|
1
|
Batista-Dantas FE, Ozaki CY, Santana KG, Nunes VS, Uscata BA, Siess-Portugal C, Reis LC, Yamashiro-Kanashiro EH, Tafuri WL, Duarte-Neto AN, Sotto MN, Goto H, Cazita PM. The impact of cholesteryl ester transfer protein on the progression of cutaneous leishmaniasis. Front Immunol 2024; 15:1389551. [PMID: 38966642 PMCID: PMC11222338 DOI: 10.3389/fimmu.2024.1389551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 05/08/2024] [Indexed: 07/06/2024] Open
Abstract
Introduction Pathogenesis of cutaneous leishmaniases involves parasite growth, persistent inflammation, and likely participation of lipoproteins (LP). The cholesteryl ester transfer protein (CETP), involved in LP remodeling, has been shown to participate in the inflammatory response and the evolution of infectious conditions. Methods We evaluated the impact of the presence of CETP on infection by Leishmania (L.) amazonensis in an experimental model of cutaneous leishmaniasis using C57BL6/J mice transgenic for human CETP (CETP), having as control their littermates that do not express the protein, wild-type (WT) mice. The progression of the lesion after infection in the footpad was monitored for 12 weeks. Two groups of animals were formed to collect the plantar pad in the 4th and 12th week post-infection. Results The lesion increased from the 3rd week onwards, in both groups, with a gradual decrease from the 10th week onwards in the CETP group compared to the WT group, showing a reduction in parasitism and an improvement in the healing process, a reduction in CD68+ cells, and an increase in CD163+ and CD206, characterizing a population of M2 macrophages. A reduction in ARG1+ cells and an increase in INOS+ cells were observed. During infection, the LP profile showed an increase in triglycerides in the VLDL fraction in the CETP group at 12 weeks. Gene expression revealed a decrease in the CD36 receptor in the CETP group at 12 weeks, correlating with healing and parasite reduction. In vitro, macrophages derived from bone marrow cells from CETP mice showed lower parasite load at 48 h and, a reduction in arginase activity at 4 h accompanied by increased NO production at 4 and 24 h compared to WT macrophages, corroborating the in vivo findings. Discussion The data indicate that the presence of CETP plays an important role in resolving Leishmania (L.) amazonensis infection, reducing parasitism, and modulating the inflammatory response in controlling infection and tissue repair.
Collapse
Affiliation(s)
- Francisca Elda Batista-Dantas
- Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Christiane Yumi Ozaki
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Kelly Gomes Santana
- Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Valéria Sutti Nunes
- Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Bernardina Amorin Uscata
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Cinthia Siess-Portugal
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Luiza Campos Reis
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil
- Facultad de Medicina, Universidad Nacional Toribio Rodriguez de Mendoza de Amazonas, Chachapoyas, Peru
| | | | - Wagner Luiz Tafuri
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Amaro Nunes Duarte-Neto
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Mirian Nacagami Sotto
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Hiro Goto
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil
- Departamento de Medicina Preventiva, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Patrícia Miralda Cazita
- Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| |
Collapse
|
|
2
|
Lodge S, Litton E, Gray N, Ryan M, Millet O, Fear M, Raby E, Currie A, Wood F, Holmes E, Wist J, Nicholson JK. Stratification of Sepsis Patients on Admission into the Intensive Care Unit According to Differential Plasma Metabolic Phenotypes. J Proteome Res 2024; 23:1328-1340. [PMID: 38513133 PMCID: PMC11002934 DOI: 10.1021/acs.jproteome.3c00803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/15/2024] [Accepted: 03/07/2024] [Indexed: 03/23/2024]
Abstract
Delayed diagnosis of patients with sepsis or septic shock is associated with increased mortality and morbidity. UPLC-MS and NMR spectroscopy were used to measure panels of lipoproteins, lipids, biogenic amines, amino acids, and tryptophan pathway metabolites in blood plasma samples collected from 152 patients within 48 h of admission into the Intensive Care Unit (ICU) where 62 patients had no sepsis, 71 patients had sepsis, and 19 patients had septic shock. Patients with sepsis or septic shock had higher concentrations of neopterin and lower levels of HDL cholesterol and phospholipid particles in comparison to nonsepsis patients. Septic shock could be differentiated from sepsis patients based on different concentrations of 10 lipids, including significantly lower concentrations of five phosphatidylcholine species, three cholesterol esters, one dihydroceramide, and one phosphatidylethanolamine. The Supramolecular Phospholipid Composite (SPC) was reduced in all ICU patients, while the composite markers of acute phase glycoproteins were increased in the sepsis and septic shock patients within 48 h admission into ICU. We show that the plasma metabolic phenotype obtained within 48 h of ICU admission is diagnostic for the presence of sepsis and that septic shock can be differentiated from sepsis based on the lipid profile.
Collapse
Affiliation(s)
- Samantha Lodge
- Australian
National Phenome Center, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA6150, Australia
- Center
for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA 6150, Australia
| | - Edward Litton
- Intensive
Care Unit, Fiona Stanley Hospital, Murdoch, WA 6150, Australia
- Intensive
Care Unit, St John of God Hospital, Subiaco, WA 6009, Australia
- School
of Medicine, University of Western Australia, Crawley, WA 6009, Australia
| | - Nicola Gray
- Australian
National Phenome Center, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA6150, Australia
- Center
for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA 6150, Australia
| | - Monique Ryan
- Australian
National Phenome Center, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA6150, Australia
- Center
for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA 6150, Australia
| | - Oscar Millet
- Precision
Medicine and Metabolism Laboratory, CIC
bioGUNE, Parque Tecnológico
de Bizkaia, Bld. 800, Derio 48160, Spain
| | - Mark Fear
- Burn
Injury Research Unit, School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia
- Fiona
Wood Foundation, Perth, WA 6150, Australia
| | - Edward Raby
- Department
of Infectious Diseases, Fiona Stanley Hospital, Murdoch, WA 6150, Australia
| | - Andrew Currie
- School
of Medical, Molecular & Forensic Sciences, Murdoch University, Perth, WA 6150, Australia
- Centre
for Molecular Medicine & Innovative Therapeutics, Murdoch University, Perth, WA 6150, Australia
- Wesfarmers
Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Perth, WA 6009, Australia
| | - Fiona Wood
- Burn
Injury Research Unit, School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia
- Fiona
Wood Foundation, Perth, WA 6150, Australia
- Burns
service of Western Australia, WA Department
of Health, Murdoch, WA 6150, Australia
| | - Elaine Holmes
- Center
for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA 6150, Australia
- Institute
of Global Health Innovation, Faculty of Medicine, Imperial College London, Level 1, Faculty Building, South Kensington Campus, London SW7 2NA, U.K.
| | - Julien Wist
- Australian
National Phenome Center, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA6150, Australia
- Center
for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA 6150, Australia
- Chemistry
Department, Universidad del Valle, Cali 76001, Colombia
- Department of Metabolism, Digestion and
Reproduction, Faculty of Medicine, Imperial
College London, Sir Alexander
Fleming Building, South Kensington, London SW7 2AZ, U.K.
| | - Jeremy K. Nicholson
- Australian
National Phenome Center, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, WA6150, Australia
- Department of Metabolism, Digestion and
Reproduction, Faculty of Medicine, Imperial
College London, Sir Alexander
Fleming Building, South Kensington, London SW7 2AZ, U.K.
| |
Collapse
|
|
3
|
Szakmany T, Fitzgerald E, Garlant HN, Whitehouse T, Molnar T, Shah S, Tong D, Hall JE, Ball GR, Kempsell KE. The 'analysis of gene expression and biomarkers for point-of-care decision support in Sepsis' study; temporal clinical parameter analysis and validation of early diagnostic biomarker signatures for severe inflammation andsepsis-SIRS discrimination. Front Immunol 2024; 14:1308530. [PMID: 38332914 PMCID: PMC10850284 DOI: 10.3389/fimmu.2023.1308530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 12/26/2023] [Indexed: 02/10/2024] Open
Abstract
Introduction Early diagnosis of sepsis and discrimination from SIRS is crucial for clinicians to provide appropriate care, management and treatment to critically ill patients. We describe identification of mRNA biomarkers from peripheral blood leukocytes, able to identify severe, systemic inflammation (irrespective of origin) and differentiate Sepsis from SIRS, in adult patients within a multi-center clinical study. Methods Participants were recruited in Intensive Care Units (ICUs) from multiple UK hospitals, including fifty-nine patients with abdominal sepsis, eighty-four patients with pulmonary sepsis, forty-two SIRS patients with Out-of-Hospital Cardiac Arrest (OOHCA), sampled at four time points, in addition to thirty healthy control donors. Multiple clinical parameters were measured, including SOFA score, with many differences observed between SIRS and sepsis groups. Differential gene expression analyses were performed using microarray hybridization and data analyzed using a combination of parametric and non-parametric statistical tools. Results Nineteen high-performance, differentially expressed mRNA biomarkers were identified between control and combined SIRS/Sepsis groups (FC>20.0, p<0.05), termed 'indicators of inflammation' (I°I), including CD177, FAM20A and OLAH. Best-performing minimal signatures e.g. FAM20A/OLAH showed good accuracy for determination of severe, systemic inflammation (AUC>0.99). Twenty entities, termed 'SIRS or Sepsis' (S°S) biomarkers, were differentially expressed between sepsis and SIRS (FC>2·0, p-value<0.05). Discussion The best performing signature for discriminating sepsis from SIRS was CMTM5/CETP/PLA2G7/MIA/MPP3 (AUC=0.9758). The I°I and S°S signatures performed variably in other independent gene expression datasets, this may be due to technical variation in the study/assay platform.
Collapse
Affiliation(s)
- Tamas Szakmany
- Department of Anaesthesia, Intensive Care and Pain Medicine, Division of Population Medicine, Cardiff University, Cardiff, United Kingdom
- Anaesthesia, Critical Care and Theatres Directorate, Cwm Taf Morgannwg University Health Board, Royal Glamorgan Hospital, Llantrisant, United Kingdom
| | | | | | - Tony Whitehouse
- NIHR Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital, Mindelsohn Way Edgbaston, Birmingham, United Kingdom
| | - Tamas Molnar
- Critical Care Directorate, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom
| | - Sanjoy Shah
- Critical Care Directorate, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom
| | - Dong Ling Tong
- Faculty of Information and Communication Technology, Universiti Tunku Abdul Rahman, Kampar, Perak, Malaysia
| | - Judith E. Hall
- Department of Anaesthesia, Intensive Care and Pain Medicine, Division of Population Medicine, Cardiff University, Cardiff, United Kingdom
| | - Graham R. Ball
- Medical Technology Research Facility, Anglia Ruskin University, Essex, United Kingdom
| | | |
Collapse
|
|
4
|
Rentz T, Dorighello GG, dos Santos RR, Barreto LM, Freitas IN, Lazaro CM, Razolli DS, Cazita PM, Oliveira HCF. CETP Expression in Bone-Marrow-Derived Cells Reduces the Inflammatory Features of Atherosclerosis in Hypercholesterolemic Mice. Biomolecules 2023; 13:1556. [PMID: 37892238 PMCID: PMC10605246 DOI: 10.3390/biom13101556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/13/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
CETP activity reduces plasma HDL-cholesterol concentrations, a correlate of an increased risk of atherosclerotic events. However, our recent findings suggest that CETP expression in macrophages promotes an intracellular antioxidant state, reduces free cholesterol accumulation and phagocytosis, and attenuates pro-inflammatory gene expression. To determine whether CETP expression in macrophages affects atherosclerosis development, we transplanted bone marrow from transgenic mice expressing simian CETP or non-expressing littermates into hypercholesterolemic LDL-receptor-deficient mice. The CETP expression did not change the lipid-stained lesion areas but decreased the macrophage content (CD68), neutrophil accumulation (LY6G), and TNF-α aorta content of young male transplanted mice and decreased LY6G, TNF-α, iNOS, and nitrotyrosine (3-NT) in aged female transplanted mice. These findings suggest that CETP expression in bone-marrow-derived cells reduces the inflammatory features of atherosclerosis. These novel mechanistic observations may help to explain the failure of CETP inhibitors in reducing atherosclerotic events in humans.
Collapse
Affiliation(s)
- Thiago Rentz
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-862, SP, Brazil; (T.R.); (G.G.D.); (L.M.B.); (I.N.F.); (C.M.L.)
| | - Gabriel G. Dorighello
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-862, SP, Brazil; (T.R.); (G.G.D.); (L.M.B.); (I.N.F.); (C.M.L.)
| | - Renata R. dos Santos
- Division of Radiotherapy, Medical School Hospital, Faculty of Medical Sciences, State University of Campinas, Campinas 13083-887, SP, Brazil;
| | - Lohanna M. Barreto
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-862, SP, Brazil; (T.R.); (G.G.D.); (L.M.B.); (I.N.F.); (C.M.L.)
| | - Israelle N. Freitas
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-862, SP, Brazil; (T.R.); (G.G.D.); (L.M.B.); (I.N.F.); (C.M.L.)
| | - Carolina M. Lazaro
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-862, SP, Brazil; (T.R.); (G.G.D.); (L.M.B.); (I.N.F.); (C.M.L.)
| | - Daniela S. Razolli
- Obesity and Comorbidities Research Center, State University of Campinas, Campinas 13083-864, SP, Brazil;
| | - Patricia M. Cazita
- Laboratório de Lípides (LIM10), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-903, SP, Brazil;
| | - Helena C. F. Oliveira
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-862, SP, Brazil; (T.R.); (G.G.D.); (L.M.B.); (I.N.F.); (C.M.L.)
- Obesity and Comorbidities Research Center, State University of Campinas, Campinas 13083-864, SP, Brazil;
| |
Collapse
|
|
5
|
Piko P, Jenei T, Kosa Z, Sandor J, Kovacs N, Seres I, Paragh G, Adany R. Association of CETP Gene Polymorphisms and Haplotypes with Cardiovascular Risk. Int J Mol Sci 2023; 24:10281. [PMID: 37373432 PMCID: PMC10299660 DOI: 10.3390/ijms241210281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/07/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Cholesteryl ester transfer protein (CETP) is known to influence HDL-C levels, potentially altering the profile of HDL subfractions and consequently cardiovascular risk (CVR). This study aimed to investigate the effect of five single-nucleotide polymorphisms (SNPs; rs1532624, rs5882, rs708272, rs7499892, and rs9989419) and their haplotypes (H) in the CETP gene on 10-year CVR estimated by the Systematic Coronary Risk Evaluation (SCORE), the Framingham Risk Score for Coronary Heart Disease (FRSCHD) and Cardiovascular Disease (FRSCVD) algorithms. Adjusted linear and logistic regression analyses were used to investigate the association of SNPs and 10 haplotypes (H1-H10) on 368 samples from the Hungarian general and Roma populations. The T allele of rs7499892 showed a significant association with increased CVR estimated by FRS. H5, H7, and H8 showed a significant association with increased CVR based on at least one of the algorithms. The impact of H5 was due to its effect on TG and HDL-C levels, while H7 showed a significant association with FRSCHD and H8 with FRSCVD mediated by a mechanism affecting neither TG nor HDL-C levels. Our results suggest that polymorphisms in the CETP gene may have a significant effect on CVR and that this is not mediated exclusively by their effect on TG and HDL-C levels but also by presently unknown mechanisms.
Collapse
Affiliation(s)
- Peter Piko
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (P.P.); (T.J.); (J.S.); (N.K.)
- National Laboratory for Health Security, Center for Epidemiology and Surveillance, Semmelweis University, 1089 Budapest, Hungary
| | - Tibor Jenei
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (P.P.); (T.J.); (J.S.); (N.K.)
| | - Zsigmond Kosa
- Department of Health Methodology and Public Health, Faculty of Health, University of Debrecen, 4400 Nyíregyhza, Hungary;
| | - Janos Sandor
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (P.P.); (T.J.); (J.S.); (N.K.)
- ELKH-DE Public Health Research Group, Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4028 Debrecen, Hungary
| | - Nora Kovacs
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (P.P.); (T.J.); (J.S.); (N.K.)
- ELKH-DE Public Health Research Group, Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4028 Debrecen, Hungary
| | - Ildiko Seres
- Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (G.P.)
| | - Gyorgy Paragh
- Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (G.P.)
| | - Roza Adany
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (P.P.); (T.J.); (J.S.); (N.K.)
- National Laboratory for Health Security, Center for Epidemiology and Surveillance, Semmelweis University, 1089 Budapest, Hungary
- ELKH-DE Public Health Research Group, Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4028 Debrecen, Hungary
- Department of Public Health, Semmelweis University, 1089 Budapest, Hungary
| |
Collapse
|
|
6
|
Liu G, Jiang L, Kerchberger VE, Oeser A, Ihegword A, Dickson AL, Daniel LL, Shaffer C, Linton MF, Cox N, Chung CP, Wei W, Stein CM, Feng Q. The relationship between high density lipoprotein cholesterol and sepsis: A clinical and genetic approach. Clin Transl Sci 2023; 16:489-501. [PMID: 36645160 PMCID: PMC10014701 DOI: 10.1111/cts.13462] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 11/08/2022] [Accepted: 11/14/2022] [Indexed: 01/17/2023] Open
Abstract
Sepsis accounts for one in three hospital deaths. Higher concentrations of high-density lipoprotein cholesterol (HDL-C) are associated with apparent protection from sepsis, suggesting a potential therapeutic role for HDL-C or drugs, such as cholesteryl ester transport protein (CETP) inhibitors that increase HDL-C. However, these beneficial clinical associations might be due to confounding; genetic approaches can address this possibility. We identified 73,406 White adults admitted to Vanderbilt University Medical Center with infection; 11,612 had HDL-C levels, and 12,377 had genotype information from which we constructed polygenic risk scores (PRS) for HDL-C and the effect of CETP on HDL-C. We tested the associations between predictors (measured HDL-C, HDL-C PRS, CETP PRS, and rs1800777) and outcomes: sepsis, septic shock, respiratory failure, and in-hospital death. In unadjusted analyses, lower measured HDL-C concentrations were significantly associated with increased risk of sepsis (p = 2.4 × 10-23 ), septic shock (p = 4.1 × 10-12 ), respiratory failure (p = 2.8 × 10-8 ), and in-hospital death (p = 1.0 × 10-8 ). After adjustment (age, sex, electronic health record length, comorbidity score, LDL-C, triglycerides, and body mass index), these associations were markedly attenuated: sepsis (p = 2.6 × 10-3 ), septic shock (p = 8.1 × 10-3 ), respiratory failure (p = 0.11), and in-hospital death (p = 4.5 × 10-3 ). HDL-C PRS, CETP PRS, and rs1800777 significantly predicted HDL-C (p < 2 × 10-16 ), but none were associated with sepsis outcomes. Concordant findings were observed in 13,254 Black patients hospitalized with infections. Lower measured HDL-C levels were significantly associated with increased risk of sepsis and related outcomes in patients with infection, but a causal relationship is unlikely because no association was found between the HDL-C PRS or the CETP PRS and the risk of adverse sepsis outcomes.
