Elsevier

The Lancet

Volume 368, Issue 9530, 8–14 July 2006, Pages 157-169
The Lancet

Review
Neutrophils in development of multiple organ failure in sepsis

https://doi.org/10.1016/S0140-6736(06)69005-3Get rights and content

Summary

Multiple organ failure is a major threat to the survival of patients with sepsis and systemic inflammation. In the UK and in the USA, mortality rates are currently comparable with and projected to exceed those from myocardial infarction. The immune system combats microbial infections but, in severe sepsis, its untoward activity seems to contribute to organ dysfunction. In this Review we propose that an inappropriate activation and positioning of neutrophils within the microvasculature contributes to the pathological manifestations of multiple organ failure. We further suggest that targeting neutrophils and their interactions with blood vessel walls could be a worthwhile therapeutic strategy for sepsis.

Section snippets

Neutrophils and organ failure

Neutrophils are ideally suited to the elimination of pathogenic bacteria because of their large stores of proteolytic enzymes and rapid production of reactive oxygen species to degrade internalised pathogens.15 If these lytic factors16 or pro-inflammatory cytokines17 are released extracellularly from tissue-infiltrating neutrophils, local damage will ensue.18, 19, 20, 21 Indeed, neutrophil-induced tissue injury occurs at sites of localised bacterial infection, which, in its extreme form, leads

Abnormal numbers of blood neutrophils

Neutrophils have a 14-day development in the bone marrow and stay temporarily in a storage pool before release into the blood, where they spend 12–14 h in transit from a circulating pool (axial stream) into a marginating pool (contact with blood vessel walls). Thereafter, in the absence of any bacterial infections, neutrophils enter reticuloendothelial organs, such as the liver,37 or even return to the bone marrow38 to undergo apoptosis (programmed cell death).39 The ageing neutrophils shrink

Tissue extravasation

Bacterial elimination is dependent on the rapid recruitment of blood neutrophils into sites of infection. The neutrophils must first adhere to blood vessel walls before actively migrating into the surrounding tissue in response to chemical stimuli (chemotaxis). Here, we discuss all these stages with respect to the behaviour of neutrophils in sepsis.

Neutrophil priming, survival, and circulating factors

Neutrophils exist in three states: resting (unstimulated), primed (encounter with an inflammatory agonist or microbial-derived product that has lowered the threshold stimulus needed for activation), and activated (undertaking a defined function). The transition of neutrophils from a resting state in the circulation to an activated state at a site of infection is triggered by an ordered sequence of signals from priming stimuli—eg, C5a, lipopolysaccharide, and cytokines.97, 98, 99 This effect

Recognition and phagocytosis of bacteria

Neutrophils from sepsis patients show enhanced internalisation and destruction of micro-organisms (table 2),74, 82, 83 although opinion is divided as to whether phagocytosis is augmented or impeded at sites of infection in animals.118, 119 So far, most investigations of the phagocytic potential of neutrophils in patients with sepsis have focused on the distribution and expression of neutrophil receptors implicated in bacterial recognition and internalisation rather than the functional

Limitations to the understanding of neutrophils in sepsis

Elucidation of the functional status of neutrophils in patients with sepsis is hampered by insufficient studies in some areas (eg, phagocytosis) and conflicting data in others (eg, expression of adhesion molecules). The apparent inconsistencies probably relate to inadequate stratification of patients, variable drug intervention (eg, steroids), and differences in experimental design. A meaningful assessment of neutrophil behaviour in sepsis needs longitudinal studies of individual patients,

Neutrophil-endothelial interactions and sepsis-related organ failure

In severe sepsis, there seems to be a functional dichotomy of neutrophils with respect to responsiveness to bacterial infections. In non-pulmonary tissue, the extravasation of neutrophils into sites of infection is impeded possibly because of excessive endothelial binding and reduced chemotactic responsiveness, by contrast with the intense infiltration of these cells into infected pulmonary tissue (figure 3). The sequestration of neutrophils could be a key stage in the initiation of multiple

Neutrophil adhesion molecules

If the untoward binding of neutrophils to endothelium is relevant to the induction of organ dysfunction in sepsis, is clinical benefit likely to accrue from inhibition of this interaction? Antagonism of CD18 reverses the lung vascular injury induced by neutrophils in experimentally induced sepsis.161 Similar approaches have not been undertaken in the clinical setting but use of anti-CD18 antibodies for patients with traumatic shock162 or with myocardial infarction163 have been disappointing,

Conclusions

During sepsis, the immune response is deemed to be suppressed, as shown by the hyporeactivity of lymphocytes and by the depletion of their numbers due to increased apoptosis. By contrast, circulating numbers of neutrophils are often increased, survival is extended, and functional responses (apart from chemotaxis) are enhanced (table 2).

In sepsis, neutrophils engage in repelling invading pathogens while simultaneously inducing collateral damage in which organ function is the casualty. At

Search strategy and selection criteria

We searched the library of the Royal Society of Medicine, UK (1960–2005) and MEDLINE (1960–2005). We used the search terms “neutrophils”, “sepsis”, and “organ failure”. We largely selected publications in the past 10 years, but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Review articles and book chapters are cited to provide more

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