Protective effect of a human C5a receptor antagonist against hepatic ischaemia-reperfusion injury in rats

Arumugam, Thiruma V.; Woodruff, Trent M.; Stocks, Shelli Z.; Proctor, Lavinia M.; Pollitt, Sandra; Shiels, Ian A.; Reid, Robert C.; Fairlie, David P.; Taylor, Stephen M.

doi:10.1016/j.jhep.2004.02.017

Cited by 60 publications

(32 citation statements)

References 46 publications

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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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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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“…These studies have variously shown that complement inhibition with soluble complement receptor 1 (sCR1) reduces Kupffer cell activation, neutrophil accumulation, and microvascular dysfunction and injury in rat liver (8)(9)(10)(11). C1-inhibitor and C5a receptor antagonist have also been shown to be protective in rat models of hepatic IRI (9)(10)(11), and a role for the terminal cytolytic membrane attack complex (MAC) is indicated by a study showing that deficiency of complement component 6 (C6) (a component of the MAC) is associated with protection from injury, following hepatic IRI in rats (12).…”

Section: Introductionmentioning

confidence: 99%

A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice

He¹,

Atkinson²,

Qiao³

et al. 2009

J. Clin. Invest.

125

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Massive liver resection and small-for-size liver transplantation pose a therapeutic challenge, due to increased susceptibility of the remnant/graft to ischemia reperfusion injury (IRI) and impaired regeneration. We investigated the dual role of complement in IRI versus regeneration in mice. Complement component 3 (C3) deficiency and complement inhibition with complement receptor 2-complement receptor 1-related protein y (CR2-Crry, an inhibitor of C3 activation) provided protection from hepatic IRI, and while C3 deficiency also impaired liver regeneration following partial hepatectomy (PHx), the effect of CR2-Crry in this context was dose dependent. In a combined model of IRI and PHx, either C3 deficiency or high-dose CR2-Crry resulted in steatosis, severe hepatic injury, and high mortality, whereas low-dose CR2-Crry was protective and actually increased hepatic proliferative responses relative to control mice. Reconstitution experiments revealed an important role for the C3a degradation product acylation-stimulating protein (ASP) in the balance between inflammation/injury versus regeneration. Furthermore, liver regeneration was dependent on the putative ASP receptor, C5L2. Several potential mechanisms of hepatoprotection and recovery were identified in mice treated with low-dose CR2-Crry, including enhanced IL-6 expression and STAT3 activation, reduced hepatic ATP depletion, and attenuated oxidative stress. These data indicate that a threshold of complement activation, involving ASP and C5L2, promotes liver regeneration and suggest a balance between complement-dependent injury and regeneration.

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“…In the single reported study that uses a mouse model of hepatic IRI to investigate the role of complement, the classical/lectin pathway is similarly implicated since transgenic mice overexpressing C1 inhibitor display reduced endothelial injury following hepatic I/R (14). A role for C5a in hepatic IRI is indicated by the finding that C5a receptor antagonist treatment attenuates tissue injury following partial hepatic I/R in rats (15). It is important to note that C3a and C5a also play important roles in liver regeneration, either through direct signaling or via their effects on cytokine production, and these C3 and C5 activation products may also have protective effects by promoting cellular regeneration and tissue repair following IRI (16 -18).…”

mentioning

confidence: 99%

A Role for Complement in the Enhanced Susceptibility of Steatotic Livers to Ischemia and Reperfusion Injury

Atkinson²,

Evans

et al. 2009

The Journal of Immunology

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Hepatic steatosis typically renders the donor organ unusable, as donor organs with >30% steatosis are more likely to develop graft failure. The mechanisms leading to failure are not well defined, but steatosis enhances hepatic susceptibility to ischemia reperfusion injury (IRI). We investigated the role of complement in hepatic IRI in lean and steatotic (diet-induced) mice. Steatotic mice were significantly more susceptible to total warm hepatic IRI than lean mice as determined by serum alanine aminotransferase, histopathologically assessed damage, and 24-h survival. C3 deficiency protected both lean and steatotic mice from IRI, as determined by all measured outcomes. Furthermore, treatment of wild-type mice with the complement inhibitor CR2-Crry provided protection equivalent to that seen in C3-deficient mice. Importantly, although steatotic livers were much more susceptible to IRI than lean livers, by most measures there was no statistical difference between the level of IRI to steatotic or lean livers when complement was inhibited. To investigate the clinical relevance of these findings in the context of transplantation, we treated recipients of lean or steatotic liver grafts with saline or CR2-Crry. There was a marked reduction in graft inflammation and injury and significantly improved 7-day survival in CR2-Crry-treated recipients of either lean or steatotic grafts. These data indicate that complement plays a key role in the enhanced susceptibility of steatotic livers to IRI and suggest that complement inhibition represents a potential strategy to reduce the donor shortage by allowing the more routine use of marginal steatotic donor livers.

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Protective effect of a human C5a receptor antagonist against hepatic ischaemia-reperfusion injury in rats

Cited by 60 publications

References 46 publications

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

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

A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice

A Role for Complement in the Enhanced Susceptibility of Steatotic Livers to Ischemia and Reperfusion Injury

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