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Ma A, Zhang C, Gong Y, Ma X, Yan N. The association between blood urea nitrogen to serum albumin ratio and 28 day in-hospital mortality in patients with chronic heart failure and sepsis: a pilot retrospective study. Front Cardiovasc Med 2025; 12:1491331. [PMID: 40104144 PMCID: PMC11914131 DOI: 10.3389/fcvm.2025.1491331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 02/18/2025] [Indexed: 03/20/2025] Open
Abstract
Aims The purpose of this study was to explore the relationship between blood urea nitrogen to serum albumin ratio and 28-day in-hospital mortality in patients with chronic heart failure complicated by sepsis admitted to the intensive care unit (ICU). Methods This retrospective study included 723 patients with chronic heart failure complicated by sepsis from the eICU database. Smooth curve fitting assessed the association between BAR and mortality. Multivariable Cox regression analysis was conducted to calculate the adjusted hazard ratio (HR) and 95% confidence interval (CI). Kaplan-Meier curves compared survival rates across BAR tertiles. Subgroup analysis was stratified based on relevant covariates and a forest plot was drawn to verify the stability of the results. Results Among 723 chronic heart failure patients with sepsis, the 28-day mortality rate was 20.33% (147/723). After adjusting for confounders, with BAR as a categorical variable, patients in the highest tertile of BAR had a significantly higher death risk than those in the lowest tertile [HR: 1.87, 95% CI (1.09,3.19), p: 0.023]. When BAR was a continuous variable, each unit increase in BAR raised in-hospital mortality by 2% [HR: 1.02, 95% CI (1.01, 1.04), p = 0.0038]. Stratified analysis showed no interaction, and E-value analysis indicated robustness to unmeasured confounding, highlighting the stable and significant relationship between BAR and 28-day mortality in these patients. Conclusion In the context of critically ill patients with chronic heart failure complicated by sepsis, there exists a significant correlation between blood urea nitrogen to serum albumin ratio (BAR) and 28-day mortality. Specifically, higher BAR levels are associated with an elevated risk of 28-day mortality in these patients. However, these findings require further research for confirmation.
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Affiliation(s)
- Ali Ma
- First Clinical College, Ningxia Medical University, Yinchuan, China
- Heart Centre & Department of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Chen Zhang
- First Clinical College, Ningxia Medical University, Yinchuan, China
- Heart Centre & Department of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Ying Gong
- First Clinical College, Ningxia Medical University, Yinchuan, China
- Heart Centre & Department of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Xueping Ma
- Heart Centre & Department of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, China
- Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Ning Yan
- Heart Centre & Department of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, China
- Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China
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Rao M, McGonagill PW, Brackenridge S, Remy KE, Caldwell CC, Hotchkiss RS, Moldawer LL, Griffith TS, Badovinac VP. FUNCTIONAL IMMUNOPHENOTYPING FOR PRECISION THERAPIES IN SEPSIS. Shock 2025; 63:189-201. [PMID: 39617419 DOI: 10.1097/shk.0000000000002511] [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] [Indexed: 01/24/2025]
Abstract
ABSTRACT Sepsis remains a significant cause of morbidity and mortality worldwide. Although many more patients are surviving the acute event, a substantial number enters a state of persistent inflammation and immunosuppression, rendering them more vulnerable to infections. Modulating the host immune response has been a focus of sepsis research for the past 50 years, yet novel therapies have been few and far between. Although many septic patients have similar clinical phenotypes, pathways affected by the septic event differ not only between individuals but also within an individual over the course of illness. These differences ultimately impact overall immune function and response to treatment. Defining the immune state, or endotype, of an individual is critical to understanding which patients will respond to a particular therapy. In this review, we highlight current approaches to define the immune endotype and propose that these technologies may be used to "prescreen" individuals to determine which therapies are most likely to be beneficial.
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Affiliation(s)
- Mahil Rao
- Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Patrick W McGonagill
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Scott Brackenridge
- Department of Surgery, Harborview Medical Center, University of Washington School of Medicine, Seattle, Washington
| | - Kenneth E Remy
- Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Charles C Caldwell
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | | | - Lyle L Moldawer
- Sepsis and Critical Illness Research Center, Department of Surgery, University of Florida College of Medicine, Gainesville, Florida
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Degregori EB, Caye P, Soares ABU, Schiefler OHDM, Antunes BN, Reinstein RDS, Pozzobon FM, Tostes VP, Rovêda RA, Cadiñanos VDS, de Andrade CM, Brun MV, de Mendonça Müller DC. Effects of postoperative hyperbaric oxygen therapy on hematological and biochemical parameters in patients diagnoses with pyometra in sepsis. Top Companion Anim Med 2025; 64:100943. [PMID: 39675624 DOI: 10.1016/j.tcam.2024.100943] [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: 02/12/2024] [Revised: 11/21/2024] [Accepted: 12/09/2024] [Indexed: 12/17/2024]
Abstract
The aim of this study was to evaluate the impact of hyperbaric oxygen therapy (HBOT) on hematologic and biochemical markers in dogs with pyometra in sepsis. Eighteen patients were equally distributed between the control group (CG) and the hyperbaric group (HG). All patients underwent ovariohysterectomy, supportive therapy, and insertion of a central venous catheter. HG attended three HBOT sessions (2 absolute atmospheres, 45 min) postoperatively. Blood tests were performed on admission, 1 h postoperatively, 24 h, 48 h, and 72 h postoperatively. Both groups showed a significant reduction in red blood cells (Hm) and hematocrit (Hto) after surgery, but this effect was reversed after three HBO sessions and maintained in CG. Despite the initial reduction in hemoglobin (Hg) in HG, the values increased again after the end of the protocol. A reduction of >50 % in leukocytes was noted in HG in the last evaluation in relation to the values at admission. Significant reduction was also found for neutrophils, metamyelocytes and rods in HG. There was no difference in biochemical markers. HBO associated with OVH and supportive therapy can be considered in the treatment of pyometra, with rapid and marked improvement, after three sessions, in the e red blood cells and leukogram.
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Affiliation(s)
- Emanuelle Bortolotto Degregori
- Graduate Program in Veterinary Medicine, Federal University of Santa Maria, University Veterinary Hospital, CEP, Camobi Av. Roraima - 1000, building 97, room 126 97105-900, Santa Maria-RS, Brazil.
| | - Pâmela Caye
- Graduate Program in Veterinary Medicine, Federal University of Santa Maria, University Veterinary Hospital, CEP, Camobi Av. Roraima - 1000, building 97, room 126 97105-900, Santa Maria-RS, Brazil
| | - Ana Barbara Uchoa Soares
- Graduate Program in Veterinary Medicine, Federal University of Santa Maria, University Veterinary Hospital, CEP, Camobi Av. Roraima - 1000, building 97, room 126 97105-900, Santa Maria-RS, Brazil
| | - Otávio Henrique de Melo Schiefler
- Graduate Program in Veterinary Medicine, Federal University of Santa Maria, University Veterinary Hospital, CEP, Camobi Av. Roraima - 1000, building 97, room 126 97105-900, Santa Maria-RS, Brazil
| | - Bernardo Nascimento Antunes
- Graduate Program in Veterinary Medicine, Federal University of Santa Maria, University Veterinary Hospital, CEP, Camobi Av. Roraima - 1000, building 97, room 126 97105-900, Santa Maria-RS, Brazil
| | - Rainer Da Silva Reinstein
- Graduate Program in Veterinary Medicine, Federal University of Santa Maria, University Veterinary Hospital, CEP, Camobi Av. Roraima - 1000, building 97, room 126 97105-900, Santa Maria-RS, Brazil
| | - Francieli Mallmann Pozzobon
- Graduate Program in Veterinary Medicine, Federal University of Santa Maria, University Veterinary Hospital, CEP, Camobi Av. Roraima - 1000, building 97, room 126 97105-900, Santa Maria-RS, Brazil
| | - Vitória Pina Tostes
- Undergraduate student in Veterinary Medicine at the Federal University of Santa Maria
| | | | | | - Cinthia Melazzo de Andrade
- Graduate Program in Veterinary Medicine, Federal University of Santa Maria, University Veterinary Hospital, CEP, Camobi Av. Roraima - 1000, building 97, room 126 97105-900, Santa Maria-RS, Brazil
| | - Maurício Veloso Brun
- Graduate Program in Veterinary Medicine, Federal University of Santa Maria, University Veterinary Hospital, CEP, Camobi Av. Roraima - 1000, building 97, room 126 97105-900, Santa Maria-RS, Brazil
| | - Daniel Curvello de Mendonça Müller
- Graduate Program in Veterinary Medicine, Federal University of Santa Maria, University Veterinary Hospital, CEP, Camobi Av. Roraima - 1000, building 97, room 126 97105-900, Santa Maria-RS, Brazil
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Lira AL, Taskin B, Puy C, Keshari RS, Silasi R, Pang J, Aslan JE, Shatzel JJ, Lorentz CU, Tucker EI, Schmaier AH, Gailani D, Lupu F, McCarty OJT. The physicochemical properties of lipopolysaccharide chemotypes regulate activation of the contact pathway of blood coagulation. J Biol Chem 2025; 301:108110. [PMID: 39706265 PMCID: PMC11773025 DOI: 10.1016/j.jbc.2024.108110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/15/2024] [Accepted: 12/11/2024] [Indexed: 12/23/2024] Open
Abstract
Lipopolysaccharide (LPS) is the primary pathogenic factor in Gram-negative sepsis. While the presence of LPS in the bloodstream during infection is associated with disseminated intravascular coagulation, the mechanistic link between LPS and blood coagulation activation remains ill-defined. The contact pathway of coagulation-a series of biochemical reactions that initiates blood clotting when plasma factors XII (FXII) and XI (FXI), prekallikrein (PK), and high molecular weight kininogen interact with anionic surfaces-has been shown to be activated in Gram-negative septic patients. In this study, using an in vivo baboon model of Gram-negative Escherichia coli sepsis, we observed activation of the contact pathway including FXII, FXI, and PK. We examined whether E.coli LPS molecules could bind and activate contact pathway members by quantifying the interaction and activation of either FXII, FXI, or PK with each of the three chemotypes of LPS: O111:B4, O26:B6, or Rd2. The LPS chemotypes exhibited distinct physicochemical properties as aggregates and formed complexes with FXII, FXI, and PK. The LPS chemotype O26:B6 uniquely promoted the autoactivation of FXII to FXIIa and, in complex with FXIIa, promoted the cleavage of FXI and PK to generate FXIa and plasma kallikrein, respectively. Furthermore, in complex with the active forms of FXI or PK, LPS chemotypes were able to regulate the catalytic activity of FXIa and plasma kallikrein, respectively, despite the inability to promote the autoactivation of either zymogen. These data suggest that the procoagulant phenotype of E.coli is influenced by bacterial strain and the physicochemical properties of the LPS chemotypes.
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Affiliation(s)
- André L Lira
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
| | - Berk Taskin
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA
| | - Cristina Puy
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA
| | - Ravi S Keshari
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Robert Silasi
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Jiaqing Pang
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA
| | - Joseph E Aslan
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA; Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Joseph J Shatzel
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA; Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Christina U Lorentz
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA; Aronora, Inc, Portland, Oregon, USA
| | - Erik I Tucker
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA; Aronora, Inc, Portland, Oregon, USA
| | - Alvin H Schmaier
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - David Gailani
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Florea Lupu
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Owen J T McCarty
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA; Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA
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Kala K, Mallik SK, Shahi N, Pathak R, Sharma P, Chandra S, Patiyal RS, Pande V, Pandey N, Pande A, Pandey PK. Emergence of Aeromonas salmonicida subsp. masoucida MHJM250: unveiling pathological characteristics and antimicrobial susceptibility in golden mahseer, Tor putitora (Hamilton, 1822) in India. Vet Res Commun 2024; 48:3751-3772. [PMID: 39269671 DOI: 10.1007/s11259-024-10518-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024]
Abstract
Aeromonas salmonicida subsp. masoucida, designated as laboratory strain MHJM250, was characterized from a naturally infected farmed golden mahseer, Tor putitora. The infected fish exhibited clinical signs of erosion at the caudal fin and hemorrhage onx the ventral body surface. Molecular identification through 16 S rDNA and phylogenetic analysis revealed 100% similarity with a known strain A. salmonicida subsp. masoucida (MT122821.1). MHJM250 exhibited positive reactions for oxidase, catalase, esculin, MR-VP, O/F and utilized arginine and lysine. It also demonstrated siderophore activity, thrived at various NaCl concentrations, hydrolyzed gelatinase, skimmed milk and casinase. In vitro studies exhibited its hemolytic nature, significant biofilm production in glucose-rich tryptone soya broth and beta-hemolysis. MHJM250 didn't produce slime and was non-precipitated upon boiling. It showed crystal violet binding characteristics and auto-agglutination with relatively weak hydrophobicity (25%). In the challenge assay, intraperitoneal administration of MHJM250 to T. pitutora fingerlings at 108 CFU mL-1 resulted in pathogenicity with 3% mortality and mild hemorrhagic symptoms. Histopathological analysis revealed degenerative changes in gill, kidney, liver, muscle, and intestine samples. The bacterium displayed resistance to several antibiotics (µg/disc); ampicillin (10 µg), ampicillin/ sulbactam (10/10 µg), clindamycin (2 µg), linezolid (30 µg), penicillin G (10 µg) and rifampicin (5 µg) and varied minimum inhibitory concentrations against oxytetracycline, erythromycin and florfenicol. Transmission electron microscopy showed its rod-shaped structure with single polar flagellum and lophotrichous flagella. An investigation on the molecular basis for virulence factors of A. salmonicida subsp. masoucida MHJM250 may offer crucial understandings to formulate disease prevention and control strategies in aquaculture.
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Affiliation(s)
- Krishna Kala
- ICAR-Directorate of Coldwater Fisheries Research (ICAR-DCFR), Anusandhan Bhavan, Bhimtal, Nainital, 263 136, Uttarakhand, India
| | - Sumanta Kumar Mallik
- ICAR-Directorate of Coldwater Fisheries Research (ICAR-DCFR), Anusandhan Bhavan, Bhimtal, Nainital, 263 136, Uttarakhand, India
| | - Neetu Shahi
- ICAR-Directorate of Coldwater Fisheries Research (ICAR-DCFR), Anusandhan Bhavan, Bhimtal, Nainital, 263 136, Uttarakhand, India
| | - Richa Pathak
- ICAR-Directorate of Coldwater Fisheries Research (ICAR-DCFR), Anusandhan Bhavan, Bhimtal, Nainital, 263 136, Uttarakhand, India
| | - Prerna Sharma
- ICAR-Directorate of Coldwater Fisheries Research (ICAR-DCFR), Anusandhan Bhavan, Bhimtal, Nainital, 263 136, Uttarakhand, India
| | - Suresh Chandra
- ICAR-Directorate of Coldwater Fisheries Research (ICAR-DCFR), Anusandhan Bhavan, Bhimtal, Nainital, 263 136, Uttarakhand, India
| | - R S Patiyal
- ICAR-Directorate of Coldwater Fisheries Research (ICAR-DCFR), Anusandhan Bhavan, Bhimtal, Nainital, 263 136, Uttarakhand, India
| | - Veena Pande
- Department of Biotechnology, Bhimtal Campus, Kumaun University, Bhimtal, Nainital, 263 136, Uttarakhand, India
| | - Nityanand Pandey
- ICAR-Directorate of Coldwater Fisheries Research (ICAR-DCFR), Anusandhan Bhavan, Bhimtal, Nainital, 263 136, Uttarakhand, India
| | - Amit Pande
- ICAR-Directorate of Coldwater Fisheries Research (ICAR-DCFR), Anusandhan Bhavan, Bhimtal, Nainital, 263 136, Uttarakhand, India
| | - Pramod Kumar Pandey
- ICAR-Directorate of Coldwater Fisheries Research (ICAR-DCFR), Anusandhan Bhavan, Bhimtal, Nainital, 263 136, Uttarakhand, India.
