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

He, Songqing; Atkinson, Carl; Evans, Zachary; Ellett, Justin D.; Southwood, Mark; Elvington, Andrew; Chavin, Kenneth D.; Tomlinson, Stephen

doi:10.4049/jimmunol.0900550

Cited by 40 publications

(44 citation statements)

References 52 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result further suggests that complement such as C3a, C5a, and MAC may play a critical role in hepatic IRI in liver transplantation. These results are consistent with findings reported by He et al 24 It is well established that C3a and C5a bind with high affinity to the C5a receptor (C5aR) on polymorphonuclear leukocytes, monocytes, and macrophages 29 to stimulate oxidative metabolism and the production of reactive oxygen species in neutrophils and T cells, thereby leading to the amplification of inflammatory responses. 65,66 It is worth noting that we did not have any primary reasons to select AST instead of ALT as a main parameter for the detection of the degree of liver injury in our experiments.…”

Section: Cd59 and Complement Insupporting

confidence: 93%

“…20 -22 Experimental and clinical evidence indicates that IR triggers complement activation in several organs. 23 Recently, using a novel inhibitor CR2-Crry to inhibit MAC formation and C3 activation at the site of complement activation, He et al 24 demonstrated that an enhanced susceptibility to IRI of steatotic livers was associated with complement activation in a mouse model. 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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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

show abstract

Section: Cd59 and Complement Insupporting

confidence: 93%

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

View full text Add to dashboard Cite

show abstract

“…Strategies to limit hepatic ischemic/reperfusion injury in both obese and non-obese patients are clearly important but may be of greatest utility in those with steatosis. Steatosis may portend a greater risk for ischemia-reperfusion injury, 26,27 which has led to broader basic efforts to further understand this theory. Further understanding of this relationship will have important clinical implications in hepatic surgery and transplantation, and the assessment of patient risk.…”

Section: Discussionmentioning

confidence: 99%

Influence of Body Mass Index on Complications and Oncologic Outcomes Following Hepatectomy for Malignancy

Mathur

Ghaferi

Sell

et al. 2010

Journal of Gastrointestinal Surgery

View full text Add to dashboard Cite

show abstract

“…Recent evidence from several studies has suggested that the complement system is involved in the pathogenesis of a variety of liver disorders, including liver fibrosis, viral hepatitis, alcoholic liver disease and hepatic ischemia/reperfusion injury (IRI) [12]–[16]. In these disease settings, complement activation products promote tissue inflammation and injury, particularly via the generation of the complement activation products C3a and C5a, which promote inflammation via direct and indirect mechanisms by interacting with their receptors [17]–[19].…”

Section: Introductionmentioning

confidence: 99%

Complement and the Alternative Pathway Play an Important Role in LPS/D-GalN-Induced Fulminant Hepatic Failure

et al. 2011

Self Cite

View full text Add to dashboard Cite

Fulminant hepatic failure (FHF) is a clinically severe type of liver injury with an extremely high mortality rate. Although the pathological mechanisms of FHF are not well understood, evidence suggests that the complement system is involved in the pathogenesis of a variety of liver disorders. In the present study, to investigate the role of complement in FHF, we examined groups of mice following intraperitoneal injection of LPS/D-GalN: wild-type C57BL/6 mice, wild-type mice treated with a C3aR antagonist, C5aR monoclonal antibody (C5aRmAb) or CR2-Factor H (CR2-fH, an inhibitor of the alternative pathway), and C3 deficient mice (C3−/− mice). The animals were euthanized and samples analyzed at specific times after LPS/D-GalN injection. The results show that intraperitoneal administration of LPS/D-GalN activated the complement pathway, as evidenced by the hepatic deposition of C3 and C5b-9 and elevated serum levels of the complement activation product C3a, the level of which was associated with the severity of the liver damage. C3a receptor (C3aR) and C5a receptor (C5aR) expression was also upregulated. Compared with wild-type mice, C3−/− mice survived significantly longer and displayed reduced liver inflammation and attenuated pathological damage following LPS/D-GalN injection. Similar levels of protection were seen in mice treated with C3aR antagonist,C5aRmAb or CR2-fH. These data indicate an important role for the C3a and C5a generated by the alternative pathway in LPS/D-GalN-induced FHF. The data further suggest that complement inhibition may be an effective strategy for the adjunctive treatment of fulminant hepatic failure.

show abstract

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

Cited by 40 publications

References 52 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

Influence of Body Mass Index on Complications and Oncologic Outcomes Following Hepatectomy for Malignancy

Complement and the Alternative Pathway Play an Important Role in LPS/D-GalN-Induced Fulminant Hepatic Failure

Contact Info

Product

Resources

About