PMID- 22221603
OWN - NLM
STAT- MEDLINE
DCOM- 20121002
LR  - 20131121
IS  - 1095-8673 (Electronic)
IS  - 0022-4804 (Linking)
VI  - 176
IP  - 2
DP  - 2012 Aug
TI  - Reduction of liver ischemia reperfusion injury by silencing of TNF-alpha gene with 
      shRNA.
PG  - 614-20
LID - 10.1016/j.jss.2011.10.004 [doi]
AB  - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a central mediator in the 
      hepatic response to ischemia/reperfusion. Short hairpin RNA (shRNA) has been 
      proven to be an effective means of harnessing the RNA interference pathway in 
      mammalian cells. In the current study, we investigated whether silencing TNF-alpha 
      gene with shRNA can prevent liver ischemic reperfusion injury (IRI). METHODS: 
      Male BalB/c mice were randomized to TNF-alpha shRNA, scramble shRNA, or sham 
      operation groups. TNF-alpha shRNA and scramble shRNA groups were injected 48 h before 
      inducing IRI. IRI was induced via microaneurysm clamps applied to the left 
      hepatic artery and portal vein. Six hours after reperfusion, IRI injury was 
      examined by serum level of alanine aminotransferase (ALT) and aspartate 
      aminotransferase (AST), liver histopathology, MPO, and MDA level, as well as by 
      relative quantities of TNF-alpha mRNA. RESULTS: TNF-alpha expression induced by ischemia 
      reperfusion in the liver was significantly suppressed after treatment with TNF-alpha 
      shRNA compared with the group treated with scramble shRNA (P < 0.001). Mice 
      treated with TNF-alpha shRNA showed lower peak values of AST and ALT than scramble 
      shRNA treated mice (P < 0.001). On histopathologic slides, mice treated with 
      TNF-alpha shRNA had significantly less ischemia/reperfusion injury based on Suzuki 
      score than the scramble shRNA group, 3.57 +/- 2.30 and 8.83 +/- 0.98 respectively (P 
      < 0.001), while the sham group was not significantly different from the TNF-alpha 
      shRNA group, 0 +/- 0 and 3.57 +/- 2.30, respectively (P = 0.075). Liver tissue MDA 
      levels were significantly lower in mice treated with TNF-alpha shRNA as compared with 
      the group treated with scramble shRNA (P < 0.01). Immunohistochemical staining 
      for MPO was significantly lower in mice treated with TNF-alpha shRNA compared with 
      the group treated with shRNA (compared with treated with scramble shRNA group.) 
      CONCLUSIONS: Liver IRI can be minimized through gene silencing of TNF-alpha. This may 
      represent a novel therapy in the setting of transplantation and in other 
      conditions associated with IRI of the liver.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Hernandez-Alejandro, Roberto
AU  - Hernandez-Alejandro R
AD  - Multi-Organ Transplant Program, London Health Sciences Centre, The University of 
      Western Ontario, London, Canada. roberto.hernandezalejandro@lhsc.on.ca
FAU - Zhang, Xusheng
AU  - Zhang X
FAU - Croome, Kris P
AU  - Croome KP
FAU - Zheng, Xiufen
AU  - Zheng X
FAU - Parfitt, Jeremy
AU  - Parfitt J
FAU - Chen, Dong
AU  - Chen D
FAU - Jevnikar, Anthony
AU  - Jevnikar A
FAU - Wall, William
AU  - Wall W
FAU - Min, Wei-Ping
AU  - Min WP
FAU - Quan, Douglas
AU  - Quan D
LA  - eng
PT  - Journal Article
DEP - 20111101
PL  - United States
TA  - J Surg Res
JT  - The Journal of surgical research
JID - 0376340
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 4Y8F71G49Q (Malondialdehyde)
RN  - EC 1.11.1.7 (Peroxidase)
RN  - EC 2.6.1.1 (Aspartate Aminotransferases)
RN  - EC 2.6.1.2 (Alanine Transaminase)
SB  - IM
MH  - Alanine Transaminase/blood
MH  - Animals
MH  - Aspartate Aminotransferases/blood
MH  - Down-Regulation/genetics
MH  - Genetic Therapy/*methods
MH  - Liver/pathology/*physiology
MH  - Male
MH  - Malondialdehyde/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Peroxidase/metabolism
MH  - RNA, Small Interfering/genetics/*pharmacology
MH  - Reperfusion Injury/*genetics/pathology/*therapy
MH  - Tumor Necrosis Factor-alpha/*genetics
EDAT- 2012/01/10 06:00
MHDA- 2012/10/04 06:00
CRDT- 2012/01/07 06:00
PHST- 2011/07/24 00:00 [received]
PHST- 2011/09/23 00:00 [revised]
PHST- 2011/10/06 00:00 [accepted]
PHST- 2012/01/07 06:00 [entrez]
PHST- 2012/01/10 06:00 [pubmed]
PHST- 2012/10/04 06:00 [medline]
AID - S0022-4804(11)00834-1 [pii]
AID - 10.1016/j.jss.2011.10.004 [doi]
PST - ppublish
SO  - J Surg Res. 2012 Aug;176(2):614-20. doi: 10.1016/j.jss.2011.10.004. Epub 2011 Nov 
      1.