Elsevier

Injury

Volume 38, Issue 12, December 2007, Pages 1409-1422
Injury

Role of biological modifiers regulating the immune response after trauma

https://doi.org/10.1016/j.injury.2007.09.023Get rights and content

Summary

Trauma induces a profound immunological dysfunction. This is characterised by an early state of hyperinflammation, followed by a phase of immunosuppression with increased susceptibility to infection and multiple organ failure. Therapeutic strategies directed at restoring immune homeostasis after traumatic injuries have largely failed in translation from “bench to bedside”. The present review illustrates the role of biological modifiers of the posttraumatic immune response by portraying different modalities of therapeutic immune modulation. The emphasis is placed on anti-inflammatory (steroids) and immune-stimulatory (interferon) pharmacological strategies and modified resuscitative strategies, as well as more unconventional immunomodulatory approaches, such as immunonutrition.

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).

References (181)

  • S.D. Fleming et al.

    Complement, natural antibodies, autoantibodies and tissue injury

    Autoimmun Rev

    (2006)
  • O. Gajic et al.

    Transfusion-related acute lung injury

    Mayo Clin Proc

    (2005)
  • P.V. Giannoudis et al.

    When should we operate on major fractures in patients with severe head injuries?

    Am J Surg

    (2002)
  • R.D. Griffiths et al.

    Infection, multiple organ failure, and survival in the intensive care unit: influence of glutamine-supplemented parenteral nutrition on acquired infection

    Nutrition

    (2002)
  • M.R. Grotz et al.

    Traumatic brain injury and stabilisation of long bone fractures: an update

    Injury

    (2004)
  • V.M. Holers et al.

    The alternative pathway of complement in disease: opportunities for therapeutic targeting

    Mol Immunol

    (2004)
  • E.E. Husebye et al.

    The influence of a one-step reamer-irrigator-aspirator technique on the intramedullary pressure in the pig femur

    Injury

    (2006)
  • M. Keel et al.

    Pathophysiology of polytrauma

    Injury

    (2005)
  • S.M. Knoblach et al.

    Interleukin-10 improves outcome and alters proinflammatory cytokine expression after experimental traumatic brain injury

    Exp Neurol

    (1998)
  • I. Leinhase et al.

    Pharmacological complement inhibition at the C3 convertase level promotes neuronal survival, neuroprotective intracerebral gene expression, and neurological outcome after traumatic brain injury

    Exp Neurol

    (2006)
  • F.Y. Liew et al.

    The role of innate mediators in inflammatory response

    Mol Immunol

    (2002)
  • D. Mastellos et al.

    Complement: more than a ’guard’ against invading pathogens?

    Trends Immunol

    (2002)
  • I.B. McInnes et al.

    Interleukin-15: a new cytokine target for the treatment of inflammatory diseases

    Curr Opin Pharmacol

    (2004)
  • J.M. Adams et al.

    The immunomodulatory effects of damage control abdominal packing on local and systemic neutrophil activity

    J Trauma

    (2001)
  • J. Aiboshi et al.

    Blood transfusion and the two-insult model of post-injury multiple organ failure

    Shock

    (2001)
  • P. Alderson et al.

    Corticosteroids in acute traumatic brain injury: systematic review of randomised controlled trials

    BMJ

    (1997)
  • Alderson P, Roberts I. Corticosteroids for acute traumatic brain injury. Cochrane Database Syst Rev 2005;...
  • S. Arbabi et al.

    Beta-blocker use is associated with improved outcomes in adult trauma patients

    J Trauma

    (2007)
  • C. Atkinson et al.

    Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection

    J Clin Invest

    (2005)
  • B. Attuwaybi et al.

    Hypertonic saline prevents inflammation, injury, and impaired intestinal transit after gut ischemia/reperfusion by inducing heme oxygenase 1 enzyme

    J Trauma

    (2004)
  • R. Barrington et al.

    The role of complement in inflammation and adaptive immunity

    Immunol Rev

    (2001)
  • A.E. Baue et al.

    Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle?

    Shock

    (1998)
  • B.M. Bellander et al.

    Complement activation in the human brain after traumatic head injury

    J Neurotrauma

    (2001)
  • A. Bhardwaj et al.

    Hypertonic saline solutions in brain injury

    Curr Opin Crit Care

    (2004)
  • M. Bhatia et al.

    Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome

    J Pathol

    (2004)
  • M.E. Bianchi

    DAMPs, PAMPs and alarmins: all we need to know about danger

    J Leukoc Biol

    (2007)
  • W.L. Biffl et al.

    Interleukin-6 potentiates neutrophil priming with platelet-activating factor

    Arch Surg

    (1994)
  • W.L. Biffl et al.

    Plasma from aged stored red blood cells delays neutrophil apoptosis and primes for cytotoxicity: abrogation by poststorage washing but not prestorage leukoreduction

    J Trauma

    (2001)
  • M.A. Blajchman

    The clinical benefits of the leukoreduction of blood products

    J Trauma

    (2006)
  • L.B. Bone et al.

    Early versus delayed stabilization of femoral fractures: a prospective randomized study. 1989

    Clin Orthop Relat Res

    (2004)
  • R.C. Bone

    Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation

    Crit Care Med

    (1996)
  • A.J. Botha et al.

    Postinjury neutrophil priming and activation: an early vulnerable window

    Surgery

    (1995)
  • A.J. Botha et al.

    Early neutrophil sequestration after injury: a pathogenic mechanism for multiple organ failure

    J Trauma

    (1995)
  • J.P. Bouvet et al.

    Silent antibodies

    Arch Inst Pasteur Tunis

    (2005)
  • M.B. Bracken

    Methylprednisolone and acute spinal cord injury: an update of the randomized evidence

    Spine

    (2001)
  • Bracken MB. Steroids for acute spinal cord injury. Cochrane Database Syst Rev 2002;...
  • M.B. Bracken

    CRASH (corticosteroid randomization after significant head injury trial): landmark and storm warning

    Neurosurgery

    (2005)
  • I.F. Charo et al.

    The many roles of chemokines and chemokine receptors in inflammation

    N Engl J Med

    (2006)
  • R. Chung et al.

    Roles of neutrophil-mediated inflammatory response in the bony repair of injured growth plate cartilage in young rats

    J Leukoc Biol

    (2006)
  • D.J. Ciesla et al.

    The role of the lung in postinjury multiple organ failure

    Surgery

    (2005)
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