Protective effect of lipopolysaccharide preconditioning in hepatic ischaemia reperfusion injury.
BACKGROUND
Preconditioning using lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) ligand, has been demonstrated to reduce ischaemia/reperfusion injury (IRI) in some organs, but its effect in the liver has not been elucidated. We examined the liver protective mechanism and correlated signalling pathway of LPS preconditioning in mice.


METHODS
BALB/c and TLR4 mutant mice underwent 90 min of 70% hepatic ischaemia. Lipopolysaccharide (100 µg/kg) was injected intraperitoneally 20 h or 30 min before ischaemia. Liver damage after reperfusion was examined using serum samples and liver specimens. To analyse the mechanism of preconditioning in detail, phosphorylation of representative signalling mediators to nuclear factor-κB (NF-κB) activation, Akt and interleukin-1 receptor-associated kinase-1 (IRAK-1), and expression of a negative feedback inhibitor, suppressor of cytokine signalling-1 (SOCS-1), were evaluated by Western blotting.


RESULTS
Pretreatment with LPS only 20 h before ischaemia elicited a preconditioning effect; however, preconditioning was absent in TLR4 mutant mice. Lipopolysaccharide significantly decreased serum alanine aminotransferase, tumour necrosis factor-α, hepatocyte necrosis and NF-κB activity after reperfusion. Phosphorylated IRAK-1 was suppressed by LPS, whereas no difference was observed in phosphorylated Akt. Pre-ischaemic LPS provided early induction of SOCS-1.


CONCLUSIONS
Late-phase LPS preconditioning provided liver protection against IRI through the downregulation of the TLR4 cascade derived from early induction of SOCS-1 during ischaemia/reperfusion.
Sano
Takanori
T
Department of Gastroenterological Surgery, Federation of Public Services and Affiliated Personnel Aid Associations, Takamatsu Hospital, Kagawa, Japan. sanocchi14@hotmail.com
Izuishi
Kunihiko
K
Hossain
Mohammad A
MA
Kakinoki
Keitaro
K
Okano
Keiichi
K
Masaki
Tsutomu
T
Suzuki
Yasuyuki
Y
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000172:deficiency / Q000235:genetics
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000410:Alanine Transaminase; D019869:Phosphatidylinositol 3-Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt