Role of biological modifiers regulating the immune response after trauma
Introduction
Severe trauma is associated with altered host defence, characterised by an early over-activation of innate immune responses (hyperinflammation), followed by a delayed attenuation of adaptive immunity with decreased T-cell function (immunosuppression) and enhanced susceptibility to infection, sepsis, and multiple organ failure.10, 65, 74, 87, 96, 180 During both phases of hyper- (“systemic inflammatory response syndrome”, SIRS) and hypo-inflammation (“compensatory anti-inflammatory response syndrome”, CARS), injured patients are highly susceptible to “2nd hits” which exacerbate the pathophysiological cascade leading to sepsis, multiple organ failure, and death.10, 87, 116 The objectives of immunomodulatory therapies are aimed at attenuating the detrimental side-effects of the early hyperinflammatory cascade and preventing additional insults which can provoke the inflammatory host response into a “host response failure disease” with adverse outcome. Concomitantly, the cell-mediated, adaptive immune response must be supported to overcome the delayed posttraumatic functional immune paralysis (Fig. 1).
Section snippets
Innate immunity
The innate immune response is crucial as an immediate “first line of defence” against antigens recognised as non-self entities. These include infectious agents, such as viruses, bacteria, and parasites, as well as host-generated dangers, such as malignant tumours. A traumatic impact is also capable of inducing an activation of innate immune responses.66, 74, 131, 141, 159 The trauma-induced immune response may be limited locally, as in monotrauma, or result in a massive systemic immune
Pharmacological immunomodulation
Treatment strategies for controlling the extent of posttraumatic inflammation have undergone a major evolutionary change in recent years. While new recombinant molecules became available for immunomodulatory therapies, other more conventional and “broader” anti-inflammatory agents, such as corticosteroids, underwent a therapeutic re-evaluation in the setting of trauma.5, 26, 43, 46, 162, 165, 168, 177
Blood transfusion management
The available literature incriminates early blood transfusion as a consistent predictor of infection, ARDS, MOF, and death following major trauma.138, 146, 152 While it has been assumed that the need for blood transfusion reflects the presence of shock, the popular alternative explanation is that blood transfusions are immunoactive and thus contribute to infectious complications that cause late MOF.106 The hypothesis that blood transfusions are also immunosuppressive and thus responsible for
Immunonutrition
After severe trauma, the metabolism is reoriented towards supporting the organism's immune response at the cost of enhanced proteinolysis of skeletal muscle. The physical and psychological stimulation of the neuroendocrine axis through fear, stress, pain, inflammation and shock increases the caloric turnover significantly above the baseline situation in healthy individuals.51, 87 The state of hypercatabolism after severe injury can lead to severe complications associated with posttraumatic
Current challenges and future directions
Despite thorough insights into the pathophysiological mechanisms of innate and adaptive immune responses after trauma, clinical trials aimed at modulating the posttraumatic immune response have so far failed in translation from “bench to bedside”. This notion has been dramatically exemplified by the failure of the “CRASH” trial,133 as outlined earlier in this paper. The disappointing awareness of this failure in the clinical setting indicates that the complex processes of posttraumatic
Conclusions
During the evolution of mankind, the immune system primarily developed towards the efficient recognition and clearance of microbial antigens and molecular patterns (PAMPs). In addition, trauma-induced danger signals have evolved and contributed to a wide range of antigens capable of inducing innate immune responses, even in the absence of a bacterial challenge (DAMPs). This immunological “first line of defence” was phylogenetically aimed at clearance of necrotic tissue, induction of repair
Conflict of interest
None.
Acknowledgments
PFS was supported by grants from the German Research Foundation (DFG) No. STA 635/1-1, STA 635/1-2, STA 635/2-1, STA 635/2-2, and TR 742/1-1. EEM was supported by NIH grants P50 GM 49222 and U54 GM 62119. WRS was supported by a project grant from the Orthopaedic Trauma Association (OTA).
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