The systemic inflammatory response induced by trauma is reflected by multiple phenotypes of blood neutrophils

Summary

Secondary morbidity and mortality after trauma are mainly due to a dysfunctional immune system. Severe injury can trigger a systemic inflammatory response, which is characterised by pre-activation or priming of neutrophils in peripheral blood. Signals initiated as result of local tissue damage can further activate these neutrophils leading to post-injury inflammatory complications. Additional trauma caused by surgical intervention can worsen the inflammatory response, thereby increasing the risk of these inflammatory complications. Limiting surgical procedures through damage control principles can reduce the risk of secondary morbidity.

Inflammatory complications after injury cannot adequately be predicted using the current anatomical and physiological-based scoring systems. In this review we propose a methodology focussing on the activation state of the systemic inflammatory response with focus on neutrophils to aid in the risk assessment of secondary morbidity after trauma. Neutrophils are essential effector cells during the post-injury systemic inflammatory response. Neutrophils differentially express an array of surface receptors by which the cells can respond and adapt to changing environmental signals. The determination of specific expression profiles of neutrophil receptors can aid in phenotyping and quantifying the systemic inflammatory response. This article reviews the application of these specific signatures of neutrophil receptors as a consequence of severe injury.

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.