PMID- 38291524 OWN - NLM STAT- MEDLINE DCOM- 20240208 LR - 20240404 IS - 1466-609X (Electronic) IS - 1364-8535 (Print) IS - 1364-8535 (Linking) VI - 28 IP - 1 DP - 2024 Jan 30 TI - The protective effect of apolipoprotein H in paediatric sepsis. PG - 36 LID - 10.1186/s13054-024-04809-2 [doi] LID - 36 AB - BACKGROUND: Sepsis is a severe condition characterized by acute organ dysfunction resulting from an imbalanced host immune response to infections. Apolipoprotein H (APOH) is a critical plasma protein that plays a crucial role in regulating various biological processes. However, the precise role of APOH in the immunopathology of paediatric sepsis remains unclear. METHODS: In this study, we evaluated the concentration of APOH in paediatric patients with sepsis and healthy individuals. In an experimental sepsis model of caecal ligation and puncture (CLP), the impact of APOH on survival, organ injury, and inflammation was measured. Furthermore, the anti-inflammatory effects of APOH were investigated across diverse immune cell types, encompassing peripheral blood mononuclear cells (PBMCs), peritoneal macrophages (PMs), bone marrow-derived macrophages (BMDMs), and RAW 264.7 macrophages. RESULTS: In the pilot cohort, the relative abundance of APOH was found to be decreased in patients with sepsis (2.94 +/- 0.61) compared to healthy controls (1.13 +/- 0.84) (p < 0.001), non-survivors had lower levels of APOH (0.50 +/- 0.37) compared to survivors (1.45 +/- 0.83) (p < 0.05). In the validation cohort, the serum concentration of APOH was significantly decreased in patients with sepsis (202.0 +/- 22.5 ng/ml) compared to healthy controls (409.5 +/- 182.9 ng/ml) (p < 0.0001). The application of recombinant APOH protein as a therapeutic intervention significantly lowered the mortality rate, mitigated organ injury, and suppressed inflammation in mice with severe sepsis. In contrast, neutralizing APOH with an anti-APOH monoclonal antibody increased the mortality rate, exacerbated organ injury, and intensified inflammation in mice with non-severe sepsis. Intriguingly, APOH exhibited minimal effects on the bacterial burden, neutrophil, and macrophage counts in the sepsis mouse model, along with negligible effects on bacterial phagocytosis and killing during Pseudomonas aeruginosa infection in PMs, RAW 264.7 cells, and PBMCs. Mechanistic investigations in PMs and RAW 264.7 cells revealed that APOH inhibited M1 polarization in macrophages by suppressing toll-like receptor 4 (TLR4)/nuclear factor-kappaB (NF-kappaB) signalling pathway. CONCLUSION: This proof-of-concept study demonstrated that APOH has a protective role in the host defense response to sepsis, highlighting the potential therapeutic value of APOH in sepsis treatment. CI - (c) 2024. The Author(s). FAU - Yu, Zhicai AU - Yu Z AD - Department of Critical Care Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China. FAU - Xiao, Changxue AU - Xiao C AD - Department of Critical Care Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China. FAU - Liu, Rong AU - Liu R AD - Department of Critical Care Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China. FAU - Pi, Dandan AU - Pi D AD - Department of Critical Care Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China. FAU - Jin, Bian AU - Jin B AD - Department of Critical Care Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China. FAU - Zou, Zhen AU - Zou Z AUID- ORCID: 0000-0002-1651-591X AD - Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China. zouzhen@cqmu.edu.cn. FAU - Xu, Feng AU - Xu F AD - Department of Critical Care Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China. xufeng9899@163.com. AD - Department of Pediatric Intensive Care Unit, Children's Hospital Affiliated to Chongqing Medical University, Chongqing, 400014, China. xufeng9899@163.com. LA - eng GR - NCRCCHD-2021-KP-03/Key Program of Chongqing Clinical Medical Research/ PT - Journal Article DEP - 20240130 PL - England TA - Crit Care JT - Critical care (London, England) JID - 9801902 RN - 0 (beta 2-Glycoprotein I) RN - 0 (NF-kappa B) RN - 0 (Apolipoproteins) SB - IM MH - Animals MH - Child MH - Humans MH - Mice MH - beta 2-Glycoprotein I MH - Inflammation MH - *Leukocytes, Mononuclear/metabolism MH - Mice, Inbred C57BL MH - NF-kappa B/metabolism/pharmacology/therapeutic use MH - Phagocytosis MH - *Sepsis MH - Apolipoproteins/metabolism PMC - PMC10826270 OTO - NOTNLM OT - Apolipoprotein H OT - Macrophage polarization OT - Sepsis OT - TLR4/NF-kappaB COIS- The authors are preparing the application for Chinese patent that using of APOH in the diagnosis and potential treatment for paediatric sepsis. EDAT- 2024/01/31 00:42 MHDA- 2024/02/01 06:42 PMCR- 2024/01/30 CRDT- 2024/01/30 23:45 PHST- 2023/09/06 00:00 [received] PHST- 2024/01/12 00:00 [accepted] PHST- 2024/02/01 06:42 [medline] PHST- 2024/01/31 00:42 [pubmed] PHST- 2024/01/30 23:45 [entrez] PHST- 2024/01/30 00:00 [pmc-release] AID - 10.1186/s13054-024-04809-2 [pii] AID - 4809 [pii] AID - 10.1186/s13054-024-04809-2 [doi] PST - epublish SO - Crit Care. 2024 Jan 30;28(1):36. doi: 10.1186/s13054-024-04809-2.