Competing interestsThe authors declare that they have no competin

Competing interestsThe authors declare that they have no competing interests.NotesSee related research by Krebs et al., http://ccforum.com/content/13/5/R160
Trauma remains the leading cause of mortality for patients between 1 and 40 years of age and eclipses cancer, heart so disease and HIV/AIDS [1]. Although there remain a large proportion of trauma victims who die early from overwhelming injury, trauma patients who survive their initial injury do not die from their injury per se, but from an overwhelming inflammatory dysregulation leading to organ dysfunction, nosocomial infection, and ultimately multiorgan failure [2,3]. The mechanisms that initiate this sterile inflammatory process are still not completely understood.

It has been known for several years that severe trauma is associated with an early systemic inflammatory response syndrome (SIRS) followed by a compensatory anti-inflammatory response syndrome (CARS), although the molecular mechanisms responsible for this altered host defense are not well understood [3-5]. However, recent studies have provided new information on the molecular mechanisms that lead to this early inflammatory response. Complement and alarmins have been shown to play an important role as endogenous triggers of trauma-associated inflammation. The complement system appears to represent one of the key mediators of the innate immune response after ischemia-reperfusion and trauma [6-8]. Once activated through the Mannose Binding Lechtin pathway, the activation of complement is amplified via the alternative pathway [9,10].

Complement plays a critical role as a chemoattractant for phagocytes and polymorphonuclear leukocytes and recruits these immune cells to the site of injury. C3a and C5a bind to their receptors on endothelial cells eliciting an inflammatory response via the activation of the Mitogen-activated protein kinases. Finally, the generation of C5b by cleavage of C5 generates the membrane attack complex that can lyse eukaryotic cells [8,11].The second class of early proinflammatory mediators is called alarmins and represents the correlate of pathogen-associated molecular patterns (PAMPs) for all non-pathogen-derived danger signals that originate from tissue injury [12,13]. These include heat shock proteins, annexins, defensins, S100 protein and high mobility group box nuclear protein 1 (HMGB1).

These alarmins are endogenous molecules capable of activating innate immune responses as a signal of tissue damage and cell injury. Among the alarmins, HMGB1 is a DNA nuclear binding protein that has recently been shown to be involved in the triggering of Carfilzomib sterile inflammation [14]. HMGB1 release has been described in both necrotic and apoptotic cells as well as via a non-classical pathway in immune and non-immune cells [14]. HMGB1 has become the archytypal mediator of cellular alarm after sterile stress or injury.

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