Abstract
Ischemia/reperfusion (I/R) injury is a severe inflammatory insult associated with numerous pathologies, such as myocardial infarction, stroke and acute kidney injury. I/R injury is characterized by a rapid influx of activated neutrophils secreting toxic free radical species and degrading enzymes that can irreversibly damage the tissue, thus impairing organ functions. Significant efforts have been invested in identifying therapeutic targets to suppress neutrophil recruitment and activation post‐I/R injury. In this context, pharmacological targeting of neutrophil elastase (NE) has shown promising anti‐inflammatory efficacy in a number of experimental and clinical settings of I/R injury and is considered a plausible clinical strategy for organ care. However, the mechanisms of action of NE, and hence its inhibitors, in this process are not fully understood. Here we conducted a comprehensive analysis of the impact of NE genetic deletion on neutrophil infiltration in four murine models of I/R injury as induced in the heart, kidneys, intestine and cremaster muscle. In all models, neutrophil migration into ischemic regions was significantly suppressed in NE−/− mice as compared with wild‐type controls. Analysis of inflamed cremaster muscle and mesenteric microvessels by intravital and confocal microscopy revealed a selective entrapment of neutrophils within venular walls, most notably at the level of the venular basement membrane (BM) following NE deletion/pharmacological blockade. This effect was associated with the suppression of NE‐mediated remodeling of the low matrix protein expressing regions within the venular BM used by transmigrating neutrophils as exit portals. Furthermore, whilst NE deficiency led to reduced neutrophil activation and vascular leakage, levels of monocytes and prohealing M2 macrophages were reduced in tissues of NE−/− mice subjected to I/R. Collectively our results identify a vital and non‐redundant role for NE in supporting neutrophil breaching of the venular BM post‐I/R injury but also suggest a protective role for NE in promoting tissue repair. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Ischemia/reperfusion (I/R) injury is a common feature of many cardiovascular pathologies such as myocardial infarction, cerebral stroke and clinical complications associated with organ transplantation surgeries [1,2,3,4]
To ascertain the role of neutrophil elastase (NE) in neutrophil recruitment in clinically relevant models of I/R injury, we investigated the impact of genetic deletion of NE in murine models of myocardial and kidney I/R injury
With respect to the heart injury model, WT and NE-/- animals were subjected to myocardial infarction (MI) for 25 min followed by 2 h of reperfusion
Summary
Ischemia/reperfusion (I/R) injury is a common feature of many cardiovascular pathologies such as myocardial infarction, cerebral stroke and clinical complications associated with organ transplantation surgeries [1,2,3,4]. The occurrence of I/R injury is paradoxical in that it is induced following the often life-saving process of restoration of blood flow to ischemic tissues. Whilst this practice is aimed at providing nutrients and oxygen to affected regions, and preventing tissue necrosis, the procedure can lead to vascular dysfunction [5], acute inflammation and increase in tissue-cell death [6]. This pathophysiological response is largely the consequence of a rapid activation of the vascular endothelium and an intense recruitment of pro-inflammatory leukocytes [7]. There remains a need for alternative therapeutic approaches for suppressing neutrophil migration and their destructive potential following I/R injury
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