{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T02:25:19Z","timestamp":1792031119061,"version":"4.4.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":3714,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,7]]},"abstract":"<jats:sec>\n            <jats:title>Abstract<\/jats:title>\n            <jats:p>\n                                 <jats:bold>An orthotopic liver transplant model in the rat was used to evaluate the role of tumor necrosis factor alpha (TNF-\u03b1) in liver transplant rejection. There were significantly increased levels of TNF-\u03b1 mRNA and parallel increases in 8-hydroxy-2\u2032 deoxyguanosine (8-OHdG) indicative of oxidative DNA damage present 7 to 12 days after transplantation. Cells staining positively for 8-OHdG were localized to the cytoplasm of hepatocytes adjacent to the TNF-\u03b1 expressing inflammatory cells in the portal areas or in patches surrounded by inflammatory cells in the hepatic sinusoids. Significantly more cells staining for 8-OHdG were found in the allogeneic grafts that were strongly rejected than in the syngeneic controls or in the grafts placed in species that accepted the allograft permanently after a rejection episode. TUNEL reactivity lagged 2 days behind peak reactivity for 8-OHdG. On day 12 after transplantation, many cells stained for both 8-OHdG and TUNEL, indicating that the cells suffering oxidative DNA injury were undergoing apoptosis or death. Oxidative injury resulted in mtDNA deletion consisting of 4,834 base-pairs. Studies of hepatocytes cultured from normal rats displayed dose-dependent relationships between TNF-\u03b1 concentration and 8-OHdG and mtDNA mutation. Repetitive intraperitoneal injection of Enbrel, a TNF receptor blocker, significantly decreased hepatocyte 8-OHdG levels and the frequency of deleted mtDNA while greatly extending graft survival time.<\/jats:bold>\n                                 <jats:underline>In conclusion<\/jats:underline>\n                                 <jats:bold>, the data presented implicate TNF-\u03b1 as being capable of causing oxidative DNA damage and mtDNA mutation in hepatocytes. (Hepatology 2005;42:208\u2013215.)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.20755","type":"journal-article","created":{"date-parts":[[2005,6,16]],"date-time":"2005-06-16T21:18:30Z","timestamp":1118956710000},"page":"208-215","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":40,"title":["Oxidative Mitochondrial DNA Damage and Deletion in Hepatocytes of Rejecting Liver Allografts in Rats: Role of TNF-\u03b1 *"],"prefix":"10.1097","volume":"42","author":[{"given":"Yuichi","family":"Nagakawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George 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