Transfer of the interleukin-1 receptor antagonist gene into rat liver abrogates hepatic ischemia-reperfusion injury.
BACKGROUND
The anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) is known to reduce hepatic ischemia-reperfusion injury. Therefore, we wished to examine the effect of IL-1Ra gene delivery into the rat liver on hepatic ischemia-reperfusion injury.


METHODS
IL-1Ra cDNA was delivered into the rat liver by a single injection of the transgene vector into the portal vein using either the plasmid-cationic liposome or the recombinant adenoviral vector. At 24 hours after the gene delivery, rats were subjected to partial liver ischemia for 90 minutes followed by reperfusion. Liver tissue and serum samples were taken at 180 minutes of reperfusion, and the degree of the liver injury as well as the expression level of pro-inflammatory cytokines in the serum and tissue were investigated. In addition, we assessed the effect of IL-1Ra gene delivery on the 7-day survival rate when the nonischemic liver lobe was partially excised immediately following reperfusion.


RESULTS
In both cases of delivery methods, gene transfer of IL-1Ra resulted in significant elevation of serum IL-1Ra concentration, which reached maximal levels at 24 hours following the delivery. However, the highest serum concentration with the adenoviral vector was 1,000-fold of that in the liposome-treated animals. In the IL-1Ra delivered rats, liver damage, as well as production of pro-inflammatory cytokines, at 180 minutes of reperfusion was significantly reduced in a concentration-dependent manner of the circulating IL-1Ra protein. Rats subjected to the adenoviral vector gene delivery had higher 7-day survival rates compared with control animals.


CONCLUSIONS
IL-1Ra gene delivery into the liver may be of therapeutic use for abrogating hepatic ischemia-reperfusion injury after transplantation.
Harada
Hirohisa
H
Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
Wakabayashi
Go
G
Takayanagi
Atsushi
A
Shimazu
Motohide
M
Matsumoto
Kenji
K
Obara
Hideaki
H
Shimizu
Nobuyoshi
N
Kitajima
Masaki
M
D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6 / Q000096:biosynthesis; D007511:Ischemia / Q000628:therapy*; D008099:Liver / Q000098:blood supply* / Q000378:metabolism*; D016031:Liver Transplantation; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000401:mortality / Q000628:therapy*; D012795:Sialoglycoproteins / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha