Blocking complement activation in general, and complement factor 5a in particular, inhibits intimal hyperplasia and accelerated atherosclerosis in murine vein grafts

2006 ◽  
Vol 45 (3) ◽  
pp. e1 ◽  
Author(s):  
A. Schepers ◽  
M.R. de Vries ◽  
M. Daha ◽  
J.H. van Bockel ◽  
P.H.A. Quax
Keyword(s):  
Complement Activation ◽  
Intimal Hyperplasia ◽  
Complement Factor ◽  
Accelerated Atherosclerosis ◽  
Vein Grafts

Platelet adhesion on endothelium early after vein grafting mediates leukocyte recruitment and intimal hyperplasia in a murine model

2015 ◽  
Vol 113 (04) ◽  
pp. 813-825 ◽  
Author(s):  
Chi-Nan Tseng ◽  
Ya-Ting Chang ◽  
Mariette Lengquist ◽  
Malin Kronqvist ◽  
Ulf Hedin ◽  
...  
Keyword(s):  
Early Intervention ◽  
Intimal Hyperplasia ◽  
Platelet Adhesion ◽  
Leukocyte Adhesion ◽  
Vena Cava ◽  
Specific Treatment ◽  
Leukocyte Recruitment ◽  
Blocking Antibody ◽  
Accelerated Atherosclerosis ◽  
Vein Grafts

SummaryIntimal hyperplasia (IH) is the substrate for accelerated atherosclerosis and limited patency of vein grafts. However, there is still no specific treatment targeting IH following graft surgery. In this study, we used a mouse model of vein grafting to investigate the potential for early intervention with platelet function for later development of graft IH. We transferred the inferior vena cava (IVC) from donor C57BL/6 mice to the carotid artery in recipients using a cuff technique. We found extensive endothelial injury and platelet adhesion one hour following grafting. Adhesion of leukocytes was distinct in areas of platelet adhesion. Platelet and leukocyte adhesion was strongly reduced in mice receiving a function-blocking antibody against the integrin αIIbβ3. This was followed by a reduction of IH one month following grafting. Depletion of platelets using antiserum also reduced IH at later time points. These findings indicate platelets as pivotal to leukocyte recruitment to the wall of vein grafts. In conclusion, the data also highlight early intervention of platelets and inflammation as potential treatment for later formation of IH and accelerated atherosclerosis following bypass surgery.

Intimal Hyperplasia in Reversed and in Situ Vein Grafts: An Intra-Individual Canine Study

1994 ◽  
Vol 7 (2) ◽  
pp. 159-165 ◽  
Author(s):  
M. J. M. Segers ◽  
F. L. Moll ◽  
F. J. J. M. v.d. Molengrar ◽  
P. J. Klopper
Keyword(s):  
Intimal Hyperplasia ◽  
Vein Grafts ◽  
Canine Study

scholarly journals Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts

2005 ◽  
Vol 129 (6) ◽  
pp. 1405-1413 ◽  
Author(s):  
Jonathan A. Hata ◽  
Jason A. Petrofski ◽  
Jacob N. Schroder ◽  
Matthew L. Williams ◽  
Sarah H. Timberlake ◽  
...  
Keyword(s):  
Saphenous Vein ◽  
Intimal Hyperplasia ◽  
Kinase Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Vein Grafts ◽  
Saphenous Vein Grafts ◽  
Phosphatidylinositol 3

scholarly journals Promoting Vasa Vasorum Neovascularization of Vein Grafts Extenuates Hypoxia of the Wall and Its Subsequent Influence on Intimal Hyperplasia

2017 ◽  
Vol 130 (11) ◽  
pp. 1327-1332
Author(s):  
Rong-Jiang Zou ◽  
Zheng-Hua Wang ◽  
Chen-Xi Wang ◽  
Song Xue
Keyword(s):  
Intimal Hyperplasia ◽  
Vasa Vasorum ◽  
Vein Grafts

scholarly journals P0531CONTINUOUS HEMODIAFILTRATION WITH PMMA HEMOFILTER MODULATED COMPLEMENT ACTIVATION AND RENAL DYSFUNCTION IN A SWINE MODEL OF SEPSIS-INDUCED ACUTE KIDNEY INJURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Alessandra Stasi ◽  
ROSSANA FRANZIN ◽  
Fabio Sallustio ◽  
Chiara Divella ◽  
Claudia Curci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Kidney Injury ◽  
Complement Activation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Kidney Injury ◽  
Swine Model ◽  
Complement Factor ◽  
Factor B ◽  
Renal Biopsies

