Nature Medicine
- 12, 682 - 687 (2006)
Published online: 21 May 2006; | doi:10.1038/nm1419
Generation of C5a in the absence of C3: a new complement activation pathwayMarkus Huber-Lang1, 6, J Vidya Sarma2, 6, Firas S Zetoune2, 6, Daniel Rittirsch2, Thomas A Neff2, Stephanie R McGuire2, John D Lambris3, Roscoe L Warner2, Michael A Flierl2, Laszlo M Hoesel2, Florian Gebhard1, John G Younger4, Scott M Drouin5, Rick A Wetsel5 & Peter A Ward21
Department of Traumatology, Hand and Reconstructive Surgery, University of Ulm Medical School, Steinhoevelstrasse 9, D-89075 Ulm, Germany. 2
Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, Michigan 48109, USA. 3
Department of Pathology, University of Pennsylvania, 401 Stellar Chance, Philadelphia, Pennsylvania 19104, USA. 4
Department of Emergency Medicine, University of Michigan Medical School, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, USA. 5
Institute for Molecular Medicine, University of Texas, Houston Health Sciences Center, 2121 W. Holcombe Blvd., Houston, Texas 77030, USA. 6
These authors contributed equally to this work.
Correspondence should be addressed to Peter A Ward pward@umich.edu 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.
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