Inhibition of classical complement activation attenuates liver ischaemia and reperfusion injury in a rat model.
Activation of the complement system contributes to the pathogenesis of ischaemia/reperfusion (I/R) injury. We evaluated inhibition of the classical pathway of complement using C1-inhibitor (C1-inh) in a model of 70% partial liver I/R injury in male Wistar rats (n = 35). C1-inh was administered at 100, 200 or 400 IU/kg bodyweight, 5 min before 60 min ischaemia (pre-I) or 5 min before 24 h reperfusion (end-I). One hundred IU/kg bodyweight significantly reduced the increase of plasma levels of activated C4 as compared to albumin-treated control rats and attenuated the increase of alanine aminotransferase (ALT). These effects were not better with higher doses of C1-inh. Administration of C1-inh pre-I resulted in lower ALT levels and higher bile secretion after 24 h of reperfusion than administration at end-I. Immunohistochemical assessment indicated that activated C3, the membrane attack complex C5b9 and C-reactive protein (CRP) colocalized in hepatocytes within midzonal areas, suggesting CRP is a mediator of I/R-induced, classical complement activation in rats. Pre-ischaemic administration of C1-inh is an effective pharmacological intervention to protect against liver I/R injury.
Heijnen
B H M
BH
Department of Surgery, Surgical Laboratory, Academic Medical Centre, Amsterdam, The Netherlands.
Straatsburg
I H
IH
Padilla
N D
ND
Van Mierlo
G J
GJ
Hack
C E
CE
Van Gulik
T M
TM
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001646:Bile / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D050718:Complement C1 Inhibitor Protein / Q000627:therapeutic use*; D015926:Complement C3a / Q000032:analysis; D015934:Complement C4a / Q000032:analysis; D015938:Complement Membrane Attack Complex; D003171:Complement Pathway, Classical / Q000187:drug effects*; D003165:Complement System Proteins / Q000032:analysis; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D006023:Glycoproteins / Q000032:analysis; D006651:Histocytochemistry / Q000379:methods; D007511:Ischemia / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D008099:Liver / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D015415:Biomarkers; D050718:Complement C1 Inhibitor Protein; D015938:Complement Membrane Attack Complex; D006023:Glycoproteins; C047610:SC5b-9 protein complex; D015926:Complement C3a; D015934:Complement C4a; D003165:Complement System Proteins; D002097:C-Reactive Protein; D000410:Alanine Transaminase