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Nehring P, Przybyłkowski A. Genetic Determinants of Colonic Diverticulosis-A Systematic Review. Genes (Basel) 2025; 16:581. [PMID: 40428403 PMCID: PMC12111319 DOI: 10.3390/genes16050581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2025] [Revised: 05/11/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Colonic diverticulosis is a common condition, particularly in the elderly population. While dietary habits, obesity, smoking, and physical inactivity contribute to its pathogenesis, emerging evidence highlights a genetic predisposition affecting extracellular matrix (ECM) remodeling, inflammation, and connective tissue integrity. The aim of this systematic review was to summarize genetic determinants of colonic diverticulosis. Methods: The PubMed® database was searched for original studies in humans. The inclusion criteria were named genetic factor and confirmed diverticulosis. Patients with diverticulitis and diverticular diseases were excluded from this review. Results: Out of 137 publications, 10 articles met the inclusion criteria: six large association studies (GWAS) and four cross-sectional studies. The genes regulating ECM turnover, including TIMP1, MMP3, and MMP9, are involved in diverticulosis development. The TIMP1 (rs4898) T allele has been associated with increased susceptibility, potentially due to its role in ECM remodeling. Similarly, MMP3 (rs3025058) and MMP9 (rs3918242) polymorphisms contribute to altered collagen degradation. The COL3A1 (rs3134646) variant coding modified collagen type III may promote diverticular formation. Other genes, such as ARHGAP15 (rs4662344, rs6736741), affect cytoskeletal dynamics. Identified in GWAS studies, gene candidates may be grouped into blood group and immune system-related genes (ABO, HLA-DQA1, HLA-H, OAS1, TNFSF13, FADD), extracellular matrix and connective tissue genes (COL6A1, COLQ, EFEMP1, ELN, HAS2, TIMP2), signaling and cell communication (BMPR1B, WNT4, RHOU, PHGR1, PCSK5), nervous system and neurodevelopment (BDNF, CACNB2, GPR158, SIRT1, SCAPER, TRPS1), metabolism and transporters (SLC25A28, SLC35F3, RBKS, PPP1R14A, PPP1R16B), lipids and cholesterol (LDAH, LYPLAL1, STARD13), transcription and gene regulation (ZBTB4, UBTF, TNRC6B), apoptosis (FADD, PIAS1), and poorly characterized genes (C1TNF7, ENSG00000224849, ENSG00000251283, LINC01082, DISP2, SNX24, THEM4, UBL4B, UNC50, WDR70, SREK1IP1). Conclusions: There are a number of gene variants that probably predispose to colonic diverticulosis. Detailed characterization of the multigene background of diverticulosis will enable appropriate therapeutic or preventive interventions in the future.
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Affiliation(s)
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland;
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Häußler D, Manevski D, Frädrich J, Brunner V, Prokopchuk O, Sommer A, Toledo B, Knolle P, Martignoni ME, Friess H, Waterhouse P, Krüger A. Extent of N-glycosylation of the metalloproteinase inhibitor and cytokine TIMP-1 determines pancreatic cancer cell proliferation and survival via CD63. J Biol Chem 2025:110211. [PMID: 40345589 DOI: 10.1016/j.jbc.2025.110211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/09/2025] [Accepted: 04/16/2025] [Indexed: 05/11/2025] Open
Abstract
Glycosylation emerges as a critical determinant of protein function in cancer, yet its impact on multifunctional secreted factors remains understudied. Here, we identified tissue inhibitor of metalloproteinases-1 (TIMP-1), a glycoprotein with glycosylation sites at N30 and N78 harboring both a canonical anti-proteolytic and non-canonical cytokine-like activity, as one of the most-upregulated secreted glycoproteins circulating in the blood of pancreatic cancer (PC) patients. Whereas plasma from healthy donors contained similar amounts of double- (TIMP-1glyc1/1), single-(N78 and not N30) (TIMP-1glyc0/1), and non-glycosylated (TIMP-1glyc0/0) TIMP-1, TIMP-1glyc1/1 predominated in plasma from PC patients. scRNAseq and in vitro validation linked this shift to tumor progression-associated upregulation of the oligosaccharyltransferase (OST)-complex in epithelial cells. In human PC cell lines, OST complex activity was critical for synthesis of TIMP-1glyc1/1. Importantly, tumor cell-survival and proliferation-promoting activity via CD63 were dependent on TIMP-1 glycosylation, which required N30-glycosylation. In contrast, glycosylation was not necessary for the anti-proteolytic activity of TIMP-1 towards different matrix metalloproteinases (MMPs) (collagenases MMP-1, MMP-8; gelatinases MMP-2, MMP-9; stromelysin MMP-3; Matrilysin MMP-7) but modulated the respective inhibitory efficacy. Analysis of a published glycoproteome data set, allowing assessment of individual glycosylation site occupancy in TIMP-1, revealed that N30 site occupation correlated with poor survival, while N78 site occupation showed no prognostic value, corroborating the impact of double-glycosylation of TIMP-1, as observed in patients, on tumor-promotion. The glycosylation-dependent modulation of the multifunctionality of tumor-secreted TIMP-1 thus provide a molecular basis for its long-debated cancer-promoting role. Finally, it exemplifies the impact of glycosylation macroheterogeneity on disease-relevant modulation of protein function.
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Affiliation(s)
- Daniel Häußler
- TUM School of Medicine and Health, Institute of Experimental Oncology and Therapy Research, Technical University of Munich, 81675 Munich, Germany
| | - Damjan Manevski
- TUM School of Medicine and Health, Institute of Experimental Oncology and Therapy Research, Technical University of Munich, 81675 Munich, Germany
| | - Julian Frädrich
- TUM School of Medicine and Health, Institute of Experimental Oncology and Therapy Research, Technical University of Munich, 81675 Munich, Germany
| | - Vanessa Brunner
- TUM School of Medicine and Health, Institute of Experimental Oncology and Therapy Research, Technical University of Munich, 81675 Munich, Germany
| | - Olga Prokopchuk
- TUM School of Medicine and Health, Institute of Experimental Oncology and Therapy Research, Technical University of Munich, 81675 Munich, Germany; TUM School of Medicine and Health, Institute of Molecular Immunology, Technical University of Munich, 81675 Munich, Germany
| | - Alexander Sommer
- TUM School of Medicine and Health, Institute of Experimental Oncology and Therapy Research, Technical University of Munich, 81675 Munich, Germany
| | - Batu Toledo
- TUM School of Medicine and Health, Institute of Experimental Oncology and Therapy Research, Technical University of Munich, 81675 Munich, Germany
| | - Percy Knolle
- TUM School of Medicine and Health, Institute of Molecular Immunology, Technical University of Munich, 81675 Munich, Germany
| | - Marc E Martignoni
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Paul Waterhouse
- Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Achim Krüger
- TUM School of Medicine and Health, Institute of Experimental Oncology and Therapy Research, Technical University of Munich, 81675 Munich, Germany.
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Beklen A, Yavuz MB, Uckan D. Interleukin-37 reduces lipopolysaccharide induced matrix metalloproteinase-9 in gingival epithelial cells. BMC Oral Health 2025; 25:637. [PMID: 40281482 PMCID: PMC12023668 DOI: 10.1186/s12903-025-06016-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND In periodontal diseases, the recognition of pathogen-associated molecular patterns (PAMPs) triggers signaling cascades that lead to the release of matrix metalloproteinases (MMPs). Interleukin-37 (IL-37) is recognized as a key suppressor of the immune response. This study aimed to detect the expression and distribution of IL-37 in gingival tissues and analyze its suppressor role in MMP-9 in response to lipopolysaccharide (LPS)-stimulated gingival epithelial cells. METHODS Immunohistochemistry localized IL-37 in gingival tissues from periodontitis patients and healthy controls (N = 10). The induction of IL-37 expression by LPS was analyzed using the conditioned medium of gingival epithelial cells through enzyme-linked immunosorbent assay (ELISA). To determine the relevant MMP-9 levels in epithelial cells following exposure to LPS alone or in combination with IL-37, both quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) were performed. RESULTS Cultured epithelial cells secreted significantly higher levels of IL-37 when stimulated with LPS compared to unstimulated controls. Both ELISA and qPCR showed that LPS stimulation significantly increased MMP-9 levels. However, co-culture with IL-37 markedly reduced LPS-induced MMP-9 expression at both the protein and mRNA levels. Furthermore, immunohistochemistry revealed increased IL-37 expression in periodontitis tissues, both in epithelial cells and connective tissue. CONCLUSIONS Gingival epithelial cells may contribute to tissue responses in periodontitis through the secretion of MMP-9 in response to PAMPs. Furthermore, IL-37 appears to have a potential role in modulating and reducing this response, as observed in the decreased MMP-9 expression following IL-37 co-stimulation.
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Affiliation(s)
- Arzu Beklen
- Translational Immunology Research Program (TRIMM), Research Program Unit (RPU), University of Helsinki, Helsinki, Finland.
- Department of Periodontology, Faculty of Dentistry, Eskisehir Osmangazi University, Eskisehir, Turkey.
| | - Muhammet Burak Yavuz
- Department of Periodontology, Faculty of Dentistry, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Deniz Uckan
- Bogazici University, Medico-Social Dental Clinic, Istanbul, Turkey
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Brito HO, Reis RC, Bini I, Wilhelms D, Engblom D, Gil da Costa RM, Brito LO, Nascimento MDDSB, de Andrade MS, Zampronio AR, Cavichiollo CC. NK1 receptor mediates cerebral cellular and extracellular morphological changes during the LPS-induced febrile response. Brain Res 2024; 1842:149107. [PMID: 38977236 DOI: 10.1016/j.brainres.2024.149107] [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: 02/24/2024] [Revised: 06/11/2024] [Accepted: 07/01/2024] [Indexed: 07/10/2024]
Abstract
Fever elicited by bacterial lypopolyssacharide (LPS) is mediated by pro-inflammatory cytokines, which activate central mediators and regulate the hypothalamic temperature setpoint. This response is often accompanied by morphological changes involving the extracellular matrix, neurons and glial cells, with significant health impacts. The NK1 receptor is involved in the febrile response induced by LPS but its effects over the extracellular matrix in the context of neuroinflammation remain unknown. The present work aims to clarify the extracellular changes associated with NK1 signaling in LPS-induced fever. Male Wistar rats were exposed to LPS intraperitoneally. Experimental groups were pre-treated intracerebroventricularly with the NK1 selective inhibitor SR140333B or saline. Histological changes involving the brain extracellular matrix were evaluated using hematoxylin and eosin, Mason's trichrome, picrosirius, alcian blue, periodic acid Schiff's stains. The expression of matrix metalloproteinase 9 (MMP9) was studied using confocal microscopy. Fever was accompanied by edema, perivascular lymphoplamacytic and neutrophylic infiltration, spongiosis and MMP9 overexpression. SR140333B significantly reduced LPS-induced fever (p < 0.0001), MMP9 overexpression (p < 0.01) and associated histological changes. These results contribute to characterize cerebral extracellular matrix changes associated with LPS-induced fever. Overall, the present work supports a role for NK1 receptor in these neuroinflammatory changes, involving MMP9 overexpression, edema and leukocytic infiltration.
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Affiliation(s)
- Haissa O Brito
- Post-Graduate Programme in Adult Health (PPGSAD), Federal University of Maranhão, São Luís, Brazil; Department of Morphology, Federal University of Maranhão, São Luís, Brazil.
| | - Renata C Reis
- Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil
| | - Israel Bini
- Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil
| | | | | | - Rui M Gil da Costa
- Post-Graduate Programme in Adult Health (PPGSAD), Federal University of Maranhão, São Luís, Brazil; Department of Morphology, Federal University of Maranhão, São Luís, Brazil; LEPABE - Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Porto, Portugal; ALiCE - Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Porto, Portugal; Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Institute of Oncology of Porto (IPO-Porto), Porto Comprehensive Cancer Center (Porto.CCC), Porto, Portugal.
| | - Luciane O Brito
- Post-Graduate Programme in Adult Health (PPGSAD), Federal University of Maranhão, São Luís, Brazil
| | | | - Marcelo Souza de Andrade
- Post-Graduate Programme in Adult Health (PPGSAD), Federal University of Maranhão, São Luís, Brazil
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Yan H, Wang Y, Guo R, Jia Z, Liu J, Li B. Association between TIMP1 polymorphism and female neuromyelitis optica spectrum disorder in Chinese population. Heliyon 2024; 10:e37091. [PMID: 39296182 PMCID: PMC11409102 DOI: 10.1016/j.heliyon.2024.e37091] [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: 02/14/2024] [Revised: 08/18/2024] [Accepted: 08/27/2024] [Indexed: 09/21/2024] Open
Abstract
Aims Earlier studies have indicated an association between the TIMP1 polymorphism and the risk of certain autoimmune diseases, as well as a link between higher TIMP1 levels and blood-brain barrier (BBB) disruption in neuromyelitis optica spectrum disorders (NMOSD). This study aimed to explore the correlation between TIMP1 polymorphism and NMOSD phenotypes. Methods Genotyping of three loci (rs4898, rs2070584, rs6609533) in the TIMP1 gene was performed in 126 NMOSD patients and 213 healthy controls (HCs) from North China using the SNaPshot sequencing technique, and a correlation analysis was done between phenotypes and TIMP1 genotype. Results The frequency of the rs4898-T, rs2070584-T, and rs6609533-G alleles was significantly higher in NMOSD patients than those in HCs (p < 0.05). Accordingly, the rs4898-TT, rs2070584-TT, and rs6609533-GG genotypes were found at a higher frequency in patients than in controls (p < 0.05). Haplotype analysis showed TIMP1 T-T-G (rs4898-rs2070584-rs6609533) frequency was higher in female NMOSD patients (p = 0.019), and the frequency of T-T-G haplotypes in the BBB disrupted group was higher compared with that in the BBB normal group (p = 0.04). Conclusions TIMP1 rs4898-T, rs2070584-T, and rs6609533 polymorphism may contribute to the susceptibility of Female NMOSD patients in the Chinese Population. TIMP1 T-T-G (rs4898-rs2070584-rs6609533) haplotype is more common among female NMOSD patients and is linked to heightened disruption of the BBB.
