title: Complement and the alternative pathway play an important role in LPS/D-GalN-induced fulminant hepatic failure.
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.
authors: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors: Shihui
authors: S
authors: Sun
authors: Yan
authors: Y
authors: Guo
authors: Guangyu
authors: G
authors: Zhao
authors: Xiaojun
authors: X
authors: Zhou
authors: Junfeng
authors: J
authors: Li
authors: Jingya
authors: J
authors: Hu
authors: Hong
authors: H
authors: Yu
authors: Yu
authors: Y
authors: Chen
authors: Hongbin
authors: H
authors: Song
authors: Fei
authors: F
authors: Qiao
authors: Guilian
authors: G
authors: Xu
authors: Fei
authors: F
authors: Yang
authors: Yuzhang
authors: Y
authors: Wu
authors: Stephen
authors: S
authors: Tomlinson
authors: Zhongping
authors: Z
authors: Duan
authors: Yusen
authors: Y
authors: Zhou
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000502:physiology*; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D004195:Disease Models, Animal; D004338:Drug Combinations; D005688:Galactosamine / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism; D011951:Receptors, Complement / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D003176:Complement C3; D015938:Complement Membrane Attack Complex; D004338:Drug Combinations; D008070:Lipopolysaccharides; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C085567:complement C3a receptor; D005688:Galactosamine