75 Review Inflammatory Mediators in Animal Burn Models DISCUSSION Burn injury induces a multitude of reactions in the body that can be harmful to healthy tissues. Detailed information on burn-induced immune reactions and related inflammatory mediators is needed to support the design of targeted interventions to treat derailed inflammation. Here, we clearly showed that burn injury stimulates the immune system, thereby enhancing the production of numerous mediators. There was one exception: the level of IL-12 was reduced. Burn severity and various model parameters influenced the response levels and expression pattern of IL-1β, IL-6, IL-10, IFN-γ and TNF-α significantly, which might have implications for both experimental setups and management of human burn injuries. To improve our understanding of the burn-induced immune mechanisms, it is paramount to link cellular reactions to cytokine profiles. Previously, we reported massive recruitment of neutrophils to the blood and burn tissue until at least PBD 21 in animal burn models [8]. This phenomenon is caused by an emergency response whereby surges of immature neutrophils are released from bone marrow (left-shift response) [20,21]. Here, we found a concurrent increase in circulatory levels of IL-1β, IL-6, TNF-α and G-CSF (Figure 5). This finding emphasizes that IL-6 and G-CSF are important regulators of neutrophil traffic during inflammation [21–23]. Next to that, IL-1β and TNF-α are known to increase neutrophil migration and activation [24–26]. Moreover, we showed increased levels of CXCL1 and CXCL8, which are also important chemoattractants for neutrophils [27,28]. HMGB1was more prevalent after burn injury and is known to promote inflammation and increase neutrophil extracellular trap formation, thereby increasing the risk of secondary tissue damage and necrosis [29,30]. Although neutrophil migration and inflammatory mediator production were increased after burn, antibacterial activity was actually decreased [8]. Neutrophils might therefore be highly activated, yet less efficient at bacterial killing, which in turn is detrimental for wound healing and increases susceptibility to infection. Intervening with the overrepresentation or hyperactivity of neutrophils through inhibition of neutrophil-related inflammatory mediators might be an interesting approach to reduce inflammation in burn patients. Monocytes play an active role in the immune response and differentiate into macrophages or dendritic cells as they migrate to the skin to remove damaged structures and invading bacteria [31]. The increase in CCL2 in blood and wound tissue we found here coincided with a gradual increase in blood monocytes from PBD 2-4 up to PBD 10-14 that we reported before [8]. CCL2 is an important chemoattractant for monocytes and is secreted by endothelial cells and fibroblasts in response to tissue damage [32]. Beyond chemotaxis, CCL2 plays a pivotal role in immune cell activation, differentiation 3
RkJQdWJsaXNoZXIy MTk4NDMw