Abstract
Sepsis-associated multiple organ failure still represents a challenging disease with high mortality. Thus far, experimental studies have shown that endotoxinemia causes parenchymal organ dysfunction via the release of cytokines, the activation of leukocytes and alteration of the microcirculation with, finally, apoptotic cell death. Therefore the aim of our study was to evaluate whether a temporary blockade of p53 with pifithrin-α is capable to reduce apoptotic cell death and organ dysfunction in LPS-induced endotoxinemia in rats. Male Sprague-Dawley rats were either treated with pifithrin-α (PFT-α, 2.2 mg/kg bw, ip, n = 7) or with the vehicle (DMSO, 1 mg/kg bw, control, n = 11) 30 min before induction of endotoxinemia (LPS 10 mg/kg bw, iv). After 16 h of endotoxinemia, animals underwent anesthesia and median laparotomy. The common bile duct was cannulated and the left liver lobe was exteriorized for intravital microscopy. After i.a. injection of fluorescent dyes, hepatocellular apoptosis (bisbenzimide, H33342,2 μmol/kg), sinusoidal perfusion (Na-fluoresceine, 2 μmol/kg), leukocyte adherence (rhodamin 6G, 0.1 μmol/kg) and Kupffer cell phagocytic activity (fluorescently labelled latex particles, 3×108/kg) were analysed. Bile flow served as an indicator for hepatocellular excretory function. After 16 h of endotoxinemia, PFT-αpretreatment caused a significant decrease of the mortality rate and a reduction of the number of apoptotic hepatocytes. Moreover PFT-α treatment caused a significant decrease of the leukocytic inflammatory response with, concomitantly, a significantly higher percentage of perfused sinusoids and increased bile production. Finally, PFT-αnormalised the endotoxinemia-associated depression of Kupffer cell phagocytic activity. The present study demonstrates for the first time attenuation of mortality rate, apoptotic cell death and organ dysfunction by PFT-αin a rat model of endotoxinemia. Thus, temporary p53-inhibition seems to be a promising novel tool in the treatment of septic shock conditions.
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Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286: 1869–1878
Kosai K, Matsumoto K, Funakoshi H, Nakamura T (1999) Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice. Hepatology 30: 151–159
Kam PCA and Ferch NI (2000) Apoptosis: mechanisms and clinical implications. Anaesthesia 2000: 1081–1093
Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV, Gudkov AV (1999) A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285: 1733–1737
Schäfer T, Berrevoet F, Vollmar B, Scheuer C, Römer K and Menger MD (2001) Reduction of apoptotic cell injury and inflammatory response after warm ischemia in rat liver by p53-inhibition with pifithrin-α. Eur Surg Res 33: 109
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Schäfer, T., Berrevoet, F., Vollmar, B., Scheuer, C., Römer, K., Menger, M.D. (2002). Reduktion der Endotoxinämie-induzierten inflammatorischen Antwort und hepatozellulären Apoptose durch in vivo Blockade von p53. In: Chirurgisches Forum 2002. Deutsche Gesellschaft für Chirurgie, vol 31. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-56158-0_94
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DOI: https://doi.org/10.1007/978-3-642-56158-0_94
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