Molecular mechanisms of inflammation and tissue injury after major trauma-is complement the "bad guy"?

Despite significant advances in injury prevention, prehospital resuscitation strategies, and modern intensive care, trauma remains the main cause of death in young people in the United States, resulting in more years of potential life lost before the age of 75 years than any other disease [1-4]. Until present, the pathophysiology of major trauma remains poorly understood [5,6]. In principle, the pathophysiological sequelae of major injuries are characterized by the initial traumatic impact (so-called "first hit"), followed by a cascade of subsequent immunological reactions, which render the patient susceptible to a potentially detrimental "second hit" insult [7]. The activation of innate immune response mechanisms has been characterized as a crucial event initiating the early phase of hyperinflammation within hours to days after major trauma [6-8]. While innate immunity is classically considered to be the immediate "first line of defense" against non-self antigens (e.g. infectious pathogens), a traumatic insult can induce a similarly potent acute inflammatory response [9-13]. The trauma-induced immune response may be limited locally, as in isolated injuries, or result in a massive systemic immune activation, as in patients with multiple injuries [1]. The endogenous triggers of trauma-associated inflammation have been thoroughly investigated and characterized in recent years [7,14]. The so-called "first hit" induced by a traumatic impact leads to the appearance of an arsenal of "damage-associated molecular patterns" (DAMPs) that are recognized by receptors of immune cells [15]. DAMPs represent a recently characterized large superfamily of danger signals which can activate innate immune responses after trauma or trauma-induced complications, such as infection and sepsis [7,16]. The DAMP family of danger signals includes the so-called "pathogen-associated molecular patterns" (PAMPs) and molecules termed "alarmins" [17]. The list of molecules belonging to the DAMP famil