© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Nuclear Factor-
B as a target of cyclosporin in acute hypovolemic hemorrhagic shock
aDepartment of Experimental and Clinical Medicine and Pharmacology, Section of Pharmacology, School of Medicine, University of Messina, Azienda Ospedalieria Universitaria ‘G. Martino’, Via Consolare Valeria Policlinico Gazzi Torre Biologica 5° Piano, 98125 Messina, Italy
bDepartment of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy
cDepartment of Surgical Specialties, School of Medicine, University of Messina, Azienda Ospedalieria Universitaria ‘G. Martino’, Via Consolare Valeria Policlinico Gazzi Torre Biologica 5° Piano, 98125 Messina, Italy
dDepartment of Internal Medicine, School of Medicine, University of Messina, Azienda Ospedalieria Universitaria ‘G. Martino’, Via Consolare Valeria Policlinico Gazzi Torre Biologica 5° Piano, 98125 Messina, Italy
eDepartment of Anesthesiology, School of Medicine, University of Messina, Azienda Ospedalieria Universitaria ‘G. Martino’, Via Consolare Valeria Policlinico Gazzi Torre Biologica 5° Piano, 98125 Messina, Italy
* Corresponding author. Tel.: +39-090-221-3648 or 292-1060; fax: +39-090-221-3300 francesco.squadrito{at}unime.it
Background: Cyclosporin is an immunosuppressive drug that blocks Nuclear Factor 
B (NF-B) activation. We investigated the role of NF-B in acute hypovolemic hemorrhagic (Hem) shock and the effects of cyclosporin in this model of experimental shock. Methods: Hem shock was induced in male anesthetized rats by intermittently withdrawing blood from an iliac catheter over a period of 20 min (bleeding period) until mean arterial blood pressure (MAP) fell and stabilized within the range of 20–30 mmHg. Two minutes after bleeding cessation, animals received intravenously cyclosporin (1 mg kg–1) or its vehicle. Survival rate and survival time were evaluated for 120 min after bleeding was discontinued. Plasma TNF-
levels were investigated at different time points after bleeding cessation. Moreover we investigated levels of TNF- mRNA in the liver, vascular reactivity, liver NF-B binding activity and levels of the inhibitory protein IB in the cytoplasm. Results: Hemorrhagic shocked rats died in 27±6 min following the cessation of bleeding, experienced a marked hypotension (mean arterial blood pressure=20–30 mmHg) and had enhanced plasma levels of Tumor Necrosis Factor- (208±22 pg ml–1, 20 min after the end of bleeding). Furthermore, aortas taken 20 min after bleeding from hemorrhagic shocked rats showed a marked hypo-reactivity to phenylephrine (PE: 1 nM–10 µM) compared with aortas harvested from sham shocked rats. Hem shocked rats also had increased levels of TNF- mRNA in the liver (15–20 min after the end of bleeding). Electrophoretic mobility shift assay showed that liver NF-B binding activity increased in the nucleus 10 min after the end of hemorrhage and remained elevated until the death of animals. Western blot analysis suggested that the levels of inhibitory protein IB in the cytoplasm decreased at 5 min after the end of bleeding. Cyclosporin inhibited the loss of IB protein from the cytoplasm and prevented NF-B binding activity in the nucleus. Furthermore, cyclosporin increased survival time (118±7 min; P<0.01) and survival rate (vehicle=0% and cyclosporin=80%, at 120 min after the end of bleeding), reverted the marked hypotension, decreased liver mRNA for TNF-, reduced plasma TNF- (28±7 pg ml–1), and restored to control values the hypo-reactivity to PE. Conclusions: Our results suggest that acute blood loss (50% of the estimated total blood volume over a period of 20 min) causes early activation of NF-B which triggers an inflammatory cascade leading to a fatal outcome. Cyclosporin blocks NF-B activation and protects against hypovolemic hemorrhagic shock.
KEYWORDS Blood pressure; Cytokines; Infection/inflammation; Shock
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