Collapse
Affiliation(s)
- Ge Liu
- Department of Biomedical InformaticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Lan Jiang
- Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - V. Eric Kerchberger
- Department of Biomedical InformaticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Annette Oeser
- Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Andrea Ihegword
- Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Alyson L. Dickson
- Division of Rheumatology and Immunology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Laura L. Daniel
- Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Division of Rheumatology and Immunology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Christian Shaffer
- Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - MacRae F. Linton
- Division of Cardiovascular Medicine and the Atherosclerosis Research Unit, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Department of PharmacologyVanderbilt UniversityNashvilleTennesseeUSA
| | - Nancy Cox
- Department of Medicine, Vanderbilt Genetics InstituteVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Cecilia P. Chung
- Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Division of Rheumatology and Immunology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Wei‐Qi Wei
- Department of Biomedical InformaticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - C. Michael Stein
- Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Department of PharmacologyVanderbilt UniversityNashvilleTennesseeUSA
| | - QiPing Feng
- Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Department of Medicine, Vanderbilt Genetics InstituteVanderbilt University Medical CenterNashvilleTennesseeUSA
| |
Collapse
|
|
7
|
Kotlyarov S. Immune and metabolic cross-links in the pathogenesis of comorbid non-alcoholic fatty liver disease. World J Gastroenterol 2023; 29:597-615. [PMID: 36742172 PMCID: PMC9896611 DOI: 10.3748/wjg.v29.i4.597] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/28/2022] [Accepted: 11/10/2022] [Indexed: 01/20/2023] Open
Abstract
In recent years, there has been a steady growth of interest in non-alcoholic fatty liver disease (NAFLD), which is associated with negative epidemiological data on the prevalence of the disease and its clinical significance. NAFLD is closely related to the metabolic syndrome and these relationships are the subject of active research. A growing body of evidence shows cross-linkages between metabolic abnormalities and the innate immune system in the development and progression of NAFLD. These links are bidirectional and largely still unclear, but a better understanding of them will improve the quality of diagnosis and management of patients. In addition, lipid metabolic disorders and the innate immune system link NAFLD with other diseases, such as atherosclerosis, which is of great clinical importance.
Collapse
Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, Ryazan 390026, Russia
| |
Collapse
|
|
8
|
Lu M, Ma A, Liu J, Zhou W, Cao P, Chu T, Fan L. Study on the expression of TRIM7 in peripheral blood mononuclear cells of patients with sepsis and its early diagnostic value. BMC Infect Dis 2022; 22:865. [PMID: 36402943 PMCID: PMC9675165 DOI: 10.1186/s12879-022-07874-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 11/14/2022] [Indexed: 11/21/2022] Open
Abstract
Background The early diagnosis of sepsis is beneficial to put forward a reasonable clinical treatment plan as soon as possible. This study was to explore the expression of Tripartite Motif 7 (TRIM7) in peripheral blood mononuclear cells (PBMCs) of patients with sepsis and its diagnostic value. Methods This is a cross-sectional study. A total of 69 patients with infectious diseases were enrolled in the emergency room. They were divided into the sepsis group (34 cases) and the non-sepsis infection group (35 cases). There were 25 healthy subjects who were selected as the control group. The expression of TRIM7 in PBMCs was observed by immunofluorescence staining. The correlation between the expression of TRIM7 mRNA and acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, white blood cell (WBC), C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor (TNF)-α and interleukin (IL)-6 was discussed. The receiver operating characteristic (ROC) curve was utilized for evaluating the value of TRIM7 expression for the early diagnosis of sepsis. Results The fluorescence intensity representing the expression level of TRIM7 in PBMCs of patients in the sepsis group was the lowest among three groups. The TRIM7 mRNA expression in PBMCs of the sepsis group was greatly decreased in comparison with that of the non-sepsis infection group and control group (P < 0.05). Spearman correlation analysis indicated that TRIM7 mRNA expression was negatively correlated with APACHE II score, SOFA score, WBC, CRP, PCT, TNF-α and IL-6. ROC curve analysis revealed that the area under curve (AUC) of TRIM7 mRNA expression in PBMCs for the diagnosis of sepsis was 0.798, with a 95% confidence interval of 0.691- 0.905, a sensitivity of 73.5%, and a specificity of 77.1%. Conclusion The expression of TRIM7 in PBMCs of patients with sepsis is significantly down-regulated, which has certain clinical value for early diagnosis of sepsis.
Collapse
Affiliation(s)
- Mingfeng Lu
- grid.268415.cDepartment of Emergency, Clinical Medical College, Yangzhou University, No 98, Nantong West Rd, Yangzhou, 225001 China
| | - Aiwen Ma
- grid.268415.cDepartment of Emergency, Clinical Medical College, Yangzhou University, No 98, Nantong West Rd, Yangzhou, 225001 China
| | - Jianwei Liu
- grid.268415.cDepartment of Emergency, Clinical Medical College, Yangzhou University, No 98, Nantong West Rd, Yangzhou, 225001 China
| | - Wenzhen Zhou
- grid.268415.cDepartment of Emergency, Clinical Medical College, Yangzhou University, No 98, Nantong West Rd, Yangzhou, 225001 China
| | - Peng Cao
- grid.268415.cDepartment of Emergency, Clinical Medical College, Yangzhou University, No 98, Nantong West Rd, Yangzhou, 225001 China
| | - Tao Chu
- grid.268415.cDepartment of Emergency, Clinical Medical College, Yangzhou University, No 98, Nantong West Rd, Yangzhou, 225001 China
| | - Lu Fan
- grid.268415.cDepartment of Emergency, Clinical Medical College, Yangzhou University, No 98, Nantong West Rd, Yangzhou, 225001 China
| |
Collapse
|
|
9
|
Novel Role of CETP in Macrophages: Reduction of Mitochondrial Oxidants Production and Modulation of Cell Immune-Metabolic Profile. Antioxidants (Basel) 2022; 11:antiox11091734. [PMID: 36139808 PMCID: PMC9495589 DOI: 10.3390/antiox11091734] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 08/26/2022] [Accepted: 08/28/2022] [Indexed: 01/22/2023] Open
Abstract
Plasma cholesteryl ester transfer protein (CETP) activity diminishes HDL-cholesterol levels and thus may increase atherosclerosis risk. Experimental evidence suggests CETP may also exhibit anti-inflammatory properties, but local tissue-specific functions of CETP have not yet been clarified. Since oxidative stress and inflammation are major features of atherogenesis, we investigated whether CETP modulates macrophage oxidant production, inflammatory and metabolic profiles. Comparing macrophages from CETP-expressing transgenic mice and non-expressing littermates, we observed that CETP expression reduced mitochondrial superoxide anion production and H2O2 release, increased maximal mitochondrial respiration rates, and induced elongation of the mitochondrial network and expression of fusion-related genes (mitofusin-2 and OPA1). The expression of pro-inflammatory genes and phagocytic activity were diminished in CETP-expressing macrophages. In addition, CETP-expressing macrophages had less unesterified cholesterol under basal conditions and after exposure to oxidized LDL, as well as increased HDL-mediated cholesterol efflux. CETP knockdown in human THP1 cells increased unesterified cholesterol and abolished the effects on mitofusin-2 and TNFα. In summary, the expression of CETP in macrophages modulates mitochondrial structure and function to promote an intracellular antioxidant state and oxidative metabolism, attenuation of pro-inflammatory gene expression, reduced cholesterol accumulation, and phagocytosis. These localized functions of CETP may be relevant for the prevention of atherosclerosis and other inflammatory diseases.
Collapse
|
|
10
|
Luo XY, Ying JH, Wang QS. miR-25-3p ameliorates SAE by targeting the TLR4/NLRP3 axis. Metab Brain Dis 2022; 37:1803-1813. [PMID: 35704145 PMCID: PMC9198415 DOI: 10.1007/s11011-022-01017-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 05/26/2022] [Indexed: 11/24/2022]
Abstract
Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis. It has been reported that miR-25-3p is closely related to the development of sepsis. However, the detailed mechanism of miR-25-3p in SAE requires further investigation. Caecum ligation and puncture (CLP) was performed to induce SAE in vivo. LPS stimulation was applied to mimic the in vitro inflammatory model. The expression levels of TLR4 and NLRP3 in the cerebral cortex were evaluated by immunofluorescence. The gene and protein expression levels were determined by qRT-PCR and a western blot analysis. ELISA was used to detect the levels of inflammatory cytokines. The interaction between miR-25-3p and TLR4 was validated by a dual luciferase reporter assay. TLR4 and NLRP3 were highly expressed in the cerebral cortex of SAE mice, while miR-25-3p was expressed at low levels. Activation of the inflammasome, increased release of cytokines and microglial activation were also observed in the SAE mouse model. The overexpression of miR-25-3p inhibited the expression of LPS-induced cytokines and microglial activation. Furthermore, miR-25-3p inhibited TLR4 expression by directly targeting TLR4. The anti-inflammatory effect of miR-25-3p in LPS-induced CHME5 was reversed by TLR4 overexpression. miR-25-3p overexpression attenuated the activation of microglia in SAE by inhibiting the NLRP3/IL-1β/IL-18 axis by directly targeting TLR4, suggesting that miR-25-3p may be a potential target for SAE diagnosis and treatment.
