The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injury

Fondevila, Constantino; Shen, Xiu-Da; Tsuchihashi, Seiichiro; Uchida, Yoichiro; Freitas, Maria Cecília S.; Ke, Bibo; Busuttil, Ronald W.; Kupiec‐Weglinski, Jerzy W.

doi:10.1002/lt.21496

Cited by 51 publications

(36 citation statements)

References 33 publications

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“…These results shed light on the critical role of MAC in the pathogenesis of hepatic IRI. Consistent with these findings, the critical role of complement (including MAC) in liver transplantation has been demonstrated in an OLT C6-deficient rat model, 25 and similarly for gastrointestinal and renal IRI in an anti-murine C5 antibody study 52 and in mice deficient in C3, C4, C5, and C6, 53 respectively. Nonetheless, the molecular and cellular mechanisms by which MAC accelerates organ IRI remain elusive.…”

Section: Discussionsupporting

confidence: 61%

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The Protective Role of CD59 and Pathogenic Role of Complement in Hepatic Ischemia and Reperfusion Injury

Zhang

Xing

et al. 2011

The American Journal of Pathology

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Hepatic ischemia-reperfusion injury (IRI) is a major factor influencing graft outcome in liver transplantation, but its mechanism is not well defined. Although complement, including the membrane attack complex (MAC), a terminal product of complement activation, is thought to be involved in the multiple reactions subsequent to the ischemia-reperfusion (IR) process, the role of MAC in the pathogenesis of hepatic IRI requires further investigation. We used a warm ischemia-reperfusion injury model in mice and a syngeneic orthotopic liver transplantation model in rats to define the role of complement, including MAC, in hepatic IR. CD59-deficient mice had more severe liver dysfunction, evidenced by increased aspartate aminotransferase levels and increased injury of liver parenchymal and nonparenchymal cells than did CD59-sufficient mice during warm hepatic IR. Furthermore, complement depletion in CD59-deficient mice by pretreatment with cobra venom factor (CVF) or the genetic introduction of C3 deficiency partially protected against development of the severe liver dysfunction that occurred in CD59-deficient mice. Severity of liver dysfunction correlated with MAC deposition, apoptotic cells, and increased inflammatory mediators such as tumor necrosis factor ␣. Liver transplantation is a routine and powerful approach for treatment of patients with acute or chronic liver failure of various causes. 1 Nevertheless, hepatic ischemia-reperfusion (IR) remains a major deleterious factor influencing graft outcome in organ transplantation. The incidence of primary graft failure (5% to 15%) and initial poor function (10% to 25%) is strongly dependent on the extent of ischemia-reperfusion injury (IRI). 2-4 IRI also initiates later graft failure by triggering irreversible intrahepatic biliary tract injury (ischemic-type biliary lesion) or by promoting rejection through activation of innate immunity. 5 At present, because of the shortage of organs for transplantation, the donor pool has been expanded by utilization of marginal organs from old donors or non-heart-beating donors, as well as grafts with prolonged cold storage, and even allografts donated after cardiac death. It is conceivable that grafts from such donors could cause severe liver injury, because they have usually experienced a long ischemia time. To improve the outcome of liver transplantation, therefore, it is imperative to better understand the mechanisms involved in IRI and to design novel therapeutic strategies for prevention of IRI.Ischemia-reperfusion injury is characterized by the presence of activated polymorphonuclear leukocytes, oxygen radical formation, 6 and cytokine release. 7,8 The process that temporarily blocks blood supply followed by blood reperfusion to the living donor after the transplantation causes attraction, activation, adhesion, and migration of neutrophils at the site of donor organ, thereby

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Section: Discussionsupporting

confidence: 61%

“…Additionally, C6 deficiency in rats protects against ischemia damage in rat orthotopic liver transplantation (OLT) recipients, which indicates the role of MAC in the pathogenesis of hepatic IRI. 25,26 Nonetheless, the protective role of CD59 and the pathogenic role of complement, including MAC, in the pathogenesis of IRI still require further investigation.…”

mentioning

confidence: 99%

The Protective Role of CD59 and Pathogenic Role of Complement in Hepatic Ischemia and Reperfusion Injury

Zhang

Xing

et al. 2011

The American Journal of Pathology

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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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“…CS slows metabolic processes, increasing the amount of time the graft can spend outside of the body. Although slowed, these processes cannot be halted, and damage to the organ invariably occurs during preservation and reperfusion [8,9]. While CS produces acceptable results for normal organs, it fails to adequately preserve marginal grafts, as evidenced by elevated rates of dysfunction, failure, and ischemic cholangiopathy in such transplantations [10].…”

Section: Cold Storage and Its Limitationsmentioning

confidence: 99%

Preclinical Foundation for Normothermic Machine Liver Preservation

et al. 2015

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Liver transplantation is the primary treatment for end-stage liver disease, but demand exceeds supply due to the shortage of available healthy donor grafts. To increase the supply of useable grafts for transplantation, innovative and better preservation methods are needed to enable the use of livers from extended criteria donors. Normothermic machine perfusion (NMP) has been extensively studied in the laboratory and holds great potential for expanding the donor pool. This review summarizes the progress that has been made in NMP over the last two decades, with emphasis on the recent studies preparing the method for clinical trials.

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The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injury

Cited by 51 publications

References 33 publications

The Protective Role of CD59 and Pathogenic Role of Complement in Hepatic Ischemia and Reperfusion Injury

The Protective Role of CD59 and Pathogenic Role of Complement in Hepatic Ischemia and Reperfusion Injury

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

Preclinical Foundation for Normothermic Machine Liver Preservation

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