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. 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.
The l-arginine/nitric oxide pathway is generally believed to generate RONS such as potent oxidizing and nitrating peroxynitrite (ONOO−). Previously, we demonstrated that despite a drastic release of arginase activity from the graft during orthotopic liver transplantation (OLT), 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 3-nitrotyrosinoalbumin (NTALB) with fully validated and reliable gas chromatography/tandem mass spectrometry methods. 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. 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 ± 0.20 versus 1.14 ± 0.21 nmol/L) and NTALB (27.7 ± 1.2 versus 13.1 ± 1.8 μmol 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 population indicate that oxidative stress is indeed elevated during end-stage liver disease. However, just as in kidney and heart transplantation, I/R does not elevate oxidative stress in OLT.
Dimitrios Tsikas, Ph.D.1
Jürgen C. Frölich, M.D.1
Jürgen Klempnauer, M.D.2
Thomas Becker, M.D., Ph.D.3
1Institute of Clinical Pharmacology and 2Clinic of Abdominal and Transplantation Surgery
Hannover Medical School
3Department of General, Visceral, Thoracic, Transplant, and Pediatric Surgery
Schleswig-Holstein University Hospital