Collapse
Affiliation(s)
- Xiao-Yan Luo
- Department of Medical Service, The Affiliated Nanhua Hospital of University of South China, Hengyang, 421002, Hunan Province, People's Republic of China
- Health school of Nuclear Indutrsy, Hengyang, 421002, Hunan Province, People's Republic of China
| | - Jian-Hua Ying
- Department of Outpatient, The Affiliated Nanhua Hospital of University of South China, Hengyang, 421002, Hunan Province, People's Republic of China
| | - Qiao-Sheng Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of University of South China, No. 69 Chuanshan Road, Hengyang, 421001, Hunan Province, People's Republic of China.
| |
Collapse
|
|
11
|
Kalantar Z, Sotoudeh G, Esmaeily Z, Rafiee M, Koohdani F. Interaction between CETP Taq1B polymorphism and HEI, DQI and DPI on metabolic biomarkers in patients with type 2 diabetes. J Hum Nutr Diet 2021; 35:651-662. [PMID: 34908197 DOI: 10.1111/jhn.12958] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 09/19/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is a multidimensional consequence of environmental and genetic factors. Cholesteryl ester transfer protein (CETP) Taq1B polymorphism has been reported as a main predictor of dyslipidaemia, comprising an important complication in persons with T2DM. However, diet could affect T2DM patients metabolic health. METHODS We investigated the combination of gene-diet effects on some metabolic biomarkers. In our cross-sectional study, blood samples of 220 patients were collected. Dietary indices (healthy eating index, dietary quality index and dietary phytochemical index) were obtained from a validated semi-quantitative food frequency questionnaire. CETP Taq1B polymorphism was genotyped by a polymerase chain reaction-restriction fragment polymorphism method. Data were analysed by analysis of covariance. RESULTS The interaction between the CETP Taq1B polymorphism and dietary indices on low density lipoprotein/high density lipoprotein was significant (p < 0.001 both crude and adjusted models). In addition, the interaction between polymorphism and dietary quality index on total antioxidant capacity (p = 0.004 crude model, p = 0.005 after adjusting) and pentraxin 3 (p = 0.01 both crude and adjusted models) was significant. Also, the interaction between polymorphism and healthy eating index on waist circumference (p = 0.005 both crude and adjusted models) and dietary phytochemical index on interleukin-18 (p = 0.03 crude model) was significant. CONCLUSIONS Our results indicated the effect of CETP Taq1B polymorphism on some inflammatory and anthropometrics markers (total antioxidant capacity, pentraxin 3, interleukin-18, low density lipoprotein/high density lipoprotein and waist circumference) with high and low adherence to dietary incides.
Collapse
Affiliation(s)
- Zahra Kalantar
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Gity Sotoudeh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Esmaeily
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Rafiee
- Department of Clinical Nutrition, School of Nutrition & Food sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fariba Koohdani
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.,Diabetic Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
12
|
Montefusco L, D'Addio F, Loretelli C, Ben Nasr M, Garziano M, Rossi A, Pastore I, Plebani L, Lunati ME, Bolla AM, Porta MD, Piuri G, Rocchio F, Abdelsalam A, Assi E, Barichella M, Maestroni A, Usuelli V, Loreggian L, Muzio F, Zuccotti GV, Cazzola R, Fiorina P. Anti-inflammatory effects of diet and caloric restriction in metabolic syndrome. J Endocrinol Invest 2021; 44:2407-2415. [PMID: 33686615 PMCID: PMC8502121 DOI: 10.1007/s40618-021-01547-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 03/01/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND Weight loss in patients with metabolic syndrome has positive effects on cardiovascular and type 2 diabetes risks, but its effects on peripheral cytokines and lipid profiles in patients are still unclear. AIM To determine the effects of diet-induced weight loss on metabolic parameters, lipids and cytokine profiles. METHODS Eighteen adult males with metabolic syndrome (defined according to IDF 2009) and Body Mass Index (BMI) between 25 and 35 kg/m2 were subjected to a balanced hypocaloric diet for 6 months to reach at least a 5% body weight loss. RESULTS After weight loss, a significant improvement in BMI, waist circumference, insulin, fasting blood glucose and HOMA-IR (homeostasis model assessment of insulin resistance) was observed. The analysis of LDL (low-density lipoprotein cholesterol) and HDL (high-density lipoprotein cholesterol) lipoproteins showed a change in their composition with a massive transfer of triacylglycerols from HDL to LDL. This was associated with a significant reduction in peripheral pro-inflammatory cytokines such as IL-6, TNF-α, IL-8 and MIP-1β, leading to an overall decreased inflammatory score. An interesting positive correlation was also observed among peripheral cytokines levels after diet and peripheral levels of CETP (cholesteryl ester transfer protein), an enzyme with a key role in lipid change. CONCLUSION Weight loss through caloric restriction is associated with an improvement in peripheral lipid and cytokine profiles that may play a major role in improving cardiovascular risk.
Collapse
Affiliation(s)
- L Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - F D'Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Di Milano, Milan, Italy
| | - C Loretelli
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Di Milano, Milan, Italy
| | - M Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Di Milano, Milan, Italy
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA
| | - M Garziano
- Department of Biomedical and Clinical Sciences, "L. Sacco", Università Di Milano, Milan, Italy
| | - A Rossi
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - I Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - L Plebani
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - M E Lunati
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - A M Bolla
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - M D Porta
- Department of Biomedical and Clinical Sciences, "L. Sacco", Università Di Milano, Milan, Italy
| | - G Piuri
- Department of Biomedical and Clinical Sciences, "L. Sacco", Università Di Milano, Milan, Italy
| | - F Rocchio
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Di Milano, Milan, Italy
| | - A Abdelsalam
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Di Milano, Milan, Italy
- Department of Biochemistry and Biotechnology, Heliopolis University, Cairo, Egypt
| | - E Assi
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Di Milano, Milan, Italy
| | - M Barichella
- Clinical Nutrition Unit, Parkinson Institute, ASST Gaetano Pini-CTO, Milan, Italy
| | - A Maestroni
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Di Milano, Milan, Italy
| | - V Usuelli
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Di Milano, Milan, Italy
| | - L Loreggian
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Di Milano, Milan, Italy
| | - F Muzio
- Clinical Nutrition and Dietetic Unit, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, Milan, Italy
| | - G V Zuccotti
- Department of Pediatrics, V. Buzzi Childrens' Hospital and Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Degli Studi Di Milano, Milan, Italy
| | - R Cazzola
- Department of Biomedical and Clinical Sciences, "L. Sacco", Università Di Milano, Milan, Italy
| | - P Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy.
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC L. Sacco, Università Di Milano, Milan, Italy.
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
| |
Collapse
|
|
13
|
Brunham LR, Trinder M, Rensen PCN, Boyd J. Response by Brunham et al to Letter Regarding Article, "Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis". Circulation 2021; 144:e122. [PMID: 34370547 DOI: 10.1161/circulationaha.121.055698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Liam R Brunham
- Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada (L.R.B., M.T., J.B.)
| | - Mark Trinder
- Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada (L.R.B., M.T., J.B.)
| | - Patrick C N Rensen
- Department of Medicine, Division of Endocrinology, Leiden University Medical Center, The Netherlands (P.C.N.R.)
| | - John Boyd
- Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada (L.R.B., M.T., J.B.)
| |
Collapse
|
|
14
|
Santana KG, Righetti RF, Breda CNDS, Domínguez-Amorocho OA, Ramalho T, Dantas FEB, Nunes VS, Tibério IDFLC, Soriano FG, Câmara NOS, Quintão ECR, Cazita PM. Cholesterol-Ester Transfer Protein Alters M1 and M2 Macrophage Polarization and Worsens Experimental Elastase-Induced Pulmonary Emphysema. Front Immunol 2021; 12:684076. [PMID: 34367144 PMCID: PMC8334866 DOI: 10.3389/fimmu.2021.684076] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/15/2021] [Indexed: 01/22/2023] Open
Abstract
Cholesterol-ester transfer protein (CETP) plays a role in atherosclerosis, the inflammatory response to endotoxemia and in experimental and human sepsis. Functional alterations in lipoprotein (LP) metabolism and immune cell populations, including macrophages, occur during sepsis and may be related to comorbidities such as chronic obstructive pulmonary disease (COPD). Macrophages are significantly associated with pulmonary emphysema, and depending on the microenvironment, might exhibit an M1 or M2 phenotype. Macrophages derived from the peritoneum and bone marrow reveal CETP that contributes to its plasma concentration. Here, we evaluated the role of CETP in macrophage polarization and elastase-induced pulmonary emphysema (ELA) in human CETP-expressing transgenic (huCETP) (line 5203, C57BL6/J background) male mice and compared it to their wild type littermates. We showed that bone marrow-derived macrophages from huCETP mice reduce polarization toward the M1 phenotype, but with increased IL-10. Compared to WT, huCETP mice exposed to elastase showed worsened lung function with an increased mean linear intercept (Lm), reflecting airspace enlargement resulting from parenchymal destruction with increased expression of arginase-1 and IL-10, which are M2 markers. The cytokine profile revealed increased IL-6 in plasma and TNF, and IL-10 in bronchoalveolar lavage (BAL), corroborating with the lung immunohistochemistry in the huCETP-ELA group compared to WT-ELA. Elastase treatment in the huCETP group increased VLDL-C and reduced HDL-C. Elastase-induced pulmonary emphysema in huCETP mice promotes lung M2-like phenotype with a deleterious effect in experimental COPD, corroborating the in vitro result in which CETP promoted M2 macrophage polarization. Our results suggest that CETP is associated with inflammatory response and influences the role of macrophages in COPD.
