PDF(Pubmed)
Abstract：
Neutrophil extracellular traps (NETs) have a dual role in the innate immune response to thermal injuries. NETs provide an early line of defence against infection. However, excessive NETosis can mediate the pathogenesis of immunothrombosis, disseminated intravascular coagulation (DIC) and multiple organ failure (MOF) in sepsis. Recent studies suggest that high interleukin-8 (IL-8) levels in intensive care unit (ICU) patients significantly contribute to excessive NET generation. This study aimed to determine whether IL-8 also mediates NET generation in patients with severe thermal injuries. IL-8 levels were measured in serum samples from thermally injured patients with ≥15% of the total body surface area (TBSA) and healthy controls (HC). Ex vivo NET generation was also investigated by treating isolated neutrophils with serum from thermal injured patients or normal serum with and without IL-8 and anti-IL-8 antibodies. IL-8 levels were significantly increased compared to HC on days 3 and 5 (p < 0.05) following thermal injury. IL-8 levels were also significantly increased at day 5 in septic versus non-septic patients (p < 0.001). IL-8 levels were also increased in patients who developed sepsis compared to HC at days 3, 5 and 7 (p < 0.001), day 10 (p < 0.05) and days 12 and 14 (p < 0.01). Serum containing either low, medium or high levels of IL-8 was shown to induce ex vivo NETosis in an IL-8-dependent manner. Furthermore, the inhibition of DNase activity in serum increased the NET-inducing activity of IL-8 in vitro by preventing NET degradation. IL-8 is a major contributor to NET formation in severe thermal injury and is increased in patients who develop sepsis. We confirmed that DNase is an important regulator of NET degradation but also a potential confounder within assays that measure serum-induced ex vivo NETosis.
摘要：
中性粒细胞胞外诱捕网（NETs）在对热损伤的先天免疫反应中具有双重作用。NET提供了抵御感染的早期防线。然而,过度NETosis可以介导免疫血栓形成的发病机制，脓毒症的弥散性血管内凝血（DIC）和多器官功能衰竭（MOF）。最近的研究表明，重症监护病房（ICU）患者的高白介素8（IL-8）水平显着导致NET产生过多。本研究旨在确定IL-8是否也介导严重热损伤患者的NET生成。在热损伤患者的血清样品中测量IL-8水平，这些患者的全身表面积（TBSA）≥15％，健康对照（HC）。还通过用来自热损伤患者的血清或具有和不具有IL-8和抗IL-8抗体的正常血清处理分离的嗜中性粒细胞来研究离体NET产生。在热损伤后第3天和第5天,IL-8水平与HC相比显著增加(p<0.05)。IL-8水平在脓毒症与非脓毒症患者中在第5天也显著增加(p<0.001)。与第3、5和7天的HC相比，发生脓毒症的患者的IL-8水平也增加（p<0.001），第10天(p<0.05)和第12天和第14天(p<0.01)。血清含量低，显示中等或高水平的IL-8以IL-8依赖性方式诱导离体NETosis。此外，血清中DNase活性的抑制通过防止NET降解而在体外增加了IL-8的NET诱导活性。IL-8是严重热损伤中NET形成的主要贡献者，并且在发生败血症的患者中增加。我们证实DNase是NET降解的重要调节剂，但在测量血清诱导的离体NETosis的测定中也是潜在的混杂因素。
