Editors' ChoiceISCHEMIA REPERFUSION

Breaking free from the NETs

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Science Translational Medicine  06 Dec 2017:
Vol. 9, Issue 419, eaar4430
DOI: 10.1126/scitranslmed.aar4430

Abstract

Neutrophil extracellular traps exacerbate ischemia reperfusion injury associated with neonatal midgut volvulus and serve as a therapeutic target.

Nets used by fishermen while trawling can ensnare creatures not intended to be caught, leading to extinction of species and widespread destruction of the ocean floor. Similarly, neutrophil extracellular traps (NETs) cause aberrant and destructive inflammation leading to tissue injury. NETs consist of neutrophil DNA and histones, and they are released by neutrophils undergoing cell death. Neutrophils are stimulated to release NETs during both sterile inflammation, including trauma, and infection. In the article by Boettcher et al., the authors examined the effect of NETs on midgut volvulus, a condition in which the midgut twists around the axis of the superior mesenteric artery, causing ischemic intestinal injury that, when untwisted, leads to reperfusion injury.

This event typically occurs in infants and is often fatal. It was recently discovered that thrombosis plays a major role in the development of intestinal infarction after volvulus, and thrombolytics have led to improved outcomes in a limited number of human neonates. In this study, the authors hypothesized that NETs released within the vasculature lead to a hypercoagulable state and thus represent a promising therapeutic target for volvulus-induced intestinal damage. To test this hypothesis, the authors used a rat model of midgut volvulus and assayed circulating markers for NETs and fibrin degradation products (component of clots). Next, they set out to mitigate the thrombotic injury by treating rats with DNase1, to disrupt NETs, or with heparin/tissue plasminogen activator (tPA), to block clot formation and degrade existing clots, alone and in combination with DNase1. Surprisingly, they found that DNase1 but not heparin/tPA reduced inflammation and injury in the intestine without altering the risk of bleeding.

Although DNase1 disrupts NETs, it does not dissolve them. The lack of dissolution could promote inflammation in other regions of the body, which is important to follow. DNase1 is currently used as an inhaled therapy for patients with cystic fibrosis but is not regularly used for intra-arterial therapy. If these findings are replicated in other models of arterial thrombosis and ischemia reperfusion, this could change the way we think about and treat post-thrombotic events. Unlike the bottom of the ocean, which in many regions has been depleted due to destructive nets, there is hope that clinicians can break free from the NETs that injure organ systems after an ischemic event.

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