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- Title
Complement and the Alternative Pathway Play an Important Role in LPS/D-GalN-Induced Fulminant Hepatic Failure.
- Authors
Shihui Sun; Yan Guo; Guangyu Zhao; Xiaojun Zhou; Junfeng Li; Jingya Hu; Hong Yu; Yu Chen; Hongbin Song; Fei Qiao; Guilian Xu; Fei Yang; Yuzhang Wu; Stephen Tomlinson; Zhongping Duan; Yusen Zhou
- Abstract
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.
- Subjects
LIVER failure; INFLAMMATION; MICE; PATHOLOGY; INTRAPERITONEAL injections
- Publication
PLoS ONE, 2011, Vol 6, Issue 11, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0026838