Local and Remote Ischemia-Reperfusion Injury Is Mitigated in Mice Overexpressing Human C1 Inhibitor

Abstract

Activation of the classical complement pathway is crucially involved in complement-mediated endothelial cell damage in ischemia-reperfusion injury. C1 inhibitor is the only known physiological inhibitor of classical complement pathway activation. Transgenic mice overexpressing human C1 inhibitor were used in a surgical lower torso and a liver ischemia-reperfusion model. Organ-specific endothelial disruption was determined by ¹²⁵I-tagged albumin extravasation. In the lower torso ischemia-reperfusion model, transgenic mice overexpressing the C1 inhibitor were protected in the muscle and the lungs from endothelial cell damage. In the liver ischemia-reperfusion model, endothelial cell integrity was preserved in transgenic animals in the liver, the gut and the lungs. Our data indicate that inhibiting complement activation by a transgenic approach is effective in protection against ischemia-reperfusion injury.

C1 Esterase Inhibitor Reduces Lower Extremity Ischemia/Reperfusion Injury and Associated Lung Damage

“…They found that muscle as well as lung tissue was protected from endothelial cell damage by measuring the amount of extravasation of 125 I-labelled albumin, reflecting a direct functional measurement of endothelial integrity [53]. We showed here for the first time in non-transgenic animals that C1 INH at a low, clinically applicable dose of 50 IU/kg significantly reduced peripheral IRI in muscle and, in particular, that also lung injury was significantly reduced.…”

“…Currently, not much is known about the mechanisms by which VE-cadherin-mediated cell-cell junctions are regulated. It could be speculated that in the present study the increase of VE-cadherin expression could be due to repair mechanisms, whereas C1 INH maintains endothelial cell integrity and avoids activation of these mechanisms [53]. However, a more detailed analysis of the mechanism of VE-cadherin regulation in IRI would be necessary to support this hypothesis, which is beyond the scope of the present study.…”

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.…”

Biological activities of C1 inhibitor

“…Beneficial effects of C1 inhibitor also have been described in other ischemia-reperfusion injury models including skeletal muscle (Nielsen et al, 2002; Toomayan et al, 2003), liver (Heijnen et al, 2006; Inderbitzin et al, 2004; Lehmann et al, 2000), middle cerebral artery occlusion (Akita et al, 2003; De Simoni et al, 2004; De Simoni et al, 2003; Storini et al, 2005), and superior mesenteric artery occlusion (Karpel-Massler et al, 2003; Lauterbach et al, 2007; Padilla et al, 2007). Interestingly, the effect of C1 inhibitor in brain ischemia-reperfusion is apparently not mediated via inhibition of C1r/C1s because C1q deficient mice were susceptible to injury and responded to treatment with C1 inhibitor (De Simoni et al, 2004).…”