Collapse
Affiliation(s)
- Kelly Gomes Santana
- Laboratorio de Lipides, LIM-10, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Renato Fraga Righetti
- Laboratório de Terapêutica Experimental I (LIM-20), Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
| | - Cristiane Naffah de Souza Breda
- Transplantation Immunobiology Lab, Department of Immunology, Institute of Biomedical Sciences, Universidade de São Paulo, Cidade Universitária, São Paulo, Brazil
| | - Omar Alberto Domínguez-Amorocho
- Transplantation Immunobiology Lab, Department of Immunology, Institute of Biomedical Sciences, Universidade de São Paulo, Cidade Universitária, São Paulo, Brazil
| | - Theresa Ramalho
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States
| | - Francisca Elda B Dantas
- Laboratorio de Lipides, LIM-10, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Valéria Sutti Nunes
- Laboratorio de Lipides, LIM-10, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | | | - Francisco Garcia Soriano
- Laboratório de Emergências Clínicas (LIM-51), Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Niels O S Câmara
- Transplantation Immunobiology Lab, Department of Immunology, Institute of Biomedical Sciences, Universidade de São Paulo, Cidade Universitária, São Paulo, Brazil
| | - Eder Carlos Rocha Quintão
- Laboratorio de Lipides, LIM-10, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Patrícia M Cazita
- Laboratorio de Lipides, LIM-10, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| |
Collapse
|
|
15
|
Pérez-Hernández EG, Delgado-Coello B, Luna-Reyes I, Mas-Oliva J. New insights into lipopolysaccharide inactivation mechanisms in sepsis. Biomed Pharmacother 2021; 141:111890. [PMID: 34229252 DOI: 10.1016/j.biopha.2021.111890] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/03/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023] Open
Abstract
The complex pathophysiology of sepsis makes it a syndrome with limited therapeutic options and a high mortality rate. Gram-negative bacteria containing lipopolysaccharides (LPS) in their outer membrane correspond to the most common cause of sepsis. Since the gut is considered an important source of LPS, intestinal damage has been considered a cause and a consequence of sepsis. Although important in the maintenance of the intestinal epithelial cell homeostasis, the microbiota has been considered a source of LPS. Recent studies have started to shed light on how sepsis is triggered by dysbiosis, and an increased inflammatory state of the intestinal epithelial cells, expanding the understanding of the gut-liver axis in sepsis. Here, we review the gut-liver interaction in Gram-negative sepsis, exploring the mechanisms of LPS inactivation, including the recently described contribution of an isoform of the cholesteryl-ester transfer protein (CETPI). Although several key questions remain to be answered when the pathophysiology of sepsis is reviewed, new contributions coming to light exploring the way LPS might be inactivated in vivo, suggest that new applications might soon reach the clinical setting.
Collapse
Affiliation(s)
| | - Blanca Delgado-Coello
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
| | - Ismael Luna-Reyes
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
| | - Jaime Mas-Oliva
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico.
| |
Collapse
|
|
16
|
Kotlyarov SN, Kotlyarova AA. Role of lipid metabolism and systemic inflammation in the development of atherosclerosis in animal models. I.P. PAVLOV RUSSIAN MEDICAL BIOLOGICAL HERALD 2021. [DOI: 10.23888/pavlovj2021291134-146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Systemic inflammation makes a significant contribution to the pathogenesis of atherosclerosis and has been the subject of numerous studies. Works aiming to analyze the mechanisms of atherosclerosis development often include experiments on animals. A primary task of such research is the characterization, justification, and selection of an adequate model.
Aim. To evaluate the peculiarities of lipid metabolism and systemic inflammation in chronic obstructive pulmonary disease (COPD) in the development of atherosclerosis in animal models.
Materials and Methods. Analyses of cross-links between species-specific peculiarities of lipid metabolism and the immune response, as well as a bioinformatic analysis of differences in Toll-like receptor 4 (TLR4) in mice, rats, and rabbits in comparison with its human homolog, were carried out. A search for and analysis of the amino acid sequences of human, mouse, rat, and rabbit TLR4 was performed in the International database GenBank of National Center of Biotechnical Information and in The Universal Protein Resource (UniProt) database. Multiple alignments of the TLR4 amino acid sequences were implemented in the Clustal Omega program, version 1.2.4. Reconstruction and visualization of molecular phylogenetic trees were performed using the MEGA7 program according to the Neighbor-Joining and Maximum Parsimony methods.
Results. Species-specific differences of the peculiarities of lipid metabolism and the innate immune response in humans, mice, and rabbits were shown that must be taken into account in analyses of study results.
Conclusion.Disorders in lipid metabolism and systemic inflammation mediated by the innate immune system participating in the pathogenesis of atherosclerosis in COPD possess species-specific differences that should be taken into account in analyses of study results.
Collapse
|
|
17
|
Dusuel A, Deckert V, Pais de Barros JP, van Dongen K, Choubley H, Charron É, Le Guern N, Labbé J, Mandard S, Grober J, Lagrost L, Gautier T. Human cholesteryl ester transfer protein lacks lipopolysaccharide transfer activity, but worsens inflammation and sepsis outcomes in mice. J Lipid Res 2020; 62:100011. [PMID: 33500240 PMCID: PMC7859855 DOI: 10.1194/jlr.ra120000704] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 11/25/2020] [Accepted: 12/09/2020] [Indexed: 02/06/2023] Open
Abstract
Bacterial lipopolysaccharides (LPSs or endotoxins) can bind most proteins of the lipid transfer/LPS-binding protein (LT/LBP) family in host organisms. The LPS-bound LT/LBP proteins then trigger either an LPS-induced proinflammatory cascade or LPS binding to lipoproteins that are involved in endotoxin inactivation and detoxification. Cholesteryl ester transfer protein (CETP) is an LT/LBP member, but its impact on LPS metabolism and sepsis outcome is unclear. Here, we performed fluorescent LPS transfer assays to assess the ability of CETP to bind and transfer LPS. The effects of intravenous (iv) infusion of purified LPS or polymicrobial infection (cecal ligation and puncture [CLP]) were compared in transgenic mice expressing human CETP and wild-type mice naturally having no CETP activity. CETP displayed no LPS transfer activity in vitro, but it tended to reduce biliary excretion of LPS in vivo. The CETP expression in mice was associated with significantly lower basal plasma lipid levels and with higher mortality rates in both models of endotoxemia and sepsis. Furthermore, CETPTg plasma modified cytokine production of macrophages in vitro. In conclusion, despite having no direct LPS binding and transfer property, human CETP worsens sepsis outcomes in mice by altering the protective effects of plasma lipoproteins against endotoxemia, inflammation, and infection.
Collapse
Affiliation(s)
- Aloïs Dusuel
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Valérie Deckert
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Jean-Paul Pais de Barros
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Kevin van Dongen
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Hélène Choubley
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Émilie Charron
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Naig Le Guern
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Jérôme Labbé
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Stéphane Mandard
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Jacques Grober
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Laurent Lagrost
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France; University Hospital of Dijon, Dijon, France
| | - Thomas Gautier
- INSERM/University of Bourgogne Franche-Comté LNC UMR1231 and LipSTIC LabEx, UFR Sciences de Santé, Dijon, France.
| |
Collapse
|
|
18
|
Trinder M, Wang Y, Madsen CM, Ponomarev T, Bohunek L, Daisely BA, Julia Kong H, Blauw LL, Nordestgaard BG, Tybjærg-Hansen A, Wurfel MM, Russell JA, Walley KR, Rensen PCN, Boyd JH, Brunham LR. Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis. Circulation 2020; 143:921-934. [PMID: 33228395 DOI: 10.1161/circulationaha.120.048568] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis. METHODS We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis. RESULTS A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87). CONCLUSIONS Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.
