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Received Oct 17, 2017; Accepted Mar 21, 2018
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1. Introduction
The severe inflammatory response after major injury is known to contribute critically to primary healing complications or to induce secondary problems in remote organs, which were not affected initially, including in acute respiratory distress syndrome (ARDS), sepsis, and multiorgan failure (MOF). Neutrophils are part of the “first line of cellular defense” and crucially modulate subsequent repair processes after tissue damage. After injury, neutrophils are rapidly recruited to the inflammation site after injury by microbe- and danger-associated molecular patterns (MAMPs and DAMPs, respectively, with MAMPs also known as PAMPs or pathogen-associated molecular patterns). Multiple inflammatory mediators are potent chemoattractants for neutrophils, including C-X-C motif ligand (CXCL) 1–3, macrophage inflammatory protein-1α, the anaphylatoxin C5a and leukotriene B4 (LTB4), and interleukin-8 (IL-8) [1, 2]. Chemoattractants as IL-8 not only promote chemotaxis but also contribute to a mobilization of immature leukocytes by the bone marrow. This release of immature and, therefore, less deformable neutrophils contributes to a subsequent sequestration in distal organs, laying the foundation to harmful side effects of neutrophils [3]. Following severe trauma or during sepsis, antiapoptotic genes are transiently upregulated, increasing the neutrophil circulation half-time [4]. At the injury site, neutrophils themselves produce a significant amount of LTB4 [5], phagocytize cellular debris and bacteria, and subsequently may undergo NETosis, forming neutrophil extracellular traps (NETs). Furthermore, they generate reactive oxygen species (ROS), antimicrobial peptides, serine proteases, and various cytokines and chemotaxins, including interleukin- (IL-) 1β, IL-6, IL-10, and monocyte chemotactic protein-1 (MCP-1), which, in turn, modulate the inflammatory response and further attract monocytes and macrophages [6] (for a comprehensive review of neutrophil-derived cytokines, see [7]). It is noteworthy that the quantitative contribution of neutrophils to the overall cytokine concentrations may be relatively low in comparison to macrophages. Nevertheless, the neutrophil response contributes to reduced inflammation and ensures adequate tissue repair [8, 9]. The mechanisms of neutrophil-mediated resolution of inflammation include the clearance of DAMPs and the production of anti-inflammatory cytokines, including IL-10 and IL-1Ra [10], and of lipid mediators...