78 Chapter 3 Translation of animal experimental data towards the human situation is challenging owing to genomic and physiological differences [14,15,65]. In addition, burn injury is known to cause immune-related complications on the long-term [66], therefore a limitation in most animals studies is the relatively short timeframe in which measurements take place. Nevertheless, a link between increased levels of inflammatory mediators IL-6, CCL2, CXCL1, CXCL8, G-CSF, IFN-γ and TNF-α and surges of innate immune cells (neutrophils and monocytes/macrophages) was also reported in blood and wound tissue from burn patients [2,3,7,66,67]. Moreover, disease severity in burn patients was associated with higher levels of CCL2, CXCL8, IL-6 and IL-10 [68]. Levels of these inflammatory mediators might therefore be useful predictors of disease progression and could be relevant for clinical decision making. Therapy of burn injury is primarily aimed at wound closure, preventing infection, relieving pain and limiting fibrosis [69]. As a malfunctioning immune system affects these aspects, future burn therapy should be more focused on the timely restoration of immune balance by modulating the intensity and duration of inflammatory responses [11]. Removal of damage associated molecular patterns such as HMGB1, could be targeted to remove inflammatory triggers [70]. This could be performed as general therapeutic approach, e.g., by early eschar debridement, or more specifically by a targeted intervention. In line with therapeutic possibilities that were developed to counteract ‘cytokine storm’ associated with SARS-Cov-2 infection and complications, anti-inflammatory therapies such as Tocilizumab, Infliximab or other cytokine-inhibitors [71] might be helpful in reducing burn-induced inflammatory reactions as well. Cytokine removal might also be achieved through hemadsorption and hemodialysis [72,73]. Neutralization of specific cytokines such as IL-6 or TNF-α might reduce immune cell infiltration and secondary tissue necrosis, as was demonstrated in rat models [74,75]. Next to such specific actions, general anti-inflammatory therapies such as corticosteroid therapy could be beneficial. Furthermore, suppression of the extreme pro-inflammatory immune cell response can possibly be achieved by anti-oxidant therapy to protect tissues from oxidative stress caused by neutrophil and macrophage activity [76,77]. Altogether, this review provides an extensive overview of the empirical evidence on the burn-induced response of inflammatory mediators. It highlights factors that influence response levels, which are useful for refinement of experimental set-ups and evidencebased clinical practice. We demonstrated that burn injury causes severe inflammation, accompanied by increased levels of predominantly pro-inflammatory mediators both systemically and locally. Understanding the temporal dynamics is essential for the design of targeted immunotherapy to re-balance the malfunctioning immune system. This review will help improve future burn research into the post-burn immune response
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