Anti-endotoxin monoclonal antibodies are protective against hepatic ischemia/reperfusion injury in steatotic mice.
Steatotic mice are particularly susceptible to hepatic ischemia/reperfusion injury compared with their lean littermates. We have previously demonstrated that livers of mice having a spontaneous mutation in the leptin gene (ob/ob), resulting in global obesity and liver steatosis, are ATP depleted, are endotoxin sensitive, and do not survive (I/R) injury. We hypothesize that administration of an anti-LPS monoclonal antibody (mAb) prior to initiation of I/R would be protective from that insult. Steatotic mice (ob/ob) were subjected to 15 min of ischemia via complete porta-hepatis occlusion and varying lengths of reperfusion with or without pre-treatment with an anti-LPS mAb. There was 14-31% survival of isotype matched control mAb treated ob/ob mice after 15 min of ischemia and 24 h of reperfusion. In contrast, 75-83% of ob/ob mice pre-treated with an anti-LPS mAb prior to initiation of I/R survived both ischemia and 24 h of reperfusion. Furthermore, there was a decrease in ALT and circulating endotoxin levels when treated with an anti-LPS mAb compared with control antibodies. Attenuation of the endotoxin load with anti-LPS mAb, prior to initiation of I/R, was cytoprotective and improved survival. Consequently, these studies might offer a solution to the problems associated with using steatotic livers in clinical transplantation.
Fiorini
Ryan N
RN
Department of Surgery, Division of Transplant, Medical University of South Carolina (MUSC), Charleston, SC, USA.
Shafizadeh
Stephen F
SF
Polito
Carmen
C
Rodwell
David W
DW
Cheng
Gang
G
Evans
Zachary
Z
Wan
Chidan
C
Belden
Sarah
S
Haines
Julia K
JK
Birsner
Jennifer
J
Lewin
David
D
Wasiluk
Karen R
KR
Dunn
David L
DL
Schmidt
Michael G
MG
Chavin
Kenneth D
KD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D004731:Endotoxins / Q000097:blood / Q000276:immunology*; D005234:Fatty Liver; D008099:Liver / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D015427:Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D004731:Endotoxins