Protective effects of a potent c5a receptor antagonist on experimental acute limb ischemia-reperfusion in rats

Woodruff, Trent M.; Shiels, Ian A.; Reid, Robert C.; Fairlie, David P.; Taylor, Stephen M.

doi:10.1016/j.jss.2003.04.001

Cited by 73 publications

(54 citation statements)

References 41 publications

(60 reference statements)

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“…6 Prevention of kidney from I/R injury by blocking specific components of the complement activation cascade has been reported. 3,15,16 We previously showed that inhibiting C3 with siRNA protected renal from I/R injury. 7,9,10 In this study, we have demonstrated that silencing the C5aR gene using siRNA can inhibit the renal expression of C5aR and that successful delivery of C5aR-siRNA to the kidneys results in the prevention of renal I/R injury.…”

Section: Discussionmentioning

confidence: 99%

Gene Silencing of Complement C5a Receptor Using siRNA for Preventing Ischemia/Reperfusion Injury

Zheng

Zhang

Feng

et al. 2008

The American Journal of Pathology

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Ischemia/reperfusion (I/R) injury in organ transplantation significantly contributes to graft failure and is untreatable using current approaches. I/R injury is associated with activation of the complement system, leading to the release of anaphylatoxins, such as C5a, and the formation of the membrane attack complex. Here, we report a novel therapy for kidney I/R injury through silencing of the C5a receptor (C5aR) gene using siRNA. Mice were injected with 50 g of C5aR siRNA 2 days before induction of ischemia. Renal ischemia was then induced through clamping of the renal vein and artery of the left kidney for 25 minutes. The therapeutic effects of siRNA on I/R were evaluated by assessment of renal function, histopathology, and inflammatory cytokines. siRNA targeting C5aR efficiently inhibited C5aR gene expression both in vitro and in vivo. Administering C5aR siRNA to mice preserved renal function from I/R injury, as evidenced by reduced levels of serum creatinine and blood urea nitrogen in the treated groups. Inhibition of C5aR also diminished in vivo production of the pro-inflammatory cytokine tumor necrosis factor-␣ and chemokines MIP-2 and KC, resulting in the reduction of neutrophils influx and cell necrosis in renal tissues. This study demonstrates that siRNA administration represents a novel approach to preventing renal I/R injury and may be used in a variety of clinical settings, including transplantation and acute tubular necrosis.

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Section: Discussionmentioning

confidence: 99%

Gene Silencing of Complement C5a Receptor Using siRNA for Preventing Ischemia/Reperfusion Injury

Zheng

Zhang

Feng

et al. 2008

The American Journal of Pathology

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“…17 The protective role of PMX53 has also been found in IRI of multiple organs. [28][29][30][31] The mechanisms are mostly related to inhibiting inflammation, including attenuation of TNF-α expression in tissue or serum, decreasing myeloperoxidase activity and reducing the number of infiltrating neutrophils and neutrophilia. 20 However, the role of PMX53 in SIRI has yet to be reported.…”

Section: Dissussionmentioning

confidence: 99%

PMX53 protects spinal cord from ischemia-reperfusion injury in rats in the short term