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Affiliation(s)
- Hongjing Yan
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Hebei Neurology, Shijiazhuang, China
- Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, China
- Department of Neurology, Handan First Hospital, Handan, China
| | - Yining Wang
- Department of Neurology, Handan First Hospital, Handan, China
| | - Ruoyi Guo
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Hebei Neurology, Shijiazhuang, China
- Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, China
| | - Zhen Jia
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Hebei Neurology, Shijiazhuang, China
- Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, China
| | - Jia Liu
- Department of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, China
| | - Bin Li
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Hebei Neurology, Shijiazhuang, China
- Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, China
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Song T, Yao Y, Papoin J, Sherry B, Diamond B, Gu H, Blanc L, Zou YR. Host factor TIMP1 sustains long-lasting myeloid-biased hematopoiesis after severe infection. J Exp Med 2023; 220:e20230018. [PMID: 37851372 PMCID: PMC10585121 DOI: 10.1084/jem.20230018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 07/10/2023] [Accepted: 10/03/2023] [Indexed: 10/19/2023] Open
Abstract
Infection is able to promote innate immunity by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, the mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. In post-infection mice, the tissue inhibitor of metalloproteinases 1 (TIMP1) is constitutively upregulated. TIMP1 antagonizes the function of ADAM10, an essential cleavage enzyme for the activation of the Notch signaling pathway, which suppresses myelopoiesis. While TIMP1 is dispensable for myelopoiesis under the steady state, increased TIMP1 enhances myelopoiesis after infection. Thus, our data establish TIMP1 as a molecular reporter of past infection in the host, sustaining hyper myelopoiesis and serving as a potential therapeutic target for modulating HSPC cell fate.
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Affiliation(s)
- Tengfei Song
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Yonghong Yao
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Julien Papoin
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Barbara Sherry
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA
| | - Betty Diamond
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA
| | - Hua Gu
- Laboratory of Molecular Immunology, Institut de Recherches Cliniques de Montréal, Montréal, Canada
| | - Lionel Blanc
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA
| | - Yong-Rui Zou
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
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Li Z, Wang C, Zhang X, Xu X, Wang M, Dong L. Crosstalk between septic shock and venous thromboembolism: a bioinformatics and immunoassay analysis. Front Cell Infect Microbiol 2023; 13:1235269. [PMID: 38029239 PMCID: PMC10666789 DOI: 10.3389/fcimb.2023.1235269] [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: 06/08/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Background Herein, we applied bioinformatics methods to analyze the crosstalk between septic shock (SS) and venous thromboembolism (VTE), focusing on the correlation with immune infiltrating cells. Methods Expression data were obtained from the Gene Expression Omnibus (GEO) database, including blood samples from SS patients (datasets GSE64457, GSE95233, and GSE57065) and VTE patients (GSE19151). We used the R package "limma" for differential expression analysis (p value<0.05,∣logFC∣≥1). Venn plots were generated to identify intersected differential genes between SS and VTE and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment analysis. The protein-protein interaction (PPI) network of intersected genes was constructed by Cytoscape software. The xCell analysis identified immune cells with significant changes in VTE and SS and correlated them with significant molecular pathways of crosstalk. Finally, we validated the mRNA expression of crosstalk genes by qPCR, while Matrix Metalloprotein-9 (MMP-9) protein levels were assessed through Western blotting (WB) and Immunohistochemistry (IHC) in human umbilical vein endothelial cells (HUVECs) and mice. Results In the present study, we conducted a comparison between 88 patients with septic shock and 55 control subjects. Additionally, we compared 70 patients with venous thromboembolism to 63 control subjects. Twelve intersected genes and their corresponding three important molecular pathways were obtained: Metabolic, Estrogen, and FOXO signaling pathways. The resulting PPI network has 194 nodes and 388 edges. The immune microenvironment analysis of the two diseases showed that the infiltration levels of M2 macrophages and Class-switched memory B cells were correlated with the enrichment scores of metabolic, estrogen, and FOXO signaling pathways. Finally, qPCR confirmed that the expression of MMP9, S100A12, ARG1, SLPI, and ANXA3 mRNA in the SS with VTE group was significantly elevated. WB and IHC experiments revealed that MMP9 protein was significantly elevated in the experimental group. Conclusion Metabolic, estrogen, and FOXO pathways play important roles in both SS and VTE and are related to the immune cell microenvironment of M2 macrophages and Class-switched memory B cells. MMP9 shows promise as a biomarker for diagnosing sepsis with venous thrombosis and a potential molecular target for treating this patient population.
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Affiliation(s)
- Zhishu Li
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, China
- Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Chaolan Wang
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Xu Zhang
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, China
| | - Xiaolin Xu
- School of Statistics, Renmin University of China, Bejing, China
| | - Meng Wang
- Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, China
| | - Lixia Dong
- Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China
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Jayawardena DP, Masciantonio MG, Wang L, Mehta S, DeGurse N, Pape C, Gill SE. Imbalance of Pulmonary Microvascular Endothelial Cell-Expression of Metalloproteinases and Their Endogenous Inhibitors Promotes Septic Barrier Dysfunction. Int J Mol Sci 2023; 24:ijms24097875. [PMID: 37175585 PMCID: PMC10178398 DOI: 10.3390/ijms24097875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 05/15/2023] Open
Abstract
Sepsis is a life-threatening disease characterized by excessive inflammation leading to organ dysfunction. During sepsis, pulmonary microvascular endothelial cells (PMVEC) lose barrier function associated with inter-PMVEC junction disruption. Matrix metalloproteinases (MMP) and a disintegrin and metalloproteinases (ADAM), which are regulated by tissue inhibitors of metalloproteinases (TIMPs), can cleave cell-cell junctional proteins, suggesting a role in PMVEC barrier dysfunction. We hypothesize that septic PMVEC barrier dysfunction is due to a disruption in the balance between PMVEC-specific metalloproteinases and TIMPs leading to increased metalloproteinase activity. The effects of sepsis on TIMPs and metalloproteinases were assessed ex vivo in PMVEC from healthy (sham) and septic (cecal ligation and perforation) mice, as well as in vitro in isolated PMVEC stimulated with cytomix, lipopolysaccharide (LPS), and cytomix + LPS vs. PBS. PMVEC had high basal Timp expression and lower metalloproteinase expression, and septic stimulation shifted expression in favour of metalloproteinases. Septic stimulation increased MMP13 and ADAM17 activity associated with a loss of inter-PMVEC junctional proteins and barrier dysfunction, which was rescued by treatment with metalloproteinase inhibitors. Collectively, our studies support a role for metalloproteinase-TIMP imbalance in septic PMVEC barrier dysfunction, and suggest that inhibition of specific metalloproteinases may be a therapeutic avenue for septic patients.
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Affiliation(s)
- Devika P Jayawardena
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Marcello G Masciantonio
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Lefeng Wang
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Sanjay Mehta
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Natalie DeGurse
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Cynthia Pape
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Sean E Gill
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
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Li XY, Liu M, Fu YJ, Jiang YJ, Zhang ZN. Alterations in levels of cytokine following treatment to predict outcome of sepsis: A meta-analysis. Cytokine 2023; 161:156056. [PMID: 36240721 DOI: 10.1016/j.cyto.2022.156056] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 09/19/2022] [Accepted: 09/24/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND The mortality rate of patients with sepsis has been increasing in recent years. Alterations of biomarkers levels during treatment are important in evaluating treatment efficacy and predicting outcomes in sepsis. This meta-analysis investigated the relationship between changes in cytokine levels after treatment compared with those on hospital admission, and their relationship with the prognosis of patients with sepsis. METHODS From conception until August 4, 2021, a complete literature search of the PubMed, Web of Science, and Cochrane Library electronic databases was done. Observational studies where the outcomes of sepsis patients were divided into non-survivors and survivors and which reported cytokine levels at least before treatment in ICU were included in the current study. Standardized mean difference (SMD) with 95% confidence intervals (CI) values from individual studies were pooled using a random-effects model. Quality assessment, subgroup analysis, publication bias, and sensitivity analyses were all carried out. RESULTS A total of 2570 patients with sepsis from 25 eligible studies were included, and 14 of them measured the cytokine levels before and after treatment in ICU. Among IL-6, TNF-α, IL-1β and IL-10 levels, those of IL-6 were significantly lower after treatment in ICU than at baseline in patients with sepsis in the survival group (SMD = -0.69, P < 0.0001), but were comparable in the non-survival group (SMD = -0.99, P = 0.0575). Similarly, post-treatment TNF-α levels were significantly lower than those at baseline only in patients with sepsis in the survival group (SMD = -0.44, P < 0.0001), but not in the non-survival group (SMD =-0.17, P = 0.0842). CONCLUSION This meta-analysis shows that reduced IL-6 and TNF-α levels after sepsis treatment in ICU may be indicators of better prognosis and survival of patients with sepsis.
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Affiliation(s)
- Xin-Yao Li
- NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang 110001, China
| | - Mei Liu
- NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang 110001, China
| | - Ya-Jing Fu
- NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang 110001, China
| | - Yong-Jun Jiang
- NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang 110001, China
| | - Zi-Ning Zhang
- NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang 110001, China.
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Li Y, Li H, Wang Y, Guo J, Zhang D. Potential Biomarkers for Early Diagnosis, Evaluation, and Prognosis of Sepsis-Induced Coagulopathy. Clin Appl Thromb Hemost 2023; 29:10760296231195089. [PMID: 37605466 PMCID: PMC10467369 DOI: 10.1177/10760296231195089] [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: 06/27/2023] [Revised: 07/23/2023] [Accepted: 07/30/2023] [Indexed: 08/23/2023] Open
Abstract
Sepsis-induced coagulopathy (SIC) is a life-threatening complication characterized by the systemic activation of coagulation in sepsis. The diagnostic criteria of SIC consist of three items, including Sequential Organ Failure Assessment (SOFA) score, platelet count, and prothrombin time (PT)-international normalized ratio (INR). SIC has a high prevalence and it can lead to a higher mortality rate and longer length of hospital and ICU stay. Thus, the early detection of SIC is extremely important. It is unfortunate that there is still no precise biomarker for early diagnosis and assessment of the prognosis of SIC. We reviewed the current literature and discovered that some potential biomarkers, such as soluble thrombomodulin (sTM), thrombin-antithrombin complex (TAT), tissue plasminogen activator-inhibitor complex (t-PAIC), α2-plasmin inhibitor-plasmin complex (PIC), C-type lectin-like receptor 2 (CLEC-2), neutrophil extracellular traps (NETs), prothrombin fragment 1.2 (F1.2), Angiopoietin-2 (Ang-2), plasminogen activator inhibitor-1 (PAI-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be useful for early diagnosis, evaluation, and prognosis of SIC. Early initiation of treatment without missing any therapeutic opportunities may improve SIC patients' prognosis. Further large-scale clinical studies are still needed to confirm the role of these biomarkers in the diagnosis and prognosis assessment of SIC.
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Affiliation(s)
- Yuting Li
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Hongxiang Li
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Youquan Wang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jianxing Guo
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Dong Zhang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
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Cut loose TIMP-1: an emerging cytokine in inflammation. Trends Cell Biol 2022; 33:413-426. [PMID: 36163148 DOI: 10.1016/j.tcb.2022.08.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 11/21/2022]
Abstract
Appreciation of the entire biological impact of an individual protein can be hampered by its original naming based on one function only. Tissue inhibitor of metalloproteinases-1 (TIMP-1), mostly known for its eponymous function to inhibit metalloproteinases, exhibits only a fraction of its cellular effects via this feature. Recently, TIMP-1 emerged as a potent cytokine acting via various cell-surface receptors, explaining a so-far under-appreciated role of TIMP-1-mediated signaling on immune cells. This, at least partly, resolved why elevated blood levels of TIMP-1 correlate with progression of numerous inflammatory diseases. Here, we emphasize the necessity of unbiased name-independent recognition of structure-function relationships to properly appreciate the biological potential of TIMP-1 and other cytokines in complex physiological processes such as inflammation.
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Lubis B, Lelo A, Amelia P, Prima A. The Effect of Thiamine, Ascorbic Acid, and the Combination of Them on the Levels of Matrix Metalloproteinase-9 (MMP-9) and Tissue Inhibitor of Matrix Metalloproteinase-1 (TIMP-1) in Sepsis Patients. Infect Drug Resist 2022; 15:5741-5751. [PMID: 36204393 PMCID: PMC9531617 DOI: 10.2147/idr.s378523] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 09/16/2022] [Indexed: 11/23/2022] Open
Abstract
Background Methods Results Conclusion
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Affiliation(s)
- Bastian Lubis
- Department of Anesthesiology and Intensive Care, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Aznan Lelo
- Department of Pharmacology and Therapeutics, Universitas Sumatera Utara, Medan, Indonesia
| | - Putri Amelia
- Department of Pediatric, Universitas Sumatera Utara, Medan, Indonesia
- Correspondence: Putri Amelia, Department of Pediatric, Hospital of Haji Adam Malik, Jl. Bunga Lau No. 17, Kemenangan Tani, Kec. Medan Tuntungan, Medan, Sumatera Utara, 20136, Indonesia, Tel +061 8360143, Email
| | - Agus Prima
- Department of Anesthesiology and Intensive Care, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
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de Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, Devel L, Dufour A. Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology. Pharmacol Rev 2022; 74:712-768. [PMID: 35738680 DOI: 10.1124/pharmrev.121.000349] [Citation(s) in RCA: 201] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.
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Affiliation(s)
- Luiz G N de Almeida
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Hayley Thode
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Yekta Eslambolchi
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Sameeksha Chopra
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Daniel Young
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Sean Gill
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Laurent Devel
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Antoine Dufour
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
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Lubis B, Amelia P, Viandy V. Correlation of Matrix Metalloproteinase-9 and Tissue Inhibitor Matrix Metalloproteinase-1 on Lactate Concentration in Sepsis patients Admitted to Intensive Care Unit. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.8700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Lactate level has been used not only as a biomarker for diagnosis and guiding treatment of sepsis but also as predictor of poor clinical outcomes. Elevated lactate does not specifically reflect cellular damage and this condition can be seen in other metabolic disorders. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) are two new promising biomarkers that have been reported to elevate significantly in sepsis. These two biomarkers can reflect physiological changes in tissue and cellular levels.