Abstract Background and Aims Sepsis-induced acute kidney injury (AKI) is a growing health care problem, refractory to conventional treatments. This disease is characterized by an overwhelmed immune response against a primary insult that become responsible for renal dysfunction and poor outcome. Therapeutic strategies based on blood purification have been developed for the treatment of this disease. The use of polymethyl methacrylate (PMMA) membrane hemofilter in continuous hemodiafiltration (CHDF) modality showed better hemodynamic stability and efficient renal support in chronic dialysis maintenance. Here we investigated the efficacy of Hemofeel PMMA membrane (TORAY, Japan) in interfering with Complement activation and renal damage in a swine model of sepsis-induced AKI. Method After 3 hours from LPS infusion, 7 hours of PMMA-CVVH treatment or 7 hours of polysulfone (PSF)-CVVH were performed. Animals were sacrificed after 24h from LPS infusion. Histologic and renal function parameters were analyzed in all pigs. Pentraxin-3 (PTX3) and C5b-9 deposits were assessed on renal biopsies. Systemic Complement activation was evaluated by Wieslab kit. Gene expression profile was obtained from isolated PBMCs by Agilent SurePrint G3 Porcine Gene Expression Microarrays. Genespring and R software were used for the analysis. Results were validated by Real-time PCR. Results Analysis of renal biopsies from septic pigs presented increased interstitial leucocyte infiltrate, extensive collagen deposition and diffuse glomerular thrombi compared to healthy pigs (p<0.05). Confocal analysis showed extensive PTX-3 and C5-b9 deposits at tubulo-interstitial level associated with significant activation of systemic complement classical and alternative pathways (p<0.05). Interestingly, PMMA-CVVH treatment significantly reduced local and systemic complement activation, leucocyte infiltrate and tubule-interstitial fibrosis (p<0.05). On the contrary, no significant improvement was observed by PSF-CVVH treatment. Then, we compared the whole-genome gene expression profiles of swine PBMC. We identified 711 differentially expressed genes comparing PBMC before LPS infusion (LPS T0) and after 24 hours from LPS infusion (LPS T24) and 913 genes comparing gene expression profiles of LPS T24 group with that of septic pigs treated with PMMA-CVVH (PMMA T24 group) (fold change >2 ; false discovery rate <0.05). The most modulated genes were Granzime B, Complement Factor B, Complement Component 4 Binding Protein Alpha, IL-12, SERPINB-1 and TIMP-2 that were closely related to sepsis-induced immunological process. Finally, quantitative PCR confirmed the microarray data indicating that Granzime B and Complement Factor B upregulation in PBMC was significantly hampered by PMMA treatment. Conclusion Our data suggest that LPS induced AKI is characterized by activation of Classical and alternative Complement pathways resulting in significant renal tissue damage. By interfering with complement activation and inflammatory response, PMMA membrane might prevent dysfunctional activation of resident renal cells with prevention of sepsis-induced AKI.

Early Inhibition of P-Selectin/P-Selectin Glycoprotein Ligand-1 Reduces Intimal Hyperplasia in Murine Vein Grafts through Platelet Adhesion

2019 ◽  
Vol 119 (12) ◽  
pp. 2014-2024
Author(s):  
Chi-Nan Tseng ◽  
Ya-Ting Chang ◽  
Cih-Yi Yen ◽  
Mariette Lengquist ◽  
Malin Kronqvist ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Intimal Hyperplasia ◽  
Vein Graft ◽  
Platelet Adhesion ◽  
Time Window ◽  
Early Time ◽  
Leukocyte Recruitment ◽  
Luminal Surface ◽  
Vein Grafts ◽  
Inflammatory Phase