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Mishra PK, Kumar A, Agrawal S, Doneria D, Singh R. A Comparison of the Efficacy of High-Dose Vitamin C Infusion and Thiamine (Vitamin B1) Infusion in Patients With Sepsis: A Prospective Randomized Controlled Trial. Cureus 2024; 16:e75296. [PMID: 39776708 PMCID: PMC11704311 DOI: 10.7759/cureus.75296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2024] [Indexed: 01/11/2025] Open
Abstract
Background and objective Vitamin C and thiamine possess properties that may mitigate the harmful effects of sepsis. However, there is a dearth of studies in the literature comparing these two vitamins with each other and with a placebo regarding their efficacy against sepsis. This study aimed to investigate the outcomes associated with high-dose infusions of vitamin C and thiamine in septic patients, thereby seeking to contribute valuable insights into the optimal management of sepsis. The primary objective was to compare the sequential organ failure assessment (SOFA) score and C-reactive protein (CRP) level improvement on Day Six among the vitamin C, thiamine, and placebo groups after the intervention for five days. Methodology This prospective randomized comparative study involved 75 patients. Patients were randomized into three groups of 25 each. The first group received high-dose vitamin C infusion along with standard treatment for sepsis; the second group received high-dose thiamine infusion along with standard treatment for sepsis; and the third group, the placebo group, received only standard treatment for sepsis for five days. The SOFA score, CRP level, and other parameters were evaluated on Day Six. Results The SOFA score (p=0.043) and CRP level (p=0.0161) on Day Six were lower in the vitamin C group than in the placebo group. The CRP level on Day Six was significantly lower in the thiamine group than in the placebo group (p=0.016). The duration of vasopressor therapy was significantly lower in the vitamin C group than in the placebo group (p=0.0276) and the thiamine group (p=0.0236). Conclusions Based on our findings, vitamin C infusion helps improve the SOFA score and CRP level in sepsis patients. It can also decrease the duration of vasopressor therapy and serious adverse events whereas thiamine can reduce CRP levels in these patients.
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Affiliation(s)
- Prashant K Mishra
- Anaesthesiology and Critical Care, Uttar Pradesh University of Medical Sciences, Etawah, IND
| | - Atit Kumar
- Anaesthesiology and Critical Care, Uttar Pradesh University of Medical Sciences, Etawah, IND
| | - Sonali Agrawal
- Anaesthesiology and Critical Care, Uttar Pradesh University of Medical Sciences, Etawah, IND
| | - Deepika Doneria
- Anaesthesiology and Critical Care, Uttar Pradesh University of Medical Sciences, Etawah, IND
| | - Raghvendra Singh
- Anaesthesiology and Critical Care, Uttar Pradesh University of Medical Sciences, Etawah, IND
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Strohl JJ, Carrión J, Huerta PT. Brain imaging and machine learning reveal uncoupled functional network for contextual threat memory in long sepsis. Sci Rep 2024; 14:27747. [PMID: 39533062 PMCID: PMC11557587 DOI: 10.1038/s41598-024-79259-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024] Open
Abstract
Positron emission tomography (PET) utilizes radiotracers like [18F]fluorodeoxyglucose (FDG) to measure brain activity in health and disease. Performing behavioral tasks between the FDG injection and the PET scan allows the FDG signal to reflect task-related brain networks. Building on this principle, we introduce an approach called behavioral task-associated PET (beta-PET) consisting of two scans: the first after a mouse is familiarized with a conditioning chamber, and the second upon recall of contextual threat. Associative threat conditioning occurs between scans. Beta-PET focuses on brain regions encoding threat memory (e.g., amygdala, prefrontal cortex) and contextual aspects (e.g., hippocampus, subiculum, entorhinal cortex). Our results show that beta-PET identifies a biologically defined network encoding contextual threat memory and its uncoupling in a mouse model of long sepsis. Moreover, machine learning algorithms (linear logistic regression) and ordinal trends analysis demonstrate that beta-PET robustly predicts the behavioral defense response and its breakdown during long sepsis.
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Affiliation(s)
- Joshua J Strohl
- Laboratory of Immune and Neural Networks, Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA
| | - Joseph Carrión
- Laboratory of Immune and Neural Networks, Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA
| | - Patricio T Huerta
- Laboratory of Immune and Neural Networks, Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
- Elmezzi Graduate School of Molecular Medicine at Northwell Health, 350 Community Drive, Manhasset, NY, 11030, USA.
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd, Hempstead, NY, 11549, USA.
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Feng J, Liu L, Liu J, Wang J. Immunological alterations in the endothelial barrier: a new predictive and therapeutic paradigm for sepsis. Expert Rev Clin Immunol 2024; 20:1205-1217. [PMID: 38850066 DOI: 10.1080/1744666x.2024.2366301] [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: 03/12/2024] [Accepted: 06/05/2024] [Indexed: 06/09/2024]
Abstract
INTRODUCTION Despite the fact incidence and mortality vary widely among regions, sepsis remains a major cause of morbidity and cost worldwide. The importance of the endothelial barrier in sepsis and infectious diseases is increasingly recognized; however, the underlying pathophysiology of the endothelial barrier in sepsis remains poorly understood. AREAS COVERED Here we review the advances in basic and clinical research for relevant papers in PubMed database. We attempt to provide an updated overview of immunological alterations in endothelial dysfunction, discussing the central role of endothelial barrier involved in sepsis to provide new predictive and therapeutic paradigm for sepsis. EXPERT OPINION Given its physiological and immunological functions in infectious diseases, the endothelial barrier has been dramatically altered in sepsis, suggesting that endothelial dysfunction may play a critical role in the pathogenesis of sepsis. Although many reliable biomarkers have been investigated to monitor endothelial activation and injury in an attempt to find diagnostic and therapeutic tools, there are no specific therapies to treat sepsis due to its complex pathophysiology. Since sepsis is initiated by both hyperinflammation and immunoparalysis occurring simultaneously, a 'one-treatment-fits-all' strategy for sepsis-induced immune injury and immunoparalysis is bound to fail, and an individualized 'precision medicine' approach is required.
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Affiliation(s)
- Jun Feng
- Department of Emergency Medicine, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lina Liu
- Department of Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junya Liu
- Department of Emergency Medicine, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junshuai Wang
- Department of Emergency Medicine, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Deng Y, Leng L, Wang C, Yang Q, Hu Y. Analyzing the molecular mechanism of Scutellaria Radix in the treatment of sepsis using RNA sequencing. BMC Infect Dis 2024; 24:695. [PMID: 38997656 PMCID: PMC11241924 DOI: 10.1186/s12879-024-09589-2] [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: 11/25/2023] [Accepted: 07/04/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND Sepsis is a life-threatening organ dysfunction, which seriously threatens human health. The clinical and experimental results have confirmed that Traditional Chinese medicine (TCM), such as Scutellariae Radix, has anti-inflammatory effects. This provides a new idea for the treatment of sepsis. This study systematically analyzed the mechanism of Scutellariae Radix treatment in sepsis based on network pharmacology, RNA sequencing and molecular docking. METHODS Gene expression analysis was performed using Bulk RNA sequencing on sepsis patients and healthy volunteers. After quality control of the results, the differentially expressed genes (DEGs) were analyzed. The active ingredients and targets of Scutellariae Radix were identified using The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Gene Ontology (GO) and Protein-Protein Interaction (PPI) analysis were performed for disease-drug intersection targets. With the help of GEO database, Survival analysis and Meta-analysis was performed on the cross-targets to evaluate the prognostic value and screen the core targets. Subsequently, single-cell RNA sequencing was used to determine where the core targets are located within the cell. Finally, in this study, molecular docking experiments were performed to further clarify the interrelationship between the active components of Scutellariae Radix and the corresponding targets. RESULTS There were 72 active ingredients of Scutellariae Radix, and 50 common targets of drug and disease. GO and PPI analysis showed that the intersection targets were mainly involved in response to chemical stress, response to oxygen levels, response to drug, regulation of immune system process. Survival analysis showed that PRKCD, EGLN1 and CFLAR were positively correlated with sepsis prognosis. Meta-analysis found that the three genes were highly expressed in sepsis survivor, while lowly in non-survivor. PRKCD was mostly found in Macrophages, while EGLN1 and CFLAR were widely expressed in immune cells. The active ingredient Apigenin regulates CFLAR expression, Baicalein regulates EGLN1 expression, and Wogonin regulates PRKCD expression. Molecular docking studies confrmed that the three active components of astragalus have good binding activities with their corresponding targets. CONCLUSIONS Apigenin, Baicalein and Wogonin, important active components of Scutellaria Radix, produce anti-sepsis effects by regulating the expression of their targets CFLAR, EGLN1 and PRKCD.
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Affiliation(s)
- Yaxing Deng
- Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, China
| | - Linghan Leng
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, China
| | - Chenglin Wang
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, China
| | - Qingqiang Yang
- Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, China.
| | - Yingchun Hu
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, China.
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Mott MD, Trusiano B, Allen IC. Buena VISTA: a promising outlook on targeting immune checkpoint regulators to combat sepsis. J Leukoc Biol 2024; 115:1002-1004. [PMID: 38526166 DOI: 10.1093/jleuko/qiae080] [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: 01/12/2024] [Revised: 02/29/2024] [Accepted: 03/12/2024] [Indexed: 03/26/2024] Open
Abstract
Regulation of T cell activation by VISTA is implicated in host organism immune response to sepsis and may be a potential therapeutic target.
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Affiliation(s)
- Madeline D Mott
- Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, 1 Riverside Circle Suite 201, Roanoke, VA 24016, United States
| | - Briana Trusiano
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, 205 Duck Pond Dr, Blacksburg, VA 24061, United States
| | - Irving Coy Allen
- Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, 1 Riverside Circle Suite 201, Roanoke, VA 24016, United States
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, 205 Duck Pond Dr, Blacksburg, VA 24061, United States
- Department of Basic Science Education, Virginia Tech Carilion School of Medicine, 2 Riverside Circle, Roanoke, VA 24016, United States
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11
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Wang J, Hou J, Peng C. Phospholipid transfer protein ameliorates sepsis-induced cardiac dysfunction through NLRP3 inflammasome inhibition. Open Med (Wars) 2024; 19:20240915. [PMID: 38584827 PMCID: PMC10996989 DOI: 10.1515/med-2024-0915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 02/03/2024] [Accepted: 02/05/2024] [Indexed: 04/09/2024] Open
Abstract
Cardiomyocyte pyroptosis is a primary contributor to sepsis-induced cardiac dysfunction (SICD). Recombinant phospholipid transfer protein (PLTP) have been demonstrated to possess anti-inflammatory and antiseptic properties. However, the effect of PLTP on SICD remains unknown. In this study, we established the in vivo and in vitro sepsis model with the recombinant PLTP treatment. The survival rates of mice, mouse cardiac function, cell viability, the protein level of proinflammatory cytokine, and lactate dehydrogenase level were evaluated. The cardiomyocyte pyroptotic changes were observed. The distribution of PLTP and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) in mouse myocardial tissue and expression of PLTP, apoptosis associated speck like protein containing a CARD (ASC), NLRP3, caspase-1, interleukin (IL)-1β, and Gasdermin D (GSDMD) were detected. PLTP ameliorated the cecal ligation and puncture-induced mouse survival rate decrease and cardiac dysfunction, inhibited the IL-1β, IL-18, and tumor necrosis factor (TNF)-α release, and blocked the NLRP3 inflammasome/GSDMD signaling pathway in septic mice. In vitro, PLTP reversed the lipopolysaccharide-induced cardiomyocyte pyroptosis, expression of IL-1β, IL-6, TNF-α, and activation of the NLRP3 inflammasome/GSDMD signal pathway. Moreover, PLTP could bind to NLRP3 and negatively regulate the activity of the NLRP3 inflammasome/GSDMD signal pathway. This study demonstrated that PLTP can ameliorate SICD by inhibiting inflammatory responses and cardiomyocyte pyroptosis by blocking the activation of the NLRP3 inflammasome/GSDMD signaling pathway.
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Affiliation(s)
- Jian Wang
- Emergency and Intensive Care Medicine Center, Guang’an People’s Hospital, Guang’an city, Sichuan 638500, PR China
| | - Jing Hou
- Emergency and Intensive Care Medicine Center, Guang’an People’s Hospital, Guang’an city, Sichuan 638500, PR China
| | - Chaohua Peng
- Emergency and Intensive Care Medicine Center, Guang’an People’s Hospital, Guang’an city, Sichuan 638500, PR China
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12
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Gupta A, Kumar S, Acharya S, Sarode R, Agrawal S, Gemnani R, Saboo K, Reddy N. Utility of Platelet Indices as Prognostic Markers of Sepsis: A Medical Intensive Care Unit-Based Cross-Sectional Study at a Rural Setup. Cureus 2024; 16:e54490. [PMID: 38516422 PMCID: PMC10955432 DOI: 10.7759/cureus.54490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 02/19/2024] [Indexed: 03/23/2024] Open
Abstract
Introduction Even after the breakthrough advancements in the management and prognostic scoring of sepsis, it remains an important cause of morbidity and mortality encountered in intensive care units (ICUs) throughout the globe. This study highlights the utility of platelet indices as prognostic markers of sepsis. Methods In the present prospective cross-sectional study, a total of 177 patients with sepsis were enrolled using the Sepsis-3 criteria. The platelet indices were then linked to severity using the Acute Physiology and Chronic Health Evaluation (APACHE) II score. The correlation of platelet indices to morbidity in terms of the length of ICU stay, need for a mechanical ventilator, types of infection, and mortality was also assessed. Results The results showed that mean platelet volume (p = 0.004) and platelet distribution width (PDW; p = 0.009) were positively correlated with the severity of sepsis. Among all the parameters, plateletcrit (%) was the best predictor of the need for an invasive mechanical ventilator at a cutoff point of ≤0.22 with a 60.90% chance of correctly predicting the need for an invasive mechanical ventilator, as was mortality at a cutoff point of ≤0.22 with a 67.30% chance of correct prediction. Among the platelet indices, only PDW showed a significant association with growth in culture because patients with growth had significantly higher PDW as compared to those who did not have growth (22.4 ± 4.47 vs 20.81 ± 4.29, p = 0.011). Conclusion The difference between the survivors and non-survivor groups was statistically significant for platelet indices, making them easily available, cost-effective, and useful prognostic markers for patients in septic shock. This will help in easy understanding and preventing its morbid complications, even at the primary care physician level.
