Effects of C1 inhibitor on endothelial cell activation in a rat hind limb ischemia-reperfusion injury model.

Zhang, Shengye; Shaw-Boden, Jane; Banz, Yara; Bongoni, Anjan K; Taddeo, Adriano; Spirig, Rolf; Nolte, Marc W; Cowan, Peter J; Rieben, Robert (2018). Effects of C1 inhibitor on endothelial cell activation in a rat hind limb ischemia-reperfusion injury model. Journal of vascular surgery, 68(6 Suppl.), 209S-221S.e2. Elsevier 10.1016/j.jvs.2017.10.072

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OBJECTIVE Ischemia-reperfusion (I/R) injury is a major clinical problem linked to vascular surgery. Currently, no drugs to prevent or to treat I/R injury are approved for clinical use. C1 inhibitor (C1 INH) is known to reduce activation of the plasma cascade systems that are involved in the pathophysiologic process of I/R injury. The aim of this study was therefore to investigate the effect of C1 INH on complement deposition and endothelial cell activation in a rat model of hind limb I/R injury. METHODS Male Wistar rats (wild type, bred at the central animal facility, University of Bern), weighing 250 to 320 g, were used. The rats underwent 2-hour ischemia and 24-hour reperfusion by unilateral clamping of the femoral artery and additional use of a tourniquet. Five groups were divided according to intravenous treatment 5 minutes before ischemia: 50 IU/kg C1 INH (n = 5); 100 IU/kg C1 INH (n = 7); vehicle control (n = 5); nontreated control (n = 7); and normal, healthy control without intervention (n = 4). At the end, muscle edema, tissue viability, and histologic features were assessed. Deposition of immunoglobulin M, C1r, C4d, and fibrin and expression of plasminogen activator inhibitor 1, heparan sulfate (HS), E-selectin, and vascular cell adhesion molecule 1 were evaluated by fluorescence staining. In addition, high-mobility group box 1 protein was measured in plasma. RESULTS Edema formation was reduced by C1 INH at two dosages, mirrored by improved histologic injury scores and preserved muscle viability. Deposition of immunoglobulin M, C4d, and fibrin was significantly decreased by 100 IU/kg C1 INH compared with nontreated controls. Pretreatment with 100 IU/kg C1 INH also significantly reduced HS shedding and expression of plasminogen activator inhibitor 1 as well as plasma levels of high-mobility group box 1 protein. CONCLUSIONS Pretreatment with both 50 and 100 IU/kg C1 INH attenuated reperfusion injury of rat hind limbs. Pretreatment with 100 IU/kg also preserved the endothelial HS layer as well as the natural, profibrinolytic phenotype of the endothelium. Prevention of endothelial cell activation by C1 INH may therefore be a promising strategy to prevent I/R injury in the clinical setting of peripheral vascular diseases and elective surgery on extremities.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Plastic and Hand Surgery
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
09 Interdisciplinary Units > Microscopy Imaging Center (MIC)

UniBE Contributor:

Zhang, Shengye; Shaw-Boden, Jane; Banz Wälti, Yara; Taddeo, Adriano; Spirig, Rolf and Rieben, Robert

Subjects:

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

ISSN:

0741-5214

Publisher:

Elsevier

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

27 Feb 2019 14:33

Last Modified:

02 Dec 2019 02:38

Publisher DOI:

10.1016/j.jvs.2017.10.072

PubMed ID:

29395422

BORIS DOI:

10.7892/boris.125553

URI:

https://boris.unibe.ch/id/eprint/125553

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