The systemic inflammatory response induced by trauma is reflected by multiple phenotypes of blood neutrophils
Introduction
Trauma is a major cause of morbidity and mortality in people under the age of 50.9 This is caused by either a direct result of injuries or post-injury immunological complications by a dysfunctional immune response.24 In general, immunity can be divided into innate and adaptive immune responses.10
Innate immune responses form the first line of defence against invading micro-organisms and rapidly respond to danger signals. Adaptive immunity is a slower antigen specific response, which requires antigen recognition during a sensibilisation phase. The post-injury immune response is mainly mediated by the innate immune response and is, therefore, subject of this review.
The innate immune response consists of both a humoural and a cellular response.39 The cellular response is typically mediated by phagocytes and dendritic cells. The initial humoural response consists of bioactive proteins (cytokines, complement and acute phase proteins) and lipids (leukotrienes and platelet-activating factor).29 These factors can activate cells from both types of immunity (innate and adaptive). The innate immune response after injury is for an important part mediated by neutrophils (Fig. 1). As these cells are essential in the first line of defence to microbial threats, the amount of neutrophils can be rapidly increased by release from bone marrow.12 Apart from immune surveillance, innate immune cells play an important role in tissue repair mechanisms after tissue injury.61 In addition to the pivotal role of neutrophils in normal homeostatic immune surveillance, aberrant activation of these cells is important in the pathogenesis of many acute and chronic inflammatory diseases.3, 47, 66
Damaged local tissue releases humoural danger signals, which attract and activate neutrophils.28, 32 In addition, these signals antagonise apoptotic signals in these cells.56 Excessive local activation of neutrophils in the tissues will lead to a vicious circle of inappropriate homing, adhesion, activation, prolonged survival and subsequent tissue damage (Fig. 2a). The role of neutrophils has clearly been shown in various models of tissue injury, such as caused by reperfusion after peripheral ischaemia. In these studies neutrophil influx into ischaemic tissue is the main cause of further tissue damage.40, 55, 63
Excessive systemic neutrophil stimulation as seen after trauma is part of a systemic inflammatory response syndrome (SIRS).6 Primed circulating neutrophils are prone to home to and become activated in the tissues when they encounter additional local inflammatory stimuli (Fig.2b).8 In particular, the lung is a preferred site for homing and activation of primed immune cells due to the large microvascular bed and long transit time.27, 52 As a consequence systemic neutrophil priming can lead to excessive local neutrophil activation in the lung. This local activation occurs when lung vascular endothelium becomes damaged and/or activated.49 This aberrantly regulated immune response can lead to functional complications when increased permeability of the alveolar–capillary barrier occurs, resulting in influx of protein-rich oedema fluid and impairment of arterial oxygenation. This is seen in clinical conditions such as the acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).
Every type of tissue injury, including surgical intervention, can lead to an inflammatory response.42 Therefore, in patients with multiple injuries, additional tissue injury induced by surgical intervention can increase the overall inflammatory reaction, and thereby increase the risk of inflammatory complications. Surgical tissue injury can be seen as an important risk factor for systemic inflammatory complications. This is particularly relevant in those patients who are already characterised by a borderline inflammatory response (i.e. a situation with a high risk to develop inflammatory complications) to the initial trauma. Minimising this surgically induced inflammatory response through limiting surgical procedures is the basis of damage control procedures.26, 54
In order to adjust surgical strategy it is essential to identify the multiple-injured patient at risk by accurately assessing and quantifying the extent and type of the inflammatory state.
Section snippets
Correlation between severity of injury and the systemic inflammatory response
Rodent studies suggest a strong correlation between injury severity and the inflammatory response. Pasquale et al. used groups with large differences in trauma loads (one or two femoral fractures combined with fixed volume haemorrhage) and showed that the severity of injury and the inflammatory response are positively correlated.46
We performed a study in a rodent model of intestinal ischaemia/reperfusion with small differences in trauma load. Ischaemia was introduced by clamping the mesenteric
Neutrophil receptors and severity of inflammation
Neutrophil receptors have been studied in the context of many chronic inflammatory conditions such as asthma, chronic obstructive pulmonary disease and rheumatoid arthritis. Exacerbation of these conditions is associated with activation of neutrophil, which is reflected by differential expression of activation epitopes.44
Complex kinetics of neutrophil phenotypes in peripheral blood after injury
Our recent studies have clearly shown that neutrophils can rapidly change their expression repertoire of relevant receptors. It is not clear whether this occurs in distinct populations of neutrophils or whether one phenotype evolves from the other. As the kinetics of change in receptor expression differs, description of these phenotypes can only be reliable when multiple comparisons are made for expression of different receptors. Future studies should, therefore, focus on subtle differences in
Conflict of interest
The authors declare that they have no financial or other relationship with people or organisations who could influence or bias the outcome and the arguments stated in this article.
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2019, Blood AdvancesCitation Excerpt :These seemingly contradicting effects of neutrophils on adaptive immune responses suggest a regulatory role. Increasing evidence is found supporting the presence of multiple neutrophil phenotypes.35-38 These different phenotypes could arise through specific differentiation programs in the bone marrow or they may be induced by extracellular signals such as cytokines and chemokines.34