AbstractInflammatory processes contribute to intimal hyperplasia (IH) and long-term failure of vein grafts used in bypass surgery. Leukocyte recruitment on endothelial cells of vessels during inflammation is regulated by P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), which also mediates the interaction between platelets and endothelial cells in vein grafts transferred to arteries. However, how this pathway causes IH in vein grafts is unclear. In this study, we used a murine model of vein grafting to investigate P-selectin-mediated platelet adhesion, followed by IH. On the luminal surface of the vein graft, leukocyte recruitment occurred mainly in areas with adhered platelets rather than on endothelial cells without adherent platelets 1 hour after vein grafting. Blockage of either P-selectin or PSGL-1 reduced platelet adhesion and leukocyte recruitment on the luminal surface of vein grafts. Inhibition of the P-selectin pathway in vein grafts significantly reduced platelet-mediated leukocyte recruitment and IH of vein grafts 28 days after surgery. The study demonstrates that functional blockage of the P-selectin/PSGL-1 pathway in the early inflammatory phase after vein grafting reduced leukocyte invasion in the vein graft wall and later IH development. The findings imply an attractive early time window for prevention of vein graft failure by manipulating platelet adhesion.

scholarly journals Gene delivery to aortocoronary saphenous vein grafts in a large animal model of intimal hyperplasia

2004 ◽  
Vol 127 (1) ◽  
pp. 27-33 ◽  
Author(s):  
Jason A Petrofski ◽  
Jonathan A Hata ◽  
Thomas R Gehrig ◽  
Steven I Hanish ◽  
Matthew L Williams ◽  
...  
Keyword(s):  
Animal Model ◽  
Gene Delivery ◽  
Saphenous Vein ◽  
Intimal Hyperplasia ◽  
Large Animal Model ◽  
Large Animal ◽  
Vein Grafts ◽  
Saphenous Vein Grafts

scholarly journals Upregulation of MicroRNA-146a by Hepatitis B Virus X Protein Contributes to Hepatitis Development by Downregulating Complement Factor H

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Jun-Feng Li ◽  
Xiao-Peng Dai ◽  
Wei Zhang ◽  
Shi-Hui Sun ◽  
Yang Zeng ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Complement Activation ◽  
Factor H ◽  
Hbv Infection ◽  
Complement Factor ◽  
Liver Inflammation ◽  
X Protein ◽  
B Virus

ABSTRACT Hepatic injuries in hepatitis B virus (HBV) patients are caused by immune responses of the host. In our previous study, microRNA-146a (miR-146a), an innate immunity-related miRNA, and complement factor H (CFH), an important negative regulator of the alternative pathway of complement activation, were differentially expressed in HBV-expressing and HBV-free hepatocytes. Here, the roles of these factors in HBV-related liver inflammation were analyzed in detail. The expression levels of miR-146a and CFH in HBV-expressing hepatocytes were assessed via analyses of hepatocyte cell lines, transgenic mice, adenovirus-infected mice, and HBV-positive human liver samples. The expression level of miR-146a was upregulated in HBV-expressing Huh-7 hepatocytes, HBV-expressing mice, and patients with HBV infection. Further results demonstrated that the HBV X protein (HBx) was responsible for its effects on miR-146a expression through NF-κB-mediated enhancement of miR-146a promoter activity. HBV/HBx also downregulated the expression of CFH mRNA in hepatocyte cell lines and the livers of humans and transgenic mice. Furthermore, overexpression and inhibition of miR-146a in Huh-7 cells downregulated and upregulated CFH mRNA levels, respectively. Luciferase reporter assays demonstrated that miR-146a downregulated CFH mRNA expression in hepatocytes via 3′-untranslated-region (UTR) pairing. The overall effect of this process in vivo is to promote liver inflammation. These results demonstrate that the HBx–miR-146a–CFH–complement activation regulation pathway might play an important role in the immunopathogenesis of chronic HBV infection. These findings have important implications for understanding the immunopathogenesis of chronic hepatitis B and developing effective therapeutic interventions. IMPORTANCE Hepatitis B virus (HBV) remains an important pathogen and can cause severe liver diseases, including hepatitis, liver cirrhosis, and hepatocellular carcinoma. Although HBV was found in 1966, the molecular mechanisms of pathogenesis are still poorly understood. In the present study, we found that the HBV X protein (HBx) promoted the expression of miR-146a, an innate immunity-related miRNA, through the NF-κB signal pathway and that increasingly expressed miR-146a downregulated its target complement factor H (CFH), an important negative regulator of the complement alternative pathway, leading to the promotion of liver inflammation. We demonstrated that the HBx–miR-146a–CFH–complement activation regulation pathway is potentially an important mechanism of immunopathogenesis caused by chronic HBV infection. Our data provide a novel molecular mechanism of HBV pathogenesis and thus help to understand the correlations between the complement system, an important part of innate immunity, and HBV-associated disease. These findings will also be important to identify potential therapeutic targets for HBV infection.

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