240 Chapter 8 NEUTROPHIL RESPONSE TO BURN INJURY IS SEVERE AND MIGHT HAMPER WOUND HEALING One of the first immune cells to respond to trauma are neutrophils [40–42]. The metaanalysis in Chapter 2 shows the immediate accumulation of neutrophils both in blood and wound tissue from experimental animal models. The neutrophil response in burn patients is very similar and surges of neutrophils can remain even 4 weeks after injury, as we showed in Chapter 3 and Chapter 4. While textbook schemes dictate that the neutrophil response during wound healing is attenuated within a couple of days [2,8,43], we clearly showed that this is not the case after burn injury. In-depth analysis of blood from burn patients revealed an enormous and long-lasting influx of immature (CD10¯) neutrophils (Chapter 4). The release of immature neutrophils is part of an emergency compensatory response of the bone marrow (i.e. left-shift) and is associated with inflammatory disorders, bone marrow dysfunction and cancer [44–47]. Neutrophils were highly active in the circulation, evidenced by increased levels of elastase, myeloperoxidase, citrullinated histone H3 and complement factor C3a, likely worsening the condition of burn patients [48]. In burn tissue, we only found mature neutrophils (Chapter 5), suggesting that immature neutrophils are trapped in the circulation and are only able to migrate into the skin after they reach maturity. Likely, chemotactic activity increases with age because the flexibility of nucleus increases when neutrophils mature [49]. Literature on behavior of immature neutrophils in blood is indecisive as to whether immature neutrophils are beneficial or detrimental for wound healing [40,50]. Several studies suggest that immature neutrophils are highly active, undirected and show enhanced production of factors such as reactive oxygen species, elastase, myeloperoxidase and neutrophil extracellular traps, causing damage to surrounding tissues [51–56]. Additional damage to tissues can convert the zone of stasis (i.e. salvageable area of decreased tissue perfusion) into an area of complete tissue loss [57,58]. This will expand the wound area and worsen disease complications. Other studies indicate that circulating immature neutrophils exhibit reduced oxidative burst and phagocytic activity and less potency to support innate immune defenses [59–61]. We also showed reduced antibacterial activity of neutrophils in animal burn models, in Chapter 2. Thus, from the results in this thesis, we can conclude that neutrophils accumulate in blood and wound tissue for weeks after burn injury and their activity might be increased, yet they are less efficient at killing bacteria, thereby increasing susceptibility to infection and possibly hampering recovery of burn patients.
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