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Studies describing the role of neutrophils in acute lung injury (ALI) show divergent results. Some support a pivotal role for neutrophils in the development of lung injury, with improvements in outcomes following inhibition of neutrophil recruitment or their granular contents. Others describe poorer outcomes in patients with neutropenia and no improvements in clinical outcomes or inflammatory biomarkers following interventions which target neutrophils. This has led to uncertainty about whether neutrophils are a therapeutic target in this condition. The recent publication by Blázquez-Prieto et al provides some insight into why different studies may vary in outcome. It describes increased inflammation and a poorer recovery in a murine model where neutrophils are depleted 24 hours after a ventilator-induced lung injury (VILI), and links tissue repair to the sustained activity of neutrophil-derived matrix metalloproteinase (MMP)-9 in cellular, animal and human studies. These data suggest the timing of targeting neutrophils may be critical for improving outcomes in ALI. This editorial explores the evidence for this finding and discusses heterogeneous neutrophil populations in disease and the role of MMP-9 in tissue repair.
Our current understanding of the pathogenesis of ALI includes a paradox which incorporates the following four pieces of evidence.
First, in human and animal studies, neutrophil numbers in bronchoalveolar lavage fluid (BALF) correlate with ALI severity and are predictive of mortality.1 Furthermore, there is evidence of increased neutrophil proteinase (especially neutrophil elastase) and oxidant2 activity in ALI which correlate with the severity of the clinical syndrome. This suggests that neutrophils are centrally implicated in the onset and progression of ALI, where endothelial and epithelial injuries are associated with microvascular permeability, increased tissue oedema and an early accumulation of activated neutrophils to the lung.
Second, in animal models of ALI, reducing neutrophil accumulation to the lung (eg, by targeting CXCR2) or/and inhibiting the …
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