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Affiliation(s)
- Anusha Gupta
- Department of Gastroenterology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Sunil Kumar
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Sourya Acharya
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Rajesh Sarode
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Sachin Agrawal
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Rinkle Gemnani
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Keyur Saboo
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Nikhil Reddy
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
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13
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Çevik D, Gümral N, Aslankoç R, Özmen Ö, Yalçın A, Kavrık O. Protective effect of pregabalin on renal and renal endothelial damage in sepsis induced by lipopolysaccharide. Immunopharmacol Immunotoxicol 2024; 46:55-66. [PMID: 37606510 DOI: 10.1080/08923973.2023.2250911] [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: 03/18/2023] [Accepted: 08/16/2023] [Indexed: 08/23/2023]
Abstract
OBJECTIVE We investigated the protective effects of pregabalin (PRG) on kidney and renal endothelial damage in sepsis induced by Lipopolysaccharide (LPS). MATERIALS AND METHODS Rats were randomly divided into three groups as control, LPS and LPS+PRG. Saline solution was administered 30 mg/kg orally and 5 mg/kg intraperitoneally (i.p.) to the control group. LPS was applied as 5 mg/kg, i.p. to the LPS group. In the LPS+PRG group, PRG at 30 mg/kg orally and one hour before LPS administration, one hour later 5 mg/kg i.p. LPS was applied. Rats were sacrificed 6 hours after LPS administration. RESULTS White Blood Cell (WBC), granulocyte, Blood Urea Nitrogen (BUN), creatinine, uric asid, Total Oxidant Status (TOS) and Oxidative Stress Index (OSI) significantly increased (p<0.05); platelets (PLT), activated partial thromboplastin time (aPTT) and Total Antioxidant Status (TAS) significantly decreased in the LPS group compared to the control group (p<0.05). In the LPS+PRG group WBC, granulocyte, BUN, creatinine, uric asid, TOS and OSI significantly decreased (p<0.05); PLT, aPTT and TAS significantly increased compared to the LPS group(p<0.05). Histopathological examinations showed that kidney and renal endothelial damage in the LPS group decreased in the LPS+PRG group. Immunohistochemically IL1-β, IL-6, IL-10, TNF-α expressions in kidney tissue and Toll-Like Receptors-4 (TLR-4) and NF-κB expressions in the renal endothelial tissue significantly increased in the LPS group compared to the control group and significantly decreased in the LPS+PRG group compared to the LPS group (p<0.001). CONCLUSIONS Sepsis causes kidney and renal endothelial damage and PRG reduces this damage. Therefore PRG can be used in prophylactic treatment in sepsis, supported by more studies.
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Affiliation(s)
- Dilek Çevik
- Department of Physiology, Suleyman Demirel University, Isparta, Turkey
| | - Nurhan Gümral
- Department of Physiology, Suleyman Demirel University, Isparta, Turkey
| | - Rahime Aslankoç
- Department of Physiology, Suleyman Demirel University, Isparta, Turkey
| | - Özlem Özmen
- Department of Pathology, Burdur Mehmet Akif Ersoy University Faculty of Veterinary, Burdur, Turkey
| | - Arzu Yalçın
- Department of Physiology, Suleyman Demirel University, Isparta, Turkey
| | - Oğuzhan Kavrık
- Department of Physiology, Suleyman Demirel University, Isparta, Turkey
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14
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Balsamo F, Li B, Chusilp S, Lee D, Biouss G, Lee C, Maynes JT, Pierro A. Argon inhalation attenuates systemic inflammation and rescues lung architecture during experimental neonatal sepsis. Pediatr Surg Int 2023; 40:21. [PMID: 38108911 DOI: 10.1007/s00383-023-05596-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/05/2023] [Indexed: 12/19/2023]
Abstract
PURPOSE Neonatal sepsis is a systemic inflammatory infection common in premature infants and a leading cause of mortality. Argon is an emerging interest in the field of noble gas therapy. Neonates with severe sepsis are frequently mechanically ventilated creating an opportunity for inhalation therapy. We aimed to investigate argon inhalation as a novel experimental therapy in neonatal sepsis. METHODS Sepsis was established in C57BL/6 neonatal mice by a lipopolysaccharide intraperitoneal injection on postnatal day 9. Septic pup mice were exposed to room air as well as non-septic controls. In the argon group, septic pup mice were exposed to argon (70% Ar, 30% O2) for 6 h in a temperature-controlled environment. RESULTS At 6 h, survival was significantly enhanced when septic mice received argon compared to septic controls. Serum profiles of cytokine release were significantly attenuated as well as lung architecture restored. CONCLUSIONS Our findings suggest that argon inhalation as a novel treatment for neonatal sepsis, reducing mortality and counteracting the acute systemic inflammatory response in the blood and preserving the architecture of the lung. This research can contribute to a paradigm shift in the treatment and outcome of neonates with sepsis.
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Affiliation(s)
- Felicia Balsamo
- Translational Medicine Program, Division of General and Thoracic Surgery, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada
| | - Bo Li
- Translational Medicine Program, Division of General and Thoracic Surgery, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada
| | - Sinobol Chusilp
- Translational Medicine Program, Division of General and Thoracic Surgery, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada
| | - Dorothy Lee
- Translational Medicine Program, Division of General and Thoracic Surgery, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada
| | - George Biouss
- Translational Medicine Program, Division of General and Thoracic Surgery, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada
| | - Carol Lee
- Translational Medicine Program, Division of General and Thoracic Surgery, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada
| | - Jason T Maynes
- Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, Canada
- Department of Biochemistry, Faculty of Medicine , University of Toronto, Toronto, Canada
| | - Agostino Pierro
- Translational Medicine Program, Division of General and Thoracic Surgery, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada.
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Kim B, Yu JE, Yeo IJ, Son DJ, Lee HP, Roh YS, Lim KH, Yun J, Park H, Han SB, Hong JT. (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol alleviates inflammatory responses in LPS-induced mice liver sepsis through inhibition of STAT3 phosphorylation. Int Immunopharmacol 2023; 125:111124. [PMID: 37977740 DOI: 10.1016/j.intimp.2023.111124] [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: 07/07/2023] [Revised: 10/13/2023] [Accepted: 10/20/2023] [Indexed: 11/19/2023]
Abstract
Sepsis is a life-threatening disease with limited treatment options, and the inflammatory process represents an important factor affecting its progression. Many studies have demonstrated the critical roles of signal transducer and activator of transcription 3 (STAT3) in sepsis pathophysiology and pro-inflammatory responses. Inhibition of STAT3 activity may therefore represent a promising treatment option for sepsis. We here used a mouse model to demonstrate that (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) treatment prevented the liver sepsis-related mortality induced by 30 mg/kg lipopolysaccharide (LPS) treatment and reduced LPS-induced increase in alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels, all of which are markers of liver sepsis progression. These recovery effects were associated with decreased LPS-induced STAT3, p65, and JAK1 phosphorylation and proinflammatory cytokine (interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha) level; expression of cyclooxygenase-2 and induced nitric oxide synthase were also reduced by MMPP. In an in vitro study using the normal liver cell line THLE-2, MMPP treatment prevented the LPS-induced increase of STAT3, p65, and JAK1 phosphorylation and inflammatory protein expression in a dose-dependent manner, and this effect was enhanced by combination treatment with MMPP and STAT3 inhibitor. The results clearly indicate that MMPP treatment prevents LPS-induced mortality by inhibiting the inflammatory response via STAT3 activity inhibition. Thus, MMPP represents a novel agent for alleviating LPS-induced liver sepsis.
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Affiliation(s)
- Boyoung Kim
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
| | - Ji Eun Yu
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
| | - In Jun Yeo
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
| | - Dong Ju Son
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
| | - Hee Pom Lee
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
| | - Yoon Seok Roh
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
| | - Key-Hwan Lim
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
| | - Jaesuk Yun
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
| | - Hanseul Park
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
| | - Sang Bae Han
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
| | - Jin Tae Hong
- College of Pharmacy & Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-21, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 28160, Republic of Korea.
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16
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Dincer B, Cinar I, Erol HS, Demirci B, Terzi F. Gossypin mitigates oxidative damage by downregulating the molecular signaling pathway in oleic acid-induced acute lung injury. J Mol Recognit 2023; 36:e3058. [PMID: 37696682 DOI: 10.1002/jmr.3058] [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: 04/20/2023] [Revised: 07/16/2023] [Accepted: 08/29/2023] [Indexed: 09/13/2023]
Abstract
One of the leading causes of acute lung injury, which is linked to a high death rate, is pulmonary fat embolism. Increases in proinflammatory cytokines and the production of free radicals are related to the pathophysiology of acute lung injury. Antioxidants that scavenge free radicals play a protective role against acute lung injury. Gossypin has been proven to have antioxidant, antimicrobial, and anti-inflammatory properties. In this study, we compared the role of Gossypin with the therapeutically used drug Dexamethasone in the acute lung injury model caused by oleic acid in rats. Thirty rats were divided into five groups; Sham, Oleic acid model, Oleic acid+Dexamethasone (0.1 mg/kg), Oleic acid+Gossypin (10 and 20 mg/kg). Two hours after pretreatment with Dexamethasone or Gossypin, the acute lung injury model was created by injecting 1 g/kg oleic acid into the femoral vein. Three hours following the oleic acid injection, rats were decapitated. Lung tissues were extracted for histological, immunohistochemical, biochemical, PCR, and SEM imaging assessment. The oleic acid injection caused an increase in lipid peroxidation and catalase activity, pathological changes in lung tissue, decreased superoxide dismutase activity, and glutathione level, and increased TNF-α, IL-1β, IL-6, and IL-8 expression. However, these changes were attenuated after treatment with Gossypin and Dexamethasone. By reducing the expression of proinflammatory cytokines and attenuating oxidative stress, Gossypin pretreatment provides a new target that is equally effective as dexamethasone in the treatment of oleic acid-induced acute lung injury.
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Affiliation(s)
- Busra Dincer
- Department of Pharmacology, Faculty of Pharmacy, Ondokuz Mayis University, Samsun, Turkey
| | - Irfan Cinar
- Department of Pharmacology, Faculty of Medicine, Kastamonu University, Kastamonu, Turkey
| | - Huseyin Serkan Erol
- Department of Biochemistry, Faculty of Veterinary Medicine, Kastamonu University, Kastamonu, Turkey
| | - Beste Demirci
- Department of Anatomy, Faculty of Veterinary Medicine, Kastamonu University, Kastamonu, Turkey
| | - Funda Terzi
- Department of Pathology, Faculty of Veterinary Medicine, Kastamonu University, Kastamonu, Turkey
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Lin S, Mao X, He W. Causal association of circulating cytokines with sepsis: a Mendelian randomization study. Front Immunol 2023; 14:1281845. [PMID: 37915587 PMCID: PMC10616607 DOI: 10.3389/fimmu.2023.1281845] [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: 08/24/2023] [Accepted: 10/05/2023] [Indexed: 11/03/2023] Open
Abstract
BACKGROUND Observational studies have reported an association between circulating cytokines and sepsis. However, the precise causal relationship between these factors remains unclear. The objective of this study was to explore the causal link between circulating cytokines and sepsis using genetic data within the framework of Mendelian Randomization (MR). METHODS We performed a two-sample MR analysis to investigate this causality relationship in individuals of European ancestry. The publicly available genome-wide association studies (GWAS) statistics were used. We selected eligible instrumental single nucleotide polymorphisms (SNPs) that were significantly related to the circulating cytokines. Multiple MR analysis approaches were carried out, which included inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. RESULTS We found evidence to support the causal role of genetically predicted circulating levels on decreased risk of sepsis, including RANTES (OR = 0.920, 95% CI: 0.849-0.997, P = 0.041) and basic fibroblast growth factor (basic-FGF) (OR = 0.869, 95% CI: 0.766-0.986, P = 0.029). Additionally, MR analysis positive causal association of between beta-nerve growth factor (β-NGF) and sepsis (OR = 1.120, 95% CI: 1.037-1.211, P = 0.004). The results of MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods were consistent with the IVW estimates. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates. CONCLUSION This MR study provides first novel evidence that genetically predicted causal association of circulating levels of RANTES, basic-FGF, and β-NGF with altered sepsis risk. The findings shed light on the potential involvement of these cytokines in sepsis pathogenesis. Although requiring additional confirmation, the results contribute new insights into cytokine mediators in sepsis and suggest promising future research directions.
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Affiliation(s)
- Shan Lin
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Xueyan Mao
- Department of Medical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Wanmei He
- Department of Medical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
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18
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Manandhar S, Chambers S, Miller A, Ishii I, Bhatia M. Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial Cells. Int J Mol Sci 2023; 24:13650. [PMID: 37686458 PMCID: PMC10487872 DOI: 10.3390/ijms241713650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Hydrogen sulfide (H2S), synthesized by cystathionine gamma-lyase (Cth), contributes to the inflammatory response observed in sepsis. This study examines the effect of Cth-derived H2S in adhesion molecules on endothelial cells of vital organs in mice in a cecal ligation puncture (CLP)-induced model of sepsis, using two different and complementary approaches: Cth gene deletion and pharmacological inhibition. Our findings revealed a decreased level of H2S-synthesizing activity (via Cth) in both Cth-/- mice and PAG-treated wild-type (WT) mice following CLP-induced sepsis. Both treatment groups had reduced MPO activity and expression of chemokines (MCP-1 and MIP-2α), adhesion molecules (ICAM-1 and VCAM-1), ERK1/2 phosphorylation, and NF-κB in the liver and lung compared with in CLP-WT mice. Additionally, we found that PAG treatment in Cth-/- mice had no additional effect on the expression of ERK1/2 phosphorylation, NF-κB, or the production of chemokines and adhesion molecules in the liver and lung compared to Cth-/- mice following CLP-induced sepsis. The WT group with sepsis had an increased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung than the WT sham-operated control. The Cth-/-, PAG-treated WT, and Cth-/- groups of mice showed decreased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung following sepsis. Inhibition of H2S production via both approaches reduced adhesion molecule expression on endothelial cells and reduced liver and lung injury in mice with sepsis. In conclusion, this study demonstrates that H2S has an important role in the pathogenesis of sepsis and validates PAG use as a suited tool for investigating the Cth/H2S-signalling axis in sepsis.
