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Ma H, Suleman M, Zhang F, Cao T, Wen S, Sun D, Chen L, Jiang B, Wang Y, Lin F, Wang J, Li B, Li Q. Pirin Inhibits FAS-Mediated Apoptosis to Support Colorectal Cancer Survival. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2301476. [PMID: 38148593 PMCID: PMC10933653 DOI: 10.1002/advs.202301476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 11/17/2023] [Indexed: 12/28/2023]
Abstract
Resistance to immunotherapy in colorectal cancer (CRC) is associated with obstruction of FAS (Apo-1 or CD95)-dependent apoptosis, a hallmark of cancer. Here it is demonstrated that the upregulation of pirin (PIR) protein in colon cancers promotes tumorigenesis. Knockout or inhibition of PIR dramatically increases FAS expression, FAS-dependent apoptosis and attenuates colorectal tumor formation in mice. Specifically, NFκB2 is a direct transcriptional activator of FAS and robustly suppressed by PIR in dual mechanisms. One is the disruption of NFκB2 complex (p52-RELB) association with FAS promoter, the other is the inhibition of NIK-mediated NFκB2 activation and nuclear translocation, leading to the inability of active NFκB2 complex toward the transcription of FAS. Furthermore, PIR interacts with FAS and recruits it in cytosol, preventing its membrane translocation and assembling. Importantly, knockdown or knockout of PIR dramatically sensitizes cells to FAS mAb- or active CD8+ T cells-triggered cell death. Taken together, a PIR-NIK-NFκB2-FAS survival pathway is established, which plays a key role in supporting CRC survival.
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Affiliation(s)
- Huanhuan Ma
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Muhammad Suleman
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Fengqiong Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Tingyan Cao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Shixiong Wen
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Dachao Sun
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Lili Chen
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Bin Jiang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Yue Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Furong Lin
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Jinyang Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Boan Li
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
| | - Qinxi Li
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life SciencesXiamen UniversityXiamen361102China
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Lorente L, Martín MM, Ortiz-López R, González-Rivero AF, González-Mesa A, Villacampa-Jiménez JJ, Jiménez A, Pérez-Cejas A. Serum Fas levels during first week of sepsis are associated with severity and mortality. Expert Rev Mol Diagn 2023; 23:181-185. [PMID: 36779960 DOI: 10.1080/14737159.2023.2179876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2023]
Abstract
INTRODUCTION The aim of our study was to explore whether there is an association of serum sFas (cell death apoptosis receptor) concentrations during the first week of sepsis with sepsis severity and sepsis mortality. METHODS In this observational study, septic patients were recruited. Serum sFas concentrations were determined on days 1, 4, and 8 of sepsis diagnosis. Thirty-day mortality was the outcome variable. RESULTS Surviving patients (n = 181) compared to non-survivors (n = 101) presented lower serum sFas levels on day 1 (p < 0.001), day 4 (p < 0.001) and day 8 (p < 0.001), and lower SOFA on day 1 (p < 0.001), day 4 (p < 0.001) and day 8 (p < 0.001). Logistic regression analyses showed associations between 30-day mortality and serum sFas levels controlling for SOFA on day 1 (OR = 1.005; 95% CI = 1.003-1.007; p < 0.001), day 4 (OR = 1.044; 95% CI = 1.029-1.060; p < 0.001) and day 8 (OR = 1.012; 95% CI = 1.002-1.022; p = 0.02). CONCLUSIONS The association of serum sFas concentrations during the first week of sepsis with sepsis severity and sepsis mortality were our new findings.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias. Ofra, La Laguna, Spain
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz Tenerife, Spain
| | | | | | | | | | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias. Ofra, La Laguna, Spain
| | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias. Ofra, La Laguna, Spain
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Lorente L, Martín MM, Ortiz-López R, González-Rivero AF, Pérez-Cejas A, Martín M, Gonzalez V, Pérez A, Rodin M, Jiménez A. Blood caspase-8 concentrations and mortality among septic patients. Med Intensiva 2022; 46:8-13. [PMID: 34991877 DOI: 10.1016/j.medine.2020.06.015] [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: 04/19/2020] [Accepted: 06/27/2020] [Indexed: 06/14/2023]
