Inhibition of classical complement activation attenuates liver ischaemia and reperfusion injury in a rat model

Abstract

SummaryActivation 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.

A Role for Complement in the Enhanced Susceptibility of Steatotic Livers to Ischemia and Reperfusion Injury

“…Previous studies have demonstrated the presence of complement in the ischemically injured liver, with complement deposition on hepatocytes and sinusoidal endothelial cells, cells that are reported to express low levels of complement regulatory proteins (12,45). We similarly demonstrated the presence of C3d on hepatocytes and the sinusoidal endothelium in wt lean and steatotic mice after I/R and after transplantation.…”

Therapeutic Targeting of Classical and Lectin Pathways of Complement Protects from Ischemia-Reperfusion-Induced Renal Damage

“…[27][28][29][30] Moreover, C1INH limited leukocyte adhesion and neutrophil infiltration in a model of ischemia-reperfusion in the liver. [31][32][33] We observed that rhC1INH was very effective in limiting complement activation in renal tissue, as showed by the dramatic reduction of C4d and C5b-9 deposition. It is well known that early activation of complement leads to the release of active substances including C3a and C5a that can increase the recruitment of inflammatory cells.…”

Medroxyprogesterone acetate prevents the cardioprotective and anti-inflammatory effects of 17β-estradiol in an in vivo model of myocardial ischemia and reperfusion

“…The proposed mechanism of CRP involvement is through local activation of the complement cascade (39), and increased levels of CRP are reported to correlate with an increase in tissue injury after ischemia and reperfusion (3,13). Pharmacological inhibition of one or more of the multiple pathways of the inflammatory response has been demonstrated to reduce the extent of irreversible tissue injury after ischemia and reperfusion (15,36). Previous studies have shown that estrogen has the ability to reduce infarct size in the reperfused myocardium, possibly through modulation of the complement cascade, by reduction of CRP (5), or by an estrogen receptor-mediated anti-inflammatory mechanism (25,38).…”