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Affiliation(s)
- Sumeet Manandhar
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (S.M.); (S.C.); (A.M.)
| | - Stephen Chambers
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (S.M.); (S.C.); (A.M.)
| | - Andrew Miller
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (S.M.); (S.C.); (A.M.)
| | - Isao Ishii
- Department of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan;
| | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (S.M.); (S.C.); (A.M.)
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19
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Hussain J, Ousley CG, Krauklis SA, Dray EL, Drnevich J, McKim DB. Prophylactic simvastatin increased survival during endotoxemia and inhibited granulocyte trafficking in a cell-intrinsic manner. Immunobiology 2023; 228:152411. [PMID: 37329824 DOI: 10.1016/j.imbio.2023.152411] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/02/2023] [Accepted: 06/02/2023] [Indexed: 06/19/2023]
Abstract
Cross sectional studies have shown that statin-users have improved odds of surviving severe sepsis. Meanwhile controlled clinical trials failed to demonstrate improved sepsis survival with acute statin administration following hospitalization. Here, a lethal murine peritoneal lipopolysaccharide (LPS) endotoxemia model was used to assess the efficacy of chronic versus acute simvastatin on survival. Mirroring clinical observations, chronic but not acute treatment with simvastatin significantly increased survival. At a pre-mortality time point in LPS-treated mice, chronic simvastatin suppressed granulocyte trafficking in to the lungs and peritoneum without otherwise suppressing emergency myelopoiesis, myeloid cells in circulation, or inflammatory cytokines. Chronic simvastatin treatment significantly downregulated inflammatory chemokine gene signature in the lungs of LPS-treated mice. Thus, it was unclear if simvastatin was inhibiting granulocyte chemotaxis in a cell intrinsic or extrinsic manner. Adoptive transfer of fluorescently labeled granulocytes from statin and vehicle treated mice into LPS-treated mice showed that simvastatin inhibited lung-granulocyte trafficking in a cell intrinsic manner. Congruent with this, chemotaxis experiments using in vitro macrophages and ex vivo granulocytes demonstrated that simvastatin inhibited chemotaxis in a cell-intrinsic manner. Collectively, chronic but not acute simvastatin treatment improved survival in murine endotoxemia, and this was associated with cell-intrinsic inhibition of granulocyte chemotaxis.
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Affiliation(s)
- Jamal Hussain
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, United States; Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, United States
| | - Carey G Ousley
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, United States
| | - Steven A Krauklis
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, United States; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, United States
| | - Evan L Dray
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, United States
| | - Jenny Drnevich
- Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign, United States
| | - Daniel B McKim
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, United States; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, United States; Neuroscience Program, University of Illinois at Urbana-Champaign, United States; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, United States; Beckman Institute, University of Illinois at Urbana-Champaign, United States.
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Yilmaz S, Doğanyiğit Z, Oflamaz AO, Ateş Ş, Uçar S, Söylemez ESA. Detection of melatonin protective effects in sepsis via argyrophilic nucleolar regulatory region-associated protein synthesis and TLR4/NF-κB signaling pathway. Chem Biol Drug Des 2023; 101:915-926. [PMID: 36546873 DOI: 10.1111/cbdd.14199] [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: 11/17/2022] [Revised: 11/30/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
In this study, the protective effect of melatonin was investigated in lipopolysaccharide induced sepsis model. Twenty-eight rats were randomly divided: Control, Melatonin, LPS and LPS + Melatonin. After LPS application, surgically remove kidney and liver tissues. The level of malondialdehyde (MDA) an oxidative stress marker and the immunoreactivity of Toll-like receptor-4 (TLR4), tumor necrosis factor-α (TNF-α), and transcription factor NF-κB were evaluated immunohistochemically. Expression levels for TLR4, TNF-α, NF-kB, IL-1β (interleukin 1 beta), and IL-6 (interleukin 6) were evaluated. Additionally, Argyrophilic NOR staining was performed in tissues. Vacuolization and inflammation were more intense in the kidney and liver sections in the LPS group compared to the other groups. It was observed that vacuolization and inflammation were decreased in LPS + Melatonin applied groups. It was determined that glomerular damage was increased in the LPS and LPS-melatonin groups, but the damage rate LPS-Melatonin group was decrease in the LPS group. It was determined that the MDA level in tissues of the LPS group was importantly increased compared to other groups. Additionally, TAA/NA ratio statistically significant differences were discovered between the groups. This study supports the potential protective effects of 10 mg/kg melatonin by modulating critical markers of local immune reaction in a model of LPS-induced sepsis.
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Affiliation(s)
- Seher Yilmaz
- Department of Anatomy, Faculty of Medicine, Yozgat Bozok University, Yozgat, Turkey
| | - Züleyha Doğanyiğit
- Department of Histology and Embriology, Faculty of Medicine, Yozgat Bozok University, Yozgat, Turkey
| | - Aslı Okan Oflamaz
- Department of Histology and Embriology, Faculty of Medicine, Yozgat Bozok University, Yozgat, Turkey
| | - Şükrü Ateş
- Department of Anatomy, Faculty of Medicine, Yozgat Bozok University, Yozgat, Turkey
| | - Sümeyye Uçar
- Department of Anatomy, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Evrim Suna Arıkan Söylemez
- Department of Medical Biology, Faculty of Medicine, Afyonkarahisar Health Sciences University, Afyon, Turkey
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21
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Al Shawous A, Soliman A, Fahmy S, Mohamed A. Therapeutic Efficacy of Anodonta cygnea and Crayfish Procambarus clarkii Hemolymph Extracts on Sepsis-Induced Acute Liver Injury in Neonate Rats. INT J PHARMACOL 2023. [DOI: 10.3923/ijp.2023.185.196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023]
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22
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Mehta Y, Paul R, Ansari AS, Banerjee T, Gunaydin S, Nassiri AA, Pappalardo F, Premužić V, Sathe P, Singh V, Vela ER. Extracorporeal blood purification strategies in sepsis and septic shock: An insight into recent advancements. World J Crit Care Med 2023; 12:71-88. [PMID: 37034019 PMCID: PMC10075046 DOI: 10.5492/wjccm.v12.i2.71] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/05/2023] [Accepted: 02/17/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Despite various therapies to treat sepsis, it is one of the leading causes of mortality in the intensive care unit patients globally. Knowledge about the pathophysiology of sepsis has sparked interest in extracorporeal therapies (ECT) which are intended to balance the dysregulation of the immune system by removing excessive levels of inflammatory mediators.
AIM To review recent data on the use of ECT in sepsis and to assess their effects on various inflammatory and clinical outcomes.
METHODS In this review, an extensive English literature search was conducted from the last two decades to identify the use of ECT in sepsis. A total of 68 articles from peer-reviewed and indexed journals were selected excluding publications with only abstracts.
RESULTS Results showed that ECT techniques such as high-volume hemofiltration, coupled plasma adsorption/filtration, resin or polymer adsorbers, and CytoSorb® are emerging as adjunct therapies to improve hemodynamic stability in sepsis. CytoSorb® has the most published data in regard to the use in the field of septic shock with reports on improved survival rates and lowered sequential organ failure assessment scores, lactate levels, total leucocyte count, platelet count, interleukin- IL-6, IL-10, and TNF levels.
CONCLUSION Clinical acceptance of ECT in sepsis and septic shock is currently still limited due to a lack of large random clinical trials. In addition to patient-tailored therapies, future research developments with therapies targeting the cellular level of the immune response are expected.
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Affiliation(s)
- Yatin Mehta
- Institute of Critical Care and Anesthesiology, Medanta the Medicity, Gurugram 12201, India
| | - Rajib Paul
- Department of Internal Medicine, Apollo Hospitals, Jubilee Hills, Hyderabad 500033, India
| | - Abdul Samad Ansari
- Department of Critical Care, Nanavati Max Super Specialty Hospital, Mumbai 400065, India
| | - Tanmay Banerjee
- Department of Internal Medicine & Critical Care, Medica Institute of Critical Care Medicine, Medica Superspecialty Hospital, Kolkata 700099, India
| | - Serdar Gunaydin
- Department of Cardiovascular Surgery, University of Health Sciences, Ankara City Hospital Campus, Ankara 06933, Turkey
| | - Amir Ahmad Nassiri
- Department of Nephrology, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Federico Pappalardo
- Cardiothoracic and Vascular Anesthesia and Intensive Care, AO SS Antonio e Biagio e Cesare Arrigo, Alessandria 15121, Italy
| | - Vedran Premužić
- Department of Nephrology, Clinical Hospital Zagreb, Clinic for internal diseases, Zagreb 10000, Croatia
| | - Prachee Sathe
- Department of Critical Care Medicine, D.Y. Patil Medical College, Sant Tukaram Nagar, Pimpri Colony, Pimpri-Chinchwad, Pune 411018, India
| | - Vinod Singh
- Department of Critical Care Medicine, Institute of critical care Medicine, Hospital Name - Sir Ganga Ram Hospital, New Delhi 110001, India
| | - Emilio Rey Vela
- Cardiac Surgery Intensive Care Unit, Samaritan University Hospital, Bogotá 11, Colombia
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23
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Prado Y, Echeverría C, Feijóo CG, Riedel CA, Cabello-Verrugio C, Santibanez JF, Simon F. Effect of Dietary Supplements with ω-3 Fatty Acids, Ascorbic Acid, and Polyphenolic Antioxidant Flavonoid on Gene Expression, Organ Failure, and Mortality in Endotoxemia-Induced Septic Rats. Antioxidants (Basel) 2023; 12:659. [PMID: 36978907 PMCID: PMC10044831 DOI: 10.3390/antiox12030659] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/03/2023] [Accepted: 03/04/2023] [Indexed: 03/09/2023] Open
Abstract
Sepsis syndrome develops through enhanced secretion of pro-inflammatory cytokines and the generation of reactive oxygen species (ROS). Sepsis syndrome is characterized by vascular hyperpermeability, hypotension, multiple organ dysfunction syndrome (MODS), and increased mortality, among others. Endotoxemia-derived sepsis is an important cause of sepsis syndrome. During endotoxemia, circulating endotoxin interacts with endothelial cells (ECs), inducing detrimental effects on endothelium function. The endotoxin induces the conversion of ECs into fibroblasts, which are characterized by a massive change in the endothelial gene-expression pattern. This downregulates the endothelial markers and upregulates fibrotic proteins, mesenchymal transcription factors, and extracellular matrix proteins, producing endothelial fibrosis. Sepsis progression is modulated by the consumption of specific nutrients, including ω-3 fatty acids, ascorbic acid, and polyphenolic antioxidant flavonoids. However, the underlying mechanism is poorly described. The notion that gene expression is modulated during inflammatory conditions by nutrient consumption has been reported. However, it is not known whether nutrient consumption modulates the fibrotic endothelial gene-expression pattern during sepsis as a mechanism to decrease vascular hyperpermeability, hypotension, MODS, and mortality. Therefore, the aim of this study was to investigate the impact of the consumption of dietary ω-3 fatty acids, ascorbic acid, and polyphenolic antioxidant flavonoid supplements on the modulation of fibrotic endothelial gene-expression patterns during sepsis and to determine the effects on sepsis outcomes. Our results indicate that the consumption of supplements based on ω-3 fatty acids and polyphenolic antioxidant flavonoids was effective for improving endotoxemia outcomes through prophylactic ingestion and therapeutic usage. Thus, our findings indicated that specific nutrient consumption improves sepsis outcomes and should be considered in treatment.
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Affiliation(s)
- Yolanda Prado
- Laboratory of Integrative Physiopathology, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8331150, Chile
| | - Cesar Echeverría
- Laboratory of Molecular Biology, Nanomedicine and Genomics, Faculty of Medicine, University of Atacama, Copiapo 1532502, Chile
| | - Carmen G. Feijóo
- Fish Immunology Laboratory, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile
| | - Claudia A. Riedel
- Millennium Institute on Immunology and Immunotherapy, Santiago 8331150, Chile
- Laboratory of Endocrinology-Immunology, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile
| | - Claudio Cabello-Verrugio
- Millennium Institute on Immunology and Immunotherapy, Santiago 8331150, Chile
- Laboratory of Muscle Pathology, Fragility and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
| | - Juan F. Santibanez
- Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia
- Integrative Center for Biology and Applied Chemistry (CIBQA), Bernardo O’Higgins University, Santiago 8370993, Chile
| | - Felipe Simon
- Laboratory of Integrative Physiopathology, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8331150, Chile
- Millennium Nucleus of Ion Channel-Associated Diseases, Santiago 8380453, Chile
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Wu Y, Wang G, Huang Z, Yang B, Yang T, Liu J, Li P, Li J. Diagnostic and therapeutic value of biomarkers in urosepsis. Ther Adv Urol 2023; 15:17562872231151852. [PMID: 36744043 PMCID: PMC9893402 DOI: 10.1177/17562872231151852] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 01/03/2023] [Indexed: 02/02/2023] Open
Abstract
Urosepsis is sepsis caused by urogenital tract infection and is one of the most common critical illnesses in urology. If urosepsis is not diagnosed early, it can rapidly progress and worsen, leading to increased mortality. In recent years, with the increase of urinary tract surgery, the incidence of urosepsis continues to rise, posing a serious threat to patients. Early diagnosis of urosepsis, timely and effective treatment can greatly reduce the mortality of patients. Biomarkers such as WBC, NLR, PCT, IL-6, CRP, lactate, and LncRNA all play specific roles in the early diagnosis or prognosis of urosepsis. In addition to the abnormal increase of WBC, we should be more alert to the rapid decline of WBC. NLR values were superior to WBC counts alone in predicting infection severity. Compared with several other biomarkers, PCT values can differentiate between bacterial and non-bacterial sepsis. IL-6 always has high sensitivity and specificity for the diagnosis of sepsis, and CRP also has high sensitivity and specificity for the diagnosis of urosepsis. Lactic acid is closely related to the prognosis of patients with urosepsis. LncRNAs may be potential biomarkers of urosepsis. This article summarizes the main biomarkers, hoping to provide a reference for the timely diagnosis and evaluation of urosepsis.
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Affiliation(s)
| | | | - Ziye Huang
- The Department of Urology, The Second
Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R.
China
| | - Bowei Yang
- The Department of Urology, The Second
Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R.
China
| | - Tongxin Yang
- The Department of Urology, The Second
Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R.
China
| | - Jianhe Liu
- The Department of Urology, The Second
Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R.