Collapse
Affiliation(s)
- Mark Trinder
- Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.,Experimental Medicine Program (M.T., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada
| | - Yanan Wang
- Department of Medicine, Division of Endocrinology (Y.W., L.L.B., P.C.N.R.), Leiden University Medical Center, The Netherlands
| | - Christian M Madsen
- Department of Clinical Biochemistry (C.M.M., B.G.N., J.A.R.), Copenhagen University Hospital, Denmark.,The Copenhagen General Population Study (C.M.M., B.G.N., A.T.-H.), Copenhagen University Hospital, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (C.M.M., B.G.N., A.T.-H.)
| | - Tatjana Ponomarev
- Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada
| | | | - Brendan A Daisely
- Department of Microbiology and Immunology, The University of Western Ontario, London, Canada (B.A.D.)
| | - HyeJin Julia Kong
- Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada
| | - Lisanne L Blauw
- Department of Medicine, Division of Endocrinology (Y.W., L.L.B., P.C.N.R.), Leiden University Medical Center, The Netherlands
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry (C.M.M., B.G.N., J.A.R.), Copenhagen University Hospital, Denmark.,The Copenhagen General Population Study (C.M.M., B.G.N., A.T.-H.), Copenhagen University Hospital, Denmark.,The Copenhagen City Heart Study, Frederiksberg Hospital (B.G.N., A.T.-H.), Copenhagen University Hospital, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (C.M.M., B.G.N., A.T.-H.)
| | - Anne Tybjærg-Hansen
- The Copenhagen General Population Study (C.M.M., B.G.N., A.T.-H.), Copenhagen University Hospital, Denmark.,Herlev Gentofte Hospital, Department of Clinical Biochemistry, Rigshospitalet (A.T.-H.), Copenhagen University Hospital, Denmark.,The Copenhagen City Heart Study, Frederiksberg Hospital (B.G.N., A.T.-H.), Copenhagen University Hospital, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (C.M.M., B.G.N., A.T.-H.)
| | - Mark M Wurfel
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle (M.M.W., K.R.W.)
| | - James A Russell
- Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.,Department of Clinical Biochemistry (C.M.M., B.G.N., J.A.R.), Copenhagen University Hospital, Denmark
| | - Keith R Walley
- Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.,Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle (M.M.W., K.R.W.)
| | - Patrick C N Rensen
- Department of Medicine, Division of Endocrinology (Y.W., L.L.B., P.C.N.R.), Leiden University Medical Center, The Netherlands
| | - John H Boyd
- Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.,Experimental Medicine Program (M.T., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.,Department of Medicine (J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada
| | - Liam R Brunham
- Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.,Experimental Medicine Program (M.T., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.,Department of Medicine (J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada
| |
Collapse
|
|
19
|
Shu T, Ning W, Wu D, Xu J, Han Q, Huang M, Zou X, Yang Q, Yuan Y, Bie Y, Pan S, Mu J, Han Y, Yang X, Zhou H, Li R, Ren Y, Chen X, Yao S, Qiu Y, Zhang DY, Xue Y, Shang Y, Zhou X. Plasma Proteomics Identify Biomarkers and Pathogenesis of COVID-19. Immunity 2020; 53:1108-1122.e5. [PMID: 33128875 PMCID: PMC7574896 DOI: 10.1016/j.immuni.2020.10.008] [Citation(s) in RCA: 216] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 08/11/2020] [Accepted: 10/14/2020] [Indexed: 01/08/2023]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is a global public health crisis. However, little is known about the pathogenesis and biomarkers of COVID-19. Here, we profiled host responses to COVID-19 by performing plasma proteomics of a cohort of COVID-19 patients, including non-survivors and survivors recovered from mild or severe symptoms, and uncovered numerous COVID-19-associated alterations of plasma proteins. We developed a machine-learning-based pipeline to identify 11 proteins as biomarkers and a set of biomarker combinations, which were validated by an independent cohort and accurately distinguished and predicted COVID-19 outcomes. Some of the biomarkers were further validated by enzyme-linked immunosorbent assay (ELISA) using a larger cohort. These markedly altered proteins, including the biomarkers, mediate pathophysiological pathways, such as immune or inflammatory responses, platelet degranulation and coagulation, and metabolism, that likely contribute to the pathogenesis. Our findings provide valuable knowledge about COVID-19 biomarkers and shed light on the pathogenesis and potential therapeutic targets of COVID-19.
Collapse
Affiliation(s)
- Ting Shu
- Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China; Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China
| | - Wanshan Ning
- MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430074, China
| | - Di Wu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, CAS, Wuhan, Hubei 430023, China
| | - Jiqian Xu
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, HUST, Wuhan, Hubei 430030, China
| | - Qiangqiang Han
- SpecAlly Life Technology Co., Ltd., Wuhan, Hubei 430075, China
| | - Muhan Huang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, CAS, Wuhan, Hubei 430023, China
| | - Xiaojing Zou
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, HUST, Wuhan, Hubei 430030, China
| | - Qingyu Yang
- Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China; Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China
| | - Yang Yuan
- Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China; Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China
| | - Yuanyuan Bie
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shangwen Pan
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, HUST, Wuhan, Hubei 430030, China
| | - Jingfang Mu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, CAS, Wuhan, Hubei 430023, China
| | - Yang Han
- Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China; Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China
| | - Xiaobo Yang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, HUST, Wuhan, Hubei 430030, China
| | - Hong Zhou
- Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China; Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China
| | - Ruiting Li
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, HUST, Wuhan, Hubei 430030, China
| | - Yujie Ren
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, CAS, Wuhan, Hubei 430023, China
| | - Xi Chen
- SpecAlly Life Technology Co., Ltd., Wuhan, Hubei 430075, China
| | - Shanglong Yao
- Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, HUST, Wuhan, Hubei 430030, China; Clinical Research Center for Anesthesiology of Hubei Province, Wuhan 430030, China
| | - Yang Qiu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China; Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, CAS, Wuhan, Hubei 430023, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Ding-Yu Zhang
- Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China; Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China; Center for Biosafety Mega-Science, CAS, Wuhan, Hubei 430071, China.
| | - Yu Xue
- MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430074, China.
| | - You Shang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, HUST, Wuhan, Hubei 430030, China; Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, HUST, Wuhan, Hubei 430030, China; Clinical Research Center for Anesthesiology of Hubei Province, Wuhan 430030, China; Center for Biosafety Mega-Science, CAS, Wuhan, Hubei 430071, China.
| | - Xi Zhou
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China; Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, Hubei 430023, China; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, CAS, Wuhan, Hubei 430023, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| |
Collapse
|
|
20
|
Blauw LL, Wang Y, Willems van Dijk K, Rensen PCN. A Novel Role for CETP as Immunological Gatekeeper: Raising HDL to Cure Sepsis? Trends Endocrinol Metab 2020; 31:334-343. [PMID: 32033866 DOI: 10.1016/j.tem.2020.01.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 11/11/2019] [Accepted: 01/09/2020] [Indexed: 12/26/2022]
Abstract
Raising HDL using cholesteryl ester transfer protein (CETP) inhibitors failed to show a clinically relevant risk reduction of cardiovascular disease in clinical trials, inviting reconsideration of the role of CETP and HDL in human physiology. Based on solid evidence from studies with isolated macrophages, rodents, and humans, we propose that a major function of CETP may be to modulate HDL in order to help resolve bacterial infections. When gram-negative bacteria invade the blood, as occurs in sepsis, Kupffer cells lose their expression of CETP to increase HDL levels. This rise in HDL prevents systemic endotoxemia by binding lipopolysaccharide and induces a systemic proinflammatory response in macrophages to mediate bacterial clearance. This raises the interesting possibility to repurpose CETP inhibitors for the treatment of sepsis.
Collapse
Affiliation(s)
- Lisanne L Blauw
- Department of Internal Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
| | - Yanan Wang
- Department of Internal Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Ko Willems van Dijk
- Department of Internal Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Patrick C N Rensen
- Department of Internal Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
|
21
|
Trinder M, Genga KR, Kong HJ, Blauw LL, Lo C, Li X, Cirstea M, Wang Y, Rensen PCN, Russell JA, Walley KR, Boyd JH, Brunham LR. Cholesteryl Ester Transfer Protein Influences High-Density Lipoprotein Levels and Survival in Sepsis. Am J Respir Crit Care Med 2020; 199:854-862. [PMID: 30321485 DOI: 10.1164/rccm.201806-1157oc] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
RATIONALE High-density lipoprotein (HDL) cholesterol (HDL-C) levels decline during sepsis, and lower levels are associated with worse survival. However, the genetic mechanisms underlying changes in HDL-C during sepsis, and whether the relationship with survival is causative, are largely unknown. OBJECTIVES We hypothesized that variation in genes involved in HDL metabolism would contribute to changes in HDL-C levels and clinical outcomes during sepsis. METHODS We performed targeted resequencing of HDL-related genes in 200 patients admitted to an emergency department with sepsis (Early Infection cohort). We examined the association of genetic variants with HDL-C levels, 28-day survival, 90-day survival, organ dysfunction, and need for vasopressor or ventilatory support. Candidate variants were further assessed in the VASST (Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Trial) cohort (n = 632) and St. Paul's Hospital Intensive Care Unit 2 (SPHICU2) cohort (n = 203). MEASUREMENTS AND MAIN RESULTS We identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777-A) that was associated with significant reductions in HDL-C levels during sepsis. Carriers of the A allele (n = 10) had decreased survival, more organ failure, and greater need for organ support compared with noncarriers. We replicated this finding in the VASST and SPHICU2 cohorts, in which carriers of rs1800777-A (n = 35 and n = 12, respectively) had significantly reduced 28-day survival. Mendelian randomization was consistent with genetically reduced HDL levels being a causal factor for decreased sepsis survival. CONCLUSIONS Our results identify CETP as a critical regulator of HDL levels and clinical outcomes during sepsis. These data point toward a critical role for HDL in sepsis.