Abstract
OBJECTIVE No data are available on blood caspase-8 concentrations (the initiator caspase in the extrinsic apoptosis pathway) in septic patients. The present study thus describes the blood caspase-8 concentrations in survivors and non-survivors, and examines the possible association between blood caspase-8 concentrations and mortality in septic patients. DESIGN A prospective observational study was carried out. SETTING Three Spanish Intensive Care Units. PATIENTS Septic patients. INTERVENTIONS Serum caspase-8 concentrations were determined at the diagnosis of sepsis. MAIN VARIABLE OF INTEREST Mortality after 30 days. RESULTS Patients not surviving at day 30 (n=81) compared to surviving patients (n=140) showed higher serum caspase-8 levels (p<0.001). Multiple logistic regression analysis found an association between serum caspase-8 levels>43.5ng/ml and mortality (OR=3.306; 95%CI=1.619-6.753; p=0.001). The area under the curve (AUC) for mortality predicted by serum caspase-8 levels was 67% (95% CI=60-73%; p<0.001). CONCLUSIONS The novel findings of our study were that blood caspase-8 concentrations are higher in non-survivors than in survivors, and that there is an association between blood caspase-8 concentrations and mortality in septic patients.
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Affiliation(s)
- L Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna 38320, Tenerife, Spain.
| | - M M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Crta Rosario s/n., Santa Cruz Tenerife 38010, Spain
| | - R Ortiz-López
- Intensive Care Unit, Hospital General de La Palma, Buenavista de Arriba s/n, Breña Alta, La Palma 38713, Spain
| | - A F González-Rivero
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n., La Laguna 38320, Santa Cruz de Tenerife, Spain
| | - A Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n., La Laguna 38320, Tenerife, Spain
| | - M Martín
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n., La Laguna, Santa Cruz de Tenerife 38320, Spain
| | - V Gonzalez
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n., La Laguna, Santa Cruz de Tenerife 38320, Spain
| | - A Pérez
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n., La Laguna, Santa Cruz de Tenerife 38320, Spain
| | - M Rodin
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n., La Laguna, Santa Cruz de Tenerife 38320, Spain
| | - A Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna 38320, Tenerife, Spain
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Lorente L, Martín MM, Ortiz-López R, González-Rivero AF, Pérez-Cejas A, Pastor E, Domínguez-Curell C, Raja L, Lorenzo L, Jiménez A. Association of serum soluble Fas concentrations and mortality of septic patients. ENFERMEDADES INFECCIOSAS Y MICROBIOLOGIA CLINICA (ENGLISH ED.) 2021; 39:493-497. [PMID: 34865710 DOI: 10.1016/j.eimce.2020.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/12/2020] [Indexed: 06/13/2023]
Abstract
INTRODUCTION Scarce data on Fas, one of the main receptors that activates the apoptosis extrinsic pathway, in septic patients exists. Higher blood soluble Fas (sFas) concentrations in non-survivor septic patients compared with survivors have been found in small studies; however, the association of blood sFas concentrations with mortality controlling for sepsis severity has not been stablished due to this small sample size in those studies. Thus, our main objective study was to determine whether an association between blood sFas concentrations and sepsis mortality controlling for sepsis severity exists. METHODS We included septic patients in this observational and prospective study carried out in three Spanish Intensive Care Units. We obtained serum samples at sepsis diagnosis sepsis for sFas levels determination. RESULTS Thirty-day non-surviving patients (n=85) compared to surviving patients (n=151) had higher serum sFas levels (p<0.001). We found in multiple logistic regression analysis an association of serum sFas levels with mortality controlling for age and SOFA (OR=1.004; 95% CI=1.002-1.006; p<0.001), and for age and APACHE-II (OR=1.004; 95% CI=1.002-1.006; p<0.001). Serum sFas levels showed and area under the curve for mortality prediction of 71% (95% CI=65-71%; p<0.001). Kaplan-Meier analysis showed higher mortality rate in patients with serum sFas levels>83.5ng/mL (Hazard ratio=3.2; 95% CI=2.1-5.0; p<0.001). CONCLUSIONS That an association between blood sFas concentrations and sepsis mortality controlling for sepsis severity exists was our main new finding study.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Crta Rosario s/n., Santa Cruz Tenerife, Spain
| | - Raquel Ortiz-López
- Intensive Care Unit, Hospital General de La Palma, Buenavista de Arriba s/n, Breña Alta, La Palma, Spain