China
| | - Pei Li
- The Department of Urology, The Second
Affiliated Hospital of Kunming Medical University, No. 374 Dian-Mian Avenue,
Kunming 650101, Yunnan, P.R. China
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25
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A Novel Scientometrics Research on the Interaction between Oxidative Stress and Hematopoietic Stem Cell Transplantation Complications: From Graft-versus-Host Disease to Sepsis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:7708085. [PMID: 36743696 PMCID: PMC9897927 DOI: 10.1155/2023/7708085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/07/2022] [Accepted: 11/24/2022] [Indexed: 01/30/2023]
Abstract
As major and serious complications after hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) and sepsis are the chief causes of low survival rates as well as mortality and for HSCT recipients. Although the overall treatment outcomes of HSCT have improved significantly in recent years, there is still an increased incidence rate of complications and mortality after transplantation. In the immediate past, with a deeper understanding of oxidative stress, more and more shreds of evidence have shown that it is closely related to transplantation-related sepsis. However, there is currently a precious little research on the interaction between oxidative stress and complications after HSCT, and the major mechanism has not yet been clarified. The objective of this study was to assess the internal connection between and potential mechanisms as well as visualized the scientometrics results of all important literature related to the topic. Through exhaustive scientometrics analysis, we searched and carefully screened 286 related publications from the Web of Science Core Collection (WoSCC) with "((HSCT) OR (hematopoietic stem cell transplantation)) AND (oxidative stress)" as the search strategy. Then, detailed visualization of the overall information analysis was made by scientific and rigorous bibliometrics software or website. Next, we analyzed retrieved articles extensively and then 59 publications that are relevant to this topic were selected for nuanced analysis and summary. The assessment of these studies proved the validity of the interaction between oxidative stress and complications after HSCT objectively and directly.
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26
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Xu S, Cai J, Doomi A, Shi J. A prognostic assessment predicated by blood culture-based bacteria clustering from real-world evidence: Novel strategies and perspectives on prevention and management of sepsis. Front Mol Biosci 2023; 10:1160146. [PMID: 37065451 PMCID: PMC10098072 DOI: 10.3389/fmolb.2023.1160146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 03/17/2023] [Indexed: 04/18/2023] Open
Abstract
Sepsis, a syndrome with disturbed host response to severe infection, is a critical health problem worldwide. It is urged to develop and update novel therapeutic strategies for improving the outcome of sepsis. In this study, we demonstrated that different bacteria clustering in sepsis patients may generate differences of prognosis results. We extracted all the sepsis patients from Medical Information Mart for Intensive Care IV 2.0 (MIMIC-IV 2.0) critical care data set according to certain standards and clinical score, a total of 2,339 patients were included in our study. Then we used multiple data analytics and machine learning methods to make all data deeply analyzed and elucidated. The results showed that the types of bacteria infected by patients with different ages, sex and race are different, the types of bacteria infected by patients with different SIRS values and GCS scores of the first day are different, and the severity of patients with different clusters is different, and most importantly, the survival rate of patients with different clusters also has this significant difference. We concluded prognostic assessment predicated by bacteria clustering might be a relatively potentially novel strategies and perspectives on prevention and management for sepsis in the future.
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Affiliation(s)
- Shaokang Xu
- Department of Hematology and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jizhen Cai
- Department of Hematology and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ahmed Doomi
- Miller School of Medicine, University of Miami, Miami, FL, United States
- Jackson Memorial Hospital, Miami, FL, United States
| | - Jian Shi
- Department of Hematology and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Jian Shi,
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27
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Consoli DC, Spitznagel BD, Owen BM, Kang H, Williams Roberson S, Pandharipande P, Wesley Ely E, Nobis WP, Bastarache JA, Harrison FE. Altered EEG, disrupted hippocampal long-term potentiation and neurobehavioral deficits implicate a delirium-like state in a mouse model of sepsis. Brain Behav Immun 2023; 107:165-178. [PMID: 36243287 PMCID: PMC10010333 DOI: 10.1016/j.bbi.2022.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 09/26/2022] [Accepted: 10/09/2022] [Indexed: 11/06/2022] Open
Abstract
Sepsis and systemic inflammation are often accompanied by severe encephalopathy, sleep disruption and delirium that strongly correlate with poor clinical outcomes including long-term cognitive deficits. The cardinal manifestations of delirium are fluctuating altered mental status and inattention, identified in critically ill patients by interactive bedside assessment. The lack of analogous assessments in mouse models or clear biomarkers is a challenge to preclinical studies of delirium. In this study, we utilized concurrent measures of telemetric EEG recordings and neurobehavioral tasks in mice to characterize inattention and persistent cognitive deficits following polymicrobial sepsis. During the 24-hour critical illness period for the mice, slow-wave EEG dominance, sleep disruption, and hypersensitivity to auditory stimuli in neurobehavioral tasks resembled clinical observations in delirious patients in which alterations in similar outcome measurements, although measured differently in mice and humans, are reported. Mice were tested for nest building ability 7 days after sepsis induction, when sickness behaviors and spontaneous activity had returned to baseline. Animals that showed persistent deficits determined by poor nest building at 7 days also exhibited molecular changes in hippocampal long-term potentiation compared to mice that returned to baseline cognitive performance. Together, these behavioral and electrophysiological biomarkers offer a robust mouse model with which to further probe molecular pathways underlying brain and behavioral changes during and after acute illness such as sepsis.
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Affiliation(s)
- David C Consoli
- Vanderbilt University Medical Center, 7465 MRB4, Nashville, TN 37232, USA
| | | | - Benjamin M Owen
- Vanderbilt University Medical Center, 7465 MRB4, Nashville, TN 37232, USA
| | - Hakmook Kang
- Vanderbilt University Medical Center, 7465 MRB4, Nashville, TN 37232, USA
| | | | | | - E Wesley Ely
- Vanderbilt University Medical Center, 7465 MRB4, Nashville, TN 37232, USA
| | - William P Nobis
- Vanderbilt University Medical Center, 7465 MRB4, Nashville, TN 37232, USA
| | - Julie A Bastarache
- Vanderbilt University Medical Center, 7465 MRB4, Nashville, TN 37232, USA
| | - Fiona E Harrison
- Vanderbilt University Medical Center, 7465 MRB4, Nashville, TN 37232, USA.
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28
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Soni M, Handa M, Singh KK, Shukla R. Recent nanoengineered diagnostic and therapeutic advancements in management of Sepsis. J Control Release 2022; 352:931-945. [PMID: 36273527 PMCID: PMC9665001 DOI: 10.1016/j.jconrel.2022.10.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/15/2022] [Accepted: 10/17/2022] [Indexed: 11/17/2022]
Abstract
COVID-19 acquired symptoms have affected the worldwide population and increased the load of Intensive care unit (ICU) patient admissions. A large number of patients admitted to ICU end with a deadly fate of mortality. A high mortality rate of patients was reported with hospital-acquired septic shock that leads to multiple organ failures and ultimately ends with death. The patients who overcome this septic shock suffer from morbidity that also affects their caretakers. To overcome these situations, scientists are exploring progressive theragnostic techniques with advanced techniques based on biosensors, biomarkers, biozymes, vesicles, and others. These advanced techniques pave the novel way for early detection of sepsis-associated symptoms and timely treatment with appropriate antibiotics and immunomodulators and prevent the undue effect on other parts of the body. There are other techniques like externally modulated electric-based devices working on the principle of piezoelectric mechanism that not only sense the endotoxin levels but also target them with a loaded antibiotic to neutralize the onset of inflammatory response. Recently researchers have developed a lipopolysaccharide (LPS) neutralizing cartridge that not only senses the LPS but also appropriately neutralizes with dual mechanistic insights of antibiotic and anti-inflammatory effects. This review will highlight recent developments in the new nanotechnology-based approaches for the diagnosis and therapeutics of sepsis that is responsible for the high number of deaths of patients suffering from this critical disease.
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Affiliation(s)
- Mukesh Soni
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, U.P., India
| | - Mayank Handa
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, U.P., India
| | - Kamalinder K. Singh
- School of Pharmacy and Biomedical Sciences, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK,Correspondence to: Prof. Kamalinder K. Singh, School of Pharmacy and Biomedical Sciences, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, United Kingdom
| | - Rahul Shukla
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, U.P., India,School of Pharmacy and Biomedical Sciences, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK,Correspondence to: Dr. Rahul Shukla (M. Pharm. PhD), National Institute of Pharmaceutical Education and Research (NIPER-Raebareli), Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow 226002, UP, India
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29
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Gong J, Yang J, He Y, Chen X, Yang G, Sun R. Construction of m7G subtype classification on heterogeneity of sepsis. Front Genet 2022; 13:1021770. [PMID: 36506322 PMCID: PMC9729242 DOI: 10.3389/fgene.2022.1021770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 10/31/2022] [Indexed: 11/27/2022] Open
Abstract
Sepsis is a highly heterogeneous disease and a major factor in increasing mortality from infection. N7-Methylguanosine (m7G) is a widely RNA modification in eukaryotes, which involved in regulation of different biological processes. Researchers have found that m7G methylation contributes to a variety of human diseases, but its research in sepsis is still limited. Here, we aim to establish the molecular classification of m7G gene-related sepsis, reveal its heterogeneity and explore the underlying mechanism. We first identified eight m7G related prognostic genes, and identified two different molecular subtypes of sepsis through Consensus Clustering. Among them, the prognosis of C2 subtype is worse than that of C1 subtype. The signal pathways enriched by the two subtypes were analyzed by ssGSEA, and the results showed that the amino acid metabolism activity of C2 subtype was more active than that of C1 subtype. In addition, the difference of immune microenvironment among different subtypes was explored through CIBERSORT algorithm, and the results showed that the contents of macrophages M0 and NK cells activated were significantly increased in C2 subtype, while the content of NK cells resting decreased significantly in C2 subtype. We further explored the relationship between immune regulatory genes and inflammation related genes between C2 subtype and C1 subtype, and found that C2 subtype showed higher expression of immune regulatory genes and inflammation related genes. Finally, we screened the key genes in sepsis by WGCNA analysis, namely NUDT4 and PARN, and verified their expression patterns in sepsis in the datasets GSE131761 and GSE65682. The RT-PCR test further confirmed the increased expression of NUDTA4 in sepsis patients. In conclusion, sepsis clustering based on eight m7G-related genes can well distinguish the heterogeneity of sepsis patients and help guide the personalized treatment of sepsis patients.
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Affiliation(s)
- Jinru Gong
- Department of Pulmonary and Critical Care Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Jiasheng Yang
- Department of Pulmonary and Critical Care Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Yaowei He
- Department of Pulmonary and Critical Care Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Xiaoxuan Chen
- Department of Pulmonary and Critical Care Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Guangyu Yang
- Department of Pulmonary and Critical Care Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Ruilin Sun
- Department of Pulmonary and Critical Care Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China,*Correspondence: Ruilin Sun,
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30
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Baig H, Al Tell T, Ashraf MH, Al Failakawi A, Khan QI, Nasar AM, Lucocq J. The Variation in Outcomes of Septic Patients: A Dual-Centre Comparative Study. Cureus 2022; 14:e30677. [PMID: 36439613 PMCID: PMC9689890 DOI: 10.7759/cureus.30677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2022] [Indexed: 06/16/2023] Open
Abstract
Introduction Despite significant advances in the field of medicine, sepsis is constantly growing as a major public health concern. The global epidemic of sepsis imposes a significant economic burden on healthcare systems world-over. Furthermore, its high prevalence in society is inevitably paralleled by an excessive mortality rate, with approximately six million deaths reported every year. The primary aim of this study was to evaluate and compare, the management of acutely septic patients against outcomes in a tertiary teaching institution in Pakistan versus a similar one in the United Kingdom. Methods This study was a dual-centred, retrospective comparative analysis comparing all patients admitted through the emergency department at the respective tertiary centres. Patient details were collected and compared across the two sites to evaluate the effect of individual characteristics on prognosis. The outcomes of these presentations were analysed by comparing rates of in-hospital mortality, admission to the ICU or discharge. Results The total number of patients identified as having sepsis was 60 in the Pakistan cohort, and 92 in the Aberdeen cohort. No significant difference was found when comparing genders, and the results of basic observations were largely similar at presentation. Twenty-five per cent (25%) (n=38) of the total study population were deemed to have a poor outcome at 3 days, but 50% of the Pakistan cohort was deemed to have a poor outcome. Conclusion Managing sepsis has developed significantly in recent years, but most of this development was implemented in high-income countries. There was a significant delay in time to resuscitate septic patients in Pakistan, with significantly raised three-day morbidity and mortality. There is a need for further comparative studies of the management of sepsis in Pakistan and other low-income countries to identify the problems and tackle obstacles on every level of the healthcare system.
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Affiliation(s)
- Hassan Baig
- Department of Otorhinolaryngology, Queen Elizabeth University Hospital, Glasgow, GBR
| | - Tareq Al Tell
- Department of Trauma and Orthopaedics, Glasgow Royal Infirmary, Glasgow, GBR
| | | | - Abdulaziz Al Failakawi
- Department of General Surgery, Sabah Hospital, Kuwait, KWT
- Department of Medical Education, University of Aberdeen, Aberdeen, GBR
| | - Qaisar I Khan
- Department of Medical Education, University of Glasgow, Glasgow, GBR
- Department of General Surgery, Queen Elizabeth University Hospital, Glasgow, GBR
| | - Ahmed M Nasar
- Department of Trauma and Orthopaedics, Queen Elizabeth University Hospital, Glasgow, GBR
| | - James Lucocq
- Department of General Surgery, Victoria Hospital, Kirkcaldy, GBR
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Immunomodulation by Hemoadsorption—Changes in Hepatic Biotransformation Capacity in Sepsis and Septic Shock: A Prospective Study. Biomedicines 2022; 10:biomedicines10102340. [PMID: 36289602 PMCID: PMC9598581 DOI: 10.3390/biomedicines10102340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/26/2022] Open
Abstract
Background: Sepsis is often associated with liver dysfunction, which is an indicator of poor outcomes. Specific diagnostic tools that detect hepatic dysfunction in its early stages are scarce. So far, the immune modulatory effects of hemoadsorption with CytoSorb® on liver function are unclear. Method: We assessed the hepatic function by using the dynamic LiMAx® test and biochemical parameters in 21 patients with sepsis or septic shock receiving CytoSorb® in a prospective, observational study. Points of measurement: T1: diagnosis of sepsis or septic shock; T2 and T3: 24 h and 48 h after the start of CytoSorb®; T4: 24 h after termination of CytoSorb®. Results: The hepatic biotransformation capacity measured by LiMAx® was severely impaired in up to 95 % of patients. Despite a rapid shock reversal under CytoSorb®, a significant improvement in LiMAx® values appeared from T3 to T4. This decline and recovery of liver function were not reflected by common parameters of hepatic metabolism that remained mostly within the normal range. Conclusions: Hepatic dysfunction can effectively and safely be diagnosed with LiMAx® in ventilated ICU patients under CytoSorb®. Various static liver parameters are of limited use since they do not adequately reflect hepatic dysfunction and impaired hepatic metabolism.
