Background Excessive complement activation is an integral part of ischemia and reperfusion (IR) injury (IRI) of organs. In kidney transplantation the pathological consequence of IRI and complement activation can lead to delayed graft function which in turn is associated with acute rejection. Previous strategies to reduce complement induced IRI required systemic administration of agents, which can lead to increased susceptibility to infections/immune diseases. The objective of this study was to determine whether an increase in complement control defenses of rat kidney endothelium reduces IRI. We hypothesized that increased complement control on the endothelial barrier reduces IR-mediated complement activation and reduces kidney dysfunction. Materials and methods Fisher 344 rats underwent left kidney ischemia for 45 min. and treatment with a novel fusogenic lipid vesicle (FLVs) delivery system to decorate endothelial cells with Vaccinia virus complement control protein (VCP), followed by reperfusion for 24h. Assessment included renal function by serum creatinine and urea, myeloperoxidase assay for neutrophil infiltration, histopathology, and quantification of C3 production in kidneys. Results Animals in which the kidney endothelium was bolstered by FLVs+VCP treatment had better renal function with a significant reduction in serum creatinine as compared to vehicle controls. C3 production was significantly reduced (p<0.05) in treated animals compared to vehicle controls. Conclusion Increasing complement control at the endothelial barrier with FLVs+VCP modulates complement activation/production during the first 24h, reducing renal dysfunction following IRI.
Background Myocardial injury after heart transplantation is a consequence of pathophysiological events initiated by local ischemia/reperfusion (IR) injury that is further aggravated by the inflammatory response due to blood exposure to the pump’s artificial surfaces during cardiopulmonary bypass (CPB). The purpose of this study was to determine the effectiveness of fusogenic lipid vesicles (FLVs) in enhancing the cardioprotective effect of St. Thomas organ preservation solution (ST). We hypothesized that donor hearts preserved with ST-FLVs will stabilize the endothelium during reperfusion, which in turn will reduce both endothelial barrier dysfunction and myocardial damage. Materials and methods To examine the effect of ST-FLVs therapy in vitro, C3b deposition and adhesion molecule expression studies were performed on human umbilical vein endothelial cells (HUVECs) challenged with plastic-contact-activated plasma. To assess the therapy in vivo, a cervical heterotopic working heart transplantation model in rats was used. Donor hearts were preserved for 1 h at 27°C (15min) and 4°C (45min), and after transplant were followed for 2 h. Left ventricular (LV) function and blood cardiac troponin I (cTnI) levels were quantified. Results HUVECs treated with ST-FLVs had reduced C3b deposition and expression of adhesion molecules compared to ST alone (P<0.05). Donor hearts receiving ST-FLVs therapy had reduced LV dysfunction and cTnI compared to ST alone Conclusion We conclude that FLVs enhance the cardioprotective effect of ST and reduce post-ischemic LV dysfunction and myocardial damage. The mechanism of protection appears to be associated with the stabilization of endothelial cell membranes due to incorporation of FLV-derived lipids.
Excessive complement activation following ischemia and reperfusion (IR) of organs disrupts endothelial barrier, mediates inflammation and subsequent tissue injury. Previous strategies to reduce complement induced IR injury required systemic administration of agents, which can lead to increased susceptibility to infections/immune diseases. The objective of this project was to determine whether an increase in complement control defenses of rat kidney endothelium reduces IR injury. We hypothesized that increased complement control on the endothelial barrier reduces IR‐mediated complement activation and reduces kidney dysfunction. Fisher rats underwent left kidney ischemia for 45 min. and treatment with a novel fusogenic lipid vesicle (FLVs) delivery system to decorate endothelial cells with an anti‐complement protein, His6‐VCP followed by reperfusion for 24h. Assessment included renal function by serum creatinine and urea, myeloperoxidase assay for neutrophil infiltration, histopathology and immunohistochemistry. Animals in which the kidney endothelium was bolstered by His6‐VCP had better renal function with a significant reduction in serum creatinine as compared to controls (lactated ringer's only). Neutrophil infiltration showed a downward trend. We conclude that FLVs/His6‐VCP therapy was effective during the first 24h in reducing vascular and renal dysfunction following IR injury.
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