et al. 2015

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Study design: Experimental study. Objectives: To investigate the effect of pre-treatment with PMX53, a C5aR antagonist, on spinal cord ischemia-reperfusion injury (IRI) in rat. Setting: Department of Neurosurgery, Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi Province, China. Methods: IRI was induced in the lumbar spinal cord by applying a mini aneurysm clamp to the abdominal aorta for 60 min in adult Sprague-Dawley rats. PMX53 (1 mg kg − 1 ) was administered through femoral vein injection 30 min before ischemia on the rats in the PMX53 group (n = 18). The saline group (n = 18) was given saline at the same volume through femoral vein injection. The neurologic outcome of the posterior limbs was assessed by the Basso-Beattie-Bresnahan (BBB) score at 1, 6, 12, 24 and 48 h after reperfusion. Histologic changes of the spinal cord were detected with hematoxylin-eosin (H-E) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect myeloperoxidase (MPO) activity in the spinal cord. Immunohistochemistry was used to investigate the quantity of activated astrocytes and microglia. Results: After pre-treatment with PMX53, neurologic function improved gradually after 6, 12, 24 and 48 h reperfusion. The BBB score of the PMX53 group increased significantly (Po0.05) compared with the saline group. H-E staining showed that pathologic damage in the PMX53 group was reduced. Moreover, administration of PMX53 significantly inhibited neutrophil infiltration in the spinal cord. Levels of MPO activity in the spinal cord were remarkably lower in the PMX53 group (Po0.05). There were also more activated microglia and astrocytes in the spinal cord of the PMX53 group than in the saline group (Po0.05). INTRODUCTIONSpinal cord ischemia-reperfusion injury (SIRI) mainly occurs after operations on the descending thoracic or thoracoabdominal aorta, such as thoracoabdominal aneurysm. 1 SIRI causes various complications, including paraparesis and paraplegia. 2 These complications have been attributed to temporary or permanent ischemia of the spinal cord caused by interruption of the blood supply during aortic cross-clamping. The incidence of paraplegia has been correlated with dissection, rupture and prolonged clamp times. 3 Systemic hypothermia, spinal fluid drainage and preconditioning ischemia were considered to prevent paraplegia, 4 but the effect was limited. Recent studies indicated that pathophysiological mechanisms underlying SIRI are complicated, including the release of inflammatory factors, 5 calcium overload, 6 oxidative stress, 7 excitotoxicity 8 and neuronal apoptosis. 9,10 In addition, there are more mechanisms that remain unclear. It has been found that the inflammatory cascade is activated due to SIRI, including neutrophil and neuroglia mobilization and infiltration, as well as elevated levels of inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6. 11 The complement system, a major component of the innate immune system, is

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“…13 Another important aspect of complement activation is its role in ischemia-reperfusion (IR) injury. In several models of experimental IR injury of liver, 14 limb, 15 heart, 16 and kidney, 17,18 C5a or C5aR blockade successfully attenuated organ damage. Complement activation during ischemia and reperfusion contributes to the development of delayed graft function and tissue injury, which in turn negatively affects longterm outcome in transplantation 19 and also activates the innate immune system of the donor and the recipient.…”

mentioning

confidence: 97%

Complement 5a Receptor Inhibition Improves Renal Allograft Survival

Gueler¹,

Rong²,

Gwinner³

et al. 2008

Journal of the American Society of Nephrology

104

116

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Complement activation plays a key role in mediating apoptosis, inflammation, and transplant rejection. In this study, the role of the complement 5a receptor (C5aR) was examined in human renal allografts and in an allogenic mouse model of renal transplant rejection. In human kidney transplants with acute rejection, C5aR expression was increased in renal tissue and in cells infiltrating the tubulointerstitium. Similar findings were observed in mice. When recipient mice were treated once daily with a C5aR antagonist before transplantation, long-term renal allograft survival was markedly improved compared with vehicle-treatment (75 versus 0%), and apoptosis was reduced. Furthermore, treatment with a C5aR antagonist significantly attenuated monocyte/macrophage infiltration, perhaps a result of reduced levels of monocyte chemoattractant protein 1 and the intercellular adhesion molecule 1. In vitro, C5aR antagonism inhibited intercellular adhesion molecule 1 upregulation in primary mouse aortic endothelial cells and reduced adhesion of peripheral blood mononuclear cells. Furthermore, C5aR blockade markedly reduced alloreactive T cell priming. These results demonstrate that C5aR plays an important role in mediating acute kidney allograft rejection, suggesting that pharmaceutical targeting of C5aR may have potential in transplantation medicine.

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Protective effects of a potent c5a receptor antagonist on experimental acute limb ischemia-reperfusion in rats

Cited by 73 publications

References 41 publications

Gene Silencing of Complement C5a Receptor Using siRNA for Preventing Ischemia/Reperfusion Injury

Gene Silencing of Complement C5a Receptor Using siRNA for Preventing Ischemia/Reperfusion Injury

PMX53 protects spinal cord from ischemia-reperfusion injury in rats in the short term

Complement 5a Receptor Inhibition Improves Renal Allograft Survival

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