{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:19:22Z","timestamp":1760217562933},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,5,9]],"date-time":"2013-05-09T00:00:00Z","timestamp":1368057600000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Xenotransplantation"],"published-print":{"date-parts":[[2013,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Reactive oxygen species (<jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content>) and nitric oxide species (<jats:styled-content style=\"fixed-case\">NOS<\/jats:styled-content>) are pivotal after ischemia\u2013reperfusion. However, the role of different cells on the formation of free radical species after xenotransplantation remains elusive. We hypothesized that <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">NOS<\/jats:styled-content> formed during hyperacute rejection are dependent on leukocytes, erythrocytes, activated thrombocytes, and <jats:styled-content style=\"fixed-case\">K<\/jats:styled-content>upffer cells (<jats:styled-content style=\"fixed-case\">KC<\/jats:styled-content>s). To address this issue, we developed a model of xenoperfused rat liver and assessed the relationship between free radical production and graft dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Livers from <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>prague\u2010<jats:styled-content style=\"fixed-case\">D<\/jats:styled-content>awley rats were isolated, flushed with cold Ringer solution, and perfused at physically flow rates for 120\u00a0min after 1\u00a0h of ischemia. The control group was perfused with rat whole blood (n\u00a0=\u00a09). In the study groups, the livers were perfused with human whole blood, human plasma with erythrocytes, and plasma with erythrocytes and isolated thrombocytes (n\u00a0=\u00a09\/group). In an additional group, gadolinium chloride (<jats:styled-content style=\"fixed-case\">G<\/jats:styled-content>d<jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>l3), a selective <jats:styled-content style=\"fixed-case\">K<\/jats:styled-content>upffer cell (<jats:styled-content style=\"fixed-case\">KC<\/jats:styled-content>) toxic agent, was applied. Liver damage, hyperacute rejection, and the depletion of <jats:styled-content style=\"fixed-case\">KC<\/jats:styled-content>s were monitored histologically. Liver damage and function were determined by means of liver enzymes, portal pressure, and bile production. Malondialdehyde (<jats:styled-content style=\"fixed-case\">MDA<\/jats:styled-content>), nitric oxide formation, and peroxynitrite concentration, as well as total glutathione (t<jats:styled-content style=\"fixed-case\">GSH<\/jats:styled-content>) level, were measured as indicators for free radical formation and anti\u2010oxidative status.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Significant differences in the <jats:styled-content style=\"fixed-case\">MDA<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> NO<\/jats:styled-content>, peroxynitrite levels, and <jats:styled-content style=\"fixed-case\">GSH<\/jats:styled-content> levels after reperfusion with various cell populations were observed. Markedly high <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">RNS<\/jats:styled-content> production was evident in the <jats:styled-content style=\"fixed-case\">KC<\/jats:styled-content>s and the xenogeneic whole\u2010blood group. The oxidative stress was mainly caused by leukocytes and to lower extent by <jats:styled-content style=\"fixed-case\">KC<\/jats:styled-content>s, but only in combination with leukocytes. Neither erythrocytes, thrombocytes, nor hepatocytes had an effect on the release of <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">RNS<\/jats:styled-content>, as we could not observe significant differences in the <jats:styled-content style=\"fixed-case\">MDA<\/jats:styled-content>, peroxynitrite, and <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content> levels in these groups compared with control. Tissue injury and hyperacute rejection were more evident in the <jats:styled-content style=\"fixed-case\">KC<\/jats:styled-content> and whole\u2010blood livers. No sign of damage was observed for the control, erythrocyte, and thrombocyte group. Removal of leukocytes from the perfusate by filtration had a major protective effect on the liver function and the grade of hyperacute rejection, whereas <jats:styled-content style=\"fixed-case\">KC<\/jats:styled-content> depletion reduced the <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content> production, but did not have an impact on the hyperacute rejection and liver damage. In all xenogeneic perfused groups, the activation of the complement was histologically observed by positive <jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>3c and <jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>9b. Neither <jats:styled-content style=\"fixed-case\">KC<\/jats:styled-content> depletion nor the removal of leukocytes or thrombocytes from the perfusate had an effect on the activation of the complement system. Damage of the rat liver by the complement system was only observed in association with leukocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data revealed that various cell populations contribute to the formation of free radicals in our model. The production of free radicals was mainly linked to leukocytes and to a minor extent to <jats:styled-content style=\"fixed-case\">KC<\/jats:styled-content>s, but only in combination with leukocytes. Free radicals critically contribute to injury, rejection, and dysfunction of the xenotransplanted liver. Furthermore, hyperacute rejection in the xenogeneic perfused liver is triggered by the complement system only in the presence of leukocytes and free radical formation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/xen.12035","type":"journal-article","created":{"date-parts":[[2013,5,9]],"date-time":"2013-05-09T10:52:38Z","timestamp":1368096758000},"page":"177-187","source":"Crossref","is-referenced-by-count":10,"title":["Hyperacute rejection in the xenogenic transplanted rat liver is triggered by the complement system only in the presence of leukocytes and free radical species"],"prefix":"10.1111","volume":"20","author":[{"given":"Ba Thanh\u2010Truc","family":"Ngo","sequence":"first","affiliation":[{"name":"Institute for Surgical Research LMU University of Munich Munich Germany"},{"name":"Department of Cardiology University Medical Center Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andres","family":"Beiras\u2010Fernandez","sequence":"additional","affiliation":[{"name":"Institute for Surgical Research LMU University of Munich Munich Germany"},{"name":"Deparment of Cardiothoracic and Vascular Surgery J.W. 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