Perioperative modulation of Neutrophil Extracellular Trap Production: a translational sub-study

Introduction.
Neutrophil extracellular trap production (NETosis) is an alternative cell death mechanism that neutrophils undergo distinct from necrosis and apoptosis, which has immunological function. NETs may be both beneficial (as an antimicrobial and limiting toxin spread) and damaging (causing tissue damage)1. NETosis has been shown to be modulated in a range of conditions1. We aimed to determine the effect of high-risk surgery on NETosis.
Methods.
Blood samples were available pre- and first day post-operatively from patients having undergone major general surgery. Young and elderly healthy controls were available from the MARTINI trial (16/WM/0026) and from chronically critically ill patients (ISRCTN90103222). Neutrophils were extracted using Percol™ gradients and then NETosis was determined using a spectrophotometric assay, under unstimulated and phorbol 12-myristate 13-acetate (PMA) stimulated conditions.
Results.
Under unstimulated conditions, there was no difference between pre-and post-operative NETosis between young and healthy elderly controls and pre- and postoperative neutrophils. All these groups had significantly higher NETosis than chronic critical illness (p=0.005, 0.013, 0.013 and 0.007 respectively). When stimulated, healthy elderly controls had higher levels than the young (p=0.035). Post-operative stimulated NETosis was higher than pre-operatively (p=0.031), and higher than healthy young controls (p=0.002) and the chronically critically unwell (p=0.022).
Discussion.
Surgery does not appear to cause a rise in unstimulated NETosis but primes neutrophils to respond vigorously to a PMA stimulus, whereas chronic critical illness reduces baseline function but preserves response to stimulation. This increased reactivity of neutrophils may contribute to the adverse outcomes following post-operative complications, as seen in oesophagectomy3. Whether this priming effect proves protective, deleterious or both is yet to be fully elucidated1 and may depend on the circumstances and magnitude of the complication. Further work should focus on the implications of NETosis for infectious and non-infectious surgical complications and options for potential pharmacological manipulation.