AIM: This study aims to identify the correlation of MMP-9, TIMP-1, and MMP-9/TIMP-1 on lactate levels in sepsis patients.
METHODS: This was a cross-sectional study conducted in two hospitals, Adam Malik General Hospital, Medan, and Grand Medistra Hospital, Deli Serdang, between April 2020 and May 2021. The inclusion criteria in this study were adult sepsis patients who were admitted to ICU, with Sequential Organ Failure Assessment (SOFA) or quick SOFA score ≥ 2. We recorded the characteristics, MMP-9, TIMP-1, and lactate concentration before given any intervention. The data were then analyzed to find the correlation.
RESULTS: Sixty-four patients were included in this study which consisted of almost equal men and women. The mean age of the subjects was 52.16 ± 16.25 years old. There was no correlation between MMP-9 and TIMP-1 toward lactate concentration (p = 0.466 and p = 0.65, respectively).
CONCLUSION: Our study showed no correlation between MMP-9 and TIMP-1 toward lactate concentration.
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Chiscano-Camón L, Plata-Menchaca E, Ruiz-Rodríguez JC, Ferrer R. Fisiopatología del shock séptico. Med Intensiva 2022. [DOI: 10.1016/j.medin.2022.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Chiscano-Camón L, Plata-Menchaca E, Ruiz-Rodríguez JC, Ferrer R. [Pathophysiology of septic shock]. Med Intensiva 2022; 46 Suppl 1:1-13. [PMID: 38341256 DOI: 10.1016/j.medine.2022.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/20/2022] [Indexed: 02/12/2024]
Abstract
Sepsis and septic shock result from an inadequate host response to an infection, which causes organ dysfunction. The progression of this condition is manifested by the occurrence of successive clinical stages, resulting from the systemic inflammatory response secondary to the activation of different inflammatory mediators, leading to organ dysfunction. There is a high burden of evidence on the role of endotoxin in the pathogenesis of sepsis and its crucial role in triggering the inflammatory response in sepsis caused by gram-negative bacteria. The coagulation cascade activation in sepsis patients is part of the host's adaptive immune response to infection. The endothelium is the main target in sepsis, which is metabolically active and can.
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Affiliation(s)
- Luis Chiscano-Camón
- Servicio de Medicina Intensiva, Hospital Universitario Vall d'Hebron, Barcelona, España; Grupo de Investigación Sepsis Organ Dysfunction and Resuscitation (SODIR), Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, España; Departament de Medicina. Universitat Autònoma de Barcelona. Barcelona. España
| | - Erika Plata-Menchaca
- Servicio de Medicina Intensiva, Hospital Universitario Vall d'Hebron, Barcelona, España; Grupo de Investigación Sepsis Organ Dysfunction and Resuscitation (SODIR), Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, España
| | - Juan Carlos Ruiz-Rodríguez
- Servicio de Medicina Intensiva, Hospital Universitario Vall d'Hebron, Barcelona, España; Grupo de Investigación Sepsis Organ Dysfunction and Resuscitation (SODIR), Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, España; Departament de Medicina. Universitat Autònoma de Barcelona. Barcelona. España
| | - Ricard Ferrer
- Servicio de Medicina Intensiva, Hospital Universitario Vall d'Hebron, Barcelona, España; Grupo de Investigación Sepsis Organ Dysfunction and Resuscitation (SODIR), Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, España; Departament de Medicina. Universitat Autònoma de Barcelona. Barcelona. España.
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Jones TK, Reilly JP, Anderson BJ, Miano TA, Dunn TG, Weisman AR, Agyekum R, Feng R, Ittner CA, Shashaty MG, Meyer NJ. Elevated Plasma Levels of Matrix Metalloproteinase-3 and Tissue-Inhibitor of Matrix Metalloproteinases-1 Associate With Organ Dysfunction and Mortality in Sepsis. Shock 2022; 57:41-47. [PMID: 34265829 PMCID: PMC8663538 DOI: 10.1097/shk.0000000000001833] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 06/23/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Matrix Metalloproteinases (MMP) respond to tissue damage during sepsis. Higher plasma concentrations of MMPs and the tissue-inhibitor of matrix metalloproteinases (TIMP) have been reported in sepsis compared with healthy controls. The objective of this study was to examine if plasma levels of MMP-3, MMP-9, and TIMP-1 associate with mortality and organ dysfunction during sepsis. METHODS We conducted a prospective cohort study of critically ill patients with sepsis adjudicated per Sepsis-3 criteria at a tertiary academic medical center. We measured plasma concentrations of MMP-3, MMP-9, and TIMP-1 on intensive care unit admission. We phenotyped the subjects for shock, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and mortality at 30 days. We used logistic regression to test the associations between the MMPs and TIMP-1 with shock, ARDS, AKI, and mortality. RESULTS Higher plasma TIMP-1 levels were associated with shock (odds ratio [OR] 1.51 per log increase [95% CI 1.25, 1.83]), ARDS (OR 1.24 [95% CI 1.05, 1.46]), AKI (OR 1.18 [95% CI 1.01, 1.38]), and mortality (OR 1.20 [95% CI 1.05, 1.46]. Higher plasma MMP-3 concentrations were associated with shock (OR 1.40 [95% CI 1.12, 1.75]) and mortality (OR 1.24 [95% CI 1.03, 1.48]) whereas MMP-9 levels were not associated with outcomes. Higher plasma TIMP-1 to MMP-3 ratios were associated with shock (OR 1.41 [95% CI 1.15, 1.72], P = 0.02). CONCLUSION Elevated plasma concentrations of TIMP-1 associate with organ dysfunction and mortality in sepsis. Higher plasma levels of MMP-3 associate with shock and mortality. Plasma MMP and TIMP-1 may warrant further investigation as emerging sepsis theragnostic biomarkers.
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Affiliation(s)
- Tiffanie K. Jones
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - John P. Reilly
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Brian J. Anderson
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Todd A. Miano
- Division of Epidemiology, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Thomas G. Dunn
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ariel R. Weisman
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Roseline Agyekum
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Rui Feng
- Division of Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Caroline A.G. Ittner
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael G.S. Shashaty
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Nuala J. Meyer
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Genetic variants of tissue inhibitors of matrix metalloproteinase 1 (rs4898) and 2 (rs8179090) in diverticulosis. Eur J Gastroenterol Hepatol 2021; 33:e431-e434. [PMID: 33731593 DOI: 10.1097/meg.0000000000002122] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
INTRODUCTION Diverticulosis affects approximately 60% of population after 60th year of age. Diverticular disease is symptomatic diverticulosis characterized by abdominal pain, flatulence and bloating, and bowel habits change. Age and lifestyle are risk factors for diverticulosis, additionally genetic predisposition is postulated. The aim of the study was to assess whether tissue inhibitors of matrix metalloproteinase (TIMP) 1 rs4898 and TIMP2 rs8179090 genetic variants are related to colonic diverticulosis. METHODS The study included 220 patients, 100 with colon diverticulosis diagnosed on colonoscopy and 120 controls. TIMP1 rs4898 and TIMP2 rs8179090 variants were examined using PCR-restriction fragments length polymorphism from a blood sample. RESULTS Allele T of TIMP1 rs4898 was more frequent in male patients with diverticulosis than in controls (P < 0.01), whereas in women there were no differences in its distribution, both in heterozygotes and homozygotes or in homozygotes separately, proving a recessive effect. TIMP2 s8179090 allele G frequency was 0.95 in cases and controls, there were no CC homozygotes identified, and no associations with diverticulosis showed. CONCLUSION TIMP1 rs4898 allele T may be a genetic determinant of the risk of diverticulosis in men.
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Schoeps B, Eckfeld C, Flüter L, Keppler S, Mishra R, Knolle P, Bayerl F, Böttcher J, Hermann CD, Häußler D, Krüger A. Identification of invariant chain CD74 as a functional receptor of tissue inhibitor of metalloproteinases-1 (TIMP-1). J Biol Chem 2021; 297:101072. [PMID: 34391782 PMCID: PMC8429975 DOI: 10.1016/j.jbc.2021.101072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/04/2021] [Accepted: 08/10/2021] [Indexed: 11/29/2022] Open
Abstract
Multifunctionality of tissue inhibitor of metalloproteinases-1 (TIMP-1) comprising antiproteolytic as well as cytokinic activity has been attributed to its N-terminal and C-terminal domains, respectively. The molecular basis of the emerging proinflammatory cytokinic activity of TIMP-1 is still not completely understood. The cytokine receptor invariant chain (CD74) is involved in many inflammation-associated diseases and is highly expressed by immune cells. CD74 triggers zeta chain–associated protein kinase-70 (ZAP-70) signaling–associated activation upon interaction with its only known ligand, the macrophage migration inhibitory factor. Here, we demonstrate TIMP-1–CD74 interaction by coimmunoprecipitation and confocal microscopy in cells engineered to overexpress CD74. In silico docking in HADDOCK predicted regions of the N-terminal domain of TIMP-1 (N-TIMP-1) to interact with CD74. This was experimentally confirmed by confocal microscopy demonstrating that recombinant N-TIMP-1 lacking the entire C-terminal domain was sufficient to bind CD74. Interaction of TIMP-1 with endogenously expressed CD74 was demonstrated in the Namalwa B lymphoma cell line by dot blot binding assays as well as confocal microscopy. Functionally, we demonstrated that TIMP-1–CD74 interaction triggered intracellular ZAP-70 activation. N-TIMP-1 was sufficient to induce ZAP-70 activation and interference with the cytokine-binding site of CD74 using a synthetic peptide–abrogated TIMP-1-mediated ZAP-70 activation. Altogether, we here identified CD74 as a receptor and mediator of cytokinic TIMP-1 activity and revealed TIMP-1 as moonlighting protein harboring both cytokinic and antiproteolytic activity within its N-terminal domain. Recognition of this functional TIMP-1–CD74 interaction may shed new light on clinical attempts to therapeutically target ligand-induced CD74 activity in cancer and other inflammatory diseases.
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Affiliation(s)
- Benjamin Schoeps
- School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Celina Eckfeld
- School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Laura Flüter
- School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Selina Keppler
- School of Medicine, Institute of Clinical Chemistry and Pathobiochemistry, Technical University of Munich, Munich, Germany; TranslaTUM, Center for Translational Cancer Research, Technical University Munich, Munich, Germany
| | - Ritu Mishra
- School of Medicine, Institute of Clinical Chemistry and Pathobiochemistry, Technical University of Munich, Munich, Germany; TranslaTUM, Center for Translational Cancer Research, Technical University Munich, Munich, Germany
| | - Percy Knolle
- School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Felix Bayerl
- School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Jan Böttcher
- School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Chris D Hermann
- School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Daniel Häußler
- School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Achim Krüger
- School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany.
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Matrix metalloproteinase MMP-8, TIMP-1 and MMP-8/TIMP-1 ratio in plasma in methicillin-sensitive Staphylococcus aureus bacteremia. PLoS One 2021; 16:e0252046. [PMID: 34043679 PMCID: PMC8158883 DOI: 10.1371/journal.pone.0252046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 05/10/2021] [Indexed: 12/21/2022] Open
Abstract
Background Matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have been shown to predict prognosis in sepsis. However, MMP-8 and TIMP-1 in Staphylococcus aureus bacteremia (SAB) lacks evaluation and their role in the pathogenesis of SAB is unclear. Methods MMP-8 and TIMP-1 and MMP-8/TIMP-1 molar ratio were determined at days 3, 5 and 28 from positive blood cultures in patients with methicillin-sensitive SAB and the connection to disease severity and early mortality was determined. Results Altogether 395 SAB patients were included. Patients with severe sepsis or infection focus presented higher MMP-8 levels at day 3 and 5 (p<0.01). Higher day 3 and 5 MMP-8 levels were associated to mortality at day 14 and 28 (p<0.01) and day 90 (p<0.05). Day 3 MMP-8 cut-off value of 203 ng/ml predicted death within 14 days with an area under the curve (AUC) of 0.70 (95% CI 0.57–0.82) (p<0.01). Day 5 MMP-8 cut-off value of 239 ng/ml predicted death within 14 days with an AUC of 0.76 (95% CI 0.65–0.87) (p<0.001). The results for MMP-8/TIMP-1 resembled that of MMP-8. TIMP-1 had no prognostic impact. In Cox regression analysis day 3 or 5 MMP-8 or day 3 MMP-8/TIMP-1 had no prognostic impact whereas day 5 MMP-8/TIMP-1 predicted mortality within 14 days (HR, 4.71; CI, 95% 1.67–13.3; p<0.01). Conclusion MMP-8 and MMP-8/TIMP-1 ratio were high 3–5 days after MS-SAB diagnosis in patients with an infection focus, severe sepsis or mortality within 14 days suggesting that matrix metalloproteinase activation might play a role in severe SAB.
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Schoeps B, Eckfeld C, Prokopchuk O, Böttcher J, Häußler D, Steiger K, Demir IE, Knolle P, Soehnlein O, Jenne DE, Hermann CD, Krüger A. TIMP1 Triggers Neutrophil Extracellular Trap Formation in Pancreatic Cancer. Cancer Res 2021; 81:3568-3579. [PMID: 33941611 DOI: 10.1158/0008-5472.can-20-4125] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 03/29/2021] [Accepted: 04/29/2021] [Indexed: 11/16/2022]
Abstract
Tumor-derived protein tissue inhibitor of metalloproteinases-1 (TIMP1) correlates with poor prognosis in many cancers, including highly lethal pancreatic ductal adenocarcinoma (PDAC). The noncanonical signaling activity of TIMP1 is emerging as one basis for its contribution to cancer progression. However, TIMP1-triggered progression-related biological processes are largely unknown. Formation of neutrophil extracellular traps (NET) in the tumor microenvironment is known to drive progression of PDAC, but factors or molecular mechanisms initiating NET formation in PDAC remain elusive. In this study, gene-set enrichment analysis of a human PDAC proteome dataset revealed that TIMP1 protein expression most prominently correlates with neutrophil activation in patient-derived tumor tissues. TIMP1 directly triggered formation of NETs in primary human neutrophils, which was dependent on the interaction of TIMP1 with its receptor CD63 and subsequent ERK signaling. In genetically engineered PDAC-bearing mice, TIMP1 significantly contributed to NET formation in tumors, and abrogation of TIMP1 or NETs prolonged survival. In patient-derived PDAC tumors, NETs predominantly colocalized with areas of elevated TIMP1 expression. Furthermore, TIMP1 plasma levels correlated with DNA-bound myeloperoxidase, a NET marker, in the blood of patients with PDAC. A combination of plasma levels of TIMP1 and NETs with the clinically established marker CA19-9 allowed improved identification of prognostically distinct PDAC patient subgroups. These observations may have a broader impact, because elevated systemic levels of TIMP1 are associated with the progression of a wide range of neutrophil-involved inflammatory diseases. SIGNIFICANCE: These findings highlight the prognostic relevance of TIMP1 and neutrophil extracellular traps in highly lethal pancreatic cancer, where a noncanonical TIMP1/CD63/ERK signaling axis induces NET formation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/13/3568/F1.large.jpg.
