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Neutrophil influx into the extravascular compartments of the lungs is a defining characteristic of the Acute Respiratory Distress Syndrome (ARDS).1 During ARDS, circulating neutrophils become primed, resulting in reduced deformability and retention within the pulmonary capillary bed2 ,3 followed by migration across the endothelium, through the interstitium and across the epithelium into the airspaces.4 As neutrophils migrate, they may become activated to phagocytose invading pathogens and release oxidants, proteases and neutrophil extracellular traps, all of which play a role in killing pathogens. Although neutrophils may migrate into the airspaces without inducing an increase in protein permeability under certain conditions,5 in ARDS neutrophils and their toxic mediators can cause tissue injury, including an increase in lung epithelial and endothelial permeability6–9 which leads to the influx of protein-rich alveolar oedema and arterial hypoxaemia.10 In fact, mortality from ARDS correlates with the extent of neutrophilia in the lung.1 Treatment for ARDS is mainly supportive, consisting of low tidal volume ventilation and fluid restriction, approaches which have substantially improved outcomes. However, to further improve outcomes, specific therapies to limit inflammatory lung injury while preserving host defense are needed. Therefore, it is critical that we understand the mechanisms regulating neutrophil recruitment, priming, activation and effector functions.
Leucocyte chemokines are classified into several families based on the position of cysteine (C) residues: CXC, CC, C and CX3C.11 Neutrophil migration has classically been thought to be driven by the CXC chemokines, with CXCL8 (interleukin 8) in humans and its orthologs CXCL1 (KC) and CXCL2 (MIP2) in mice being the prototypical neutrophil chemokines.12 CXC chemokines are elevated in patients with ARDS13 and animal models of lung injury,7 ,12 and CXCL8 levels are predictive of disease development,14 severity15 and mortality.16 However, although CXC …
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