164 Chapter 5 a healthy healing process, as these cells support fibroblasts in the formation of collagen and enhance re-epithelization [8,42]. Due to the active, continuing inflammation and the presence of danger signals from tissue damage, macrophage transition might be delayed or insufficient, although more research is required to elucidate this. Immunosuppression from the adaptive arm of the immune system is essential to create an environment in which fibroblasts and keratinocytes can repair the damaged skin [44]. Here, we revealed that lymphocyte numbers, including T cells, NK cells and B cells, were increased at PBW 2-3, which is relatively late after injury [10]. This coincided with a high levels of chemokines MIP-1α, MIP-1β and RANTES (CCL5), which are known to attract lymphocytes to injured skin [10]. Particularly CCL3, CCL4 and CCL5 are involved in the activation of NK cells [45] and could lead to increased cytokine release by NK cells in burn tissue. Information on the response of NK cells and B cells in burn tissue is very limited at this moment. We here showed that after burn injury there is an increased number of NK cells and B cells in burn tissue, however, functional assays are needed in order to speculate about their behavior and involvement in the burn immune response. The levels of CCL3, CCL4, CCL5, IFN-γ, TNF-α and IP-10 (CXCL10) were associated with the number of T cells at PBW 3. IP-10 promotes chemotaxis and inflammation and is likely induced by IFN-γ. Peters et al. previously described an interplay of keratinocytes and T cells and showed that IP-10 is actively produced by keratinocytes in co-culture, even with relatively low numbers of keratinocytes [46]. This interplay is presumably also active during burn wound healing by residual, surrounding or re-epithelializing keratinocytes. Cytokines with anti-inflammatory properties such as IL-4, IL-10 and IL-13 were not detected in these burn tissue samples. Altogether, the soluble factors in burn tissue are likely to support Th1 response, resulting in more attraction of leukocytes to the wound site, while control or suppression of inflammation appears to be limited. In this study, we showed that after burn injury, the numbers of immune cells were persistently elevated, while during normal wound healing neutrophils disappear within days and lymphocytes counts start to increase in the first week [9,47,48]. Burn injury often leads to a prolonged hyperinflammatory state [2,49] and treatment of burn wounds is therefore a difficult and time-consuming process. Damage to the skin is a trigger for the immune system to recruit immune cells en masse and replenish these immune cells in the blood from the bone marrow. Ancillary damage and chemokine production by immune cells and stressed skin cells will trigger the immune system to react, thereby creating a vicious circle of prolonged inflammation in both the skin and in the blood. Therapy is often empiric due to the large diversity among patients and their injuries, e.g. burn type, size, depth and location. In the present study, there was no indication that burn size or burn cause (water versus flame) affected cellular or soluble inflammatory markers (data
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