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Affiliation(s)
- Benjamin Schoeps
- Technical University of Munich, School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Munich, Germany
| | - Celina Eckfeld
- Technical University of Munich, School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Munich, Germany
| | - Olga Prokopchuk
- Technical University of Munich, School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Munich, Germany
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Jan Böttcher
- Technical University of Munich, School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Munich, Germany
| | - Daniel Häußler
- Technical University of Munich, School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technical University of Munich, Munich, Germany and German Cancer Consortium, Munich, Germany
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Percy Knolle
- Technical University of Munich, School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Munich, Germany
| | - Oliver Soehnlein
- Institute for Experimental Pathology (ExPat), Center for Molecular Biology of Inflammation, WWU Münster, Münster, Germany
- Department of Physiology and Pharmacology (FyFa), Karolinska Institutet, Stockholm, Sweden
- Institute for Cardiovascular Prevention (IPEK), LMU Munich Hospital, Munich, Germany
| | - Dieter E Jenne
- Institute of Lung Biology and Disease (ILBD), Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, Munich, Germany
- Max Planck Institute of Neurobiology, Planegg-Martinsried, Germany
| | - Chris D Hermann
- Technical University of Munich, School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Munich, Germany
| | - Achim Krüger
- Technical University of Munich, School of Medicine, Institutes of Molecular Immunology and Experimental Oncology, Munich, Germany.
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22
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Li C, Wang P, Li M, Zheng R, Chen S, Liu S, Feng Z, Yao Y, Shang H. The current evidence for the treatment of sepsis with Xuebijing injection: Bioactive constituents, findings of clinical studies and potential mechanisms. JOURNAL OF ETHNOPHARMACOLOGY 2021; 265:113301. [PMID: 32860891 DOI: 10.1016/j.jep.2020.113301] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 11/16/2019] [Accepted: 08/08/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Xuebijing (XBJ) injection is a Chinese medicine containing extracts from Carthamus tinctorius L. (Carthami Flos, hong hua, Asteraceae), Paeonia lactiflora Pall. (Paeoniae radix rubra, chi shao, Ranunculaceae), Ligusticum chuanxiong Hort. (Chuanxiong Rhizoma, chuan xiong, Umbelliferae), Salvia miltiorrhiza Bge. (Salviae miltiorrhizae Radix Et Rhizoma, dan shen, Labiatae) and Angelica sinensis (Oliv.) Diels (Angelicae sinensis Radix, dang gui, Umbelliferae). It has been approved for the treatment of sepsis in China since 2004 and has been widely used as an add-on treatment for sepsis or septic shock with few side effects. AIM OF THE STUDY The aim of the present review was to analyse up-to-date information related to the treatment of sepsis with XBJ, including the bioactive constituents, clinical studies and potential mechanisms, and to discuss possible scientific gaps, to provide a reliable reference for future studies. MATERIALS AND METHODS Scientific resources concentrating on treating sepsis with XBJ were searched through PubMed, the Chinese National Knowledge Infrastructure (CNKI) and WanFang databases from inception to November 2018. Dissertations were also searched, and eligible dissertations were selected. Studies related to the identification of constituents, bioactive components and their targets of action or pathways, clinical trials, and animal or cellular experiments that explored pharmacological mechanisms were manually selected. The quality of reporting and methodology of the included pharmacological experiments were assessed using the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines and the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE)'s risk of bias tool. RESULTS A total of 108 relative studies were eventually included, containing 12 bioactivity research studies, 10 systematic reviews on clinical trials and 86 animal or cellular experiments. We noted that as identification methods progressed, further constituents could be detected in XBJ. XBJ was also found to have "multi-ingredient, multi-target and multi-pathway" effects. The systematic review revealed that XBJ could improve the 28-day mortality and other indexes, such as the APACHE II score, body temperature, and white blood cell (WBC) count, to some extent. A major organ protection effect was demonstrated in septic rats. Pharmacological investigations suggested that XBJ acts in both the early and late stages of sepsis by anti-inflammatory, anti-coagulation, immune regulation, vascular endothelial protection, anti-oxidative stress and other mechanisms. However, most of the included studies were poorly reported, and the risk of bias was unclear. CONCLUSIONS With respect to the multiple therapeutic mechanisms contributing to both the early and late stages of sepsis, the multiple effective constituents detected and randomized controlled trials (RCTs) performed to prove its efficacy, XBJ is a promising therapy for the treatment of sepsis. However, although XBJ has shown some efficacy for the treatment of sepsis, there are currently some scientific gaps. More studies concerning the pharmacokinetics, interactions with antibiotics, real-world efficacy and safety, pharmacological mechanisms of the bioactive components and large-scale clinical trials should be conducted in the future.
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Affiliation(s)
- Chengyu Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing, 100700, China.
| | - Ping Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Sunny South Street, Fangshan District, Beijing, 102488, China.
| | - Min Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing, 100700, China.
| | - Rui Zheng
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing, 100700, China.
| | - Shiqi Chen
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing, 100700, China.
| | - Si Liu
- Tianjin Chase Sun Pharmaceutical Co. LTD, 20 Quanfa Road, Tianjin Wuqing Development Area, Tianjin, 300170, China.
| | - Zhiqiao Feng
- Tianjin Chase Sun Pharmaceutical Co. LTD, 20 Quanfa Road, Tianjin Wuqing Development Area, Tianjin, 300170, China.
| | - Yongming Yao
- First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, 51 Bucheng Road, Haidian District, Beijing, 100048, China.
| | - Hongcai Shang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing, 100700, China.
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23
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Barton AK, Richter IG, Ahrens T, Merle R, Alalwani A, Lilge S, Purschke K, Barnewitz D, Gehlen H. MMP-9 Concentration in Peritoneal Fluid Is a Valuable Biomarker Associated with Endotoxemia in Equine Colic. Mediators Inflamm 2021; 2021:9501478. [PMID: 33488296 PMCID: PMC7803393 DOI: 10.1155/2021/9501478] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 12/03/2020] [Accepted: 12/28/2020] [Indexed: 11/21/2022] Open
Abstract
The purpose of the study was to compare the results of sepsis scoring (clinical examination and clinical pathology) to the concentrations of matrix-metalloproteinases (MMPs) -2, -8, and -9; tissue-inhibitor of metalloproteinases (TIMPs) -1 and -2; and inflammatory chemokines interleukin (IL) 1β and tumor-necrosis-factor-alpha (TNF-α) in plasma and peritoneal fluid of equine colic patients. A modified sepsis scoring including general condition, heart and respiratory rate, rectal temperature, mucous membranes, white blood cell count (WBC), and ionized calcium was applied in 47 horses presented with clinical signs of colic. Using this scoring system, horses were classified as negative (n = 32, ≤6/19 points), questionable (n = 9, 7-9/19 points), or positive (n = 6, ≥10/19 points) for sepsis. MMPs, TIMPs, IL-1β, and TNF-α concentrations were evaluated in plasma and peritoneal fluid using species-specific sandwich ELISA kits. In a linear discriminant analysis, all parameters of sepsis scoring apart from calcium separated well between sepsis severity groups (P < 0.05). MMP-9 was the only biomarker of high diagnostic value, while all others remained insignificant. A significant influence of overall sepsis scoring on MMP-9 was found for peritoneal fluid (P = 0.005) with a regression coefficient of 0.092, while no association was found for plasma (P = 0.085). Using a MMP-9 concentration of >113 ng/ml in the peritoneal fluid was found to be the ideal cutoff to identify positive sepsis scoring (≥10/19 points; sensitivity of 83.3% and specificity of 82.9%). In conclusion, MMP-9 was found to be a biomarker of high diagnostic value for sepsis and endotoxemia in equine colic. The evaluation of peritoneal fluid seems preferable in comparison to plasma. As abdominocentesis is commonly performed in the diagnostic work-up of equine colic, a pen-side assay would be useful and easy-to-perform diagnostic support in the decision for therapeutic intervention.
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Affiliation(s)
| | - Ina-Gabriele Richter
- Research Centre of Medical Technology and Biotechnology, Bad Langensalza, Germany
| | - Tanja Ahrens
- Equine Clinic, Freie Universitaet Berlin, Berlin, Germany
| | - Roswitha Merle
- Institute for Veterinary Epidemiology, Freie Universitaet Berlin, Berlin, Germany
| | | | - Svenja Lilge
- Equine Clinic, Freie Universitaet Berlin, Berlin, Germany
| | | | - Dirk Barnewitz
- Research Centre of Medical Technology and Biotechnology, Bad Langensalza, Germany
| | - Heidrun Gehlen
- Equine Clinic, Freie Universitaet Berlin, Berlin, Germany
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24
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Fischer T, Riedl R. Challenges with matrix metalloproteinase inhibition and future drug discovery avenues. Expert Opin Drug Discov 2020; 16:75-88. [PMID: 32921161 DOI: 10.1080/17460441.2020.1819235] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Matrix metalloproteinases have been in the scope of pharmaceutical drug discovery for decades as promising targets for drug development. Until present, no modulator of the enzyme class survived clinical trials, all failing for various reasons. Nevertheless, the target family did not lose its attractiveness and there is ever more evidence that MMP modulators are likely to overcome the hurdles and result in successful clinical therapies. AREAS COVERED This review provides an overview of past efforts that were taken in the development of MMP inhibitors and insight into promising strategies that might enable drug discovery in the field in the future. Small molecule inhibitors as well as biomolecules are reviewed. EXPERT OPINION Despite the lack of successful clinical trials in the past, there is ongoing research in the field of MMP modulation, proving the target class has not lost its appeal to pharmaceutical research. With ever-growing insights from different scientific fields that shed light on previously unknown correlations, it is now time to use synergies deriving from biological knowledge, chemical structure generation, and clinical application to reach the ultimate goal of bringing MMP derived drugs on a broad front for the benefit of patients into therapeutic use.
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Affiliation(s)
- Thomas Fischer
- Center of Organic and Medicinal Chemistry, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences ZHAW , 8820 Wädenswil, Switzerland
| | - Rainer Riedl
- Center of Organic and Medicinal Chemistry, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences ZHAW , 8820 Wädenswil, Switzerland
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25
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Duda I, Krzych Ł, Jędrzejowska-Szypułka H, Lewin-Kowalik J. Plasma Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 as Prognostic Biomarkers in Critically Ill Patients. Open Med (Wars) 2020; 15:50-56. [PMID: 32190734 PMCID: PMC7065420 DOI: 10.1515/med-2020-0008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 11/14/2019] [Indexed: 11/15/2022] Open
Abstract
Matrix metalloproteinase 9 (MMP-9) plays an important role in inflammatory and pathological processes by enabling the inflow of leukocytes to the site of infection or tissue damage. MMP-9 and tissue inhibitor of metalloproteinase 1 (TIMP-1) have been described as potential prognostic biomarkers in various clinical settings. The aim of the study was to evaluate the usefulness of plasma levels of MMP-9 and TIMP-1 as well as the MMP-9/ TIMP-1 ratio in predicting the outcome in patients admitted to the intensive care unit (ICU). The study included 56 critically ill patients with multiple organ failure. Plasma levels of MMP-9 and TIMP-1 were determined on hospitalization day 1, 2, 3 and 7. Nineteen (35.7%) patients died. The level of TIMP-1 was statistically significantly higher on day 1 and 7 of hospitalization in non-survivors, as compared to survivors (p=0.01). A statistically significant positive correlation was found between MMP-9 and TIMP-1. The MMP-9/TIMP-1 ratio was comparable in both groups during of observation (0.62 on day 1). The MMP-9/TIMP-1 ratio was positively correlated with the level of lactate and negatively correlated with platelet count. Likewise, TIMP-1 was positively correlated with the level of lactate. The level of MMP-9 was higher in the non-survivor group only on day 7 of observation. In conclusion, although TIMP-1 and MMP-9 concentrations were higher in non-survivors and the MMP-9/TIMP-1 ratio was related to some parameters of critical illness, further research is needed to verify whether they can serve as reliable biomarkers for early prognostication of ICU patients.
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Affiliation(s)
- Izabela Duda
- Medical University of Silesia School of Medicine in Katowice, Katowice, Poland
| | - Łukasz Krzych
- Department of Anesthesiology and Intensive Care, Faculty of Medicine in Katowice, Medical University of Silesia in Katowice Katowice, Poland
| | - Halina Jędrzejowska-Szypułka
- Department of Physiology, Faculty of Medicine in Katowice, Medical University of Silesia in Katowice, Katowice Poland
| | - Joana Lewin-Kowalik
- Department of Physiology, Faculty of Medicine in Katowice, Medical University of Silesia in Katowice, Katowice Poland
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26
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Jordakieva G, Budge-Wolfram RM, Budinsky AC, Nikfardjam M, Delle-Karth G, Girard A, Godnic-Cvar J, Crevenna R, Heinz G. Plasma MMP-9 and TIMP-1 levels on ICU admission are associated with 30-day survival. Wien Klin Wochenschr 2020; 133:86-95. [PMID: 31932967 PMCID: PMC7875947 DOI: 10.1007/s00508-019-01592-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 12/03/2019] [Indexed: 01/06/2023]
Abstract
Background Matrix metalloproteinases (MMPs) are involved in systemic inflammatory responses and organ failure. The aim of this study was to evaluate early circulating plasma levels of MMP‑2, MMP‑9 and their inhibitors TIMP‑1 and TIMP‑2 and their prognostic significance in critically ill patients on admission to the intensive care unit (ICU). Methods In a single center prospective study 120 consecutive patients (72.5% male, mean age 66.8 ± 13.3 years, mean simplified acute physiology score [SAPS II] score 52.9 ± 21.9) were enrolled on transfer to the ICU of a cardiology department. The most common underlying conditions were cardiac diseases (n = 42.5%), respiratory failure (n = 10.8%) and sepsis (n = 6.7%). Blood samples were taken within 12 h of ICU admission. The MMP‑2, MMP‑9, TIMP‑1 and TIMP‑2 levels in plasma were evaluated in terms of 30-day survival, underlying condition and clinical score. Results On ICU admission 30-day survivors had significantly lower plasma MMP‑9 (odds ratio, OR 1.67 per 1 SD; 95% confidence interval, CI 1.10−2.53; p = 0.016) and TIMP‑1 (OR 2.15 per 1 SD; 95% CI 1.27−3.64; p = 0.004) levels than non-survivors; furthermore, MMP‑9 and TIMP‑1 correlated well with SAPS II (both p < 0.01). In patients with underlying cardiac diseases, MMP‑9 (p = 0.002) and TIMP‑1 (p = 0.01) were independent predictors of survival (Cox regression). No significant correlation was found between MMP‑2 and TIMP‑2 levels, MMP/TIMP ratios and 30-day mortality. Conclusion The MMP‑9 and TIMP‑1 levels are significantly elevated in acute critical care settings with increased short-term mortality risk, especially in patients with underlying heart disease. These findings support the value of MMPs and TIMPs as prognostic markers and potential therapeutic targets in conditions leading to systemic inflammation and acute organ failure.
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Affiliation(s)
- Galateja Jordakieva
- Department of Physical Medicine, Rehabilitation and Occupational Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Roswitha M Budge-Wolfram
- Division of Angiology; Department of Internal Medicine II, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
- International Hospital Development & Hospital Management, Abu Dhabi, United Arab Emirates.
| | - Alexandra C Budinsky
- Department of Laboratory Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Mariam Nikfardjam
- Department of Cardiology and Intensive Care, Wilhelminen Hospital Vienna, Vienna, Austria
| | | | - Angelika Girard
- Department of Laboratory Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Jasminka Godnic-Cvar
- Department of Physical Medicine, Rehabilitation and Occupational Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Richard Crevenna
- Department of Physical Medicine, Rehabilitation and Occupational Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Gottfried Heinz
- Division of Cardiology/Intensive Care Unit 13H3; Department of Internal Medicine II Medical, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
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27
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Weber B, Lackner I, Haffner-Luntzer M, Palmer A, Pressmar J, Scharffetter-Kochanek K, Knöll B, Schrezenemeier H, Relja B, Kalbitz M. Modeling trauma in rats: similarities to humans and potential pitfalls to consider. J Transl Med 2019; 17:305. [PMID: 31488164 PMCID: PMC6728963 DOI: 10.1186/s12967-019-2052-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 08/29/2019] [Indexed: 12/27/2022] Open
Abstract
Trauma is the leading cause of mortality in humans below the age of 40. Patients injured by accidents frequently suffer severe multiple trauma, which is life-threatening and leads to death in many cases. In multiply injured patients, thoracic trauma constitutes the third most common cause of mortality after abdominal injury and head trauma. Furthermore, 40-50% of all trauma-related deaths within the first 48 h after hospital admission result from uncontrolled hemorrhage. Physical trauma and hemorrhage are frequently associated with complex pathophysiological and immunological responses. To develop a greater understanding of the mechanisms of single and/or multiple trauma, reliable and reproducible animal models, fulfilling the ethical 3 R's criteria (Replacement, Reduction and Refinement), established by Russell and Burch in 'The Principles of Human Experimental Technique' (published 1959), are required. These should reflect both the complex pathophysiological and the immunological alterations induced by trauma, with the objective to translate the findings to the human situation, providing new clinical treatment approaches for patients affected by severe trauma. Small animal models are the most frequently used in trauma research. Rattus norvegicus was the first mammalian species domesticated for scientific research, dating back to 1830. To date, there exist numerous well-established procedures to mimic different forms of injury patterns in rats, animals that are uncomplicated in handling and housing. Nevertheless, there are some physiological and genetic differences between humans and rats, which should be carefully considered when rats are chosen as a model organism. The aim of this review is to illustrate the advantages as well as the disadvantages of rat models, which should be considered in trauma research when selecting an appropriate in vivo model. Being the most common and important models in trauma research, this review focuses on hemorrhagic shock, blunt chest trauma, bone fracture, skin and soft-tissue trauma, burns, traumatic brain injury and polytrauma.
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Affiliation(s)
- Birte Weber
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Ina Lackner
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Melanie Haffner-Luntzer
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany
| | - Annette Palmer
- Institute of Clinical and Experimental Trauma-Immunology, University of Ulm, Ulm, Germany
| | - Jochen Pressmar
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | | | - Bernd Knöll
- Institute of Physiological Chemistry, University of Ulm, Ulm, Germany
| | - Hubert Schrezenemeier
- Institute of Transfusion Medicine, University of Ulm and Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg – Hessen and University Hospital Ulm, Ulm, Germany
| | - Borna Relja
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, Frankfurt, Germany
- Department of Radiology and Nuclear Medicine, Experimental Radiology, Otto-von-Guericke University, Magdeburg, Germany
| | - Miriam Kalbitz
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081 Ulm, Germany
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Fischer T, Riedl R. Inhibitory Antibodies Designed for Matrix Metalloproteinase Modulation. Molecules 2019; 24:molecules24122265. [PMID: 31216704 PMCID: PMC6631688 DOI: 10.3390/molecules24122265] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/13/2019] [Accepted: 06/14/2019] [Indexed: 01/20/2023] Open
Abstract
The family of matrix metalloproteinases (MMPs) consists of a set of biological targets that are involved in a multitude of severe pathogenic events such as different forms of cancers or arthritis. Modulation of the target class with small molecule drugs has not led to the anticipated success until present, as all clinical trials failed due to unacceptable side effects or a lack of therapeutic outcome. Monoclonal antibodies offer a tremendous therapeutic potential given their high target selectivity and good pharmacokinetic profiles. For the treatment of a variety of diseases there are already antibody therapies available and the number is increasing. Recently, several antibodies were developed for the selective inhibition of single MMPs that showed high potency and were therefore investigated in in vivo studies with promising results. In this review, we highlight the progress that has been achieved toward the design of inhibitory antibodies that successfully modulate MMP-9 and MMP-14.
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Affiliation(s)
- Thomas Fischer
- Institute of Chemistry and Biotechnology, Center of Organic and Medicinal Chemistry, Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland.
| | - Rainer Riedl
- Institute of Chemistry and Biotechnology, Center of Organic and Medicinal Chemistry, Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland.
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29
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Bermúdez-Mejía C, Torres-Cordón MF, Becerra-Bayona S, Páez CM, Vargas CI, Cárdenas ME, Serrano SE, Baquero I, Martínez-Vega R, Schulz R, Ilarraza R, Pazin Filho A, Torres-Dueñas D. Prognostic Value of MMP-9 -1562 C/T Gene Polymorphism in Patients With Sepsis. Biomark Insights 2019; 14:1177271919847951. [PMID: 31205414 PMCID: PMC6535903 DOI: 10.1177/1177271919847951] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 04/11/2019] [Indexed: 12/17/2022] Open
Abstract
Introduction: Matrix metalloproteinase-9 (MMP-9) plays an important role in the pathophysiology of sepsis. A single-nucleotide polymorphism (SNP) at position -1562 (C/T) in the MMP-9 gene has been associated with differential MMP-9 expression, being higher when the -1562 T allele is present. We evaluated the association of the SNP MMP9 -1562 C/T with severity and mortality in patients with sepsis to establish whether the prognosis of the disease is affected. Materials and Methods: A case-control study exploratory was carried out in a cohort of infected patients. 540 individuals were selected in total, 270 patients with sepsis and 270 controls (infected but non-septic), classified according to the 2016 consensus (Sepsis-3). The presence of the single-nucleotide polymorphism (SNP; allele T and/or allele C) was determined through analyses of restriction fragment length polymorphism and plasma levels of MMP-9 were determined through enzyme-linked immunosorbent assay immunoassay. Results: SNP MMP-9 -1562 has two known alleles (T and C), with predominance of the C over the T allele; in the group of patients with sepsis, T allele was found in 7.2% of cases, while C allele in the rest (92.8%); in comparison, in the group of infected but non-septic patients, frequencies were 9.4% for T allele and 90.6% for the C allele (P = .33). Also, the presence of the polymorphic T allele was not related to the levels of MMP-9 in patients with sepsis in comparison with infected but non-septic patients 780 (397-1375) ng/mL vs 646 (172-1249) ng/mL (P = .64). There was also no association between the SNP and sepsis mortality (P = .78). Conclusions: We concluded that there was no association between the SNP MMP9 -1562 C/T and sepsis or between the SNP MMP9 -1562 C/T and sepsis mortality in the Northeastern Colombian septic patient cohort. Further research is needed to clarify the correlation among sepsis, genetic factors with allele T and MMP-9 plasma concentration.
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Affiliation(s)
- César Bermúdez-Mejía
- Department of Medicine, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), Bucaramanga, Colombia.,Department of Sciences, Faculty of Health, Universidad Industrial de Santander (UIS), Bucaramanga, Colombia
| | - Melissa F Torres-Cordón
- Department of Medicine, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), Bucaramanga, Colombia
| | - Silvia Becerra-Bayona
- Department of Medicine, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), Bucaramanga, Colombia
| | - Carolina María Páez
- Department of Medicine, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), Bucaramanga, Colombia
| | - Clara Inés Vargas
- Department of Sciences, Faculty of Health, Universidad Industrial de Santander (UIS), Bucaramanga, Colombia
| | - María Eugenia Cárdenas
- Department of Medicine, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), Bucaramanga, Colombia
| | - Sergio Eduardo Serrano
- Department of Sciences, Faculty of Health, Universidad Industrial de Santander (UIS), Bucaramanga, Colombia
| | - Ingrid Baquero
- Division of Health Sciences, Medicine Program, Universidad del Norte, Barranquilla, Colombia
| | - Ruth Martínez-Vega
- Epidemiology department, Organización Latinoamericana para el Fomento de la investigación en Salud, Bucaramanga, Colombia
| | - Richard Schulz
- Departments of Pediatrics and Pharmacology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada
| | - Ramses Ilarraza
- Departments of Pediatrics and Pharmacology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada
| | - Antonio Pazin Filho
- Department of Pharmacology, Faculty of Medicine, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Diego Torres-Dueñas
- Department of Medicine, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), Bucaramanga, Colombia
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Fischer T, Senn N, Riedl R. Design and Structural Evolution of Matrix Metalloproteinase Inhibitors. Chemistry 2019; 25:7960-7980. [DOI: 10.1002/chem.201805361] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 01/09/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Thomas Fischer
- Center of Organic and Medicinal Chemistry, Institute of Chemistry, and BiotechnologyZurich University of Applied Sciences (ZHAW) Einsiedlerstrasse 31 8820 Wädenswil Switzerland
| | - Nicole Senn
- Center of Organic and Medicinal Chemistry, Institute of Chemistry, and BiotechnologyZurich University of Applied Sciences (ZHAW) Einsiedlerstrasse 31 8820 Wädenswil Switzerland
| | - Rainer Riedl
- Center of Organic and Medicinal Chemistry, Institute of Chemistry, and BiotechnologyZurich University of Applied Sciences (ZHAW) Einsiedlerstrasse 31 8820 Wädenswil Switzerland
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Lorente L. New prognostic biomarkers of mortality in patients undergoing liver transplantation for hepatocellular carcinoma. World J Gastroenterol 2018; 24:4230-4242. [PMID: 30310256 PMCID: PMC6175764 DOI: 10.3748/wjg.v24.i37.4230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/18/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
The outcome prediction of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) was classically established using various macromorphological factors and serum alpha-fetoprotein levels prior to LT. However, other biomarkers have recently been reported to be associated with the prognosis of HCC patients undergoing to LT. This review summarizes clinical data on these new biomarkers. High blood levels of malondialdehyde, total antioxidant capacity, caspase-cleaved cytokeratin-18, soluble CD40 ligand, substance P, C-reactive protein, and vascular endothelial growth factor, increased neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in blood, high peripheral blood expression of human telomerase reverse transcriptase messenger ribonucleic acid, and high HCC expression of dickkopf-1 have recently been associated with decreased survival rates. In addition, high blood levels of des-gamma-carboxy prothrombin, and high HCC expression of glypican-3, E-cadherin and beta-catenin have been associated with increased HCC recurrence. Additional research is necessary to establish the prognostic role of these biomarkers in HCC prior to LT. Furthermore, some of these biomarkers are also interesting because their potential modulation could help to create new research lines for improving the outcomes of those patients.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife 38320, Spain
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Han Y, Li X, Gao S, Liu X, Kang L, Li X, Lang Y, Li X, Sun M, Gai Z, Yu S. Interleukin 17 is an important pathogenicity gene in pediatric sepsis. J Cell Biochem 2018; 120:3664-3671. [PMID: 30216518 DOI: 10.1002/jcb.27644] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 08/14/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Yujie Han
- Neonatal Department Qilu Children's Hospital of Shandong University Jinan Shandong China
| | - Xiaoying Li
- Neonatal Department Qilu Children's Hospital of Shandong University Jinan Shandong China
| | - Shasha Gao
- Neonatal Department Children's Hospital of Soochow University Suzhou Jiangsu China
| | - Xianghong Liu
- Neonatal Department Qilu Children's Hospital of Shandong University Jinan Shandong China
| | - Lili Kang
- Neonatal Department Qilu Children's Hospital of Shandong University Jinan Shandong China
| | - Xiaomei Li
- Neonatal Department Qilu Children's Hospital of Shandong University Jinan Shandong China
| | - Yujie Lang
- Neonatal Department Qilu Children's Hospital of Shandong University Jinan Shandong China
| | - Xiao Li
- Neonatal Department Qilu Children's Hospital of Shandong University Jinan Shandong China
| | - Mingying Sun
- Neonatal Department Qilu Children's Hospital of Shandong University Jinan Shandong China
| | - Zhongtao Gai
- Pediatric Research Institute, Qilu Children's Hospital of Shandong University Jinan Shandong China
| | - Shenglin Yu
- Neonatal Department Children's Hospital of Soochow University Suzhou Jiangsu China
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Lorente L, Martín MM, Pérez-Cejas A, Abreu-González P, López RO, Ferreres J, Solé-Violán J, Labarta L, Díaz C, Palmero S, Jiménez A. Serum total antioxidant capacity during the first week of sepsis and mortality. J Crit Care 2018; 47:139-144. [PMID: 29981999 DOI: 10.1016/j.jcrc.2018.06.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/03/2018] [Accepted: 06/29/2018] [Indexed: 01/22/2023]
Abstract
PURPOSE Higher circulating total antioxidant capacity (TAC) concentrations have been found in non-survivor than in survivor septic patients at moment of sepsis diagnosis. The objectives of this study were to determine whether serum TAC levels during the first week of sepsis are associated with lipid peroxidation, sepsis severity, and sepsis mortality, and whether could be used as a prognostic biomarker. METHODS This prospective and observational study with 319 septic patients admitted to Intensive Care Units was carried out in 8 Spanish hospitals. We determined serum concentrations of malondialdehyde (to estimate lipid peroxidation) and TAC at days 1, 4 and 8 of sepsis. Mortality at 30 days was the end-point study. RESULTS We found that serum TAC concentrations at days 1, 4 and 8 could predict 30-day mortality according to ROC curve analyses (p < 0.001), that were associated with 30-day mortality according to regression analyses (p < 0.001), and that were associated with serum levels of malondialdehyde and SOFA score. CONCLUSIONS The new findings of our study were that serum TAC levels during the first week of sepsis are associated with lipid peroxidation, sepsis severity, and sepsis mortality, and that could be used as a prognostic biomarker.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna 38320, Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Crta Rosario s/n, Santa Cruz Tenerife 38010, Spain
| | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n, La Laguna 38320, Tenerife, Spain
| | - Pedro Abreu-González
- Department of Physiology, Faculty of Medicine, University of the La Laguna, Ofra, s/n, La Laguna 38320, Santa Cruz de Tenerife, Spain.
| | - Raquel Ortiz López
- Intensive Care Unit, Hospital General de La Palma, Buenavista de Arriba s/n, Breña Alta 38713, La Palma, Spain
| | - José Ferreres
- Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda, Blasco Ibáñez n°17-19, Valencia 46004, Spain
| | - Jordi Solé-Violán
- Intensive Care Unit, Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n, Las Palmas de Gran Canaria 35010, Spain.
| | - Lorenzo Labarta
- Intensive Care Unit, Hospital San Jorge de Huesca, Avenida Martínez de Velasco n°36, Huesca 22004, Spain.
| | - César Díaz
- Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, Las Palmas de Gran Canaria 35016, Spain
| | - Salomé Palmero
- Intensive Care Unit, Hospital Quirón Tenerife, Poeta Rodriguez Herrera n°1, Santa Cruz de Tenerife 38006, Spain
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna 38320, Tenerife, Spain
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Tipoe TL, Wu WKK, Chung L, Gong M, Dong M, Liu T, Roever L, Ho J, Wong MCS, Chan MTV, Tse G, Wu JCY, Wong SH. Plasminogen Activator Inhibitor 1 for Predicting Sepsis Severity and Mortality Outcomes: A Systematic Review and Meta-Analysis. Front Immunol 2018; 9:1218. [PMID: 29967603 PMCID: PMC6015919 DOI: 10.3389/fimmu.2018.01218] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/15/2018] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVES Plasminogen activator inhibitor-1 (PAI-1), a crucial regulator of fibrinolysis, is increased in sepsis, but its values in predicting disease severity or mortality outcomes have been controversial. Therefore, we conducted a systematic review and meta-analysis of its predictive values in sepsis. METHODS PubMed and Embase were searched until August 18, 2017 for studies that evaluated the relationships between PAI-1 levels and disease severity or mortality in sepsis. RESULTS A total of 112 and 251 entries were retrieved from the databases, of which 18 studies were included in the final meta-analysis. A total of 4,467 patients (36% male, mean age: 62 years, mean follow-up duration: 36 days) were analyzed. PAI-1 levels were significantly higher in non-survivors than survivors [odds ratios (OR): 3.93, 95% confidence interval (CI): 2.31-6.67, P < 0.0001] and in patients with severe sepsis than in those less severe sepsis (OR: 3.26, 95% CI: 1.37-7.75, P = 0.008). CONCLUSION PAI-1 is a significant predictor of disease severity and all-cause mortality in sepsis. Although the predictive values of PAI-1 reached statistical significance, the clinical utility of PAI-1 in predicting outcomes will require carefully designed prospective trials.
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Affiliation(s)
- Timothy L. Tipoe
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - William K. K. Wu
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Lilianna Chung
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Mengqi Gong
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Mei Dong
- Department of Clinical Research, Federal University of Uberlândia, Uberlândia, Brazil
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Leonardo Roever
- Department of Clinical Research, Federal University of Uberlândia, Uberlândia, Brazil
| | - Jeffery Ho
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Martin C. S. Wong
- JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Matthew T. V. Chan
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Gary Tse
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Justin C. Y. Wu
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Sunny H. Wong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 in Sepsis after Major Abdominal Surgery. DISEASE MARKERS 2018; 2018:5064684. [PMID: 29861795 PMCID: PMC5976929 DOI: 10.1155/2018/5064684] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 03/28/2018] [Indexed: 12/12/2022]
Abstract
Background The role of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in sepsis after major abdominal surgery and sepsis-associated organ dysfunction is unexplored. Materials and Methods Fifty-three patients with sepsis after major abdominal surgery were compared to 50 operated and 50 nonoperated controls. MMP-9, TIMP-1, biomarkers of inflammation, kidney and liver injury, coagulation, and metabolic disorders were measured daily during 96 h following diagnosis of sepsis and once in controls. MMP-9/TIMP-1 ratios and disease severity scores were calculated. Use of vasopressors/inotropes, mechanical ventilation, and survival were recorded. Results Septic patients had lower MMP-9 and MMP-9/TIMP-1 ratios but higher TIMP-1 levels compared to controls. AUC-ROC for diagnosis of sepsis was 0.940 and 0.854 for TIMP-1 and 0.924 and 0.788 for MMP-9/TIMP-1 ratio (sepsis versus nonoperated and sepsis versus operated controls, resp.). Lower MMP-9 and MMP-9/TIMP-1 ratio and higher TIMP-1 levels were associated with shorter survival. MMP-9, TIMP-1, and MMP-9/TIMP-1 ratio correlated with biomarkers of inflammation, kidney and liver injury, coagulation, metabolic disorders, and disease severity scores. Use of vasopressors/inotropes was associated with higher TIMP-1 levels. Conclusions MMP-9, TIMP-1, and MMP-9/TIMP ratio were good diagnostic or prognostic biomarkers of sepsis after major abdominal surgery and were linked to sepsis-associated organ dysfunction.
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Linder R, Rönmark E, Pourazar J, Behndig AF, Blomberg A, Lindberg A. Proteolytic biomarkers are related to prognosis in COPD- report from a population-based cohort. Respir Res 2018; 19:64. [PMID: 29650051 PMCID: PMC5897990 DOI: 10.1186/s12931-018-0772-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 04/04/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The imbalance between proteases and anti-proteases is considered to contribute to the development of COPD. Our aim was to evaluate the protease MMP-9, the antiprotease TIMP-1 and the MMP-9/TIMP-1-ratio as biomarkers in relation to prognosis. Prognosis was assessed as lung function decline and mortality. This was done among subjects with COPD in a population-based cohort. METHODS In 2005, clinical examinations including spirometry and peripheral blood sampling, were made in a longitudinal population-based cohort. In total, 1542 individuals participated, whereof 594 with COPD. In 2010, 1031 subjects participated in clinical examinations, and 952 subjects underwent spirometry in both 2005 and 2010. Serum MMP-9 and TIMP-1 concentrations were measured with enzyme linked immunosorbent assay (ELISA). Mortality data were collected from the Swedish national mortality register from the date of examination in 2005 until 31st December 2010. RESULTS The correlation between biomarkers and lung function decline was similar in non-COPD and COPD, but only significant for MMP-9 and MMP-9/TIMP-1-ratio in non-COPD. Mortality was higher in COPD than non-COPD (16% vs. 10%, p = 0.008). MMP-9 concentrations and MMP-9/TIMP-1 ratios in 2005 were higher among those who died during follow up, as well as among those alive but not participating in 2010, when compared to those participating in the 2010-examination. In non-COPD, male sex, age, burden of smoking, heart disease and MMP-9/TIMP-1 ratio were associated with increased risk for death, while increased TIMP-1 was protective. Among those with COPD, age, current smoking, increased MMP-9 and MMP-9/TIMP-1 ratio were associated with an increased risk for death. CONCLUSIONS The expected association between these biomarkers and lung function decline in COPD was not confirmed in this population-based study, probably due to a healthy survivor effect. Still, it is suggested that increased proteolytic imbalance may be of greater prognostic importance in COPD than in non-COPD.
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Affiliation(s)
- Robert Linder
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, SE-90187 Umeå, Sweden
| | - Eva Rönmark
- Department of Public Health and Clinical Medicine, the OLIN unit, Division of Occupational and Environmental Medicine, Umeå University, SE-90187 Umeå, Sweden
| | - Jamshid Pourazar
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, SE-90187 Umeå, Sweden
| | - Annelie F. Behndig
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, SE-90187 Umeå, Sweden
| | - Anders Blomberg
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, SE-90187 Umeå, Sweden
| | - Anne Lindberg
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, SE-90187 Umeå, Sweden
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Abstract
INTRODUCTION Lipopolysaccharide (LPS) is known to induce vascular derangements. The pathophysiology involved therein is unknown, but matrix metalloproteinases (MMPs) may be an important mediator. We hypothesized that in vitro LPS provokes vascular permeability, damages endothelial structural proteins, and increases MMP activity; that in vivo LPS increases permeability and fluid requirements; and that the MMP inhibitor doxycycline mitigates such changes. METHODS Rat lung microvascular endothelial cells were divided into four groups: control, LPS, LPS plus doxycycline, and doxycycline. Permeability, structural proteins β-catenin and Filamentous-actin, and MMP-9 activity were examined. Sprauge Dawley rats were divided into sham, IV LPS, and IV LPS plus IV doxycycline groups. Mesenteric postcapillary venules were observed. Blood pressure was measured as animals were resuscitated and fluid requirements were compared. Statistical analysis was conducted using Student's t-test and ANOVA. RESULTS In vitro LPS increased permeability, damaged adherens junctions, induced actin stress fiber formation, and increased MMP-9 enzyme activity. In vivo, IV LPS administration induced vascular permeability. During resuscitation, significantly more fluid was necessary to maintain normotension in the IV LPS group. Doxycycline mitigated all derangements observed. CONCLUSIONS We conclude that LPS increases permeability, damages structural proteins, and increases MMP-9 activity in endothelial cells. Additionally, endotoxemia induces hyperpermeability and increases the amount of IV fluid required to maintain normotension in vivo. Doxycycline mitigates such changes both in vitro and in vivo. Our findings illuminate the possible role of matrix metalloproteinases in the pathophysiology of lipopolysaccharide-induced microvascular hyperpermeability and pave the way for better understanding and treatment of this process.
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Zonneveld R, Jongman RM, Juliana A, Molema G, van Meurs M, Plötz FB. Serum concentrations of endothelial cell adhesion molecules and their shedding enzymes and early onset sepsis in newborns in Suriname. BMJ Paediatr Open 2018; 2:e000312. [PMID: 30397669 PMCID: PMC6203012 DOI: 10.1136/bmjpo-2018-000312] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/30/2018] [Accepted: 08/01/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Early onset sepsis (EOS) is defined as onset of sepsis within 72 hours after birth. Leucocyte-endothelial interactions play a pivotal part in EOS pathophysiology. Endothelial cell adhesion molecules (CAMs) orchestrate these interactions and their soluble isoforms (sCAMs) are released into the vasculature by enzymes called sheddases. PURPOSE This study was undertaken to explore further the pathophysiology of EOS and to investigate the potential of sCAM and their sheddases as potential biomarkers for EOS. METHODS Stored serum aliquots were used from 71 Surinamese newborns suspected of EOS and 20 healthy newborns from an earlier study. Serum had been collected within 72 hours after birth and six (8.6%) newborns had a positive blood culture with gram-negative pathogens. Concentrations of sCAMs sP-selectin, sE-selectin, soluble vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and platelet and endothelial cell adhesion molecule-1, sheddases matrix metalloproteinase-9 (MMP-9) and neutrophil elastase (NE) and sheddase antagonist tissue-inhibitor of metalloproteinases-1 (TIMP-1) were measured simultaneously with Luminex and ELISA. RESULTS MMP-9 and TIMP-1 levels were measured in serum of n=91 newborns and sCAMs and NE levels in serum of n=80 newborns, respectively. We found no differences in median concentrations of sCAMs, MMP-9 and TIMP-1 or NE between blood culture positive EOS, blood culture negative EOS and control groups at start of antibiotic treatment. CONCLUSIONS Our data indicate that serum concentrations of sCAMs and their sheddases have no clinical utility as biomarkers for EOS. TRIAL REGISTRATION NUMBER NCT02486783. Results.