| | - Agustín F González-Rivero
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Santa Cruz de Tenerife, Spain
| | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Tenerife, Spain
| | - Eduardo Pastor
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Santa Cruz de Tenerife, Spain
| | - Claudia Domínguez-Curell
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Santa Cruz de Tenerife, Spain
| | - Lorena Raja
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Santa Cruz de Tenerife, Spain
| | - Lisset Lorenzo
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Santa Cruz de Tenerife, Spain
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Tenerife, Spain
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Abstract
INTRODUCTION Levels of the apoptosis regulator Fas ligand (FasL) are associated with severity of sepsis, but its association with the mortality of sepsis and necroptosis, a regulated cell death mechanism, is not yet clear. We aimed to assess the association of FasL level with outcomes of sepsis and receptor interacting protein kinase-3 (RIPK3), an essential necroptosis mediator, for determining the relationship between FasL and necroptosis. METHODS Plasma FasL and RIPK3 levels were measured by ELISA from prospectively enrolled critically-ill adult patients. The best cut-off level of FasL for 28-day mortality prediction was determined by Youden's index. The association between plasma levels of FasL and RIPK3 was assessed by a linear regression method. RESULTS Among 188 patients, 58 (30.9%) were diagnosed with sepsis and 84 (44.7%) with septic shock, respectively. Plasma levels of FasL increased in the group order of control, sepsis, and septic shock groups (P for trend < 0.001). For 142 patients with sepsis, organ dysfunction and septic shock were more prevalent in the group with plasma FasL levels that were higher than the best cut-off level. A significant difference in mortality between high and low FasL patients was observed up to 90 days (Log-rank P = 0.013). FasL levels did not significantly change over day 3 and day 7. FasL levels were not correlated with those of RIPK3. CONCLUSIONS The plasma level of FasL was associated with severity of sepsis and was predictive of mortality. However, it was not correlated with RIPK3 level.
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Lorente L, Martín MM, Ortiz-López R, González-Rivero AF, Pérez-Cejas A, Pastor E, Domínguez-Curell C, Raja L, Lorenzo L, Jiménez A. Association of serum soluble Fas concentrations and mortality of septic patients. Enferm Infecc Microbiol Clin 2020; 39:S0213-005X(20)30268-8. [PMID: 32972791 DOI: 10.1016/j.eimc.2020.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Scarce data on Fas, one of the main receptors that activates the apoptosis extrinsic pathway, in septic patients exists. Higher blood soluble Fas (sFas) concentrations in non-survivor septic patients compared with survivors have been found in small studies; however, the association of blood sFas concentrations with mortality controlling for sepsis severity has not been stablished due to this small sample size in those studies. Thus, our main objective study was to determine whether an association between blood sFas concentrations and sepsis mortality controlling for sepsis severity exists. METHODS We included septic patients in this observational and prospective study carried out in three Spanish Intensive Care Units. We obtained serum samples at sepsis diagnosis sepsis for sFas levels determination. RESULTS Thirty-day non-surviving patients (n=85) compared to surviving patients (n=151) had higher serum sFas levels (p<0.001). We found in multiple logistic regression analysis an association of serum sFas levels with mortality controlling for age and SOFA (OR=1.004; 95% CI=1.002-1.006; p<0.001), and for age and APACHE-II (OR=1.004; 95% CI=1.002-1.006; p<0.001). Serum sFas levels showed and area under the curve for mortality prediction of 71% (95% CI=65-71%; p<0.001). Kaplan-Meier analysis showed higher mortality rate in patients with serum sFas levels>83.5ng/mL (Hazard ratio=3.2; 95% CI=2.1-5.0; p<0.001). CONCLUSIONS That an association between blood sFas concentrations and sepsis mortality controlling for sepsis severity exists was our main new finding study.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Crta Rosario s/n., Santa Cruz Tenerife, Spain
| | - Raquel Ortiz-López
- Intensive Care Unit, Hospital General de La Palma, Buenavista de Arriba s/n, Breña Alta, La Palma, Spain
| | - Agustín F González-Rivero
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Santa Cruz de Tenerife, Spain
| | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Tenerife, Spain
| | - Eduardo Pastor
