Review
Adenosine: a potential mediator of immunosuppression in multiple organ failure

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Abstract

Multiple organ failure following a variety of insults, including, trauma, shock and pancreatitis, is the cause of 50–80% of all deaths in surgical intensive care units. In most patients, infections secondary to a general immunosuppressive state serve to trigger the development of multiple organ failure. This immunosuppressive state may be a consequence of excessive release of adenosine into the extracellular space, as adenosine has multiple immunosuppressive effects. Activation of adenosine receptors on immune cells inhibits the production of proinflammatory cytokines such as tumor necrosis factor α and interleukin (IL)-12, and increases the production of the anti-inflammatory cytokine IL-10. In addition, adenosine receptor activation appears to suppress cellular immunity by decreasing T helper cell (Th)1 and increasing Th2 responses. A deeper understanding of the role of adenosine in multiple organ failure may facilitate the development of adenosine-based therapeutic strategies.

Introduction

Multiple organ failure (MOF) is the cause of 50–80% of all deaths in surgical intensive care units [1]. Although MOF was first described more than 20 years ago, the cause of the condition is still poorly understood, treatment is still largely supportive and the mortality rate (30–70% in most series) is little improved [2]. Although initially proposed as a sign of occult or uncontrolled infection, MOF has now been documented to occur after several diverse clinical conditions, including mechanical and thermal trauma, pancreatitis and shock [1].

In 1992, the term systemic inflammatory response syndrome (SIRS) was introduced to describe the underlying massive inflammatory reaction of the body that contributes to the development of MOF [3]. The SIRS, or hyperinflammatory, theory of MOF states that in response to an inciting event, the body unleashes an inflammatory reaction consisting of an overproduction of a host of proinflammatory mediators. In the past few years, multiple clinical trials have been carried out aiming to counteract many of the SIRS-inducing pro-inflammatory mediators. Unfortunately, all of these trials failed to demonstrate any benefit from treatment [4]. Based on the failure of these trials, it was suggested that the SIRS model had a fundamental flaw, because it did not take into consideration the fact that, although the clinical symptoms follow a relatively predictable and consistent course, diverse pathophysiological processes underlie the manifestation of MOF [5]. Most importantly, it was overlooked that, in response to the original insult, the body also mounts a compensatory anti-inflammatory response (CARS). This immune paralysis that develops as a result of an overwhelming anti-inflammatory response manifests itself as anergy and an increased susceptibility to infection. It was postulated that it is the balance of proinflammatory and anti-inflammatory events that is lost in MOF, resulting in either a destructive systemic inflammatory state — SIRS — or a state of excessive immunosuppression — CARS. In addition, it appears that whereas SIRS appears early after the original insult, in most patients CARS only becomes manifest later, after a period of relative clinical stability. Although in some patients SIRS will lead to MOF, it appears that the majority of patients survive the initial SIRS response. In fact, the subsequent development of infection, secondary to the immunosuppressed CARS state, is the major cause of the development of MOF in a high number of patients [6]. This observation can explain why clinical trials employing anti-inflammatory strategies resulted in disappointment and suggests that novel therapies aiming to offset CARS may be more beneficial.

In the first section of this review, we will briefly overview our current understanding of the altered macrophage and T-cell function characteristic of CARS, leading to decreased antibacterial cellular immune responses and thereby MOF. In the latter part of this paper, we will attempt to summarize our current knowledge of how increased extracellular levels of the stress mediator adenosine can contribute to macrophage and T-cell dysfunction during CARS.

Section snippets

Monocyte/macrophage function and T-cell responsiveness

It has recently become evident that T-cell hyporesponsiveness and monocyte/macrophage dysfunction are two of the most important factors contributing to the immune paralysis seen during MOF 6., 7., 8.. With respect to macrophage function, it appears that the factors released by macrophages shift from proinflammatory to anti-inflammatory ones, resulting in immune paralysis. For example, in MOF, macrophages manifest a decreased ability to produce the proinflammatory cytokines tumor necrosis factor

Adenosine is released in excess in multiple organ failure

The purine adenosine is now considered an important stress hormone that is released in excessive amounts in the vicinity of immune cells during both systemic and cellular stress [13]. The predominant source of extracellular adenosine during systemic activation of the stress system is the sympathetic nervous system. We have recently demonstrated that stimulation of sympathetic nerve terminals in immune organs results in the release of not only the classical neurotransmitter noradrenaline but

Conclusions

The evidence summarized here indicates that adenosine is likely to be an important contributor to the immune paralysis seen in the CARS stage of MOF, as adenosine appears to contribute to the development of an immune compromised state. The most important therapeutic implication arising from these data is that preventing the action of endogenous adenosine may be beneficial in MOF states that are dominated by immunosuppressive events. The immunosuppressive action of high levels of endogenously

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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