Effect of C1-INH on ischemia/reperfusion injury in a porcine limb ex vivo perfusion model.

Abd El Hafez, Mai Moustafa Ahmed; Shaw-Boden, Jane; Sutter, Damian; Schnider, Jonas Thomas; Banz Wälti, Yara; Jenni, Hansjörg; Vögelin, Esther; Constantinescu, Mihai Adrian; Rieben, Robert (2017). Effect of C1-INH on ischemia/reperfusion injury in a porcine limb ex vivo perfusion model. Molecular immunology, 88, pp. 116-124. Elsevier 10.1016/j.molimm.2017.06.021

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Revascularization of an amputated limb within 4-6h is essential to avoid extensive ischemia/reperfusion (I/R) injury leading to vascular leakage, edema and tissue necrosis. I/R injury is a pathological inflammatory condition that occurs during reperfusion of an organ or tissue after prolonged ischemia. It is characterized by a complex crosstalk between endothelial cell activation and the activation of plasma cascades. Vasculoprotective pharmacological intervention to prevent I/R injury might be an option to prolong the time window between limb amputation and successful replantation. We used C1-easterase inhibitor (C1-INH) in this study because of its known inhibitory effects on the activation of the complement, coagulation and kinin cascades. Forelimbs of 8 large white pigs were amputated, subjected to ischemia, and then reperfused with autologous whole blood. All limbs were exposed to 9h of cold ischemia at 4°C. After 2h of cold ischemia the limbs were either perfused with of C1-INH (1U/ml in hydroxyethyl starch, n=8) or hydroxyethyl starch alone (n=7). After completion of the 9-h ischemia period, all limbs were ex vivo perfused with heparinized autologous whole blood for 12h using a pediatric heart lung machine to simulate in vivo revascularization. Our results show that I/R injury in the control group led to a significant elevation of tissue deposition of IgG and IgM, complement C3b/c, C5b-9 and MBL. Also, activation of the kinin system was significantly increased, namely bradykinin in plasma, and expression of bradykinin receptors 1 and 2 in tissue. In addition, markers for endothelial integrity like expression of CD31, VE-cadherin and heparan sulfate proteoglycans were decreased in reperfused tissue. Limb I/R injury also led to activation of the coagulation cascade with a significant elevation of fibrin and thrombin deposition and increased fibrinogen-like protein-2 expression. C1-INH treated limbs showed much less activation of plasma cascades and better protection of endothelial integrity compared to the reperfused control limbs. In conclusion, the use of the cytoprotective drug C1-INH significantly reduced I/R injury by protecting the vascular endothelium as well as the muscle tissue from deposition of immunoglobulins, complement and fibrin.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Herz und Gefässe
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Handchirurgie
04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Plastic and Hand Surgery
04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Plastic and Hand Surgery > Plastic, Reconstructive and Aesthetic Surgery
04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Plastic and Hand Surgery > Hand Surgery
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Unit Tiefenau Hospital (discontinued) > Forschungsgruppe Vasoaktive Peptide (discontinued)

UniBE Contributor:

Abd El Hafez, Mai Moustafa Ahmed; Shaw-Boden, Jane; Sutter, Damian; Schnider, Jonas Thomas; Banz Wälti, Yara; Vögelin, Esther; Constantinescu, Mihai Adrian and Rieben, Robert

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0161-5890

Publisher:

Elsevier

Language:

English

Submitter:

Veronika Picha

Date Deposited:

27 Jul 2017 08:57

Last Modified:

06 Feb 2018 10:45

Publisher DOI:

10.1016/j.molimm.2017.06.021

PubMed ID:

28641140

Uncontrolled Keywords:

C1-INH; Endothelial cell; Ischemia reperfusion injury; Plasma cascade systems; Skeletal muscle

BORIS DOI:

10.7892/boris.102328

URI:

https://boris.unibe.ch/id/eprint/102328

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