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32
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Praxenthaler J, Kirchner C, Schwier E, Altmann S, Wittmer A, Henzler D, Köhler T. Case report: Early detection of mesenteric ischemia by intravital microscopy in a patient with septic shock. Front Med (Lausanne) 2022; 9:985977. [PMID: 36091703 PMCID: PMC9458872 DOI: 10.3389/fmed.2022.985977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/04/2022] [Indexed: 11/17/2022] Open
Abstract
Gut ischemia is a frequent but underdiagnosed complication, especially in critically ill intensive care patients, and represents a special diagnostic challenge that can only be solved in an interdisciplinary manner. We report a case of a 54-year-old woman with acute mesenteric ischemia (AMI) as a cause of septic shock diagnosed by intravital microscopy (IVM) 2 days before visible necrotic changes in a multimodality approach. We show that intravital microscopy can be a serious alternative for the early diagnosis of mesenteric ischemia in the hands of the skilled. We use this case to discuss the value and clinical perspective of IVM in the intensive care setting.
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Affiliation(s)
- Janina Praxenthaler
- Department of Anesthesiology, Surgical Intensive Care, Emergency and Pain Medicine, Klinikum Herford, Ruhr University Bochum, Herford, Germany
- Department of Anesthesiology, Intensive Care and Pain Medicine, Kliniken Südostbayern, Klinikum Traunstein, Traunstein, Germany
| | - Carmen Kirchner
- Department of General and Visceral Surgery, Thoracic Surgery and Proctology, Klinikum Herford, Ruhr University Bochum, Herford, Germany
| | - Elke Schwier
- Department of Anesthesiology, Surgical Intensive Care, Emergency and Pain Medicine, Klinikum Herford, Ruhr University Bochum, Herford, Germany
| | - Simon Altmann
- Department of Anesthesiology, Surgical Intensive Care, Emergency and Pain Medicine, Klinikum Herford, Ruhr University Bochum, Herford, Germany
- Department of Anesthesiology, Intensive Care and Pain Medicine, Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Bochum, Germany
| | - Axel Wittmer
- Institute of Pathology, Klinikum Herford, Herford, Germany
| | - Dietrich Henzler
- Department of Anesthesiology, Surgical Intensive Care, Emergency and Pain Medicine, Klinikum Herford, Ruhr University Bochum, Herford, Germany
| | - Thomas Köhler
- Department of Anesthesiology, Surgical Intensive Care, Emergency and Pain Medicine, Klinikum Herford, Ruhr University Bochum, Herford, Germany
- Department of Anesthesiology and Intensive Care Medicine, AMEOS-Klinikum Halberstadt, Halberstadt, Germany
- *Correspondence: Thomas Köhler,
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Ye M, Zhao Y, Wang Y, Xie R, Tong Y, Sauer JD, Gong S. NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis. NATURE NANOTECHNOLOGY 2022; 17:880-890. [PMID: 35668170 PMCID: PMC10044491 DOI: 10.1038/s41565-022-01137-w] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 04/08/2022] [Indexed: 05/14/2023]
Abstract
Sepsis is a life-threatening organ dysfunction responsible for nearly 270,000 deaths annually in the United States alone. Nicotinamide adenine dinucleotide (NAD+), an immunomodulator, can potentially treat sepsis; however, clinical application of NAD+ is hindered by its inability to be directly taken up by cells. To address this challenge, a family of nanoparticles (NPs) loaded with either NAD+ or the reduced form of NAD+ (NADH), hereafter NAD(H)-loaded NPs, were engineered to enable direct cellular transport and replenishment of NAD(H). The NAD(H)-loaded NPs improved cellular energy supply, suppressed inflammation and prevented inflammation-induced cell pyroptosis and apoptosis. Therefore, the NPs can help maintain immune homoeostasis and vascular function, two key factors in the pathogenesis of sepsis. The NAD(H)-loaded NPs demonstrated excellent therapeutic efficacies in treating endotoxemia and multidrug-resistant pathogen-induced bacteremia. In addition, the NAD(H)-loaded NPs prevented caecal ligation and puncture-induced multiorgan injury and improved outcomes of secondary Pseudomonas aeruginosa infections following caecal ligation and puncture, thus potentially leading to a highly innovative and translational approach to treat sepsis efficiently and safely.
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Affiliation(s)
- Mingzhou Ye
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Yi Zhao
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Yuyuan Wang
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Ruosen Xie
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Yao Tong
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - John-Demian Sauer
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA
| | - Shaoqin Gong
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA.
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA.
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Efficacy of High-Dose Vitamin C Infusion on Outcomes in Sepsis Requiring Mechanical Ventilation: A Double-Blind Randomized Controlled Trial. Anesthesiol Res Pract 2022; 2022:4057215. [PMID: 35873893 PMCID: PMC9307402 DOI: 10.1155/2022/4057215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 06/15/2022] [Indexed: 11/17/2022] Open
Abstract
Background. Critically ill patients have an increased requirement for vitamin C in sepsis and these patients have low levels of vitamin C. The researchers validated the efficacy of high-dose vitamin C intravenous infusion (IVI) in patients with sepsis requiring mechanical ventilation. Methods. Forty patients were randomly assigned to 2 groups (20 each) in a 1 : 1 ratio in accordance with the vitamin C treatment regimen: Group I (GI): patients received 1.5 g/6 h vitamin C in 50 ml of dextrose 5% in water (D5W) IVI over 30 minutes for 4 consecutive days; Group II (GII): patients received 100 mg vitamin C/day as a first single dose in 50 ml of D5W IVI over 30 minutes and the other three subsequent doses were 50 ml of plain D5W IVI over 30 minutes for 4 consecutive days. Primary outcomes were the change in sequential organ failure assessment (SOFA) score at day 7, the incidence of ventilator-associated pneumonia (VAP), and the plasma vitamin C level. The glutathione peroxidase (GPX) activity, C-reactive protein (CRP) level, duration of vasopressor therapy, and 28-day mortality were secondary outcomes. Results. The change in SOFA score at day 7 showed a significant difference between GI and GII (
). The incidence of early VAP was significantly lower in GI (
). Vitamin C levels showed a significant rise in GI at day 1 and day 4 (
and
, respectively). GPX activity of day 4 and day 7 was significantly higher in GI (
and
, respectively). CRP levels of day 4 and day 7 were significantly higher in GII (
and
, respectively). There was a significant difference in 28-day mortality (
) and duration of vasopressor therapy (
) in GI compared to GII. Conclusion. The early use of high-dose vitamin C intravenous infusion in patients with sepsis requiring mechanical ventilation in combination with the standard treatment for sepsis lowered the incidence of VAP, increased the antioxidant status, and improved the illness severity. Trial Registration. This trial is registered with ClinicalTrials.gov Identifier (NCT04029675).
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Mo K, Gupta A, Al Farii H, Raad M, Musharbash F, Tran B, Zheng M, Lee SH. 30-day postoperative sepsis risk factors following laminectomy for intradural extramedullary tumors. JOURNAL OF SPINE SURGERY (HONG KONG) 2022; 8:204-213. [PMID: 35875628 PMCID: PMC9263737 DOI: 10.21037/jss-22-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/19/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Posterior laminectomy (LA) for resection of intradural extramedullary tumors (IDEMTs) is associated with postoperative complications, including sepsis. Sepsis is an uncommon but serious complication that can lead to increased morbidity and mortality, prolonged hospital stays, and greater costs. Given the susceptibility of a solid tumor patients to sepsis-related complications, it is important to recognize IDEMT patients as a unique population when assessing the risk factors for sepsis after laminectomy. METHODS The study design was a retrospective cohort study. Adult patients undergoing LA for IDEMTs from 2012 to 2018 were identified in the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database. Baseline patient characteristics/comorbidities, operative and hospital variables, and 30-day postoperative complications were collected. RESULTS Of 2,027 total patients undergoing LA for IDEMTs, 38 (2%) had postoperative sepsis. On bivariate analysis sepsis was associated with superficial surgical site infection [odds ratio (OR) 11.62, P<0.001], deep surgical site infection (OR 10.67, P<0.001), deep vein thrombosis (OR 10.75, P<0.001), pulmonary embolism (OR 15.27, P<0.001), transfusion (OR 6.18, P<0.001), length of stay greater than five days (OR 5.41, P<0.001), and return to the operating room within thirty days (OR 8.72, P<0.001). Subsequent multivariate analysis identified the following independent risk factors for sepsis and septic shock: operative time ≥50th percentile (OR 2.11, P=0.032), higher anesthesia class (OR 1.76, P=0.046), dependent functional status (OR 2.23, P=0.001), diabetes (OR 2.31, P=0.037), and chronic obstructive pulmonary disease (OR 3.56, P=0.037). CONCLUSIONS These findings can help spine surgeons identify high-risk patients and proactively deploy measures to avoid this potentially devastating complication in individuals who may be more vulnerable than the general elective spine population.
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Affiliation(s)
- Kevin Mo
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, USA
| | - Arjun Gupta
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, USA
| | - Humaid Al Farii
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, USA
| | - Micheal Raad
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, USA
| | - Farah Musharbash
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, USA
| | - Britni Tran
- Western University of Health Sciences, Pomona, CA, USA
| | - Ming Zheng
- Western University of Health Sciences, Pomona, CA, USA
| | - Sang Hun Lee
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, USA
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Sacchetti B, Travis J, Steed LL, Webb G. Effects of COVID-19 on Blood Culture Contamination at a Tertiary Care Academic Medical Center. Microbiol Spectr 2022; 10:e0027722. [PMID: 35352957 PMCID: PMC9045291 DOI: 10.1128/spectrum.00277-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/11/2022] [Indexed: 01/09/2023] Open
Abstract
The COVID-19 pandemic has changed health care, from increased needs of personal protective equipment (PPE) to overloaded staff and influxes of patients. Blood cultures are frequently used to detect bloodstream infections in critically ill patients, but it is unknown whether the COVID-19 pandemic has had an impact on blood culture contamination rates. A total of 88,332 blood cultures taken over a 33-month period were analyzed to compare blood culture contamination rates before the COVID-19 pandemic to rates during the pandemic. A significant increase in the average number of monthly nurse-drawn and peripherally collected cultures occurred after the start of the pandemic, but there was a decrease in the average number of phlebotomy cultures. A significant increase in contamination rates (P < 0.001) was found in all nonemergency hospital departments during the COVID-19 pandemic, increasing from 2.1% to 2.5%. Increased rates during the COVID-19 pandemic were also found for nursing staff (2.0% to 2.4%) and both peripheral (2.1% to 2.5%) and indwelling line draws (1.1% to 1.7). The number of cultures drawn monthly increased in acute adult departments and both adult and pediatric emergency departments. Blood culture contamination rates in adult acute, adult emergency, and pediatric intensive care units increased after the start of the pandemic by 23%, 75%, and 59%, respectively. A positive correlation was found between blood culture contamination rates and COVID-19 incidence rates. Additional periodic staff training on proper blood collection technique and awareness of the workload of health care workers are recommended to decrease contamination rates during the COVID-19 pandemic. IMPORTANCE Understanding factors that contribute to blood culture contamination is important in order to take steps to limit contamination events. Here, we examine the effect the COVID-19 pandemic has had on blood culture contamination rates and specifically detail the effects based on the staff, draw types, and unit types. The conclusions provided here can be used as hospitals and laboratories navigate the COVID-19 pandemic or other times of high patient volume.
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Affiliation(s)
- Brianna Sacchetti
- Division of Natural Sciences and Engineering, University of South Carolina Upstate, Spartanburg, South Carolina, USA
| | - Justin Travis
- Department of Psychology, University of South Carolina Upstate, Spartanburg, South Carolina, USA
| | - Lisa L. Steed
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ginny Webb
- Division of Natural Sciences and Engineering, University of South Carolina Upstate, Spartanburg, South Carolina, USA
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Gray CC, Biron-Girard B, Wakeley ME, Chung CS, Chen Y, Quiles-Ramirez Y, Tolbert JD, Ayala A. Negative Immune Checkpoint Protein, VISTA, Regulates the CD4 + T reg Population During Sepsis Progression to Promote Acute Sepsis Recovery and Survival. Front Immunol 2022; 13:861670. [PMID: 35401514 PMCID: PMC8988198 DOI: 10.3389/fimmu.2022.861670] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/25/2022] [Indexed: 02/04/2023] Open
Abstract
Sepsis is a systemic immune response to infection that is responsible for ~35% of in-hospital deaths and over 24 billion dollars in annual treatment costs. Strategic targeting of non-redundant negative immune checkpoint protein pathways can cater therapeutics to the individual septic patient and improve prognosis. B7-CD28 superfamily member V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an ideal candidate for strategic targeting in sepsis. We hypothesized that immune checkpoint regulator, VISTA, controls T-regulatory cells (Treg), in response to septic challenge, thus playing a protective role/reducing septic morbidity/mortality. Further, we investigated if changes in morbidity/mortality are due to a Treg-mediated effect during the acute response to septic challenge. To test this, we used the cecal ligation and puncture model as a proxy for polymicrobial sepsis and assessed the phenotype of CD4+ Tregs in VISTA-gene deficient (VISTA-/-) and wild-type mice. We also measured changes in survival, soluble indices of tissue injury, and circulating cytokines in the VISTA-/- and wild-type mice. We found that in wild-type mice, CD4+ Tregs exhibit a significant upregulation of VISTA which correlates with higher Treg abundance in the spleen and small intestine following septic insult. However, VISTA-/- mice have reduced Treg abundance in these compartments met with a higher expression of Foxp3, CTLA4, and CD25 compared to wild-type mice. VISTA-/- mice also have a significant survival deficit, higher levels of soluble indicators of liver injury (i.e., ALT, AST, bilirubin), and increased circulating proinflammatory cytokines (i.e., IL-6, IL-10, TNFα, IL-17F, IL-23, and MCP-1) following septic challenge. To elucidate the role of Tregs in VISTA-/- sepsis mortality, we adoptively transferred VISTA-expressing Tregs into VISTA-/- mice. This adoptive transfer rescued VISTA-/- survival to wild-type levels. Taken together, we propose a protective Treg-mediated role for VISTA by which inflammation-induced tissue injury is suppressed and improves survival in early-stage murine sepsis. Thus, enhancing VISTA expression or adoptively transferring VISTA+ Tregs in early-stage sepsis may provide a novel therapeutic approach to ameliorate inflammation-induced death.
