intraperitoneally DNA Damage inhibitor as it achieved peak values (mean of n = 8 ± SEM, p = 0.009). The effects of intraperitoneal injection of LPS (5 mg/kg) alone or combined with 165 mg/kg AGP on the liver microcirculation were then compared. AGP co-administration was associated with a significant reduction in the ability of co-administered LPS to promote leukocyte adhesion to the PSV Erismodegib research buy (Figure 3C) and to abrogate blood flow in the sinusoids (Figure 3E) but was without effect on leukocyte venular rolling (Figure 4B) and sinusoidal adhesion (Figure 3D). In order to adapt our endotoxemia

protocol to permit intravenous administration of LPS and AGP, rather than intraperitoneal dosing, a dose of 0.08 mg/kg was selected [27]; all mice survived, in spite of direct exposure to intravascular LPS. We then examined the liver microcirculation for signs of attenuated inflammation. Intravenous LPS was associated with a mean reduction in circulating leukocyte counts of approximately twofold compared to sham controls;

AGP treatment, either immediately before LPS injection or following pre-incubation with LPS, had no effect on systemic leukocyte counts (data not shown). Similarly, AGP treatment had no effect on the flux of rolling leukocytes. As shown in Figure 4C–E, although AGP treatment immediately before LPS administration reduced leukocyte adherence in the post-sinusoidal venules and the sinusoids, and increased sinusoidal perfusion, Monoiodotyrosine these changes did not reach statistical significance. In contrast, pre-incubating AGP and LPS together prior to their injection significantly reduced leukocyte adherence in both venules and sinusoids, and significantly increased sinusoidal perfusion. This study was designed to determine if AGP was a superior resuscitation fluid to normal saline or to purified albumin solutions in attenuating inflammation in the liver associated with early endotoxemia or early sepsis in mice. Because AGP has been suggested to have properties beyond its simple hydrodynamic colloidal osmotic effects, we aimed to normalize hydrodynamic effects among the groups treated with the three different resuscitation fluids. Doses of AGP, HAS, and saline were selected with the goal of achieving similar intravascular fluid volumes after resuscitation in the presence of bacterial danger signals (either endotoxin or the multiple signals of bacterial infection liberated in the CLP procedure).