The Impact of a Nitric Oxide Synthase Inhibitor (L-NAME) on Ischemia–Reperfusion Injury of Cholestatic Livers by Pringle Maneuver and Liver Resection after Bile Duct Ligation in Rats
by
Junji Iwasaki 1,2
, Mamdouh Afify 1,3, Christian Bleilevens 4, Uwe Klinge 5, Ralf Weiskirchen 6, Julia Steitz 1, Michael Vogt 1,2, Shintaro Yagi 7, Kazuyuki Nagai 7, Shinji Uemoto 7 and Rene H. Tolba 1,*
Junji Iwasaki 1,2, Mamdouh Afify 1,3, Christian Bleilevens 4, Uwe Klinge 5, Ralf Weiskirchen 6, Julia Steitz 1, Michael Vogt 1,2, Shintaro Yagi 7, Kazuyuki Nagai 7, Shinji Uemoto 7 and Rene H. Tolba 1,*
1
Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Medical Faculty, 52074 Aachen, Germany
2
Two Photon Imaging Facility of the Interdisciplinary Center for Clinical Research (IZKF), RWTH-Aachen University, Medical Faculty, 52074 Aachen, Germany
3
Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza Square 12211, Egypt
4
Department of Anesthesiology, RWTH-Aachen University, Medical Faculty, 52074 Aachen, Germany
5
Department of General, Visceral and Transplantation Surgery, RWTH-Aachen University, Medical Faculty, 52074 Aachen, Germany
6
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH-Aachen University, Medical Faculty, 52074 Aachen, Germany
7
Division of Hepatobiliary Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(9), 2114; https://doi.org/10.3390/ijms20092114
Received: 2 April 2019 / Revised: 19 April 2019 / Accepted: 24 April 2019 / Published: 29 April 2019
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury 2.0)
The Pringle maneuver (PM) has been widely used to control blood loss during liver resection. However, hepatic inflow occlusion can also result in hepatic ischemia–reperfusion injury (IRI), especially in patients with a cholestatic, fibrotic, or cirrhotic liver. Here we investigate a nitric oxide synthase (NOS) inhibitor N-Nitroarginine methyl ester (L-NAME) on IRI after the PM and partial hepatectomy of cholestatic livers induced by bile duct ligation (BDL) in rats. Control group (non-BDL/no treatment), BDL + T group (BDL/L-NAME treatment) and BDL group (BDL/no treatment) were analyzed. Cholestasis was induced by BDL in the L-NAME and BDL group and a 50% partial hepatectomy with PM was performed. L-NAME was injected before PM in the BDL + T group. Hepatocellular damage, portal venous flow, microcirculation, endothelial lining, and eNOS, iNOS, interleukin (IL)-6, and transforming growth factor-β (TGF-β) were evaluated. Microcirculation of the liver in the BDL + T group tended to be higher. Liver damage and apoptotic index were significantly lower and Ki-67 labeling index was higher in the BDL + T group while iNOS and TGF-β expression was decreased. This was corroborated by a better preserved endothelial lining. L-NAME attenuated IRI following PM and improved proliferation/regeneration of cholestatic livers. These positive effects were considered as the result of improved hepatic microcirculation, prevention of iNOS formation, and TGF-β mRNA upregulation.
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Keywords:
bile duct ligation; ischemia–reperfusion injury; liver; nitric oxide synthase; Pringle maneuver
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MDPI and ACS Style
Iwasaki, J.; Afify, M.; Bleilevens, C.; Klinge, U.; Weiskirchen, R.; Steitz, J.; Vogt, M.; Yagi, S.; Nagai, K.; Uemoto, S.; Tolba, R.H. The Impact of a Nitric Oxide Synthase Inhibitor (L-NAME) on Ischemia–Reperfusion Injury of Cholestatic Livers by Pringle Maneuver and Liver Resection after Bile Duct Ligation in Rats. Int. J. Mol. Sci. 2019, 20, 2114.
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