Time course of mean arterial blood pressure (MBP).

<p>Hemorrhage was induced for 20 minutes (shaded area). A: Sham group (Sham), B: Hemorrhage group (Hemorrhage), C: Sham with FR167653 treatment (FR), D: Hemorrhage with FR167653 treatment (FR+Hemorrhage). MBP decreased significantly just after hemorrhage and returned to baseline at 40 minutes, but decreased gradually in the latter phase in the Hemorrhage group (B). FR treatment did not have any effect on the primary MBP decrease, although it abolished the secondary MBP decrease after hemorrhage (D). Data are shown as mean±SE. n = 5/groups, * p<0.05 vs Sham, + p<0.05 between Hemorrhage and FR+Hemorrhage.</p

Changes in hepatic p38 MAPK activation after hemorrhage.

<p>The activation of p38 MAPK was assessed by Western blotting analysis. p38 MAPK phosphorylation levels, shown on the vertical axis in B, were determined after normalization using the density ratio of the phosphorylated p38 MAPK band (p-p38 MAPK in A) divided by the p38 MAPK band (p38 MAPK in A). Activation of p38 MAPK was significantly higher at 1 hour and returned to the baseline level at 3 hours after hemorrhage. Activation of p38 MAPK activation in the FR+Hemorrhage group did not change significantly at any time after a hemorrhage. Data are shown as mean±SE. n = 5/groups, * p<0.05 vs Sham, + p<0.05 between Hemorrhage and FR+Hemorrhage.</p

Changes in serum AST and ALT levels.

<p>The levels of liver enzymes in the Hemorrhage group increased with time and were significantly higher than in the Sham group at 5 hours after hemorrhage. Administration of FR167653 (FR+Hemorrhage group) inhibited the increase AST and ALT (A and B respectively). Data are shown as mean±SE. n = 5/groups, * p<0.05 vs Sham, + p<0.05 between Hemorrhage and FR+Hemorrhage.</p

Time course of hepatic arterial blood flow (HBF).

<p>The abbreviations are the same as those in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030124#pone-0030124-g001" target="_blank">Fig. 1</a>. The change in HBF was similar to that in MBP. Data are shown as mean±SE. n = 5/groups, * p<0.05 vs Sham, + p<0.05 between Hemorrhage and FR+Hemorrhage.</p

Light micrograph showing the liver at 5 hours post-hemorrhage.

<p>The interstitial space was edematous and the sinusoidal capillaries were dilated with diffuse congestion. Some neutrophils, which have the appearance of reddish brown precipitates, were present in the sinusoidal cavity and interstitial space in the Hemorrhage group (A). These histological changes were not observed in the FR+Hemorrhage group (B). Bar = 100 µm. Number of activated neutrophils in the liver (500 µm²) as shown in C. In the Hemorrhage group, activated neutrophils were significantly increased at 5 hours, but markedly reduced in the group treated with FR167653 (FR+Hemorrhage) at 5 hours post-hemorrhage. Data are shown as mean±SE. n = 5/groups, * p<0.05 vs Sham, + p<0.05 between Hemorrhage and FR+Hemorrhage.</p

Bacterial LPS concentration in the portal vein.

<p>There were no significant increases in the portal LPS concentration in any of the groups throughout the experimental period. Data are shown as mean±SE. n = 5/groups.</p

Changes in hepatic IL-1β mRNA expression after hemorrhage.

<p>The IL-1β mRNA level in the Hemorrhage group was highest at 3 hours post-hemorrhage, and was higher than that of the Sham group at all timepoints. On the contrary, the IL-1β mRNA level in the FR+Hemorrhage group showed no change from baseline at any timepoint after hemorrhage. Similarly, the serum IL-1β level in the Hemorrhage group was significantly increased from baseline at 3 hours after hemorrhage and then decreased over time, but was significantly higher than in the Sham group at all the timepoints post-hemorrhage as shown in C. In contrast, the serum IL-1β level in the FR+Hemorrhage group showed no change from the baseline value throughout the experiment. Data are shown as mean±SE. n = 5/groups, * p<0.05 vs Sham, + p<0.05 between Hemorrhage and FR+Hemorrhage.</p

A double blind placebo controlled randomized trial of the effect of acute uric acid changes on inflammatory markers in humans: A pilot study

<div><p>Uric acid has been linked with increased risk of chronic disease such as cardiovascular disease and this association has been attributed to a pro-inflammatory effect. Indeed, observational studies have shown that high uric acid is associated with high level of pro-inflammatory cytokines in the blood. However, whether high uric acid directly affects inflammation or rather represents a parallel defensive antioxidant mechanism in response to pathology that causes inflammation is unknown. To determine whether acute increase or decrease uric acid levels affects inflammation in healthy individuals, a randomized, placebo-controlled, double blind clinical study of uric acid or rasburicase with 20 healthy volunteers in each treatment-placebo group was conducted at the National Institute on Aging (NIA) Clinical Research Unit (CRU) at Harbor Hospital in Baltimore, MD. Change in inflammatory response was assessed by administering an oral lipid tolerance before and after the treatment of uric acid, rasburicase and placebo. Following uric acid administration, there was an accentuated increase in IL-6 during the oral lipid tolerance test (P<0.001). No significant differences were observed after lowering of uric acid with rasburicase. No side effects were reported throughout the trial. In health individuals, acute increase in uric acid results in an increased IL-6 response when challenged with lipid load. Such effect of amplification of inflammatory response may explain the higher risk of chronic diseases observed in subclinical hyperuricemia in observational studies.</p><p>Trial Registration: ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01323335" target="_blank">NCT01323335</a></p></div

Changes in uric acid levels during uric acid or rasburicase administration.

<p>Concentrations of uric acid was measured at 0, 1, 2, 4, 8, 12, and 24 hours following the administration of 500mg uric acid (A) and 0.15 mg/kg rasburicase (B) is displayed. The treatment group is displayed as dotted line (uric acid or rasburicase) and the placebo group as the solid lines. Mean and standard errors are displayed.during uric acid infusion, there was a significant difference in the change in IL-18 (P_{treatment*time} = 0.0006; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181100#pone.0181100.s002" target="_blank">S2A Fig</a>) and CRP (P_{treatment*time} = 0.045; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181100#pone.0181100.s003" target="_blank">S3B Fig</a>) over time by treatment. For IL-18 the slope was more negative in the uric acid group compared to placebo group (β_{treatment*time12} = -36.2, P = 0.0002) at the 12^th hour. For CRP, at the 8^th and 12^th hour, there slope for uric acid group was lower than the placebo group (β_{treatment*time8} = -0.14, P = 0.04, β_{treatment*time8} = -0.18, P = 0.007). There were no significant differences in change of other markers by uric acid treatment group.</p

Volcano plot of gene expression changes by rasburicase treatment.

<p>The level of gene expression was assessed at baseline and after 12 and 24 hours after infusion of 0.15mg/kg of rasburicase. The difference in gene expression by treatment group is displayed. The genes in the interferon signaling pathway that are significantly differentially expressed are shown (filled triangles).</p