The role of endogenous heme oxygenase in the initiation of liver injury following limb ischemia/reperfusion.
OBJECTIVE
Heme oxygenase (HO) derived liver protection was tested in mice following 1 h bilateral hindlimb ischemia and either 1.5 or 3 h reperfusion.


METHODS
Groups consisted of limb ischemia/reperfusion (I/R), sham (no I/R), I/R+chromium mesoporphyrin (I/R+CrMP;40 micromol/kg, i.p.), or I/R+hemin (10 mg/kg, i.p.). The vital dye propidium iodide (PI), was used to measure hepatocellular death (#/0.1 mm(3)), while the number of sinusoids perfused by red blood cells (SP(RBC)) were measured from the periportal (Pp) and pericentral (Pc) zones of liver acini using intravital microscopy. Whole organ injury was estimated from serum alanine aminotransferase (ALT).


RESULTS
SP(RBC) reduced within 1.5 h with no further decline following 3 h. CrMP resulted in a dramatic loss of SP(RBC) following 3 h only. Hemin restored perfusion in both zones. Hepatocellular death and organ injury increased at 1.5 and 3 h. At 1.5 h, CrMP further increased cell death in the Pc zone, as well as whole organ injury, while hemin restored cell viability. Increased HO mRNA, protein and activity suggested induction within 3 h.


CONCLUSIONS
HO does not protect perfusion during the early stage (1.5 h), but becomes increasingly important in preserving liver perfusion and cell viability during the later stage (3 h) of liver injury.
Nie
Robert G
RG
Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada N6A 4G5.
McCarter
Sarah D
SD
Harris
Kenneth A
KA
Lee
Patty J
PJ
Zhang
Xuchen
X
Bihari
Aurelia
A
Gray
Daryl
D
Wunder
Christian
C
Brock
Robert W
RW
Potter
Richard F
RF
D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D001794:Blood Pressure; D016923:Cell Death; D005121:Extremities / Q000098:blood supply; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology; D008099:Liver / Q000098:blood supply / Q000166:cytology / Q000201:enzymology; D008102:Liver Circulation; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008652:Mesoporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D015427:Reperfusion Injury / Q000378:metabolism*
D008565:Membrane Proteins; D008652:Mesoporphyrins; D012333:RNA, Messenger; C427471:chromium mesoporphyrin; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000410:Alanine Transaminase