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Affiliation(s)
- Rens Zonneveld
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Academic Pediatric Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname
| | - Rianne M Jongman
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Amadu Juliana
- Academic Pediatric Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname
| | - Grietje Molema
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Matijs van Meurs
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Frans B Plötz
- Department of Pediatrics, Tergooi Hospitals, Blaricum, The Netherlands
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Zaghloul N, Addorisio ME, Silverman HA, Patel HL, Valdés-Ferrer SI, Ayasolla KR, Lehner KR, Olofsson PS, Nasim M, Metz CN, Wang P, Ahmed M, Chavan SS, Diamond B, Tracey KJ, Pavlov VA. Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors. Front Immunol 2017; 8:1673. [PMID: 29326685 PMCID: PMC5736570 DOI: 10.3389/fimmu.2017.01673] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 11/14/2017] [Indexed: 12/31/2022] Open
Abstract
Sepsis, a complex disorder characterized by immune, metabolic, and neurological dysregulation, is the number one killer in the intensive care unit. Mortality remains alarmingly high even in among sepsis survivors discharged from the hospital. There is no clear strategy for managing this lethal chronic sepsis illness, which is associated with severe functional disabilities and cognitive deterioration. Providing insight into the underlying pathophysiology is desperately needed to direct new therapeutic approaches. Previous studies have shown that brain cholinergic signaling importantly regulates cognition and inflammation. Here, we studied the relationship between peripheral immunometabolic alterations and brain cholinergic and inflammatory states in mouse survivors of cecal ligation and puncture (CLP)-induced sepsis. Within 6 days, CLP resulted in 50% mortality vs. 100% survival in sham-operated controls. As compared to sham controls, sepsis survivors had significantly lower body weight, higher serum TNF, interleukin (IL)-1β, IL-6, CXCL1, IL-10, and HMGB1 levels, a lower TNF response to LPS challenge, and lower serum insulin, leptin, and plasminogen activator inhibitor-1 levels on day 14. In the basal forebrain of mouse sepsis survivors, the number of cholinergic [choline acetyltransferase (ChAT)-positive] neurons was significantly reduced. In the hippocampus and the cortex of mouse sepsis survivors, the activity of acetylcholinesterase (AChE), the enzyme that degrades acetylcholine, as well as the expression of its encoding gene were significantly increased. In addition, the expression of the gene encoding the M1 muscarinic acetylcholine receptor was decreased in the hippocampus. In parallel with these forebrain cholinergic alterations, microglial activation (in the cortex) and increased Il1b and Il6 gene expression (in the cortex), and Il1b gene expression (in the hippocampus) were observed in mouse sepsis survivors. Furthermore, microglial activation was linked to decreased cortical ChAT protein expression and increased AChE activity. These results reinforce the notion of persistent inflammation-immunosuppression and catabolic syndrome in sepsis survivors and characterize a previously unrecognized relationship between forebrain cholinergic dysfunction and neuroinflammation in sepsis survivors. This insight is of interest for new therapeutic approaches that focus on brain cholinergic signaling for patients with chronic sepsis illness, a problem with no specific treatment.
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Affiliation(s)
- Nahla Zaghloul
- Cohen Children's Medical Center, Northwell Health, New Hyde Park, NY, United States.,Neonatology Research Laboratory, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Meghan E Addorisio
- Center for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Harold A Silverman
- Center for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United States
| | - Hardik L Patel
- Neonatology Research Laboratory, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Sergio I Valdés-Ferrer
- Center for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States.,Laboratory of Neurobiology of Systemic Illness, Department of Neurology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.,Laboratory of Neurobiology of Systemic Illness, Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Kamesh R Ayasolla
- Neonatology Research Laboratory, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Kurt R Lehner
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United States
| | - Peder S Olofsson
- Center for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Mansoor Nasim
- Neuropathology-Anatomic Pathology, Northwell Health, New Hyde Park, NY, United States
| | - Christine N Metz
- Center for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United States
| | - Ping Wang
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United States.,Center for Immunology and Inflammation, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Mohamed Ahmed
- Cohen Children's Medical Center, Northwell Health, New Hyde Park, NY, United States.,Neonatology Research Laboratory, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Sangeeta S Chavan
- Center for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States.,Center for Bioelectronic Medicine, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Betty Diamond
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United States.,Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United States
| | - Kevin J Tracey
- Center for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United States.,Center for Bioelectronic Medicine, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Valentin A Pavlov
- Center for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United States.,Center for Bioelectronic Medicine, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
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Lorente L, Martín MM, Abreu-González P, Pérez-Cejas A, López RO, Ferreres J, Solé-Violán J, Labarta L, Díaz C, Llanos C, Jiménez A. Serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality. Enferm Infecc Microbiol Clin 2017; 36:544-549. [PMID: 29198774 DOI: 10.1016/j.eimc.2017.10.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 10/20/2017] [Accepted: 10/23/2017] [Indexed: 01/23/2023]
Abstract
OBJECTIVE Higher serum melatonin levels have previously been found in patients with severe sepsis who died within 30 days of diagnosis than in survivors. The objective of our study were to determine whether serum melatonin levels during the first seven days of severe sepsis diagnosis could be associated with sepsis severity and mortality. METHODS Multicentre study in eight Spanish Intensive Care Units which enrolled 308 patients with severe sepsis. We determined serum levels of melatonin, malondialdehyde (as biomarker of lipid peroxidation) and tumor necrosis factor-alpha at days 1, 4 and 8 of severe sepsis diagnosis. The study's primary endpoint was 30-day mortality. RESULTS A total of 103 patients had died and 205 survived at 30 days of severe sepsis diagnosis, with the non-survivors presenting higher serum melatonin levels at days 1 (p<0.001), 4 (p<0.001) and 8 (p<0.001) of severe sepsis diagnosis than the survivor patient group. The multiple logistic regression analysis found that serum melatonin levels at days 1, 4 and 8 of severe sepsis diagnosis (p<0.001, p=0.01 and p=0.001, respectively) were associated with mortality adjusted for age, serum lactic acid, SOFA score and diabetes mellitus. CONCLUSIONS The novel and more interesting findings of our study were that serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz Tenerife, Spain
| | - Pedro Abreu-González
- Deparment of Physiology, Faculty of Medicine, University of the La Laguna, Santa Cruz de Tenerife, Spain
| | | | | | - José Ferreres
- Intensive Care Unit, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Jordi Solé-Violán
- Intensive Care Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
| | - Lorenzo Labarta
- Intensive Care Unit, Hospital San Jorge de Huesca, Huesca, Spain
| | - César Díaz
- Intensive Care Unit, Hospital Insular, Las Palmas de Gran Canaria, Spain
| | - Celina Llanos
- Intensive Care Unit, Hospital Quirón Tenerife, Santa Cruz de Tenerife, Spain
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41
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Sustained high serum caspase-3 concentrations and mortality in septic patients. Eur J Clin Microbiol Infect Dis 2017; 37:281-288. [DOI: 10.1007/s10096-017-3129-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 10/26/2017] [Indexed: 10/18/2022]
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Serrano-Gomez S, Burgos-Angulo G, Niño-Vargas DC, Niño ME, Cárdenas ME, Chacón-Valenzuela E, McCosham DM, Peinado-Acevedo JS, Lopez MM, Cunha F, Pazin-Filho A, Ilarraza R, Schulz R, Torres-Dueñas D. Predictive Value of Matrix Metalloproteinases and Their Inhibitors for Mortality in Septic Patients: A Cohort Study. J Intensive Care Med 2017; 35:95-103. [DOI: 10.1177/0885066617732284] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Purpose: Over 170 biomarkers are being investigated regarding their prognostic and diagnostic accuracy in sepsis in order to find new tools to reduce morbidity and mortality. Matrix metalloproteinases (MMPs) and their inhibitors have been recently studied as promising new prognostic biomarkers in patients with sepsis. This study is aimed at determining the utility of several cutoff points of these biomarkers to predict mortality in patients with sepsis. Materials and Methods: A multicenter, prospective, analytic cohort study was performed in the metropolitan area of Bucaramanga, Colombia. A total of 289 patients with sepsis and septic shock were included. MMP-9, MMP-2, tissue inhibitor of metalloproteinase 1 (TIMP-1), TIMP-2, TIMP-1/MMP-9 ratio, and TIMP-2/MMP-2 ratio were determined in blood samples. Value ranges were correlated with mortality to estimate sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiving operating characteristic curve. Results: Sensitivity ranged from 33.3% (MMP-9/TIMP-1 ratio) to 60.6% (TIMP-1) and specificity varied from 38.8% (MMP-2/TIMP-2 ratio) to 58.5% (TIMP-1). As for predictive values, positive predictive value range was from 17.5% (MMP-9/TIMP-1 ratio) to 70.4% (MMP-2/TIMP-2 ratio), whereas negative predictive values were between 23.2% (MMP-2/TIMP-2 ratio) and 80.9% (TIMP-1). Finally, area under the curve scores ranged from 0.31 (MMP-9/TIMP-1 ratio) to 0.623 (TIMP-1). Conclusion: Although TIMP-1 showed higher sensitivity, specificity, and negative predictive value, with a representative population sample, we conclude that none of the evaluated biomarkers had significant predictive value for mortality.
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Affiliation(s)
- Sergio Serrano-Gomez
- Department of Public Health, Medicine Program, Hospital Universitario de Santander, Bucaramanga, Santander, Colombia
| | - Gabriel Burgos-Angulo
- Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | | | | | - María Eugenia Cárdenas
- Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | - Estephania Chacón-Valenzuela
- Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | - Diana Margarita McCosham
- Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | | | - M. Marcos Lopez
- Department of Biotechnology, Enterprise Technology Center, Fundación Cardiovascular de Colombia, Bucaramanga, Santander, Colombia
| | - Fernando Cunha
- Department of Pharmacology, Faculty of Medicine, Universidade de Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
| | - Antonio Pazin-Filho
- Department of Medical Clinics, Emergency Unit, Faculty of Medicine, Universidade de Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
| | - Ramses Ilarraza
- Departments of Pediatrics and Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Richard Schulz
- Departments of Pediatrics and Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Diego Torres-Dueñas
- Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
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Sustained Low Serum Substance P Levels in Non-Surviving Septic Patients. Int J Mol Sci 2017; 18:ijms18071531. [PMID: 28714876 PMCID: PMC5536019 DOI: 10.3390/ijms18071531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 07/12/2017] [Accepted: 07/13/2017] [Indexed: 12/14/2022] Open
Abstract
Previously, researchers found higher serum substance P (SP) concentrations in survivors of severe sepsis than in non-survivors at the time of severe sepsis diagnosis. The objectives of our current study were to determine whether there is an association between serum SP levels during the first week and sepsis mortality, sepsis severity, serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-10, and whether serum SP levels during the first week could be used as a biomarker of sepsis mortality. We determined serum concentration of SP, TNF-α, and IL-10 at days 1, 4, and 8. The end-point of the study was mortality at 30 days. We found that non-survivor (n = 104) compared to survivor patients (n = 206) showed lower serum SP levels at days 1, 4, and 8 (p < 0.001). Multiple logistic regression analyses showed an association between 30-day mortality and serum SP levels at days 1, 4, and 8 (p < 0.001) controlling for SOFA score, diabetes mellitus, age, and lactic acid levels. The most interesting findings of our study were that there is an association between serum SP levels during the first week and sepsis mortality, and that serum SP levels during the first week could be used as a biomarker of sepsis mortality.
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Jan JS, Chou YC, Cheng YW, Chen CK, Huang WJ, Hsiao G. The Novel HDAC8 Inhibitor WK2-16 Attenuates Lipopolysaccharide-Activated Matrix Metalloproteinase-9 Expression in Human Monocytic Cells and Improves Hypercytokinemia In Vivo. Int J Mol Sci 2017; 18:ijms18071394. [PMID: 28661460 PMCID: PMC5535887 DOI: 10.3390/ijms18071394] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 06/19/2017] [Accepted: 06/26/2017] [Indexed: 12/29/2022] Open
Abstract
Dysregulated human monocytes/macrophages can synthesize and secrete matrix metalloproteinases (MMPs), which play important roles in the progression of sepsis. In this study, we investigated the effects and mechanism of a novel histone deacetylase (HDAC8) inhibitor, (E)-N-hydroxy-4-methoxy-2-(biphenyl-4-yl)cinnamide (WK2-16), on MMP-9 production and activation in stimulated human monocytic THP-1 cells. Our results demonstrated that the acetylation level of structural maintenance of chromosomes 3 (SMC3) was up-regulated by WK2-16 in THP-1 cells. Consistently, an in vitro enzyme study demonstrated that WK2-16 selectively inhibited HDAC8 activity. Moreover, the WK2-16 concentration dependently suppressed MMP-9-mediated gelatinolysis induced by tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS). Additionally, WK2-16 significantly inhibited both MMP-9 protein and mRNA expression without cellular toxicity. Nevertheless, WK2-16 suppressed the extracellular levels of interleukin (IL)-6 from LPS-stimulated THP-1 cells. For the signaling studies, WK2-16 had no effect on LPS/TLR4 downstream signaling pathways, such as the NF-κB and ERK/JNK/P38 MAPK pathways. On the other hand, WK2-16 enhanced the recruitment of acetylated Yin Yang 1 (YY1) with HDAC1. Finally, in vivo studies indicated that WK2-16 could reduce the serum levels of TNF-α and IL-6 in endotoxemic mice. These results suggested that HDAC8 inhibition might provide a novel therapeutic strategy of hypercytokinemia in sepsis.
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Affiliation(s)
- Jing-Shiun Jan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Yung-Chen Chou
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Yu-Wen Cheng
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
| | - Chih-Kuang Chen
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
- School of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Wei-Jan Huang
- Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 110, Taiwan.
| | - George Hsiao
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
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Lorente L, Martín MM, Pérez-Cejas A, Ferreres J, Solé-Violán J, Labarta L, Díaz C, Jiménez A. Non-survivor septic patients have persistently higher serum sCD40L levels than survivors. J Crit Care 2017; 41:177-182. [PMID: 28570959 DOI: 10.1016/j.jcrc.2017.05.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Revised: 04/17/2017] [Accepted: 05/20/2017] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Soluble CD40 ligand (sCD40L) is a protein with proinflammatory and prothrombotic effects. Previously we found higher circulating sCD40L levels in non-survivor than in survivor patients at sepsis diagnosis. Now some questions arise such as how are serum sCD40L levels during the first week of severe sepsis?, is there an association between serum sCD40L levels during the first week and mortality?, and serum sCD40L levels during the first week could be used as sepsis mortality biomarker?. This study was developed to answer these asks. METHODS Study from 6 Spanish Intensive Care Units with 291 severe septic patients. There were determined serum levels of sCD40L and tumor necrosis factor (TNF)-alpha during the first week. The end-point study was 30-day mortality. RESULTS We found that serum sCD40L at days 1, 4, and 8 could predict mortality at 30days, and are associated with mortality. CONCLUSIONS The novel findings of our study were that there were higher serum sCD40L levels persistently during the first week in non-survivor than in survivor patients, that there is an association between serum sCD40L levels during the first week and sepsis mortality, and that serum sCD40L levels during the first week could be used as sepsis mortality biomarker.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna 38320, Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Crta Rosario s/n, Santa Cruz Tenerife 38010, Spain.
| | - Antonia Pérez-Cejas
- Laboratory Deparment, Hospital Universitario de Canarias, Ofra, s/n, La Laguna 38320, Tenerife, Spain.
| | - José Ferreres
- Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda. Blasco Ibáñez no17-19, Valencia 46004, Spain.
| | - Jordi Solé-Violán
- Intensive Care Unit. Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n, Las Palmas de Gran Canaria 35010, Spain.
| | - Lorenzo Labarta
- Intensive Care Unit, Hospital San Jorge de Huesca, Avenida Martínez de Velasco no36, Huesca 22004, Spain.
| | - César Díaz
- Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, Las Palmas de Gran Canaria 35016, Spain.
