Elsevier

Injury

Volume 38, Issue 12, December 2007, Pages 1336-1345
Injury

Systemic inflammation after trauma

https://doi.org/10.1016/j.injury.2007.10.003Get rights and content

Summary

Trauma is still one of the main reasons for death among the population worldwide. Mortality occurring early after injury is due to “first hits”, including severe organ injury, hypoxia, hypovolaemia or head trauma. Massive injury leads to activation of the immune system and the early inflammatory immune response after trauma has been defined as systemic inflammatory response syndrome (SIRS). “Second hits” such as infections, ischaemia/reperfusion or operations can further augment the pro-inflammatory immune response and have been correlated with the high morbidity and mortality in the latter times after trauma. SIRS can lead to tissue destruction in organs not originally affected by the initial trauma with subsequent development of multi-organ dysfunction (MOD). The initial pro-inflammatory response is followed by an anti-inflammatory response and can result in immune suppression with high risk of infection and sepsis. Trauma causes activation of nearly all components of the immune system. It activates the neuroendocrine system and local tissue destruction and accumulation of toxic byproducts of metabolic respiration leads to release of mediators. Extensive tissue injury may result in spillover of these mediators into the peripheral bloodstream to further maintain and augment the pro-inflammatory response. Hormones like ACTH, corticosteroids and catecholamines as well as cytokines, chemokines and alarmins play important roles in the initiation and persistence of the pro-inflammatory response after severe injury. The purpose of this review is therefore to describe the immunological events after trauma and to introduce important mediators and pathways of the inflammatory immune response.

Introduction

Trauma is the main cause of death in the general public of the United States under the age of 45.76, 47, 80 Mortality after major trauma has been divided into three separate time periods after injury. The first peak of death after injury represents the immediate effects of trauma with death at the scene (53–72%) or within the first hour.76 These deaths are really only affected by prevention measures and are usually due to massive head injury or bleeding. This is followed by a second, smaller peak in the first 24 h normally due to hypoxia, hypovolaemia or severe head trauma.62, 7, 2, 23 Should the seriously injured patient survive over these first two time peaks, there is a high risk of developing immunological dysfunction and subsequently sepsis or the systemic inflammatory response syndrome (SIRS). This can lead to multi organ dysfunction syndrome (MODS) with a high possibility of death.54, 57, 15, 5 MODS is probably a confluence of an uncontrolled systemic inflammatory response involving multiple mediators. There is a long recognised vigorous pro-inflammatory cytokine response following severe injury that involves increased serum levels of Interleukin-1 (IL-1), IL-2, tumour necrosis factor-alpha (TNF), IL-6, IL-12, and Interferon-gamma (IFN).29, 67, 58, 51 These may essentially function as acute phase hormones or danger signals to mount a response to the initial stress, and are produced by a variety of cells including monocyte/macrophages and T helper-1 lymphocytes. Both chemokines and complement have been implicated as important mediators in the pathogenesis of MODS. Complement component C3a and C5a, common to the classical and the alternative pathway, are potent neutrophil chemoattractants and excessive complement activation has been shown to play a role in organ injury. All of these early immune response pathways are simultaneously activated after severe injury, and there is often a correlation between the severity of injury as measured by the injury severity score and the degree of the pro-inflammatory immune response. The Moores have described a model of early and late MODS depending on the initial degree of injury severity and extent of shock51 (Fig. 1). Early MODS is associated with severe injury and shock and is accompanied by an early vigorous pro-inflammatory response and SIRS. MODS occurring later in the clinical course is often associated with a second, or even multiple stresses, such as additional operations or inter-current infections. This has also been accompanied by a shift from a Th-1 pro-inflammatory response to a Th-2 anti-inflammatory response that is compensatory but also may increase the risk of infection through immune suppression.

Walter Cannon performed physiological studies of the neuroendocrine response after injury, which demonstrated an adrenocortical response to stress characterised by increased production of adrenocorticosteroids and catecholamines16 This fight or flight reaction has been highly conserved evolutionarily in the animal kingdom, for preservation of vital organ flow and avoidance of further injury (Table 1). Hans Selye further characterised this neuroendocrine response to stress and the hypothalamic–pituitary–adrenal axis.68 He pointed out that this was involved in what he termed ’the general adaptation syndrome’ essentially a precursor to the systemic inflammatory syndrome currently known. This neuroendocrine response is probably caused by stimulation of this axis which then hormonally drives the increase in heart rate, respiratory rate, fever, and leukocytosis seen in these patients after major injury. SIRS can be caused by a variety of insults such as trauma, burns or major surgery and is defined when two or more of the criteria apply as shown in Table 2.11 The definition of sepsis is similar but denotes the presence of a septic focus as a specific cause of SIRS.