Collapse
Affiliation(s)
- Mark Trinder
- 1 Centre for Heart Lung Innovation and.,2 Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kelly R Genga
- 1 Centre for Heart Lung Innovation and.,2 Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Lisanne L Blauw
- 3 Department of Medicine, Division of Endocrinology and.,4 Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands; and
| | - Cody Lo
- 1 Centre for Heart Lung Innovation and
| | - Xuan Li
- 1 Centre for Heart Lung Innovation and
| | | | - Yanan Wang
- 3 Department of Medicine, Division of Endocrinology and.,4 Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands; and
| | - Patrick C N Rensen
- 3 Department of Medicine, Division of Endocrinology and.,4 Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands; and
| | - James A Russell
- 1 Centre for Heart Lung Innovation and.,5 Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Keith R Walley
- 1 Centre for Heart Lung Innovation and.,5 Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - John H Boyd
- 1 Centre for Heart Lung Innovation and.,2 Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada.,5 Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Liam R Brunham
- 1 Centre for Heart Lung Innovation and.,2 Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada.,5 Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| |
Collapse
|
|
22
|
Oliveira HCF, Raposo HF. Cholesteryl Ester Transfer Protein and Lipid Metabolism and Cardiovascular Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1276:15-25. [PMID: 32705591 DOI: 10.1007/978-981-15-6082-8_2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In this chapter, we present the major advances in CETP research since the detection, isolation, and characterization of its activity in the plasma of humans and several species. Since CETP is a major modulator of HDL plasma levels, the clinical importance of CETP activity was recognized very early. We describe the participation of CETP in reverse cholesterol transport, conflicting results in animal and human genetic studies, possible new functions of CETP, and the results of the main clinical trials on CETP inhibition. Despite major setbacks in clinical trials, the hypothesis that CETP inhibitors are anti-atherogenic in humans is still being tested.
Collapse
Affiliation(s)
- Helena C F Oliveira
- Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Campinas, SP, Brazil.
| | - Helena F Raposo
- Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Campinas, SP, Brazil
| |
Collapse
|
|
23
|
Bonacina F, Pirillo A, Catapano AL, Norata GD. Cholesterol membrane content has a ubiquitous evolutionary function in immune cell activation: the role of HDL. Curr Opin Lipidol 2019; 30:462-469. [PMID: 31577612 DOI: 10.1097/mol.0000000000000642] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW Cellular cholesterol content influences the structure and function of lipid rafts, plasma membrane microdomains essential for cell signaling and activation. HDL modulate cellular cholesterol efflux, thus limiting cholesterol accumulation and controlling immune cell activation. Aim of this review is to discuss the link between HDL and cellular cholesterol metabolism in immune cells and the therapeutic potential of targeting cholesterol removal from cell membranes. RECENT FINDINGS The inverse relationship between HDL-cholesterol (HDL-C) levels and the risk of cardiovascular disease has been recently challenged by observations linking elevated levels of HDL-C with increased risk of all-cause mortality, infections and autoimmune diseases, paralleled by the failure of clinical trials with HDL-C-raising therapies. These findings suggest that improving HDL function might be more important than merely raising HDL-C levels. New approaches aimed at increasing the ability of HDL to remove cellular cholesterol have been assessed for their effect on immune cells, and the results have suggested that this could be a new effective approach. SUMMARY Cholesterol removal from plasma membrane by different means affects the activity of immune cells, suggesting that approaches aimed at increasing the ability of HDL to mobilize cholesterol from cells would represent the next step in HDL biology.
Collapse
Affiliation(s)
- Fabrizia Bonacina
- Department of Pharmacological and Biomolecular Sciences, University of Milan
| | - Angela Pirillo
- Center for the Study of Atherosclerosis, E. Bassini Hospital
- IRCCS MultiMedica, Milan, Italy
| | - Alberico L Catapano
- Department of Pharmacological and Biomolecular Sciences, University of Milan
- IRCCS MultiMedica, Milan, Italy
| | - Giuseppe D Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan
- Center for the Study of Atherosclerosis, E. Bassini Hospital
| |
Collapse
|
|
24
|
Ji ZR, Xue WL, Zhang L. Schisandrin B Attenuates Inflammation in LPS-Induced Sepsis Through miR-17-5p Downregulating TLR4. Inflammation 2019; 42:731-739. [PMID: 30506107 DOI: 10.1007/s10753-018-0931-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
To investigate the mechanism of Schisandrin B (Sch B) on the inflammation in LPS-induced sepsis. Sepsis mouse model was established by injecting LPS. qRT-PCR and western blot were used to measure the expression of miR-17-5p and TLR4. ELISA was used to test the concentrations of IL-1β and TNF-α. Sch B could increase miR-17-5p expression, promote inflammation, and decrease TLR4 expression in sepsis mice and LPS-induced macrophages. Moreover, miR-17-5p could negatively regulate TLR4. Overexpression of miR-17-5p suppressed the concentrations of inflammatory factors (IL-1β and TNF-α) in LPS induced-macrophages, while pcDNA-TLR4 could change the inhibition effect. Additionally, miR-17-5p inhibitor changed the inhibitory effects of Sch B on TLR4 expression and the concentrations of IL-1β and TNF-α in LPS induced-macrophages. Sch B could attenuate inflammation in LPS-induced sepsis through miR-17-5p downregulating TLR4.
Collapse
Affiliation(s)
- Zhi-Rong Ji
- Department of Traditional Chinese Medicine, People's Hospital of Ningxia Hui Autonomous Region, the First Affiliated Hospital of Northwest University for Nationalities, Yinchuan, 750000, Ningxia, China
| | - Wei-Liang Xue
- Department of Emergency, People's Hospital of Ningxia Hui Autonomous Region, the First Affiliated Hospital of Northwest University for Nationalities, No.301 Zhengyuan North Street, Yinchuan, 750000, Ningxia, China.
| | - Ling Zhang
- Department of Emergency, People's Hospital of Ningxia Hui Autonomous Region, the First Affiliated Hospital of Northwest University for Nationalities, No.301 Zhengyuan North Street, Yinchuan, 750000, Ningxia, China
| |
Collapse
|
|
25
|
Liu Y, Zhao J, Zhao Y, Zong S, Tian Y, Chen S, Li M, Liu H, Zhang Q, Jing X, Sun B, Wang H, Sun T, Yang C. Therapeutic effects of lentinan on inflammatory bowel disease and colitis-associated cancer. J Cell Mol Med 2019; 23:750-760. [PMID: 30472806 PMCID: PMC6349230 DOI: 10.1111/jcmm.13897] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 08/14/2018] [Indexed: 01/03/2023] Open
Abstract
In this study, we investigated the therapeutic potential of lentinan in mouse models of inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Lentinan decreased the disease activity index and macroscopic and microscopic colon tissue damage in dextran sulphate sodium (DSS)-induced or TNBS-induced models of colitis. High-dose lentinan was more effective than salicylazosulfapyridine in the mouse models of colitis. Lentinan decreased the number of tumours, inflammatory cell infiltration, atypical hyperplasia and nuclear atypia in azoxymethane/DSS-induced CAC model. It also decreased the expression of pro-inflammatory cytokines, such as IL-13 and CD30L, in IBD and CAC model mice possibly by inhibiting Toll-like receptor 4 (TLR4)/NF-κB signalling and the expression of colon cancer markers, such as carcinoembryonic antigen, cytokeratin 8, CK18 and p53, in CAC model mice. In addition, lentinan restored the intestinal bacterial microbiotal community structure in IBD model mice. Thus, it shows therapeutic potential in IBD and CAC model mice possibly by inhibiting TLR4/NF-κB signalling-mediated inflammatory responses and disruption of the intestinal microbiotal structure.
Collapse
Affiliation(s)
- Yanrong Liu
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina,Drug Safety Evaluation CenterTianjin International Joint Academy of BiomedicineTianjinChina
| | - Jianmin Zhao
- Department of PathologyHospital of Shun Yi DistrictBeijingChina
| | - Yali Zhao
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina,State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Shumin Zong
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina,State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Yixuan Tian
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina,State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Shuang Chen
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina
| | - Meng Li
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina,State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Huijuan Liu
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina
| | - Qiang Zhang
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina,State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Xueshuang Jing
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina
| | - Bo Sun
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina
| | - Hongzhi Wang
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina,State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Tao Sun
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina,State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Cheng Yang
- Tianjin Key Laboratory of Molecular Drug ResearchTianjin International Joint Academy of BiomedicineTianjinChina,State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| |
Collapse
|
|
26
|
Martinelli AEM, Maranhão RC, Carvalho PO, Freitas FR, Silva BMO, Curiati MNC, Kalil Filho R, Pereira-Barretto AC. Cholesteryl ester transfer protein (CETP), HDL capacity of receiving cholesterol and status of inflammatory cytokines in patients with severe heart failure. Lipids Health Dis 2018; 17:242. [PMID: 30342531 PMCID: PMC6195750 DOI: 10.1186/s12944-018-0888-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 10/03/2018] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Heart failure (HF) courses with chronic inflammatory process and alterations in lipid metabolism may aggravate the disease. The aim was to test whether the severity of HF, using brain natriuretic peptide (BNP) as a marker, is associated with alterations in functional aspects of HDL, such as lipid transfer, cholesterol ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT) concentration. METHODS Twenty-five HF patients in NYHA class I/II and 23 in class III/IV were enrolled. Plasma lipids, apolipoproteins, CETP, LCAT, oxidized-LDL (oxLDL) and paraoxonase-1 (PON-1) activity were determined. Lipid transfer from a donor artificial nanoparticle to HDL was measured by in vitro assay. RESULTS Total cholesterol (p = 0.049), LDL-C (p = 0.023), non-HDL-C (p = 0.029) and CETP, that promotes lipid transfer among lipoproteins (p = 0.013), were lower in III/IV than in I/II group. Triglycerides, HDL-C, apo A-I, apo B, oxLDL, LCAT, enzyme that catalyzes serum cholesterol esterification, PON-1 activity, and in vitro transfers of cholesterol, triglycerides and phospholipids to HDL, important steps in HDL metabolism, were equal. IL-8 was higher in III/IV (p = 0.025), but TNFα, IL-1β, IL-6 and MCP-1 were equal. BNP was negatively correlated with CETP (r = - 0.294; p = 0.042) and positively correlated with IL-8 (r = 0.299; p = 0.039). CONCLUSIONS Our results disclosed the relationship between CETP levels and HF severity, by comparing two HF groups and by correlation analysis. Lower CETP levels may be a marker of HF aggravation and possibly of worse prognosis. Practical applications of this initial finding, as the issue whether CETP could be protective against HF aggravation, should be explored in larger experimental and clinical studies.
