Complement factor 3 deficiency attenuates hemorrhagic shock-related hepatic injury and systemic inflammatory response syndrome.
Although complement activation is known to occur in the setting of severe hemorrhagic shock and tissue trauma (HS/T), the extent to which complement drives the initial inflammatory response and end-organ damage is uncertain. In this study, complement factor 3-deficient (C3(-/-)) mice and wild-type control mice were subjected to 1.5-h hemorrhagic shock, bilateral femur fracture, and soft tissue injury, followed by 4.5-h resuscitation (HS/T). C57BL/6 mice were also given 15 U of cobra venom factor (CVF) or phosphate-buffered saline injected intraperitoneally, followed by HS/T 24 h later. The results showed that HS/T resulted in C3 consumption in wild-type mice and C3 deposition in injured livers. C3(-/-) mice had significantly lower serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and circulating DNA levels, together with much lower circulating interleukin (IL)-6, IL-10, and high-mobility group box 1 (HMGB1) levels. Temporary C3 depletion by CVF preconditioning also led to reduced transaminases and a blunted cytokine release. C3(-/-) mice displayed well-preserved hepatic structure. C3(-/-) mice subjected to HS/T had higher levels of heme oxygenase-1, which has been associated with tissue protection in HS models. Our data indicate that complement activation contributes to inflammatory pathways and liver damage in HS/T. This suggests that targeting complement activation in the setting of severe injury could be useful.
Cai
Changchun
C
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
Gill
Roop
R
Eum
Hyun-Ae
HA
Cao
Zongxian
Z
Loughran
Patricia A
PA
Darwiche
Sophie
S
Edmonds
Rebecca D
RD
Menzel
Christoph L
CL
Billiar
Timothy R
TR
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D003167:Complement Activation; D003176:Complement C3 / Q000172:deficiency* / Q000235:genetics; D004277:DNA, Single-Stranded / Q000097:blood; D004195:Disease Models, Animal; D004546:Elapid Venoms / Q000008:administration & dosage; D005264:Femoral Fractures / Q000150:complications / Q000276:immunology; D024243:HMGB1 Protein / Q000097:blood; D006419:Heme Oxygenase (Decyclizing) / Q000097:blood; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008107:Liver Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012771:Shock, Hemorrhagic / Q000097:blood / Q000235:genetics / Q000276:immunology*; D017695:Soft Tissue Injuries / Q000150:complications / Q000276:immunology; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D013997:Time Factors
D015415:Biomarkers; D003176:Complement C3; D004277:DNA, Single-Stranded; D004546:Elapid Venoms; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D015850:Interleukin-6; C016310:cobra venom factor; D016753:Interleukin-10; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase