Search

Objective : To evaluate the influence of interleukin-1 on leukocyte-endothelial cell interactions and the microcirculation in the liver after hemorrhagic shock by means of intravital microscopy using an interleukin-1 receptor antagonist (IL-lra). Design : Prospective, randomized, blinded, controlled study. Setting : University research laboratory. Subjects : Anesthetized female Sprague Dawley rats weighing 200 to 230 g. Interventions : Hypovolemic shock was induced and maintained for 1 hr (mean arterial pressure 40 mm Hg ; cardiac output 50% of baseline). After adequate resuscitation and 5 hrs of reperfusion (mean arterial pressure >100 mm Hg ; cardiac output >120% of baseline), the microcirculation in liver sinusoids was examined by intravital fluorescence microscopy. Continuous administration of IL-lra (5 mg/kg/hr) was started at different times in a prospective, randomized, blinded fashion, either as pretreatment 5 mins before shock induction (n = 6), or as therapy at the time of resuscitation (n = 6). An additional bolus injection of 5 mg/kg of IL-1ra was given to the latter group. Measurements and Main Results : Mean arterial pressure, cardiac output, heart rate, and blood gases were comparable in all shock groups during the experiments. The percentage of permanently adherent leukocytes (adhesion time of >20 secs) in the pretreated group was significantly decreased in comparison with the control group (pretreatment group 16.9 ± 1.9% vs. control group 42.1 ± 5.4% ; p

To evaluate the effect of pentoxifylline on altered hepatocyte calcium regulation and hepatocyte oxidant injury after hemorrhagic shock.Prospective, randomized, controlled study.University research laboratory.Anesthetized, male Sprague-Dawley rats, weighing 220 to 300 g.Hemorrhagic shock was induced by bleeding rats to a mean arterial blood pressure of 40 mm Hg for 60 min. Rats were then resuscitated with 60% of shed blood and three-fold the bleed out volume of lactated Ringer's solution without and with pentoxifylline (50 mg/kg body weight). After hepatocyte isolation by portal collagenase perfusion, the rate of hepatocyte calcium influx (Ca2+in) in the absence and presence of epinephrine (100 nM), both cellular Ca2+ uptake (Ca2+up) and membrane Ca2+ flux (Ca2+flux) were determined, using 45Ca2+ incubation techniques. Hepatocyte lipid peroxidation was fluorometrically determined by thiobarbituric acid-reactive substances.Pentoxifylline inhibited the significant increase of hepatocyte Ca2+in, Ca2+up, and Ca2+flux observed in untreated rats subjected to hemorrhage/resuscitation. In shocked rats, pentoxifylline restored the impaired epinephrine-induced Ca2+ influx response and prevented increased hepatocyte lipid peroxidation.The protective effects of pentoxifylline could be attributed to its known anti-inflammatory properties reducing excessive in vivo stimulation of hepatocytes by Ca2+ agonistic mediators and attenuating oxygen radical-related disturbances of transmembrane Ca2+ transport mechanisms. Since altered cellular Ca2+ regulation is a key event of cellular dysfunction, resuscitation with pentoxifylline after hemorrhagic shock/resuscitation may provide an adjuvant therapeutic tool to prevent postischemic hepatic failure.

Objective: To investigate the effects of the recombinant 21-kilodalton N-terminal fragment of recombinant bactericidal and permeability increasing protein (rBPI 21 ) on leukocyte adhesion and the hepatic microcirculation after hemorrhagic shock. Design: Prospective, randomized, blinded, and placebo-controlled experimental study. Setting: University research laboratory. Subjects: Anesthetized Sprague-Dawley rats, weighing 220 to 250 g. Interventions: Rats were subjected to 60 mins of hemorrhagic shock and subsequent resuscitation to sufficiently restore systemic circulation. The microcirculation of the liver was investigated by intravital fluorescence microscopy 5 hrs after hemorrhagic shock. Four shock groups were compared with a sham-control group. Shock groups received either rBPI 21 (10 mg/ kg) or placebo either before or after shock period. Measurements and Main Results: No differences were observed in hemodynamic, respiratory, or metabolic parameters between the shock groups. However, the hepatic microcirculation showed severe deterioration 5 hrs after shock, indicated by significantly narrowed sinusoids in all shock groups compared with controls (8.5 ± 0.3 μm vs. 10.0 ± 0.4 μm). Leukocyte adhesion was markedly increased to comparable values in both placebo groups (619 cells/mm2 and 644 cells/mm2; sham, 168 cells/mm2). Neutralization of endotoxin by administration of rBPI 21 before or after shock resulted in plain reduction of pathologic leukocyte-endothelial interaction (138 cells/mm2 and 85 cells/mm 2 ). Conclusion: The results support the hypothesis that endotoxin induces microcirculatory alterations after shock, and further suggest a potentially beneficial role of rBPI 21 in the treatment of post-traumatic endotoxin-induced inflammatory reactions.