Severe trauma remains a dreadful health care concern, representing the first cause of qualityadjusted life-year loss in the world. While haemorrhagic shock and devastating central nervous system injuries remain the main sources of early trauma deaths, 25 to 30% of post-traumatic fatalities occur later, when patients develop secondary organ failures (SOF) in the intensive care unit (ICU). These SOFs are multifactorial but recent evidence suggests they may be associated with 1) an initially exacerbated innate immune response and 2) a secondary post-traumatic immunosuppression. The exacerbated innate immune response is proportional to the severity of trauma-induced organ injuries and to the plasma concentrations of circulating Damage-Associated Molecular Patterns (DAMPs). Also described as alarmins, DAMPs are diverse in nature (polymorphonuclear cells, complement) and trigger secondary remote injuries to endothelial and epithelial cells in distant organs (lungs, liver, kidneys), ending up in life-threatening syndromes (acute lung injury, acute respiratory distress syndrome, acute kidney injury, vasoplegia and trauma-induced coagulopathy). Besides mechanical injuries in wounded tissues and organs, resulting in the breakdown of macroscopic and microscopic barriers, trauma-induced haemorrhagic shock is a worsening factor by multiplying the release of DAMPs in hypoperfused organs and cells. Likewise, extensive surgical interventions increase the release of DAMPs in the surgical field when they are performed at the climax of trauma-induced inflammation. The secondary, post-traumatic immunosuppression (immune anergy, monocyte deactivation, type 2 lymphocytic response) initiates soon after the initial insult. However, its clinical consequences (viral reactivations, increased susceptibility to bacterial and fungal infections) only become apparent after some days in the ICU, confining the patient in a persistent state of inflammation, immunosuppression and hypercatabolism (PICS syndrome). The discovery of DAMPs and their role in trauma patients shed new light on therapeutic approaches already adopted on clinical grounds (damage-control surgery, haemostatic resuscitation, early tranexamic acid administration). It also uncovers some promising new therapeutic promises, targeting either DAMPs (dornase alfa), their receptors on polymorphonuclear cells (cyclosporine H) or the activity of innate immune response (glucocorticoids, IFNg and GM-CSF).
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