247 General Discussion levels, erythrocyte sedimentation rate and plasma viscosity [124]. It is, however, often difficult to diagnose sepsis, SIRS or compensatory anti-inflammatory response (CARS) based on these parameters, because it can be hard to discriminate bacterial from sterile sepsis. It might be worthwhile to include other inflammatory parameters such as the level of inflammatory mediators (HMGB1, IL-1α, IL-1β, IL-6, TNF-α) or specific immune cell types (neutrophil/lymphocyte ratio, presence of immature neutrophils, M1/M2 activity) in routine diagnostics of burn patients [88,125–127]. Moreover, fluid phase pattern recognition molecules, cell-free DNA, non-coding RNAs, miRNAs, proteins, metabolites or soluble receptors might also have important implications for diagnostics [127,128]. Suitable biomarkers are needed that can help in diagnosis and therapy decision-making. Modulation of the immune response Management of burn injuries is primarily focused on wound closure, preventing deepening of the wound (loss of the zone of stasis) and infection, relieving pain and limiting fibrosis [129]. Hyper-inflammatory reactions in patients with severe burns often cause a complicated clinical course, increase mortality and contribute to excessive scar development [6,123,130,131]. To further improve treatment, we should explore how manipulation of the immune reactions might benefit burn patients’ recovery [132]. Dampening excessive inflammatory responses might prevent secondary burn wound progression, saving areas in the zone of stasis and reducing disease complications [57,58]. There are multiple ways to modulate the immune response, some of which are summarized in Table 1. This list is far from complete and successful restoration of the immune balance could require a combination of strategies. Modulation could be realized by the use of immunosuppressive drugs such as glucocorticoids [133,134]. Another option is the removal of DAMPs such as HMGB1 or cytokines, to eliminate inflammatory triggers at an early stage [135]. This could be performed as a general therapeutic approach by early debridement of eschar (burn tissue) which contains high levels of pro-inflammatory cytokines (as shown in Chapter 5). More specifically, inflammatory mediators can be targeted via a blocking intervention such as Tocilizumab, Infliximab or other inhibitors [136,137]. Next to targeting inflammatory mediators, therapy could be directed at immune cells. As shown in this thesis, neutrophil and macrophage numbers rise to extreme levels in blood and wound tissue, possibly hampering wound healing via mechanisms such as respiratory burst, extracellular traps and the release of proteases [51–55]. Manipulation of the neutrophil response might be achieved by removing neutrophil chemoattractants (such as HMGB1, IL-1β, IL-6, TNF-α, G-CSF, GRO-α or IL-8) or by inhibition of released inflammatory products (among which are elastase, myeloperoxidase, citrullinated histone H3 and complement factor C3a). For macrophage activity, M1 differentiation can 8
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