Complement therapeutic strategies in trauma, hemorrhagic shock and systemic inflammation - closing Pandora's box?

After severe trauma, the immune system is challenged with a multitude of endogenous and exogenous danger molecules. The recognition of released danger patterns is one of the prime tasks of the innate immune system. In the last two decades, numerous studies have established the complement cascade as a major effector system that detects and processes such danger signals. Animal models with engineered deficiencies in certain complement proteins have demonstrated that widespread complement activation after severe injury culminates in complement dysregulation and excessive generation of complement activation fragments. Such exuberant pro-inflammatory signaling evokes systemic inflammation, causes increased susceptibility to infections and is associated with a detrimental course of the disease after injury. We discuss the underlying processes of such complementopathy and recapitulate different intervention strategies within the complement cascade. So far, several orthogonal anti-complement approaches have been tested with varying success in a large number of rodent, in several porcine and few simian studies. We illustrate the different features among those intervention strategies and highlight those that hold the greatest promise to become potential therapeutic options for the intricate disease of traumatic injury.