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna 38320, Tenerife, Spain.
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Masciantonio MG, Lee CKS, Arpino V, Mehta S, Gill SE. The Balance Between Metalloproteinases and TIMPs: Critical Regulator of Microvascular Endothelial Cell Function in Health and Disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 147:101-131. [PMID: 28413026 DOI: 10.1016/bs.pmbts.2017.01.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Endothelial cells (EC), especially the microvascular EC (MVEC), have critical functions in health and disease. For example, healthy MVEC provide a barrier between the fluid and protein found within the blood, and the surrounding tissue. Following tissue injury or infection, the microvascular barrier is often disrupted due to activation and dysfunction of the MVEC. Multiple mechanisms promote MVEC activation and dysfunction, including stimulation by cytokines, mechanical interaction with activated leukocytes, and exposure to harmful leukocyte-derived molecules, which collectively result in a loss of MVEC barrier function. However, MVEC activation is also critical to facilitate recruitment of inflammatory cells, such as neutrophils (PMNs) and monocytes, into the injured or infected tissue. Metalloproteinases, including the matrix metalloproteinases (MMPs) and the closely related, a disintegrin and metalloproteinases (ADAMs), have been implicated in regulating both MVEC barrier function, through cleavage of adherens and tight junctions proteins between adjacent MVEC and through degradation of the extracellular matrix, as well as PMN-MVEC interaction, through shedding of cell surface PMN receptors. Moreover, the tissue inhibitors of metalloproteinases (TIMPs), which collectively inhibit most MMPs and ADAMs, are critical regulators of MVEC activation and dysfunction through their ability to inhibit metalloproteinases and thereby promote MVEC stability. However, TIMPs have been also found to modulate MVEC function through metalloproteinase-independent mechanisms, such as regulation of vascular endothelial growth factor signaling. This chapter is focused on examining the role of the metalloproteinases and TIMPs in regulation of MVEC function in both health and disease.
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Affiliation(s)
- Marcello G Masciantonio
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Christopher K S Lee
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Valerie Arpino
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Sanjay Mehta
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada
| | - Sean E Gill
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
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Niño ME, Serrano SE, Niño DC, McCosham DM, Cardenas ME, Villareal VP, Lopez M, Pazin-Filho A, Jaimes FA, Cunha F, Schulz R, Torres-Dueñas D. TIMP1 and MMP9 are predictors of mortality in septic patients in the emergency department and intensive care unit unlike MMP9/TIMP1 ratio: Multivariate model. PLoS One 2017; 12:e0171191. [PMID: 28192449 PMCID: PMC5305237 DOI: 10.1371/journal.pone.0171191] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 01/18/2017] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION Matrix metalloproteinases and tissue inhibitors of metalloproteinases could be promising biomarkers for establishing prognosis during the development of sepsis. It is necessary to clarify the relationship between matrix metalloproteinases and their tissue inhibitors. We conducted a cohort study with 563 septic patients, in order to elucidate the biological role and significance of these inflammatory biomarkers and their relationship to the severity and mortality of patients with sepsis. MATERIALS AND METHODS A multicentric prospective cohort was performed. The sample was composed of patients who had sepsis as defined by the International Conference 2001. Serum procalcitonin, creatinine, urea nitrogen, C-Reactive protein, TIMP1, TIMP2, MMP2 and MMP9 were quantified; each patient was followed until death or up to 30 days. A descriptive analysis was performed by calculating the mean and the 95% confidence interval for continuous variables and proportions for categorical variables. A multivariate logistic regression model was constructed by the method of intentional selection of covariates with mortality at 30 days as dependent variable and all the other variables as predictors. RESULTS Of the 563 patients, 68 patients (12.1%) died within the first 30 days of hospitalization in the ICU. The mean values for TIMP1, TIMP2 and MMP2 were lower in survivors, MMP9 was higher in survivors. Multivariate logistic regression showed that age, SOFA and Charlson scores, along with TIMP1 concentration, were statistically associated with mortality at 30 days of septic patients; serum MMP9 was not statistically associated with mortality of patients, but was a confounder of the TIMP1 variable. CONCLUSION It could be argued that plasma levels of TIMP1 should be considered as a promising prognostic biomarker in the setting of sepsis. Additionally, this study, like other studies with large numbers of septic patients does not support the predictive value of TIMP1 / MMP9.
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Affiliation(s)
- Maria Eugenia Niño
- Department of Public Health, Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | - Sergio Eduardo Serrano
- Department of Public Health, Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | - Daniela Camila Niño
- Department of Pharmacology, Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | - Diana Margarita McCosham
- Department of Pharmacology, Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | - Maria Eugenia Cardenas
- Microbiology and Inmunology Department, Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | - Vivian Poleth Villareal
- Department of Pharmacology, Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | - Marcos Lopez
- Biotechnology Department, Enterprise Technology Center, Fundación Cardiovascular de Colombia, Bucaramanga, Santander, Colombia
| | - Antonio Pazin-Filho
- Department of Medical Clinics, Emergency unit, Faculty of Medicine, Universidade de Sao Paulo, Ribeirao preto, Sao Paulo, Brazil
| | - Fabian Alberto Jaimes
- Department of Internal Medicine, School Of Medicine, Universidad de Antioquia, Medellin, Antioquia, Colombia
| | - Fernando Cunha
- Department of Pharmacology, Faculty of Medicine, Universidade de Sao Paulo, Ribeirao preto, Sao Paulo, Brazil
| | - Richard Schulz
- Departments of Pediatrics and Pharmacology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Diego Torres-Dueñas
- Department of Pharmacology, Medicine Program, Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
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Higher serum caspase-cleaved cytokeratin-18 levels during the first week of sepsis diagnosis in non-survivor patients. ACTA ACUST UNITED AC 2017; 55:1621-1629. [DOI: 10.1515/cclm-2016-1034] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 01/26/2017] [Indexed: 02/07/2023]
Abstract
AbstractBackground:Caspase-cleaved cytokeratin (CCCK)-18 is a protein released into the blood during apoptosis. Higher circulating CCCK-18 concentrations have been found in non-survivor than in survivor septic patients at moment of sepsis diagnosis. The following questions arise now: (1) How are serum CCCK-18 levels during the first week of sepsis? (2) Is there an association between sepsis severity and mortality and serum CCCK-18 levels during the first week? The aims of this study were to answer these questions.Methods:Multicenter study with 321 severe septic patients from eight Spanish intensive care units. We determined serum concentration of CCCK-18, tumor necrosis factor (TNF)-α, and interleukin (IL)-10 during the first week. Our end-point study was 30-day mortality.Results:Non-survivor (n=108) compared to survivor patients (n=213) showed higher serum CCCK-18 levels at days 1, 4 and 8 (p<0.001). ROC curve analyses showed that serum CCCK-18 levels at days 1 (AUC=0.77; 95% CI=0.72–0.82), 4 (AUC=0.81; 95% CI=0.76–0.85) and 8 (AUC=0.83; 95% CI=0.78–0.88) could predict mortality at 30 days (p<0.001). Logistic regression analyses showed that serum CCCK-18 levels at days 1 (OR=4.367; 95% CI=2.491–7.659), 4 (OR=10.137; 95% CI=4.741–21.678) and 8 (OR=8.781; 95% CI=3.626–21.268) were associated with 30-day mortality (p<0.001). We found a positive correlation between CCCK-18, SOFA, and lactic acid at days 1, 4 and 8.Conclusions:Non-survivor septic patients showed persistently during the first week higher serum CCCK-18 levels than survivor patients, and there is an association between sepsis severity and mortality and serum CCCK-18 levels during the first week.
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Kocaturk M, Eralp-Inan O, Tvarijonaviciute A, Cansev M, Ozyigit MO, Ceron JJ, Yilmaz Z, Kahraman MM. Effects of choline treatment in concentrations of serum matrix metalloproteinases (MMPs), MMP tissue inhibitors (TIMPs) and immunoglobulins in an experimental model of canine sepsis. Vet Immunol Immunopathol 2016; 180:9-14. [PMID: 27692098 DOI: 10.1016/j.vetimm.2016.08.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/10/2016] [Accepted: 08/17/2016] [Indexed: 12/20/2022]
Abstract
The aim of the present study was to investigate effects of intravenous (i.v.) choline treatment on serum matrix metalloproteinases (MMP), MMP tissue inhibitors (TIMP) and immunoglobulins (Igs), and to determine if there were relations between serum MMPs/TIMPs and C-reactive protein (CRP) (as a marker of the acute phase response), immunoglobulin G and M (IgG and IgM) (as a maker of the Ig responses) and markers of organ damage such as muscular damage (creatine phosphokinase, [CPK]), liver damage (alanine aminotransferase [ALT]) and renal dysfunction (blood urea nitrogen [BUN] and creatinine, [Cr]) in dogs with endotoxemia. Healthy dogs (n=24) were randomized to Saline, Choline (C), Lipopolysaccharide (LPS), and LPS+C groups and received 0.9% NaCl (5mL/i.v.), choline chloride (20mg/kg/i.v.), LPS (0.02mg/kg/i.v.) and LPS (0.02mg/kg/i.v.) plus choline chloride (20mg/kg/i.v.), respectively. Serum MMPs and TIMPs concentrations were analyzed by commercial ELISA kits. MMP and TIMP increased at 1-48h (P<0.05), whereas IgG and IgM decreased at 24-48h in LPS group, compared to their baselines. Choline treatment reduced changes in serum MMPs, TIMPs and markers of organ damage, and prevented the hypoimmunoglobulinemia in LPS+C. MMPs and TIMPs were correlated positively (P<0.05) with serum CRP, CPK, ALT, BUN and Cr, but not with serum Igs. Our findings suggest that the serum MMPs, TIMPs and Igs are involved in the pathophysiology of endotoxemia, and MMPs and TIMPs are correlated with the acute phase reaction and multi-organ failure. In addition, we demonstrated a direct effect of choline administration in decreasing serum MMPs and TIMPs, and preserving serum Igs in the course of endotoxemia.
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Affiliation(s)
- Meric Kocaturk
- Department of Internal Medicine, Faculty of Veterinary Medicine, Uludag University, Bursa 16059, Turkey.
| | - Oya Eralp-Inan
- Medical-Surgical Research Center, Agricultural Faculty, Osmangazi University Eskişehir, Turkey.
| | - A Tvarijonaviciute
- Departament de Medicina i Cirurgia Animals, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain.
| | - Mehmet Cansev
- Department of Pharmacology, Medical Faculty, Uludag University, Bursa, Turkey.
| | - M Ozgur Ozyigit
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, Uludag University, Bursa, Turkey.
| | - J J Ceron
- Interdisciplinary Laboratory of Clinical Analysis (Interlab-UMU), Veterinary School, Campus of Excellence Mare Nostrum, University of Murcia, 30100 Espinardo, Murcia, Spain.
| | - Zeki Yilmaz
- Department of Internal Medicine, Faculty of Veterinary Medicine, Uludag University, Bursa 16059, Turkey.
| | - M Mufit Kahraman
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, Uludag University, Bursa, Turkey
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Bojic S, Kotur-Stevuljevic J, Kalezic N, Stevanovic P, Jelic-Ivanovic Z, Bilanovic D, Memon L, Damnjanovic M, Kalaba Z, Simic-Ogrizovic S. Diagnostic Value of Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 in Sepsis-Associated Acute Kidney Injury. TOHOKU J EXP MED 2016; 237:103-9. [PMID: 26399271 DOI: 10.1620/tjem.237.103] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Sepsis-associated acute kidney injury (SA-AKI) severely impacts morbidity and mortality in surgical patients with sepsis. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) have an important role in pathophysiology of sepsis but they have been unexplored in SA-AKI. We aimed to investigate the role of MMP-9 and TIMP-1 in septic surgical patients with SA-AKI and to evaluate them as diagnostic biomarkers of SA-AKI. This prospective observational study compared 53 major abdominal surgery patients with sepsis divided into SA-AKI (n = 37) and non-SA-AKI (n =16) group to 50 controls without sepsis matched by age, gender, comorbidities and type of surgery. Blood and urine samples from septic patients were collected on admission to ICU and 24, 48, 72 and 96 h later and once from the controls. The levels of MMP-9, TIMP-1, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, urea and creatinine were measured. MMP-9/TIMP-1 ratio and disease severity scores, such as Sequential Organ Failure Assessment (SOFA), were calculated. Septic patients with SA-AKI had higher serum TIMP-1 levels and lower serum MMP-9 levels and lower MMP-9/TIMP ratio, compared to septic patients without SA-AKI and controls. The levels of these biomarkers did not change significantly over time. MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio correlated with urea, creatinine, NGAL, and SOFA scores. Moreover, using the area under ROC curve, we showed that TIMP-1 and MMP-9/TIMP-1 ratio, but not MMP-9, were good diagnostic biomarkers of SA-AKI. We report for the first time the potential diagnostic value of TIMP-1 and MMP-9/TIMP-1 ratio in SA-AKI.
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Affiliation(s)
- Suzana Bojic
- Department of Anaesthesiology, Resuscitation and Intensive Care, Clinical Hospital Center Bezanijska Kosa
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