36 Chapter 2 DISCUSSION An improved understanding of the burn-induced immune response is necessary to prevent secondary pathologies in patients with burns as much as possible. In this study, we synthesized available literature on the post burn immune response in animals into a comprehensive systematic overview. Even though there was great heterogeneity and variation among the studies, the meta-analyses clearly displayed the dynamics of innate and adaptive immune cells after burn injury. In peripheral blood, the numbers of neutrophils, monocytes, and thrombocytes increased shortly or within 1 week after burn injury and remained increased over the first month. In contrast, lymphocyte numbers were reduced during the first 2 weeks, indicating that the response is driven by the innate arm of the immune system and that resolution of inflammation is delayed. In wound tissue, we observed an immediate surge of neutrophils and macrophages during the first 2 weeks, whereas for mast cells, a time-dependent response was observed because numbers decreased near the end of the first week and steadily increased from PBD 10 onward. Although several studies investigated the specific subsets of lymphocytes in wound tissue, there were not enough data available on total lymphocyte counts. Furthermore, burn injury affected cell function because we showed that migration of leukocytes and inflammatory mediator production by neutrophils and macrophages were increased earlier on and that antibacterial activity of neutrophils was reduced on PBDs 5‒9. In general, wound healing entails four biological phases, namely hemostasis, inflammation, proliferation, and remodeling. The immediate increase in thrombocyte and neutrophil numbers during the inflammation phase is attenuated within the first week [8,11,12]. Macrophage numbers, which are important for the transition from inflammation to proliferation [13], normalize later on, whereas lymphocyte numbers increase from the second week onward [14]. In this study, we show that at least in animals, these processes are derailed and that high numbers of circulatory thrombocytes, neutrophils, and monocytes are persistent, whereas lymphocyte numbers are actually reduced. This suggests that the timing in typical schematic depictions of the cellular immune response during wound healing does not hold true for burn injury. Unlike in humans, B-cell counts in uninjured rodents are higher than their T-cell counts[15], which could explain the larger effect of burn injury on B cells than on T cells that we found in animals. A relative increase in innate immune cells and a decrease in lymphocytes have also been detected in patients with burns [16,17]. Danger-associated molecular patterns that are released by wounded tissues are suggested to cause a continuous activation of the immune system [18,19]. In turn, a hyperactive immune system can cause damage to
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