Role of NF-kappaB on liver cold ischemia-reperfusion injury.
The role of NF-kappaB, the rapid-response transcription factor for multiple genes, in cold ischemia-reperfusion (I/R) injury was examined after syngeneic transplantation of liver grafts. Lewis rat recipients were killed 1-48 h after reperfusion of three different liver grafts: 1) uninfected control, 2) infected ex vivo with control adenoviral vector (AdEGFP), and 3) infected ex vivo with AdIkappaB. In uninfected control livers, NF-kappaB was activated biphasically at 1-3 and 12 h after reperfusion with aspartate transaminase (AST) levels of 4,244 +/- 691 IU/l. The first peak of NF-kappaB activation associated with an increase of mRNA for TNF-alpha, IL-1beta, and IL-10. AdEGFP transfection resulted in similar outcomes. Interestingly, AdIkappaB-transfected liver grafts suffered more severe I/R injury (AST >9,000 IU/l). Transfected IkappaB was detected in transplanted livers as early as 6 h, and this correlated with the abrogation of the second, but not the first, peak of NF-kappaB activation at 12-48 h and increased apoptosis. Thus inhibition of the second wave of NF-kappaB activation in IkappaB-transfected livers resulted in an increase of liver injury, suggesting that NF-kappaB may have a dual role during liver I/R injury.
Takahashi
Yoshihito
Y
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
Ganster
Raymond W
RW
Gambotto
Andrea
A
Shao
Lifang
L
Kaizu
Takashi
T
Wu
Tong
T
Yagnik
Gautam P
GP
Nakao
Atsunori
A
Tsoulfas
George
G
Ishikawa
Takashi
T
Okuda
Toyokazu
T
Geller
David A
DA
Murase
Noriko
N
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015925:Cryopreservation; D016207:Cytokines / Q000235:genetics; D004247:DNA / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007511:Ischemia / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008102:Liver Circulation; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000473:pathology*
D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D004247:DNA