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Santa Cruz de Tenerife, Spain
| | - Claudia Domínguez-Curell
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Santa Cruz de Tenerife, Spain
| | - Lorena Raja
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Santa Cruz de Tenerife, Spain
| | - Lisset Lorenzo
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Santa Cruz de Tenerife, Spain
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna, Tenerife, Spain
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Lorente L, Martín MM, Ortiz-López R, González-Rivero AF, Pérez-Cejas A, Cabrera J, García C, Uribe L, Jiménez A. Association between serum sFasL concentrations and sepsis mortality. Infect Dis (Lond) 2020; 53:38-43. [PMID: 32945711 DOI: 10.1080/23744235.2020.1819560] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND There are scarce data on soluble Fas Ligand (sFasL), one of the main ligands that activate the apoptosis extrinsic pathway, in septic patients. In a small study of septic children were found higher plasma sFasL levels in non-survivors compared with survivors; however, an association between blood sFasL levels and mortality controlling for sepsis severity was not stablished due to the small sample size of the study. Therefore, the main objective of this study was to determine whether there is an association between blood sFasL concentrations and mortality in septic patients controlling for sepsis severity. Methods: Septic patients were included in this observational and prospective study conducted in three Spanish Intensive Care Units. Serum samples at diagnosis of sepsis were obtained for serum sFasL levels determination. RESULTS Thirty-day non-surviving patients (n = 85) with respect to surviving patients (n = 151) showed higher serum sFasL levels (p<.001). Multiple logistic regression analysis found an association between serum sFasL levels and mortality (odds ratio [OR] = 1.007; 95% confidence interval [CI] = 1.003-1.010; p<.001) after controlling for age, septic shock, SOFA, INR and aPTT. The area under the curve (AUC) for mortality prediction by serum sFasL levels was of 62% (95% CI = 56-69%; p=.003). In Kaplan-Meier analysis was found that patients with serum sFasL levels >109 pg/mL had a higher mortality rate (hazard ratio = 3.6; 95% CI = 1.93-6.78; p<.001). CONCLUSIONS The main new finding from our study was that serum sFasL concentrations were associated with mortality in septic patients controlling for sepsis severity. Highlights Blood sFasL concentrations were higher in non-survivor than in survivor patients. There is an association between blood sFasL concentrations and mortality in septic patients. Blood sFasL concentrations could predict mortality of septic patients.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz de Tenerife, Spain
| | | | | | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Judith Cabrera
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Carolina García
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Luis Uribe
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
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Lorente L, Martín MM, Ortiz-López R, González-Rivero AF, Pérez-Cejas A, Martín M, Gonzalez V, Pérez A, Rodin M, Jiménez A. Blood caspase-8 concentrations and mortality among septic patients. Med Intensiva 2020; 46:S0210-5691(20)30246-1. [PMID: 32843190 DOI: 10.1016/j.medin.2020.06.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/23/2020] [Accepted: 06/27/2020] [Indexed: 12/29/2022]
Abstract
OBJECTIVE No data are available on blood caspase-8 concentrations (the initiator caspase in the extrinsic apoptosis pathway) in septic patients. The present study thus describes the blood caspase-8 concentrations in survivors and non-survivors, and examines the possible association between blood caspase-8 concentrations and mortality in septic patients. DESIGN A prospective observational study was carried out. SETTING Three Spanish Intensive Care Units. PATIENTS Septic patients. INTERVENTIONS Serum caspase-8 concentrations were determined at the diagnosis of sepsis. MAIN VARIABLE OF INTEREST Mortality after 30 days. RESULTS Patients not surviving at day 30 (n=81) compared to surviving patients (n=140) showed higher serum caspase-8 levels (p<0.001). Multiple logistic regression analysis found an association between serum caspase-8 levels>43.5ng/ml and mortality (OR=3.306; 95%CI=1.619-6.753; p=0.001). The area under the curve (AUC) for mortality predicted by serum caspase-8 levels was 67% (95% CI=60-73%; p<0.001). CONCLUSIONS The novel findings of our study were that blood caspase-8 concentrations are higher in non-survivors than in survivors, and that there is an association between blood caspase-8 concentrations and mortality in septic patients.