The immune system has been divided into an early innate and a later adaptive response. The latter is responsible for specific memory in the form of plasma cells and cytotoxic T-cells. The tasks of the immune system include recognition, activation, discrimination, regulation and eradication of intruding exogenous and pathogen derived signals. The first line of defence against invading microorganisms is the epithelial barrier. This is not only a mechanical obstacle, but also equipped with antimicrobial substances like enzymes and IgA molecules. Colonisation of the skin with normal bacterial flora represents an important mechanism of protection as well, as these often preclude pathogenic microbes from establishment in high concentrations. After penetration through this first border, invading microorganisms are recognised in minutes by the multiple components of innate immunity. The host defence response leads to activation of immune cells, cytokine secretion, activation of complement and the coagulation cascade, secretion of acute phase proteins and neuroendocrine mediators. In the normal host response to infection these processes are highly controlled and limited to the site of infection.

Section snippets

Trauma and the early immune response

Trauma also leads to the activation of the local host response with localised activation of immune cells, secretion of various kinds of mediators. This process is necessary for haemostasis, protection against invading microorganism, and for the initiation of tissue repair and wound healing. The process is tightly regulated by anti-inflammatory mediators. Depending on the magnitude of tissue damage and on the vulnerability of the host, the local immune response may fail to control the

Local inflammatory mediator production

Local mediators of inflammation include histamine, kinins, and arachidonic acid metabolites which cause increased capillary permeability, tissue oedema, and immune cell infiltration. Local mediator release is not only triggered by tissue injury in the area neutrophils are usually followed by monocyte/macrophages into the injured interstitial space. Extensive tissue injury may lead to spillover of such mediators into the peripheral bloodstream and amplify the systemic inflammatory response.

Complement

The complement cascade is a series of enzymatic cleavage reactions that are triggered by either antigen-antibody complexes (classical pathway) or bacterial cell wall components (alternate pathway) and must occur in sequential fashion to be effective. The latter pathway does not require prior immunisation for activation and thus represents a mechanism for immediate defence against any foreign antigen. Some of the cleavage products are capable of direct bacterial lysis and activated complement

Alarmins

The presence of systemic inflammation without evidence of a bacterial focus suggests the presence of endogenous triggers in immune activation after trauma. These signalling substances are called alarmins in assignment to the term danger signals, including exogenous and endogenous signals. Alarmins are characterised as a group of pathogen associated molecular pattern (PAMPs), which are released either after non-programmed cell death, excluding apoptosis, or produced and released by cells of the

Cytokines

Cytokines are secreted proteins from cells which function as means of communication between cells in both a paracrine and endocrine fashion. Over the last 20 years, cytokines have gained more attention in the understanding of physiological changes after trauma or in inflammation. They play an important role in the defence and repair mechanisms following trauma, but this highly controlled system may become over exuberant after severe injury to the host. This has been associated with SIRS and

Chemokines

IL-8 is a chemotactic cytokine, and the most potent endogenous chemoattractant. Therefore it belongs to the chemokine family and is also called CXCL8. Chemokines control the traffic of the immune cells which are the main effectors of the immune system. They are small, structurally related molecules which can be divided into two families, the CC and CXC, depending on the localisation of the two N-terminal cystein residues. An additional L (e.g. CXCL8 = IL-8) indicates the ligand while R (e.g. CXCR1

Cellular immune response

The cellular immune response following trauma includes polymorphonuclear granulocyes (PMN), lymphocytes and monocytes/macrophages and natural killer cells. PMN represents 50–60% of total circulating leukocytes and are the leading cells in the first response to severe trauma from the incident on up to the second or third day.13 Radical oxygen species produced after ischaemia and reperfusion following traumatic injury are one of the most potent activators and chemoattractants for PMN.12 While

Conclusions

Trauma represents the most ancient and greatest stressor to an organism. The initial host defence response is geared towards haemostasis and preservation of vital organ oxygenation. As part of this normal response to injury, there is a surge in the stress hormone response mediated by the hypothalamic–pituitary–adrenal axis, which leads to the typical physiological catecholamine stress response. Danger signals initiate an early innate immune response to injured tissue itself, however an overly

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