Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
Front Immunol. 2018 Apr 5;9:663. doi: 10.3389/fimmu.2018.00663. eCollection 2018.
Danger-associated molecular patterns (DAMPs) can elicit immune responses and may subsequently induce an immune-suppressed state. Previous work showed that increased plasma levels of DAMPs are associated with immune suppression and increased susceptibility toward infections in trauma patients. Like trauma, major surgical procedures, such as cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC), are also thought to cause profound DAMP release. Furthermore, the incidence of postoperative infections in these patients, ranging from 10 to 36%, is very high compared to that observed in patients undergoing other major surgical procedures. We hypothesized that the double hit of surgical trauma (CRS) in combination with HIPEC causes excessive DAMP release, which in turn contributes to the development of immune suppression. To investigate this, we assessed DAMP release in patients undergoing CRS-HIPEC, and investigated its relationship with immune suppression and postoperative infections.
In 20 patients undergoing CRS-HIPEC, blood was obtained at five time points: just before surgery (baseline), after CRS, after HIPEC, at ICU admission, and 1 day after surgery. Circulating levels of DAMPs [heat shock protein (HSP)70, high mobility group box (HMGB)1, S100A12, S100A8/S100A9, nuclear (n)DNA, mitochondrial (mt)DNA, lactate dehydrogenase (LDH), a marker of unscheduled cell death], and cytokines [tumor necrosis factor (TNF)α, IL-6, IL-8, IL-10, macrophage inflammatory protein (MIP)-1α, MIP-1β, and MCP-1] were measured. The extent of immune suppression was determined by measuring HLA-DR gene expression and leukocytic cytokine production capacity.
Plasma levels of DAMPs (maximum fold increases of HSP70: 2.1 [1.5-2.8], HMGB1: 5.9 [3.2-9.8], S100A8/S100A9: 3.6 [1.8-5.6], S100A12: 2.6 [1.8-4.3], nDNA 3.9 [1.0-10.8], LDH 1.7 [1.2-2.5]), and all measured cytokines increased profoundly following CRS-HIPEC. Evidence of immune suppression was already apparent during the procedure, illustrated by a decrease of HLA-DR expression compared with baseline (0.5-fold [0.3-0.9]) and diminished pro-inflammatory cytokine production capacity. The increase in HMGB1 levels correlated with the decrease in HLA-DR expression ( = -0.46, = 0.04), and peak HMGB1 concentrations were significantly higher in the five patients who went on to develop a postoperative infection (p = 0.04).
CRS-HIPEC is associated with profound DAMP release and immune suppression, and plasma HMGB1 levels are related with the occurrence of postoperative infections in these patients.
危险相关分子模式（DAMPs）可以引发免疫反应，并可能随后诱导免疫抑制状态。先前的研究表明，DAMPs 血浆水平的升高与免疫抑制和创伤患者感染易感性增加有关。与创伤一样，大手术，如细胞减灭术（CRS）联合腹腔内热灌注化疗（HIPEC），也被认为会导致大量 DAMPs 的释放。此外，这些患者术后感染的发生率（10%至 36%）与其他大手术患者相比非常高。我们假设手术创伤（CRS）与 HIPEC 的双重打击会导致过度的 DAMPs 释放，从而导致免疫抑制的发展。为了研究这一点，我们评估了接受 CRS-HIPEC 的患者的 DAMPs 释放情况，并研究了其与免疫抑制和术后感染的关系。
在 20 名接受 CRS-HIPEC 的患者中，在五个时间点采集血液：手术前（基线）、CRS 后、HIPEC 后、ICU 入院时和手术后 1 天。测量循环 DAMPs[热休克蛋白（HSP）70、高迁移率族蛋白（HMGB）1、S100A12、S100A8/S100A9、核（n）DNA、线粒体（mt）DNA、乳酸脱氢酶（LDH），一种非计划性细胞死亡的标志物]和细胞因子[肿瘤坏死因子（TNF）α、IL-6、IL-8、IL-10、巨噬细胞炎症蛋白（MIP）-1α、MIP-1β 和 MCP-1]的水平。通过测量 HLA-DR 基因表达和白细胞细胞因子产生能力来确定免疫抑制的程度。
CRS-HIPEC 后 DAMPs 血浆水平（HSP70 的最大倍数增加：2.1[1.5-2.8]、HMGB1：5.9[3.2-9.8]、S100A8/S100A9：3.6[1.8-5.6]、S100A12：2.6[1.8-4.3]、nDNA：3.9[1.0-10.8]、LDH：1.7[1.2-2.5]）和所有测量的细胞因子均显著增加。在手术过程中已经出现了免疫抑制的证据，与基线相比，HLA-DR 表达下降（0.5 倍[0.3-0.9]）和促炎细胞因子产生能力下降。HMGB1 水平的增加与 HLA-DR 表达的降低相关（r=-0.46，p=0.04），并且在五个发生术后感染的患者中 HMGB1 浓度峰值明显更高（p=0.04）。
CRS-HIPEC 与 DAMPs 的大量释放和免疫抑制有关，并且这些患者的血浆 HMGB1 水平与术后感染的发生有关。
