title: Generation of C5a in the absence of C3: a new complement activation pathway.
abstract: Complement-mediated tissue injury in humans occurs upon deposition of immune complexes, such as in autoimmune diseases and acute respiratory distress syndrome. Acute lung inflammatory injury in wild-type and C3-/- mice after deposition of IgG immune complexes was of equivalent intensity and was C5a dependent, but injury was greatly attenuated in Hc-/- mice (Hc encodes C5). Injury in lungs of C3-/- mice and C5a levels in bronchoalveolar lavage (BAL) fluids from these mice were greatly reduced in the presence of antithrombin III (ATIII) or hirudin but were not reduced in similarly treated C3+/+ mice. Plasma from C3-/- mice contained threefold higher levels of thrombin activity compared to plasma from C3+/+ mice. There were higher levels of F2 mRNA (encoding prothrombin) as well as prothrombin and thrombin protein in liver of C3-/- mice compared to C3+/+ mice. A potent solid-phase C5 convertase was generated using plasma from either C3+/+ or C3-/- mice. Human C5 incubated with thrombin generated C5a that was biologically active. These data suggest that, in the genetic absence of C3, thrombin substitutes for the C3-dependent C5 convertase. This linkage between the complement and coagulation pathways may represent a new pathway of complement activation.
authors.affiliation: Department of Traumatology, Hand and Reconstructive Surgery, University of Ulm Medical School, Steinhoevelstrasse 9, D-89075 Ulm, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Huber-Lang
authors.forename: J Vidya
authors.initials: JV
authors.lastname: Sarma
authors.forename: Firas S
authors.initials: FS
authors.lastname: Zetoune
authors.forename: Daniel
authors.initials: D
authors.lastname: Rittirsch
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neff
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: McGuire
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Roscoe L
authors.initials: RL
authors.lastname: Warner
authors.forename: Michael A
authors.initials: MA
authors.lastname: Flierl
authors.forename: Laszlo M
authors.initials: LM
authors.lastname: Hoesel
authors.forename: Florian
authors.initials: F
authors.lastname: Gebhard
authors.forename: John G
authors.initials: JG
authors.lastname: Younger
authors.forename: Scott M
authors.initials: SM
authors.lastname: Drouin
authors.forename: Rick A
authors.initials: RA
authors.lastname: Wetsel
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003167:Complement Activation / Q000502:physiology*; D003176:Complement C3 / Q000235:genetics / Q000276:immunology*; D015936:Complement C5a / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D055370:Lung Injury; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011516:Prothrombin / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D003176:Complement C3; D007074:Immunoglobulin G; D015936:Complement C5a; D011516:Prothrombin; D013917:Thrombin