LIVER TRANSPLANTATION 20:744–745, 2014
LETTER TO THE EDITORS
Nitrosative Stress Does Not Change During Orthotopic Liver Transplantation Received February 4, 2014; accepted February 12, 2014.
TO THE EDITORS: Ischemia/reperfusion (I/R) is considered a major contributor to tissue damage in clinical situations, including liver transplantation, but its pathophysiology remains enigmatic. Reactive oxygen and nitrogen species (RONS) are considered key initiators of I/R injury. However, although antioxidant therapy has mitigated I/R injury in animal studies, the use of antioxidants has failed to show any appreciable benefit in clinical settings.1 Recent findings from clinical I/R studies of the kidneys and heart suggest that the contribution of RONS released upon organ reoxygenation to I/R injury in humans is less than generally thought, and they challenge our current understanding of oxidative stress and RONS-mediated I/R injury.2 The L-arginine/nitric oxide pathway is generally believed to generate RONS such as potent oxidizing and nitrating peroxynitrite (ONOO2). Previously, we demonstrated that despite a drastic release of arginase activity from the graft during orthotopic liver transplantation (OLT),3 the main players of this pathway did not change remarkably. In plasma samples from the patients of that study, we determined the concentrations of free 3-nitrotyrosine (NT) and 3nitrotyrosinoalbumin (NTALB) with fully validated and reliable gas chromatography/tandem mass spectrometry methods.4 NT and NTALB are formed through the reaction of peroxynitrite with free tyrosine (Tyr) and Tyr moieties in albumin, respectively, and they serve as biomarkers of oxidative stress.5 In comparison with age- and sex-matched healthy subjects, the patients who suffered from end-stage liver disease and underwent OLT had higher baseline plasma concentrations of NT (3.99 6 0.20 versus 1.14 6 0.21 nmol/L) and NTALB (27.7 6 1.2 versus 13.1 6 1.8 lmol of NT/mol of Tyr). Figure 1 shows that neither NT nor NTALB plasma concentrations changed statistically significantly during OLT. These findings and previous findings from our group for the same patient population6 indicate that oxidative stress is indeed elevated during end-stage liver disease. However, just
Figure. 1. Time course of the plasma concentrations of (A) free NT and (B) NTALB during OLT for 8 patients with end-stage liver disease. The patient characteristics and diagnoses have been reported previously.3 The liver transplant candidates reflected the typical clinical situation of patients with different underlying liver diseases and end-stage cirrhosis. The preoperative data, including the ischemic periods, indicated homogeneous patients. The study protocol was approved by the local ethics committee, and the study was performed according to the guidelines of the Declaration of Helsinki. Written informed consent was obtained from all patients. All patients underwent full-size OLT with the standard technique without venovenous bypass between March 2002 and August 2002 at the Hannover Medical School. For comparisons at different time points, the paired Student t test was used, and this was followed by the Bonferroni post hoc test. Time 0 was the time of liver reperfusion. A probability less than 0.05 was considered significant, and the data are presented as means and standard errors.
Address reprint requests to Dimitrios Tsikas, Ph.D., Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Telephone: 149 511 532 3984; FAX: 149 511 532 2750; E-mail: [email protected] DOI 10.1002/lt.23853 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION. DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 20, No. 6, 2014
as in kidney and heart transplantation,2 I/R does not elevate oxidative stress in OLT. Dimitrios Tsikas, Ph.D.1 € lich, M.D.1 € rgen C. Fro Ju € rgen Klempnauer, M.D.2 Ju Thomas Becker, M.D., Ph.D.3 1 Institute of Clinical Pharmacology and 2Clinic of Abdominal and Transplantation Surgery Hannover Medical School Hannover, Germany 3 Department of General, Visceral, Thoracic, Transplant, and Pediatric Surgery Schleswig-Holstein University Hospital Kiel, Germany
REFERENCES 1. Giustarini D, Dalle-Donne I, Tsikas D, Rossi R. Oxidative stress and human diseases: origin, link, measurement, mechanisms, and biomarkers. Crit Rev Clin Lab Sci 2009;46:241-281.
LETTER TO THE EDITORS 745
2. de Vries DK, Kortekaas KA, Tsikas D, Wijermars LG, van Noorden CJ, Suchy MT, et al. Oxidative damage in clinical ischemia/reperfusion injury: a reappraisal. Antioxid Redox Signal 2013;19:535-545. 3. Becker T, Mevius I, de Vries DK, Schaapherder AF, zu Vilsendorf AM, Klempnauer J, et al. The L-arginine/ NO pathway in end-stage liver disease and during orthotopic liver and kidney transplantation: biological and analytical ramifications. Nitric Oxide 2009;20: 61-67. 4. Tsikas D, Schwedhelm E, Stutzer FK, Gutzki FM, Rode I, Mehls C, Fr€ olich JC. Accurate quantification of basal plasma levels of 3-nitrotyrosine and 3-nitrotyrosinoalbumin by gas chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 784:77-90. 5. Tsikas D, Duncan MW. Mass spectrometry and 3-nitrotyrosine: strategies, controversies, and our current perspective. Mass Spectrom Rev; doi:10.1002/mas. 21396. 6. Tsikas D, Rode I, Becker T, Nashan B, Klempnauer J, Fr€ olich JC. Elevated plasma and urine levels of ADMA and 15(S)-8-iso-PGF2a in end-stage liver disease. Hepatology 2003;38:1063-1064.
LETTER TO THE EDITORS
Nitrosative Stress Does Not Change During Orthotopic Liver Transplantation Received February 4, 2014; accepted February 12, 2014.
TO THE EDITORS: Ischemia/reperfusion (I/R) is considered a major contributor to tissue damage in clinical situations, including liver transplantation, but its pathophysiology remains enigmatic. Reactive oxygen and nitrogen species (RONS) are considered key initiators of I/R injury. However, although antioxidant therapy has mitigated I/R injury in animal studies, the use of antioxidants has failed to show any appreciable benefit in clinical settings.1 Recent findings from clinical I/R studies of the kidneys and heart suggest that the contribution of RONS released upon organ reoxygenation to I/R injury in humans is less than generally thought, and they challenge our current understanding of oxidative stress and RONS-mediated I/R injury.2 The L-arginine/nitric oxide pathway is generally believed to generate RONS such as potent oxidizing and nitrating peroxynitrite (ONOO2). Previously, we demonstrated that despite a drastic release of arginase activity from the graft during orthotopic liver transplantation (OLT),3 the main players of this pathway did not change remarkably. In plasma samples from the patients of that study, we determined the concentrations of free 3-nitrotyrosine (NT) and 3nitrotyrosinoalbumin (NTALB) with fully validated and reliable gas chromatography/tandem mass spectrometry methods.4 NT and NTALB are formed through the reaction of peroxynitrite with free tyrosine (Tyr) and Tyr moieties in albumin, respectively, and they serve as biomarkers of oxidative stress.5 In comparison with age- and sex-matched healthy subjects, the patients who suffered from end-stage liver disease and underwent OLT had higher baseline plasma concentrations of NT (3.99 6 0.20 versus 1.14 6 0.21 nmol/L) and NTALB (27.7 6 1.2 versus 13.1 6 1.8 lmol of NT/mol of Tyr). Figure 1 shows that neither NT nor NTALB plasma concentrations changed statistically significantly during OLT. These findings and previous findings from our group for the same patient population6 indicate that oxidative stress is indeed elevated during end-stage liver disease. However, just
Figure. 1. Time course of the plasma concentrations of (A) free NT and (B) NTALB during OLT for 8 patients with end-stage liver disease. The patient characteristics and diagnoses have been reported previously.3 The liver transplant candidates reflected the typical clinical situation of patients with different underlying liver diseases and end-stage cirrhosis. The preoperative data, including the ischemic periods, indicated homogeneous patients. The study protocol was approved by the local ethics committee, and the study was performed according to the guidelines of the Declaration of Helsinki. Written informed consent was obtained from all patients. All patients underwent full-size OLT with the standard technique without venovenous bypass between March 2002 and August 2002 at the Hannover Medical School. For comparisons at different time points, the paired Student t test was used, and this was followed by the Bonferroni post hoc test. Time 0 was the time of liver reperfusion. A probability less than 0.05 was considered significant, and the data are presented as means and standard errors.
Address reprint requests to Dimitrios Tsikas, Ph.D., Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Telephone: 149 511 532 3984; FAX: 149 511 532 2750; E-mail: [email protected] DOI 10.1002/lt.23853 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION. DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 20, No. 6, 2014
as in kidney and heart transplantation,2 I/R does not elevate oxidative stress in OLT. Dimitrios Tsikas, Ph.D.1 € lich, M.D.1 € rgen C. Fro Ju € rgen Klempnauer, M.D.2 Ju Thomas Becker, M.D., Ph.D.3 1 Institute of Clinical Pharmacology and 2Clinic of Abdominal and Transplantation Surgery Hannover Medical School Hannover, Germany 3 Department of General, Visceral, Thoracic, Transplant, and Pediatric Surgery Schleswig-Holstein University Hospital Kiel, Germany
REFERENCES 1. Giustarini D, Dalle-Donne I, Tsikas D, Rossi R. Oxidative stress and human diseases: origin, link, measurement, mechanisms, and biomarkers. Crit Rev Clin Lab Sci 2009;46:241-281.
LETTER TO THE EDITORS 745
2. de Vries DK, Kortekaas KA, Tsikas D, Wijermars LG, van Noorden CJ, Suchy MT, et al. Oxidative damage in clinical ischemia/reperfusion injury: a reappraisal. Antioxid Redox Signal 2013;19:535-545. 3. Becker T, Mevius I, de Vries DK, Schaapherder AF, zu Vilsendorf AM, Klempnauer J, et al. The L-arginine/ NO pathway in end-stage liver disease and during orthotopic liver and kidney transplantation: biological and analytical ramifications. Nitric Oxide 2009;20: 61-67. 4. Tsikas D, Schwedhelm E, Stutzer FK, Gutzki FM, Rode I, Mehls C, Fr€ olich JC. Accurate quantification of basal plasma levels of 3-nitrotyrosine and 3-nitrotyrosinoalbumin by gas chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 784:77-90. 5. Tsikas D, Duncan MW. Mass spectrometry and 3-nitrotyrosine: strategies, controversies, and our current perspective. Mass Spectrom Rev; doi:10.1002/mas. 21396. 6. Tsikas D, Rode I, Becker T, Nashan B, Klempnauer J, Fr€ olich JC. Elevated plasma and urine levels of ADMA and 15(S)-8-iso-PGF2a in end-stage liver disease. Hepatology 2003;38:1063-1064.