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Affiliation(s)
- L Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna 38320, Tenerife, Spain.
| | - M M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Crta Rosario s/n., Santa Cruz Tenerife 38010, Spain
| | - R Ortiz-López
- Intensive Care Unit, Hospital General de La Palma, Buenavista de Arriba s/n, Breña Alta, La Palma 38713, Spain
| | - A F González-Rivero
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n., La Laguna 38320, Santa Cruz de Tenerife, Spain
| | - A Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n., La Laguna 38320, Tenerife, Spain
| | - M Martín
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n., La Laguna, Santa Cruz de Tenerife 38320, Spain
| | - V Gonzalez
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n., La Laguna, Santa Cruz de Tenerife 38320, Spain
| | - A Pérez
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n., La Laguna, Santa Cruz de Tenerife 38320, Spain
| | - M Rodin
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n., La Laguna, Santa Cruz de Tenerife 38320, Spain
| | - A Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n., La Laguna 38320, Tenerife, Spain
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Ketsko YL, Lunina AV, Gusyakova OA, Petrovskaya EV, Lyamin AV, Kozlov AV, Novokshchenov SG. [The indicators of basal metabolism in inflammatory syndrome bacterial origin: predictors of prognosis or the need for timely correction?]. Klin Lab Diagn 2019; 64:122-127. [PMID: 30917255 DOI: 10.18821/0869-2084-2019-64-2-122-127] [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: 01/17/2019] [Accepted: 01/21/2019] [Indexed: 11/17/2022]
Abstract
The aim of the study was to determine the comparative significance of basal metabolism indicators and inflammatory process markers for the closest prognosis of patients in ICUs with systemic inflammation syndrome caused with infectious genesis. The paper presents the results of a retrospective analysis of the plan of treatment of 198 patients with confirmed clinical and laboratory signs of bacterial infection. The number of leukocytes, platelets, the percentage of lymphocytes, the concentration of procalcitonin, creatinine, bilirubin, C-reactive protein, acid-base balance values were determined in patients. Patients were assessed on a SOFA scale. The type of biomaterial for microbiological research was determined depending on the intended source of infectious inflammation. Identification of the isolated microorganisms was carried out using the MALDI ToF mass spectrometry method, followed by determination of antibiotic resistance. Empirical antibiotic therapy was prescribed upon admission of the patient to the ICU. Patients were switched to etiotropic antibacterial therapy after 48 hours, taking into account the results of a microbiological study. Determination of basal metabolic rate was carried out using the method of indirect calorimetry (CCM Express, Medical Graphics) with the calculation of basal metabolism, respiratory coefficient, absolute and relative amount of macronutrients. The calculation of the protein was made on the basis of the nitrogen level of the daily urine urea. Logistic analysis (ROC analysis) revealed that the antibacterial therapy strategy used, age, gender of patients, tinctorial properties of microorganisms isolated from patients, do not affect the nearest prognosis of the disease. On the contrary, SOFA score, the concentration of procalcitonin in the blood, and such parameters of the metabolic status as the need for kilocalories per kilogram of actual body weight and the percentage of protein calories significantly affect the nearest prognosis of the disease. The percentage of calories derived from protein metabolism, in the main exchange has a high reliable predictive value. The results of the study confirm the importance of adequate nutritional therapy in the treatment of patients with infectious inflammatory syndrome, including the calculation and correction of protein loss and total daily calorie.
