Ubiquinol decreases hemorrhagic shock/resuscitation-induced microvascular inflammation in rat mesenteric microcirculation.

Hemorrhagic shock (HS) is a leading cause of death in traumatic injury. Ischemia and hypoxia in HS and fluid resuscitation (FR) creates a condition that facilitates excessive generation of reactive oxygen species (ROS). This is a major factor causing increased leukocyte-endothelial cell adhesive interactions and inflammation in the microcirculation resulting in reperfusion tissue injury. The aim of this study was to determine if ubiquinol (coenzyme Q10) decreases microvascular inflammation following HS and FR. Intravital microscopy was used to measure leukocyte-endothelial cell adhesive interactions in the rat mesentery following 1-h of HS and 2-h post FR with or without ubiquinol. Hemorrhagic shock was induced by removing ~ 40% of anesthetized Sprague Dawley rats' blood volume to maintain a mean arterial blood pressure <50 mmHg for 1 h. Ubiquinol (1 mg/100 g body weight) was infused intravascularly in the ubiquinol group immediately after 1-h HS. The FR protocol included replacement of the shed blood and Lactate Ringer's in both the control and ubiquinol groups. We found that leukocyte adherence (2.3 ± 2.0), mast cell degranulation (1.02 ± 0.01), and ROS levels (159 ± 35%) in the ubiquinol group were significantly reduced compared to the control group (10.8 ± 2.3, 1.36 ± 0.03, and 343 ± 47%, respectively). In addition, vascular permeability in the control group (0.54 ± 0.11) was significantly greater than the ubiquinol group (0.34 ± 0.04). In conclusion, ubiquinol attenuates HS and FR-induced microvascular inflammation. These results suggest that ubiquinol provides protection to mesenteric microcirculation through its antioxidant properties.

Effects of intragastric fructose and dextrose on mesenteric microvascular inflammation and postprandial hyperemia in the rat.

OBJECTIVES: Fructose superfused on the mesenteric venules of rats induces microvascular inflammation via oxidative stress. It is unknown whether intragastric fructose exerts a similar effect and whether fructose impairs postprandial hyperemia (PPH). The goals were to determine whether intragastric fructose administration promotes leukocyte adherence and whether fructose, owing to its oxidative properties, may also impair nitric oxide-dependent PPH in the mesenteric microcirculation of rats. METHODS: Leukocyte adherence to mesenteric venules, arteriolar velocity, and diameter were measured in Sprague-Dawley rats before and 30 minutes after intragastric (1 mL 0.5 M, ~0.3 g/kg) dextrose (n = 5), fructose (n = 6), and fructose after intravenous injection of the antioxidant α-lipoic acid (ALA, n = 6). RESULTS: Only fructose increased leukocyte adherence: control 2.3 ± 0.3 per 100 µm; fructose 9.7 ± 1.4 per 100 µm (P < .001). This effect was independent of changes in venular shear rate: control 269 ± 48 s(-1); fructose 181 ± 27 s(-1) (P > .05, r(2) = 0.083 for shear rate vs leukocyte adherence). Dextrose had no effect on leukocyte adherence: control 1.52 ± 0.13 per 100 µm; dextrose 2.0 ± 0.7 per 100 µm (P > .05). ALA prevented fructose-induced leukocyte adherence: control 1.9 ± 0.2 per 100 µm; fructose + ALA 1.8 ± 0.3 per 100 µm (P > .05). Neither fructose nor dextrose induced PPH: arteriolar velocity: control 3.3 ± 0.49 cm/s, fructose 3.06 ± 0.34 cm/s (P > .05); control 3.3 ± 1.0 cm/s, dextrose 3.15 ± 1.1 cm/s (P > .05); arteriolar diameter: control 19.9 ± 1.10 µm, fructose 19.7 ± 1.0 µm (P > .05); control 21.5 ± 2.6, dextrose 20.0 ± 2.7 µm (P > .05). CONCLUSIONS: Intragastric fructose induced leukocyte adherence via oxidative stress. Neither dextrose nor fructose induced PPH, likely because of the inhibitory effect of anesthesia on splanchnic vasomotor tone.

Fructose, but not dextrose, induces leukocyte adherence to the mesenteric venule of the rat by oxidative stress.

Recent evidence indicates that fructose is a pro-inflammatory molecule. Oral fructose induces serum and kidney inflammatory intercellular adhesion molecule-1 (ICAM-1) in rats. Fructose also induces ICAM-1 expression in human aortic endothelial cells (HAEC) and monocyte chemoattractant protein-1 in proximal tubular renal cells. It is not known whether fructose may directly promote inflammation on the intestinal microcirculation. Accordingly, using intravital microscopy we studied the effect of topical fructose and dextrose on leukocyte adherence to the mesenteric venule of the rat. Leukocyte adherence was determined during a control period and after fructose was added to the mesentery, in the presence or absence of the NO donor spermine NONO-ate (SNO), and after i.v. injection of the antioxidant lipoic acid (LA). In separate experiments, we examined the effect of topical dextrose on leukocyte adherence to the mesenteric venule. Venular shear rate was calculated. Fructose, but not dextrose, induced significant inflammation independent of shear rate. This effect was completely blocked by SNO and LA, suggesting that fructose induces inflammation via reactive oxygen species (ROS) generation. These results suggest that fructose present in formulas may adversely affect the intestinal microcirculation of premature infants and potentially contribute to the pathogenesis of necrotizing enterocolitis (NEC).

Immunization of nonautoimmune mice with DNA binding domains of the largest subunit of RNA polymerase I results in production of anti-dsDNA and anti-Sm/RNP antibodies.

Antibodies against the N-terminal (NT) but not the basic domain (BD), DNA binding regions of the largest subunit (S1) of RNA polymerase I (RNAPI) were detected in the sera of MRL-lpr/lpr lupus mice. Antibodies against both RNAPI(S1)-NT and -BD, as well as other systemic lupus erythematosus (SLE) autoantigens (La, ribosomal P proteins and Sm/RNP) were produced by rabbits immunized with anti-DNA antibodies that had been affinity purified from SLE patients. Immunization of nonautoimmune mice (Balb/c) with RNAPI(S1)-NT, RNAPI(S1)-BD, or La in the form of GST fusion proteins, induced production of anti-double-stranded (ds) DNA and anti-Sm/RNP. GST-P1 did not induce an anti-dsDNA response in these mice. These results demonstrate that RNAPI(S1)-NT, RNAPI(S1)-BD and La can participate in an anti-autoantigen/anti-DNA antibody loop during an SLE-like autoimmune response.