PMID- 29675023 OWN - NLM STAT- MEDLINE DCOM- 20190606 LR - 20220409 IS - 1664-3224 (Print) IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 9 DP - 2018 TI - Increased Plasma Levels of Danger-Associated Molecular Patterns Are Associated With Immune Suppression and Postoperative Infections in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. PG - 663 LID - 10.3389/fimmu.2018.00663 [doi] LID - 663 AB - INTRODUCTION: 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. METHODS: 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)alpha, IL-6, IL-8, IL-10, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and MCP-1] were measured. The extent of immune suppression was determined by measuring HLA-DR gene expression and ex vivo leukocytic cytokine production capacity. RESULTS: 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 ex vivo pro-inflammatory cytokine production capacity. The increase in HMGB1 levels correlated with the decrease in HLA-DR expression (r = -0.46, p = 0.04), and peak HMGB1 concentrations were significantly higher in the five patients who went on to develop a postoperative infection (p = 0.04). CONCLUSION: 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. FAU - Leijte, Guus P AU - Leijte GP AD - Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands. AD - Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Custers, Hettie AU - Custers H AD - Department of Anesthesiology, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Gerretsen, Jelle AU - Gerretsen J AD - Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands. AD - Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Heijne, Amon AU - Heijne A AD - Department of Anesthesiology, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Roth, Johannes AU - Roth J AD - Institute of Immunology, University of Munster, Munster, Germany. FAU - Vogl, Thomas AU - Vogl T AD - Institute of Immunology, University of Munster, Munster, Germany. FAU - Scheffer, Gert J AU - Scheffer GJ AD - Department of Anesthesiology, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Pickkers, Peter AU - Pickkers P AD - Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands. AD - Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Kox, Matthijs AU - Kox M AD - Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands. AD - Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands. LA - eng PT - Journal Article PT - Observational Study DEP - 20180405 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Alarmins) RN - 0 (Cytokines) SB - IM MH - Adult MH - Aged MH - Alarmins/*blood/immunology MH - Cytokines/blood MH - *Cytoreduction Surgical Procedures MH - Female MH - Humans MH - *Hyperthermia, Induced MH - Immune Tolerance MH - Male MH - Middle Aged MH - Young Adult PMC - PMC5895648 OTO - NOTNLM OT - HLA-DR OT - cytoreductive surgery OT - danger-associated molecular patterns OT - high mobility group box 1 OT - hyperthermic intraperitoneal chemotherapy OT - immune suppression OT - postoperative infections EDAT- 2018/04/21 06:00 MHDA- 2018/04/21 06:01 PMCR- 2018/01/01 CRDT- 2018/04/21 06:00 PHST- 2017/11/17 00:00 [received] PHST- 2018/03/19 00:00 [accepted] PHST- 2018/04/21 06:00 [entrez] PHST- 2018/04/21 06:00 [pubmed] PHST- 2018/04/21 06:01 [medline] PHST- 2018/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2018.00663 [doi] PST - epublish SO - Front Immunol. 2018 Apr 5;9:663. doi: 10.3389/fimmu.2018.00663. eCollection 2018.