Recombinant N-terminal fragment of bactericidal/permeability increasing protein (rBPI21) prevents shock-induced microcirculatory alterations in the liver.

OBJECTIVE: To investigate the effects of the recombinant 21-kilodalton N-terminal fragment of recombinant bactericidal and permeability increasing protein (rBPI21) 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 rBPI21 (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 microm vs. 10.0 +/- 0.4 pm). 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 rBPI21 before or after shock resulted in plain reduction of pathologic leukocyte-endothelial interaction (138 cells/mm2 and 85 cells/mm2). CONCLUSION: The results support the hypothesis that endotoxin induces microcirculatory alterations after shock, and further suggest a potentially beneficial role of rBPI21 in the treatment of posttraumatic endotoxin-induced inflammatory reactions.

Interleukin-1 receptor antagonist attenuates leukocyte-endothelial interactions in the liver after hemorrhagic shock in the rat.

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-1ra). 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-1ra (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 < .001 by analysis of variance; sham group 9.1 +/- 1.1%). Administration of IL-1ra at the time of resuscitation also reduced firm adhesion of leukocytes to sinusoidal endothelium (treated group 28.8 +/- 3.6%, p < .01). Temporary adhesion rates of leukocytes (adhesion time of < 20 secs) were unaffected by pretreatment or treatment with IL-1ra with respect to control values. Liver microcirculation was impaired after hemorrhagic shock but not improved by IL-1ra. CONCLUSIONS: The results show that adhesion of leukocytes to hepatic sinusoidal endothelium is at least partly regulated by interleukin-1. Adherence was attenuated by the application of IL-1ra, which might be due to diminished expression of adhesion receptors by endothelial cells or leukocytes. Even administration of IL-1ra at the time of resuscitation reduces the early inflammatory response in the liver after shock, thus offering a potentially important therapeutic approach.