Remote ischemic preconditioning by hindlimb occlusion prevents liver ischemic/reperfusion injury: the role of High Mobility Group-Box 1.
BACKGROUND
Hepatocellular injury caused by ischemia-reperfusion of the liver occurs in a number of clinical situations including major trauma, elective surgery of the liver, and liver transplantation. Several strategies have been used to prevent liver injury following ischemia-reperfusion (I/R). Among these, ischemic preconditioning has shown promise as a preventative approach. In this manuscript, we hypothesized that use of remote ischemic preconditioning by brief hindlimb ischemia might prevent liver dysfunction in a mouse model of liver I/R.


METHODS
C57/B mice were subjected to 60 minutes of partial liver ischemia with or without antecedent hindlimb vascular I/R. Blood was drawn for serum alanine aminotransferase levels at times following liver reperfusion. Liver inflammation was assessed by measuring serum and liver tumor necrosis factor (TNF)-alpha protein and mRNA. The role of toll-like receptor 4 (TLR4) in mediating protection was determined using the mouse strain HeJ, which has a mutated TLR4.


RESULTS
Antecedent hindlimb ischemia (10 minutes) lessened I/R-induced elevation of serum alanine aminotransferase compared with untreated I/R animals. This protection correlated with a reduction in serum TNF-alpha protein levels as well as liver TNF-alpha mRNA and apoptosis. High Mobility Group-Box 1 (HMG-B1) levels in the blood were elevated after hindlimb ischemia and injection of HMG-B1 prior to liver recapitulated the protective effect of hindlimb occlusion. TLR4-mutant HeJ mice did not demonstrate protection with hindlimb preconditioning.


CONCLUSIONS
Brief hindlimb occlusion prevents liver I/R injury. This effect appears to be related to release of HMG-B1 and is dependent on the presence of a functional TLR4. Remote ischemia preconditioning represents a novel approach to preventing distant organ injury.
Department of Surgery, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
Feng
F
Wang
Simone E
SE
Birch
Ruijan
R
He
Patrick
P
Tawadros
Katalin
K
Szaszi
Andras
A
Kapus
Ori D
OD
Rotstein
D000818:Animals; D005260:Female; D006609:High Mobility Group Proteins / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply*; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000517:prevention & control*; D012097:Repressor Proteins / Q000502:physiology*
C486329:Hbp1 protein, mouse; D006609:High Mobility Group Proteins; D012097:Repressor Proteins