UNLABELLED: Microcirculatory derangement, energy depletion, and lipid peroxidation are associated with the development of ischemia-reperfusion injury in the liver. This study investigated the effects of a neutrophil elastase inhibitor (ONO-5046) on hepatic ischemia-reperfusion injury. Adult, male Sprague-Dawley rats were divided into four treatment groups: 1) sham-operated control (laparotomy only, no ischemia) and saline injection (1 mL/kg), n = 6; 2) ischemia control (1-h ischemia, 2-h reperfusion) and saline injection (1 mL/kg), n = 6; 3) intravenous injection with ONO-5046 at a dose of 1 mg/kg 5 min before ischemia and immediately after reperfusion plus 1-h ischemia and 2-h reperfusion, n = 6; and 4) intravenous injection with ONO-5046 at a dose of 10 mg/kg 5 min before ischemia and immediately after reperfusion plus 1-h ischemia and 2-h reperfusion, n = 6. A laser-Doppler flowmeter and in vivo microscopy were used to investigate hepatic microcirculation. Tissue malondialdehyde (MDA) and adenosine triphosphate (ATP) levels were determined at the end of the experiment. RESULTS: Compared with ischemia alone, ONO-5046 significantly reduced the extent of microcirculatory and hemodynamic derangement after ischemia-reperfusion. ONO-5046 at both doses significantly attenuated decreases in mean arterial pressure. ONO-5046 lessened adherent leukocyte count and improved flow velocity in the sinusoids and postsinusoidal venules. ONO-5046 at the dose of 10m/kg reduced MDA (1.97 +/- 0.54 micromol/g protein vs. 3.58 +/- 1.21 micromol/g protein in the ischemia and reperfusion group) and increased ATP levels (2.62 +/- 0.19 micromol/g wet wt vs. 0.57 +/- 0.37 pmol/g wet wt in the ischemia and reperfusion group), whereas ONO-5046 at a smaller dose (1 mg/kg) had lesser but significant effects on MDA and ATP alterations. This study demonstrates that treatment with ONO-5046, a neutrophil elastase inhibitor, can ameliorate ischemia-reperfusion injury of the rat liver.
UNLABELLED: Microcirculatory derangement, energy depletion, and lipid peroxidation are associated with the development of ischemia-reperfusion injury in the liver. This study investigated the effects of a neutrophil elastase inhibitor (ONO-5046) on hepatic ischemia-reperfusion injury. Adult, male Sprague-Dawley rats were divided into four treatment groups: 1) sham-operated control (laparotomy only, no ischemia) and saline injection (1 mL/kg), n = 6; 2) ischemia control (1-h ischemia, 2-h reperfusion) and saline injection (1 mL/kg), n = 6; 3) intravenous injection with ONO-5046 at a dose of 1 mg/kg 5 min before ischemia and immediately after reperfusion plus 1-h ischemia and 2-h reperfusion, n = 6; and 4) intravenous injection with ONO-5046 at a dose of 10 mg/kg 5 min before ischemia and immediately after reperfusion plus 1-h ischemia and 2-h reperfusion, n = 6. A laser-Doppler flowmeter and in vivo microscopy were used to investigate hepatic microcirculation. Tissue malondialdehyde (MDA) and adenosine triphosphate (ATP) levels were determined at the end of the experiment. RESULTS: Compared with ischemia alone, ONO-5046 significantly reduced the extent of microcirculatory and hemodynamic derangement after ischemia-reperfusion. ONO-5046 at both doses significantly attenuated decreases in mean arterial pressure. ONO-5046 lessened adherent leukocyte count and improved flow velocity in the sinusoids and postsinusoidal venules. ONO-5046 at the dose of 10m/kg reduced MDA (1.97 +/- 0.54 micromol/g protein vs. 3.58 +/- 1.21 micromol/g protein in the ischemia and reperfusion group) and increased ATP levels (2.62 +/- 0.19 micromol/g wet wt vs. 0.57 +/- 0.37 pmol/g wet wt in the ischemia and reperfusion group), whereas ONO-5046 at a smaller dose (1 mg/kg) had lesser but significant effects on MDA and ATP alterations. This study demonstrates that treatment with ONO-5046, a neutrophil elastase inhibitor, can ameliorate ischemia-reperfusion injury of the rat liver.
Authors: Almudena Ortega-Gomez; Melanie Salvermoser; Jan Rossaint; Robert Pick; Janine Brauner; Patricia Lemnitzer; Jessica Tilgner; Renske J de Jong; Remco T A Megens; Janina Jamasbi; Yvonne Döring; Christine T Pham; Christoph Scheiermann; Wolfgang Siess; Maik Drechsler; Christian Weber; Jochen Grommes; Alexander Zarbock; Barbara Walzog; Oliver Soehnlein Journal: Circulation Date: 2016-09-22 Impact factor: 29.690