Collapse
Affiliation(s)
- Ana Elisa M Martinelli
- Laboratorio de Metabolismo e Lipides, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44. 1° subsolo, São Paulo, SP, 05403-000, Brazil
| | - Raul C Maranhão
- Laboratorio de Metabolismo e Lipides, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44. 1° subsolo, São Paulo, SP, 05403-000, Brazil. .,Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, São Paulo, Brazil.
| | - Priscila O Carvalho
- Laboratorio de Metabolismo e Lipides, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44. 1° subsolo, São Paulo, SP, 05403-000, Brazil
| | - Fatima R Freitas
- Laboratorio de Metabolismo e Lipides, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44. 1° subsolo, São Paulo, SP, 05403-000, Brazil
| | - Bruna M O Silva
- Laboratorio de Metabolismo e Lipides, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44. 1° subsolo, São Paulo, SP, 05403-000, Brazil
| | - Milena N C Curiati
- Hospital Santa Marcelina, São Paulo, Brazil.,Servico de Prevencao e Reabilitacao Cardiovascular, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Roberto Kalil Filho
- Laboratorio de Metabolismo e Lipides, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44. 1° subsolo, São Paulo, SP, 05403-000, Brazil
| | - Antonio Carlos Pereira-Barretto
- Servico de Prevencao e Reabilitacao Cardiovascular, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| |
Collapse
|
|
27
|
Metabolic liver inflammation in obesity does not robustly decrease hepatic and circulating CETP. Atherosclerosis 2018; 275:149-155. [PMID: 29902703 DOI: 10.1016/j.atherosclerosis.2018.06.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 05/16/2018] [Accepted: 06/06/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS We recently showed that plasma cholesteryl ester transfer protein (CETP) is mainly derived from VSIG4-positive Kupffer cells. Activation of these cells by the bacterial endotoxin lipopolysaccharide (LPS) strongly decreases CETP expression. As Kupffer cell activation plays a detrimental role in the progression of non-alcoholic fatty liver disease (NAFLD), we aimed to study if metabolic liver inflammation is also associated with a decrease in hepatic and circulating CETP. METHODS We collected plasma and liver biopsy samples at various stages of NAFLD from 93 obese individuals who underwent bariatric surgery. Liver lobular inflammation was histologically determined, and liver CETP expression, CETP positive cells, circulating CETP concentrations, and liver VSIG4 expression were quantified. RESULTS Mean (SD) plasma CETP concentration was 2.68 (0.89) μg/mL. In the presence of liver inflammation, compared to the absence of pathology, the difference in hepatic CETP expression was -0.03 arbitrary units (95% CI -0.26, 0.20), the difference in number of hepatic CETP positive cells (range 11-140 per mm2) was -20.0 per mm2 (95% CI -41.6, 1.9), and the difference in plasma CETP was -0.35 μg/mL (95% CI -0.80, 0.10). Hepatic VSIG4 expression was not associated with liver inflammation (0.00; 95% CI -0.15, 0.15). CONCLUSIONS We found no strong evidence for a strong negative association between metabolic liver inflammation and CETP-related outcomes in obese individuals, although we observed consistent trends. These data indicate that metabolic liver inflammation does not mimic the strong effects of LPS on the hepatic expression and production of CETP by Kupffer cells.
Collapse
|
|
28
|
Shrestha S, Wu BJ, Guiney L, Barter PJ, Rye KA. Cholesteryl ester transfer protein and its inhibitors. J Lipid Res 2018; 59:772-783. [PMID: 29487091 PMCID: PMC5928430 DOI: 10.1194/jlr.r082735] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 02/10/2018] [Indexed: 12/22/2022] Open
Abstract
Most of the cholesterol in plasma is in an esterified form that is generated in potentially cardioprotective HDLs. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. Because CE originates in HDLs and TG enters the plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs, and of TG from VLDLs to LDLs and HDLs. As inhibition of CETP activity increases the concentration of HDL-cholesterol and decreases the concentration of VLDL- and LDL-cholesterol, it has the potential to reduce atherosclerotic CVD. This has led to the development of anti-CETP neutralizing monoclonal antibodies, vaccines, and antisense oligonucleotides. Small molecule inhibitors of CETP have also been developed and four of them have been studied in large scale cardiovascular clinical outcome trials. This review describes the structure of CETP and its mechanism of action. Details of its regulation and nonlipid transporting functions are discussed, and the results of the large scale clinical outcome trials of small molecule CETP inhibitors are summarized.
Collapse
Affiliation(s)
- Sudichhya Shrestha
- School of Medical Sciences, University of New South Wales Sydney, Sydney, New South Wales, Australia
| | - Ben J Wu
- School of Medical Sciences, University of New South Wales Sydney, Sydney, New South Wales, Australia
| | - Liam Guiney
- Prince of Wales Hospital, Sydney, New South Wales, Australia
| | - Philip J Barter
- School of Medical Sciences, University of New South Wales Sydney, Sydney, New South Wales, Australia
| | - Kerry-Anne Rye
- School of Medical Sciences, University of New South Wales Sydney, Sydney, New South Wales, Australia
| |
Collapse
|
|
29
|
Camargo LDN, Righetti RF, Aristóteles LRDCRB, Dos Santos TM, de Souza FCR, Fukuzaki S, Cruz MM, Alonso-Vale MIC, Saraiva-Romanholo BM, Prado CM, Martins MDA, Leick EA, Tibério IDFLC. Effects of Anti-IL-17 on Inflammation, Remodeling, and Oxidative Stress in an Experimental Model of Asthma Exacerbated by LPS. Front Immunol 2018; 8:1835. [PMID: 29379497 PMCID: PMC5760512 DOI: 10.3389/fimmu.2017.01835] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 12/05/2017] [Indexed: 12/13/2022] Open
Abstract
Inflammation plays a central role in the development of asthma, which is considered an allergic disease with a classic Th2 inflammatory profile. However, cytokine IL-17 has been examined to better understand the pathophysiology of this disease. Severe asthmatic patients experience frequent exacerbations, leading to infection, and subsequently show altered levels of inflammation that are unlikely to be due to the Th2 immune response alone. This study estimates the effects of anti-IL-17 therapy in the pulmonary parenchyma in a murine asthma model exacerbated by LPS. BALB/c mice were sensitized with intraperitoneal ovalbumin and repeatedly exposed to inhalation with ovalbumin, followed by treatment with or without anti-IL-17. Twenty-four hours prior to the end of the 29-day experimental protocol, the two groups received LPS (0.1 mg/ml intratracheal OVA-LPS and OVA-LPS IL-17). We subsequently evaluated bronchoalveolar lavage fluid, performed a lung tissue morphometric analysis, and measured IL-6 gene expression. OVA-LPS-treated animals treated with anti-IL-17 showed decreased pulmonary inflammation, edema, oxidative stress, and extracellular matrix remodeling compared to the non-treated OVA and OVA-LPS groups (p < 0.05). The anti-IL-17 treatment also decreased the numbers of dendritic cells, FOXP3, NF-κB, and Rho kinase 1- and 2-positive cells compared to the non-treated OVA and OVA-LPS groups (p < 0.05). In conclusion, these data suggest that inhibition of IL-17 is a promising therapeutic avenue, even in exacerbated asthmatic patients, and significantly contributes to the control of Th1/Th2/Th17 inflammation, chemokine expression, extracellular matrix remodeling, and oxidative stress in a murine experimental asthma model exacerbated by LPS.
Collapse
Affiliation(s)
| | - Renato Fraga Righetti
- Department of Medical Sciences, School of Medicine, University of São Paulo, São Paulo, Brazil.,Hospital Sírio-Libanês, São Paulo, Brazil
| | | | | | | | - Silvia Fukuzaki
- Department of Medical Sciences, School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Maysa Mariana Cruz
- Department of Biological Sciences, Institute of Biomedical Sciences, Federal University of São Paulo, São Paulo, Brazil
| | | | | | - Carla Máximo Prado
- Department of Biological Sciences, Federal University of São Paulo, São Paulo, Brazil
| | | | - Edna Aparecida Leick
- Department of Medical Sciences, School of Medicine, University of São Paulo, São Paulo, Brazil
| | | |
Collapse
|