Complement activation induced by ischemia-reperfusion in humans: a study in patients undergoing partial hepatectomy.
OBJECTIVE
Activation of the complement system is induced by ischemia-reperfusion (I/R) in animal models. Whether I/R also induces complement activation in humans is not known. Here, we investigated complement activation in patients undergoing major liver resection.


METHODS
In 11 of 17 patients, the hepatoduodenal ligament was clamped, making the liver transiently ischemic (HEMI+; mean ischemia time, 42 +/- 18 min); 6 patients were operated without clamping (HEMI-). Activation at plasma level (circulating activation products) was studied in blood samples collected prior to surgery and 5, 24 and 48 h thereafter. Parameters analyzed were C4b/c and C3b/c, C4d and C3d, C3a, as well as complexes between complement and C-reactive protein (CRP), which reflect CRP-induced complement activation. Activation at tissue level (C3 and C4 fixation) was studied in liver biopsies obtained before and after resection.


RESULTS
In plasma, post-operative levels of C4b/c and C3b/c were not different from baseline levels in both groups. Mean plasma levels of C4b/c and C3b/c were significantly decreased at 24 h post-surgery in the HEMI+ group (p=0.02 and p=0.07). At the same time, levels of C4d-CRP and C3d-CRP were significantly increased (p<0.01 for both parameters). At tissue level, activated complement fragments were observed intracellularly in some pericentral hepatocytes. In I/R livers, large numbers of hepatocytes were positively stained for all complement activation products.


CONCLUSIONS
Our data show that in situ complement activation via the classical route occurred during liver resection and that ischemia and/or reperfusion may have contributed to activation. Levels of complement activation products in the circulation were low, showing that transient ischemia had no severe influence on systemic complement activation, suggesting a locally contained response.
Straatsburg
I H
IH
Department of Cell Biology & Histology, Academic Medical Center, University of Amsterdam, The Netherlands. i.h.straatsburg@amc.uva.nl
Boermeester
M A
MA
Wolbink
G J
GJ
van Gulik
T M
TM
Gouma
D J
DJ
Frederiks
W M
WM
Hack
C E
CE
D000328:Adult; D000368:Aged; D003167:Complement Activation; D003176:Complement C3 / Q000276:immunology; D003181:Complement C4 / Q000276:immunology; D003168:Complement Fixation Tests; D006498:Hepatectomy; D006801:Humans; D008099:Liver / Q000276:immunology* / Q000473:pathology*; D008875:Middle Aged; D015427:Reperfusion Injury / Q000097:blood / Q000276:immunology*
D003176:Complement C3; D003181:Complement C4