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Affiliation(s)
- Chyna C. Gray
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, United States
- Division of Surgical Research, Department of Surgery, Brown University, Providence, RI, United States
| | - Bethany Biron-Girard
- Division of Surgical Research, Department of Surgery, Brown University, Providence, RI, United States
| | - Michelle E. Wakeley
- Division of Surgical Research, Department of Surgery, Brown University, Providence, RI, United States
| | - Chun-Shiang Chung
- Division of Surgical Research, Department of Surgery, Brown University, Providence, RI, United States
| | - Yaping Chen
- Division of Surgical Research, Department of Surgery, Brown University, Providence, RI, United States
| | - Yael Quiles-Ramirez
- Division of Surgical Research, Department of Surgery, Brown University, Providence, RI, United States
| | - Jessica D. Tolbert
- Division of Surgical Research, Department of Surgery, Brown University, Providence, RI, United States
| | - Alfred Ayala
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, United States
- Division of Surgical Research, Department of Surgery, Brown University, Providence, RI, United States
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38
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Beraud M, Hashami SA, Lozano M, Bah A, Keith P. Role of therapeutic plasma exchange in the management of COVID-19-induced cytokine storm syndrome. Transfus Apher Sci 2022; 61:103433. [PMID: 35341691 PMCID: PMC8942460 DOI: 10.1016/j.transci.2022.103433] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 03/14/2022] [Indexed: 12/23/2022]
Abstract
The risk of mortality in patients with coronavirus disease 2019 (COVID-19) is largely related to an excessive immune response, resulting in a hyperinflammatory and hypercoagulable condition collectively referred to as cytokine storm syndrome (CSS). Management of critically ill patients with COVID-19 has included attempts to abate this process, prevent disease progression, and reduce mortality. In this context, therapeutic plasma exchange (TPE) offers an approach to eliminate inflammatory factors and cytokines, offset the pathologic coagulopathy, and reduce the CSS effects. The aim of this review is to analyze available data on the use of TPE for the treatment of CSS in patients with COVID-19. Systematic searches of PubMed, Scopus and COVID-19 Research were conducted to identify articles published between March 1, 2020 and May 26, 2021 reporting the use of TPE for the treatment of COVID-19-induced CSS. A total of 34 peer-reviewed articles (1 randomized controlled trial, 4 matched case-control series, 15 single-group case series, and 14 case reports), including 267 patients, were selected. Despite the low evidence level of the available data, TPE appeared to be a safe intervention for critically ill patients with COVID-19-induced CSS. Although inconsistencies exist between studies, they showed a general trend for decreased interleukin-6, C-reactive protein, ferritin, D-dimer, and fibrinogen levels and increased lymphocyte counts following TPE, supporting the immunomodulatory effect of this treatment. Moreover, TPE was associated with improvements in clinical outcomes in critically ill patients with COVID-19. While TPE may offer a valuable option to treat patients with COVID-19-induced CSS, high-quality randomized controlled clinical trials are needed to confirm its potential clinical benefits, feasibility, and safety. Moreover, clear criteria should be established to identify patients with CSS who might benefit from TPE.
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Affiliation(s)
- Mickael Beraud
- Terumo Blood and Cell Technologies Europe NV, Zaventem, Belgium.
| | | | - Miquel Lozano
- Department of Hemotherapy and Hemostasis, ICMHO, University Clinic Hospital, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain.
| | - Aicha Bah
- Terumo Blood and Cell Technologies Europe NV, Zaventem, Belgium.
| | - Philip Keith
- Critical Care Medicine, Lexington Medical Center, West Columbia, SC 29169, USA.
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Hawez A, Ding Z, Taha D, Madhi R, Rahman M, Thorlacius H. c-Abl kinase regulates neutrophil extracellular trap formation and lung injury in abdominal sepsis. J Transl Med 2022; 102:263-271. [PMID: 34732849 PMCID: PMC8860741 DOI: 10.1038/s41374-021-00683-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 08/23/2021] [Accepted: 10/07/2021] [Indexed: 11/14/2022] Open
Abstract
Sepsis is associated with exaggerated neutrophil responses although mechanisms remain elusive. The aim of this study was to investigate the role of c-Abelson (c-Abl) kinase in neutrophil extracellular trap (NET) formation and inflammation in septic lung injury. Abdominal sepsis was induced by cecal ligation and puncture (CLP). NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Plasma levels of DNA-histone complexes, interleukin-6 (IL-6) and CXC chemokines were quantified. CLP-induced enhanced phosphorylation of c-Abl kinase in circulating neutrophils. Administration of the c-Abl kinase inhibitor GZD824 not only abolished activation of c-Abl kinase in neutrophils but also reduced NET formation in the lung and plasma levels of DNA-histone complexes in CLP mice. Moreover, inhibition of c-Abl kinase decreased CLP-induced lung edema and injury. Administration of GDZ824 reduced CLP-induced increases in the number of alveolar neutrophils. Inhibition of c-Abl kinase also markedly attenuated levels of CXC chemokines in the lung and plasma as well as IL-6 levels in the plasma of septic animals. Taken together, this study demonstrates that c-Abl kinase is a potent regulator of NET formation and we conclude that c-Abl kinase might be a useful target to ameliorate lung damage in abdominal sepsis.
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Affiliation(s)
- Avin Hawez
- Department of Clinical Sciences, Malmö, Section for Surgery, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden
| | - Zhiyi Ding
- Department of Clinical Sciences, Malmö, Section for Surgery, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden
| | - Dler Taha
- Department of Clinical Sciences, Malmö, Section for Surgery, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden
| | - Raed Madhi
- Department of Clinical Sciences, Malmö, Section for Surgery, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden
| | - Milladur Rahman
- Department of Clinical Sciences, Malmö, Section for Surgery, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden
| | - Henrik Thorlacius
- Department of Clinical Sciences, Malmö, Section for Surgery, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden.
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40
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Huang CM, Xu XJ, Qi WQ, Ge QM. Prognostic significance of soluble CD25 in patients with sepsis: a prospective observational study. Clin Chem Lab Med 2022; 60:952-958. [PMID: 35230752 DOI: 10.1515/cclm-2022-0068] [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: 01/25/2022] [Accepted: 02/14/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVES The diagnosis of sepsis is challenging, the need for sensitive and specific diagnostic and prognostic biomarkers has not been met. Soluble CD25 (sCD25) is a readily available biomarker reported to represent the severity of the disease. This study aimed to assess the association between sCD25 and mortality in patients with sepsis. METHODS In total, 329 adult patients with sepsis were screened through a prospective, observational study. We investigated the severity scores and sCD25 levels at admission to the intensive care unit (ICU), defined by sepsis (sepsis-3). The prognostic value of sCD25 was assessed using receiver operating characteristic (ROC) curves and binary logistic regression models in predicting unfavourable outcome. The correlations between variables and severity of disease were analysed by Spearman correlation tests. RESULTS After entering the ICU, the sCD25 level and sequential organ failure assessment (SOFA) score were significantly higher in nonsurvivors than in survivors. The prognostic values estimated by the ROC curves were 0.678 for sCD25 and 0.945 for SOFA score at ICU admission. sCD25 had a modest ability to predict poor outcome. Logistic regression showed that increased levels of sCD25 were independently associated with unfavourable outcome. Spearman correlation tests showed that sCD25 levels were positively correlated with disease severity. CONCLUSIONS In sepsis patients, increased sCD25 levels were independently associated with poor clinical outcomes. Further research is needed to improve the understanding of the pathophysiology of this relationship.
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Affiliation(s)
- Chun-Mei Huang
- Department of Emergency, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Xin-Jie Xu
- Department of Emergency, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Wen-Qi Qi
- Department of Emergency, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Qin-Min Ge
- Department of Emergency, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
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41
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Singh V, Akash R, Chaudhary G, Singh R, Choudhury S, Shukla A, Prabhu SN, Gangwar N, Garg SK. Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice. Sci Rep 2022; 12:2941. [PMID: 35190630 PMCID: PMC8861011 DOI: 10.1038/s41598-022-06949-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 02/02/2022] [Indexed: 11/25/2022] Open
Abstract
Inhibition of Notch signaling in macrophages is known to reduce inflammation, however, its role in regulating vascular hyporeactivity in sepsis is unknown. Thus we aimed to evaluate the effect of sepsis on vascular Notch signaling. Polymicrobial sepsis was induced by caecal ligation and puncture (CLP) in mice. mRNA expressions of Notch receptors (Notch1,3) and ligands (Jag1, Dll4), and downstream effector genes (Hey1, MLCK, MYPT1) were assessed by RT-qPCR. Protein level of activated Notch (NICD) was assessed by Western blot and immuno-histochemistry. Isometric tension in isolated aortic rings was measured by wire myography.CLP down-regulated aortic expression of Notch3, Jag1 and Dll4 as compared to control mice. Additionally, the protein level of NICD was found to be lesser in aortic tissue sections from CLP mice. Expression of Hey1 and MLCK were attenuated whereas MYPT1 expression was increased in septic mouse aorta. DAPT pretreatment did not improve CLP-induced vascular hyporeactivity to NA, CaCl2 and high K+ (80 mM), rather significantly attenuated the aortic response to these vasoconstrictors in control mice. Treatment with 1400 W reversed attenuated Notch3 (but not Jag1 and MLCK) expression in septic mouse aorta. In conclusion, sepsis significantly attenuated the Notch (especially Notch3) signaling in mouse aorta along with reduction in contractile gene expression and vasoconstriction response. Further, iNOS/NO pathway was involved in sepsis-induced down-regulation of Notch3 receptor. Thus systemic inhibition of Notch signaling during sepsis may have serious impact on sepsis-induced vascular hyporeactivity.
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Affiliation(s)
- Vandana Singh
- Smooth Muscle Pharmacology and Molecular Pharmacology Laboratory, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura, 281001, India
| | - Raut Akash
- Smooth Muscle Pharmacology and Molecular Pharmacology Laboratory, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura, 281001, India
| | - Gaurav Chaudhary
- Smooth Muscle Pharmacology and Molecular Pharmacology Laboratory, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura, 281001, India
| | - Rajneesh Singh
- Smooth Muscle Pharmacology and Molecular Pharmacology Laboratory, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura, 281001, India
| | - Soumen Choudhury
- Smooth Muscle Pharmacology and Molecular Pharmacology Laboratory, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura, 281001, India.
| | - Amit Shukla
- Smooth Muscle Pharmacology and Molecular Pharmacology Laboratory, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura, 281001, India
| | - Shyama N Prabhu
- Department of Veterinary Pathology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan, Mathura, 281001, India
| | - Neeraj Gangwar
- Department of Veterinary Pathology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan, Mathura, 281001, India
| | - Satish K Garg
- Smooth Muscle Pharmacology and Molecular Pharmacology Laboratory, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura, 281001, India
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Zheng Y, Cheng J, Zhang AF, Wang Y, Dai C, Li J. Acetylation of histone 3 promotes miR-29a expression and downregulates STAT3 in sepsis. Injury 2022; 53:416-421. [PMID: 34615595 DOI: 10.1016/j.injury.2021.09.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/24/2021] [Accepted: 09/12/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND MiR-29a targets signal transducers and activators of transcription 3 (STAT3) and negatively regulates its expression. Both miR-29a and STAT3 have been implicated in sepsis and upregulated miR-29a was associated with sepsis. However, the regulation of miR-29a in sepsis is not well elucidated. METHODS We treated TC-1 cells with interleukin (IL)-6 and the expression of miR-29a and STAT3 was measured. We pre-treated TC-1 cells with histone deacetylase inhibitor Trichostatin A, DNA methylation inhibitor 5-Azacytidine or histone acetyltransferase inhibitor A-485, then treated cells with IL-6 and analyzed the expression of miR-29a and STAT3. We measured the expression of histone deacetylases and histone acetyltransferase, and glycolysis in IL-6-treated TC-1 cells. We administrated miR-29a inhibitor or STAT3 inhibitor to septic mice and the survival rate and expression of anti-apoptotic factors were measured. RESUTLS IL-6 promoted miR-29a expression while suppressed STAT3 expression. Upregulation of miR-29a was associated with sepsis. Histone acetylation promoted miR-29a expression. IL-6 promoted glycolysis in TC-1 cells, which resulted in Acetyl-CoA accumulation. Inhibition of miR-29a promoted survival rate in septic mice while inhibiting STAT3 exacerbated death in mice. The protection of miR-29a inhibition against sepsis was abolished when STAT3 was inhibited. CONCLUSION Histone acetylation promoted miR-29a expression, resulting in downregulation of STAT3 and exacerbation of sepsis.
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Affiliation(s)
- Yun Zheng
- Department of Emergency ICU, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Anhui, Hefei, Shushan District, 230031, China
| | - Jun Cheng
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Anhui, Hefei, Shushan District, 230031, China
| | - AFang Zhang
- Department of Emergency ICU, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Anhui, Hefei, Shushan District, 230031, China
| | - YuYang Wang
- Department of Emergency ICU, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Anhui, Hefei, Shushan District, 230031, China
| | - ChengCai Dai
- Department of Emergency ICU, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Anhui, Hefei, Shushan District, 230031, China
| | - JiaBin Li
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Anhui, Hefei, Shushan District, 230031, China.
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Qu HQ, Snyder J, Connolly J, Glessner J, Kao C, Sleiman P, Hakonarson H. Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries. Biomedicines 2022; 10:biomedicines10020264. [PMID: 35203474 PMCID: PMC8869623 DOI: 10.3390/biomedicines10020264] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/09/2022] [Accepted: 01/13/2022] [Indexed: 02/05/2023] Open
Abstract
The novel therapeutic target cytokine LIGHT (TNFSF14) was recently shown to play a major role in COVID-19-induced acute respiratory distress syndrome (ARDS). This study aims to investigate the associations of plasma LIGHT and another potentially targetable cytokine, interleukin-18 (IL-18), with ARDS, acute hypoxic respiratory failure (AHRF), or acute kidney injury (AKI), caused by non-COVID-19 viral or bacterial sepsis. A total of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this cohort study. Day 0 plasma LIGHT and IL-18, as well as 59 other biomarkers (cytokines, chemokines, and acute-phase reactants) were measured by sensitive bead immunoassay and associated with symptom severity. We observed significantly increased LIGHT level in both bacterial sepsis patients (p = 1.80 × 10−5) and patients with sepsis from viral infections (p = 1.78 × 10−3). In bacterial sepsis, increased LIGHT level was associated with ARDS, AKI, and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failure. IL-18 levels were highly variable across individuals and consistently correlated with Apache III scores, mortality, and AKI in both bacterial and viral sepsis. There was no correlation between LIGHT and IL-18. For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failure. The association of plasma LIGHT with AHRF suggests that targeting the pathway warrants exploration, and ongoing trials may soon elucidate whether this is beneficial. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway requires precise application.
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Affiliation(s)
- Hui-Qi Qu
- The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (H.-Q.Q.); (J.S.); (J.C.); (J.G.); (C.K.); (P.S.)
| | - James Snyder
- The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (H.-Q.Q.); (J.S.); (J.C.); (J.G.); (C.K.); (P.S.)
| | - John Connolly
- The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (H.-Q.Q.); (J.S.); (J.C.); (J.G.); (C.K.); (P.S.)
| | - Joseph Glessner
- The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (H.-Q.Q.); (J.S.); (J.C.); (J.G.); (C.K.); (P.S.)
- Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Charlly Kao
- The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (H.-Q.Q.); (J.S.); (J.C.); (J.G.); (C.K.); (P.S.)
| | - Patrick Sleiman
- The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (H.-Q.Q.); (J.S.); (J.C.); (J.G.); (C.K.); (P.S.)
- Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Hakon Hakonarson
- The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (H.-Q.Q.); (J.S.); (J.C.); (J.G.); (C.K.); (P.S.)
- Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Division of Pulmonary Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Correspondence: ; Tel.: +267-426-0088
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Lazzaro A, De Girolamo G, Filippi V, Innocenti GP, Santinelli L, Ceccarelli G, Trecarichi EM, Torti C, Mastroianni CM, d’Ettorre G, Russo A. The Interplay between Host Defense, Infection, and Clinical Status in Septic Patients: A Narrative Review. Int J Mol Sci 2022; 23:ijms23020803. [PMID: 35054993 PMCID: PMC8776148 DOI: 10.3390/ijms23020803] [Citation(s) in RCA: 13] [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: 12/02/2021] [Revised: 01/05/2022] [Accepted: 01/09/2022] [Indexed: 01/08/2023] Open
Abstract
Sepsis is a life-threatening condition that arises when the body's response to an infection injures its own tissues and organs. Despite significant morbidity and mortality throughout the world, its pathogenesis and mechanisms are not clearly understood. In this narrative review, we aimed to summarize the recent developments in our understanding of the hallmarks of sepsis pathogenesis (immune and adaptive immune response, the complement system, the endothelial disfunction, and autophagy) and highlight novel laboratory diagnostic approaches. Clinical management is also discussed with pivotal consideration for antimicrobic therapy management in particular settings, such as intensive care unit, altered renal function, obesity, and burn patients.
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Affiliation(s)
- Alessandro Lazzaro
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00161 Rome, Italy; (A.L.); (G.D.G.); (V.F.); (G.P.I.); (L.S.); (G.C.); (C.M.M.); (G.d.)
| | - Gabriella De Girolamo
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00161 Rome, Italy; (A.L.); (G.D.G.); (V.F.); (G.P.I.); (L.S.); (G.C.); (C.M.M.); (G.d.)
| | - Valeria Filippi
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00161 Rome, Italy; (A.L.); (G.D.G.); (V.F.); (G.P.I.); (L.S.); (G.C.); (C.M.M.); (G.d.)
| | - Giuseppe Pietro Innocenti
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00161 Rome, Italy; (A.L.); (G.D.G.); (V.F.); (G.P.I.); (L.S.); (G.C.); (C.M.M.); (G.d.)
| | - Letizia Santinelli
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00161 Rome, Italy; (A.L.); (G.D.G.); (V.F.); (G.P.I.); (L.S.); (G.C.); (C.M.M.); (G.d.)
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00161 Rome, Italy; (A.L.); (G.D.G.); (V.F.); (G.P.I.); (L.S.); (G.C.); (C.M.M.); (G.d.)
| | - Enrico Maria Trecarichi
- Infectious and Tropical Disease Unit, Department of Medical and Surgical Sciences, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (E.M.T.); (C.T.)
| | - Carlo Torti
- Infectious and Tropical Disease Unit, Department of Medical and Surgical Sciences, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (E.M.T.); (C.T.)
| | - Claudio Maria Mastroianni
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00161 Rome, Italy; (A.L.); (G.D.G.); (V.F.); (G.P.I.); (L.S.); (G.C.); (C.M.M.); (G.d.)
| | - Gabriella d’Ettorre
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00161 Rome, Italy; (A.L.); (G.D.G.); (V.F.); (G.P.I.); (L.S.); (G.C.); (C.M.M.); (G.d.)
| | - Alessandro Russo
- Infectious and Tropical Disease Unit, Department of Medical and Surgical Sciences, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (E.M.T.); (C.T.)
- Correspondence:
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Pretreatment with 6-Gingerol Ameliorates Sepsis-Induced Immune Dysfunction by Regulating the Cytokine Balance and Reducing Lymphocyte Apoptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2021:5427153. [PMID: 35003518 PMCID: PMC8731291 DOI: 10.1155/2021/5427153] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 10/04/2021] [Accepted: 11/26/2021] [Indexed: 11/19/2022]
Abstract
Sepsis is characterized by an initial net hyperinflammatory response, followed by a period of immunosuppression, termed immunoparalysis. During this immunosuppressive phase, patients may have difficulty eradicating invading pathogens and are susceptible to life-threatening secondary hospital-acquired infections. Due to progress in antimicrobial treatment and supportive care, most patients survive early sepsis. Mortality is more frequently attributed to subsequent secondary nosocomial infections and multiorgan system failure. 6-Gingerol is the major pharmacologically active component of ginger. Although it is known to exhibit a variety of biological activities, including anti-inflammation and antioxidation, the role of 6-gingerol in sepsis-induced immune dysfunction remains elusive. Thus, we investigated whether 6-gingerol improves septic host response to infections during sepsis. 6-Gingerol-treated mice showed significantly lower mortality in polymicrobial sepsis induced by cecal ligation and puncture LPS via enhanced bacterial clearance in the peritoneum, blood, and organs (liver, spleen, and kidney) and inhibited the production of TNF-α and IL-6 in TLR2 and/or TLR4-stimulated macrophages. In addition, we demonstrated that survival improvement of secondary infection following septic insult was associated with an initial response of enhanced neutrophil numbers and function at the infection site, reduced apoptosis of immune cells, and a shift from a T helper cell type 2 (Th2) to a T helper cell type 1 (Th1) cytokine balance in the hypoinflammation phase. Our overall findings suggest that 6-gingerol potentially restores sepsis-induced immune dysfunction by shifting the balance of Th1/Th2 and by regulating apoptosis of immune cells.
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Jia Y, Wang Y, Zhang Y, Wang J, Pei Y, Wang Z, Li P, Han K. Profiling Cystathionine β/γ-Lyase in Complex Biosamples Using Novel Activatable Fluorogens. Anal Chem 2021; 94:1203-1210. [PMID: 34955022 DOI: 10.1021/acs.analchem.1c04393] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Cystathionine lyase, the key enzyme in transsulfuration and reverse transsulfuration pathways, is involved in a wide array of physiological and pathophysiological processes in both mammals and nonmammals. Though the biological significance of the hydrogen sulfide/cystathionine lyase system in disease states is extensively discussed, the absence of molecular methods for direct monitoring of cystathionine lyase in complex biosamples renders the result unreliable and perplexing. Here, we present the first attempt at designing and developing effective activatable fluorescent probes for cystathionine lyase based on the naphthylamide scaffold. CBLP and CSEP were designed based on the catalytic preference of cystathionine β-lyase (CBL) and cystathionine γ-lyase (CSE). Briefly, incorporation of cysteine/homocysteine as the recognition moiety and a carbamate ethyl sulfide group as a self-immolated linker proved to be an effective strategy for cystathionine lyase fluorescence reporting. CBLP exhibits high selectivity and sensitivity in vitro in semiquantifying CBL levels in roots of wild-type Arabidopsis thaliana and cbl mutants (cbl knockout: SALK_014740C, overexpressed: OE-CBL). Meanwhile, CSEP successfully detected CSE levels in HCC-LM3 cells, zebrafish models, and upregulated CSE in frozen section slides from the liver tissue of cecal ligation and puncture (CLP)-induced septic rats, which was also validated by Western blotting and immunohistochemical analysis. In summary, the practical design strategy facilitates profiling of cystathionine lyase activity in biological processes. It may pave the way for the development of accurate and efficient methods for the direct estimation of cystathionine lyase.
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Affiliation(s)
- Yan Jia
- State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China
| | - Yiying Wang
- Institute of Molecular Sciences and Engineering, Shandong University, Qingdao 266237, China
| | - Yongli Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, Liaoning Province 116012, China
| | - Jiayue Wang
- Department of Pharmacy, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Yanxi Pei
- School of Life Science, Shanxi University, Taiyuan 030006, China
| | - Zhiqing Wang
- School of Life Science, Shanxi University, Taiyuan 030006, China
| | - Peng Li
- Institute of Molecular Sciences and Engineering, Shandong University, Qingdao 266237, China
| | - Keli Han
- State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China
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Ding Z, Du F, Averitt V RG, Jakobsson G, Rönnow CF, Rahman M, Schiopu A, Thorlacius H. Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis. Int J Mol Sci 2021; 22:12923. [PMID: 34884728 PMCID: PMC8658007 DOI: 10.3390/ijms222312923] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/25/2021] [Accepted: 11/26/2021] [Indexed: 02/07/2023] Open
Abstract
S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.
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Affiliation(s)
- Zhiyi Ding
- Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 21428 Malmö, Sweden; (Z.D.); (F.D.); (R.G.A.V.); (C.-F.R.); (M.R.)
| | - Feifei Du
- Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 21428 Malmö, Sweden; (Z.D.); (F.D.); (R.G.A.V.); (C.-F.R.); (M.R.)
| | - Richard Garland Averitt V
- Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 21428 Malmö, Sweden; (Z.D.); (F.D.); (R.G.A.V.); (C.-F.R.); (M.R.)
| | - Gabriel Jakobsson
- Department of Clinical Sciences, Malmö, Lund University, 21428 Malmö, Sweden; (G.J.); (A.S.)
| | - Carl-Fredrik Rönnow
- Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 21428 Malmö, Sweden; (Z.D.); (F.D.); (R.G.A.V.); (C.-F.R.); (M.R.)
| | - Milladur Rahman
- Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 21428 Malmö, Sweden; (Z.D.); (F.D.); (R.G.A.V.); (C.-F.R.); (M.R.)
| | - Alexandru Schiopu
- Department of Clinical Sciences, Malmö, Lund University, 21428 Malmö, Sweden; (G.J.); (A.S.)
- Department of Internal Medicine, Skåne University Hospital, 22185 Lund, Sweden
| | - Henrik Thorlacius
- Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 21428 Malmö, Sweden; (Z.D.); (F.D.); (R.G.A.V.); (C.-F.R.); (M.R.)
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Huang Y, Chen R, Jiang L, Li S, Xue Y. Basic research and clinical progress of sepsis-associated encephalopathy. JOURNAL OF INTENSIVE MEDICINE 2021; 1:90-95. [PMID: 36788800 PMCID: PMC9923961 DOI: 10.1016/j.jointm.2021.08.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 07/22/2021] [Accepted: 08/18/2021] [Indexed: 01/02/2023]
Abstract
Sepsis-associated encephalopathy (SAE), a major cerebral complication of sepsis, occurs in 70% of patients admitted to the intensive care unit (ICU). This condition can cause serious impairment of consciousness and is associated with a high mortality rate. Thus far, several experimental screenings and radiological techniques (e.g., electroencephalography) have been used for the non-invasive assessment of the structure and function of the brain in patients with SAE. Nevertheless, the pathogenesis of SAE is complicated and remains unclear. In the present article, we reviewed the currently available literature on the epidemiology, clinical manifestations, pathology, diagnosis, and management of SAE. However, currently, there is no ideal pharmacological treatment for SAE. Treatment targeting mitochondrial dysfunction may be useful in the management of SAE.
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Affiliation(s)
- Ying Huang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xin-Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China,Corresponding author: Ying Huang, Department of Anesthesiology and Surgical Intensive Care Unit, Xin-Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
| | - Ruman Chen
- Department of Blood Purification, Hainan General Hospital Affiliated to Hainan Medical University, Haikou, Hainan 570311, China
| | - Lai Jiang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xin-Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Siyuan Li
- Department of Anesthesiology and Surgical Intensive Care Unit, Xin-Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yuchen Xue
- Department of Anesthesiology and Surgical Intensive Care Unit, Xin-Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
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Wu J, Zhang H, Chen X, Chai J, Hu Y, Xiong W, Lu W, Tian M, Chen X, Xu X. FM-CATH, A Novel Cathelicidin From Fejervarya Multistriata, Shows Therapeutic Potential for Treatment of CLP-Induced Sepsis. Front Pharmacol 2021; 12:731056. [PMID: 34483941 PMCID: PMC8415707 DOI: 10.3389/fphar.2021.731056] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 08/04/2021] [Indexed: 12/15/2022] Open
Abstract
Sepsis is an exacerbated inflammatory reaction induced by severe infection. As important defensive molecules in innate immunity, several AMPs are reported to prevent septic shock. In this study, we characterized a novel cathelicidin, FM-CATH, from the frog skin of F. multistriata. FM-CATH was found to adopt an amphipathic α-helix structural in membrane-mimetic environments and possess favorable antimicrobial effects against bacteria and fungus. In addition, it triggered the agglutination of bacteria. It could also strongly bind to LPS and LTA. Additionally, FM-CATH affected the enzymatic activities of thrombin, plasmin, β-tryptase, and tPA, leading to coagulation inhibition in vitro and in vivo. Finally, we observed that FM-CATH improved survival rate and inhibited pathological alteration, bacterial count, serum biochemistry, and pro-inflammatory cytokine expression in the cecal ligation and puncture-induced sepsis mice. Taken together, these findings suggest that FM-CATH might be served as a promising agent for the treatment of sepsis.
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Affiliation(s)
- Jiena Wu
- Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Haiyun Zhang
- Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoxin Chen
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Jinwei Chai
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Yunrui Hu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Weichen Xiong
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Wancheng Lu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Maolin Tian
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Xin Chen
- Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xueqing Xu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
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Wang Q, Peng G, Gan L, Deng Z, Zeng L, Deng J. The Value of Interleukin-10 in the Early Diagnosis of Neonatal Sepsis: A Meta-Analysis. Pediatr Crit Care Med 2021; 22:e492-e501. [PMID: 33710072 DOI: 10.1097/pcc.0000000000002706] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Interleukin-10 is a significant marker in neonatal sepsis. This meta-analysis evaluated the accuracy of interleukin-10 expression in the diagnosis of neonatal sepsis. DATA SOURCE Summary of literature review. STUDY SELECTION A literature search strategy was developed, including PubMed, EMBASE, Web of Science, MEDLINE, and the Cochrane Library. All publications published till October 1, 2020, were retrieved; the key words were "sepsis" and "interleukin-10." DATA EXTRACTION The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were used to evaluate the data, and the heterogeneity of the combined results was tested according to the I2 value. DATA SYNTHESIS A total of six articles involving 879 newborns were included in the study. The combined sensitivity was 0.82 (95% CI, 0.78-0.86), the specificity was 0.79 (95% CI, 0.75-0.82), the positive likelihood ratio was 4.17 (95% CI, 2.6-6.69), and the negative likelihood ratio was 0.25 (95% CI, 0.16-0.39). The area under the summary receiver operating characteristic curve was 0.88 (95% CI, 0.86-0.91), and the Q index was 0.81. The combined diagnostic odds ratio was 17.52 (95% CI, 8.95-34.29). CONCLUSIONS Based on the results of the meta-analysis, interleukin-10 is a useful biomarker in the early diagnosis of neonatal sepsis. Its sensitivity, specificity, and diagnostic ability are excellent. However, it needs to be combined with clinical history data for comprehensive judgment and should not be used alone for diagnosis.
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Affiliation(s)
- Qiang Wang
- Emergency Department, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
- Deyang Integrated Traditional Chinese and Western Medicine Hospital, Deyang, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Guoxuan Peng
- Emergency Department, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Lebin Gan
- Emergency Department, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Zhihong Deng
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Ling Zeng
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jin Deng
- Emergency Department, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
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