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Effects of C1 inhibitor on endothelial cell activation in a rat hind limb ischemia-reperfusion injury model
- Source :
- Journal of Vascular Surgery. 68:209S-221S.e2
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- 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.
- Subjects :
- Male
0301 basic medicine
030204 cardiovascular system & hematology
Pharmacology
chemistry.chemical_compound
0302 clinical medicine
Edema
HMGB1 Protein
610 Medicine & health
Complement Activation
biology
Hindlimb
Endothelial stem cell
medicine.anatomical_structure
Reperfusion Injury
Plasminogen activator inhibitor-1
medicine.symptom
E-Selectin
Cardiology and Cardiovascular Medicine
Complement C1 Inhibitor Protein
Endothelium
Ischemia
Vascular Cell Adhesion Molecule-1
Fibrin
03 medical and health sciences
Plasminogen Activator Inhibitor 1
E-selectin
Complement C4b
medicine
Animals
Rats, Wistar
Muscle, Skeletal
Tissue Survival
Complement C1r
business.industry
Endothelial Cells
medicine.disease
Peptide Fragments
Disease Models, Animal
Complement Inactivating Agents
030104 developmental biology
Immunoglobulin M
chemistry
biology.protein
570 Life sciences
Surgery
Heparitin Sulfate
business
Reperfusion injury
Subjects
Details
- ISSN :
- 07415214
- Volume :
- 68
- Database :
- OpenAIRE
- Journal :
- Journal of Vascular Surgery
- Accession number :
- edsair.doi.dedup.....80126942feffe8ff72bf655b7c4a121a