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Affiliation(s)
- Yu L Ketsko
- Samara State Medical University, 43099, Samara, Russia
| | - A V Lunina
- Samara State Medical University, 43099, Samara, Russia
| | - O A Gusyakova
- Samara State Medical University, 43099, Samara, Russia
| | | | - A V Lyamin
- Samara State Medical University, 43099, Samara, Russia
| | - A V Kozlov
- Samara State Medical University, 43099, Samara, Russia
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Reséndiz-Martínez J, Asbun-Bojalil J, Huerta-Yepez S, Vega M. Correlation of the expression of YY1 and Fas cell surface death receptor with apoptosis of peripheral blood mononuclear cells, and the development of multiple organ dysfunction in children with sepsis. Mol Med Rep 2017; 15:2433-2442. [PMID: 28447715 PMCID: PMC5428261 DOI: 10.3892/mmr.2017.6310] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 12/07/2016] [Indexed: 01/18/2023] Open
Abstract
Multiple organ dysfunction (MOD) is a lethal complication in children with sepsis. Apoptosis of several cell types is involved in this process, and it is associated with increased Fas cell surface death receptor (Fas) expression. As YY1 transcription factor (YY1) negatively regulates the expression of Fas in cancer models, and is associated with the clinical outcome, it may be important in MOD. The present study aimed to determine the association between the expression of Fas, YY1 and apoptosis in children with sepsis, and its association with MOD, these factors were analyzed in 30 pediatric patients that had been diagnosed with sepsis. Peripheral blood mononuclear cells were purified from patients, and YY1 and Fas protein expression was assessed by immunocytochemistry. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick‑end labeling. Sepsis was monitored using clinical parameters, pediatric logistic organ dysfunction (PELOD) score and the pediatric mortality index. The results demonstrated that Fas expression was directly correlated with apoptosis levels and the expression of YY1 was inversely correlated with apoptosis levels. Patients with high levels of apoptosis exhibited increased disease severity and poor clinical outcome. Notably, the findings of the present study demonstrated that there were higher survival rates in patients with high YY1 expression, compared with those with low YY1 expression. Additionally, patients with MOD exhibited lower proportions of apoptotic cells compared with sepsis patients without MOD. Furthermore, the PELOD score was positively correlated with Fas and inversely correlated with YY1 expression. Finally, high apoptosis and low YY1 expression were prognostic factors associated with poor survival rates. These data suggested that YY1 may be important for apoptosis induction via the regulation of Fas during sepsis. Therefore, Fas may be a potential therapeutic target to prevent MOD through regulation of YY1 expression. Furthermore, YY1 and Fas expression in PBMCs may be used to as prognostic markers.
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Affiliation(s)
- Judith Reséndiz-Martínez
- Servicio de Terapia Intensiva Pediátrica, Hospital General Dr Gaudencio González Garza, Centro Medico La Raza IMSS, 02990 Mexico City, Mexico
| | - Juan Asbun-Bojalil
- Servicio de Terapia Intensiva Pediátrica, Hospital General Dr Gaudencio González Garza, Centro Medico La Raza IMSS, 02990 Mexico City, Mexico
| | - Sara Huerta-Yepez
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez S.S.A, 06720 Mexico City, Mexico
| | - Mario Vega
- Oncology Research Unit, Oncology Hospital, Siglo XXI National Medical Center, IMSS, 06720 Mexico City, Mexico
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Reyna-Figueroa J, Lagunas-Martínez A, Galindo-Delgado P, Fernández-Bautista MF, Castro-Oteo PG, Martínez-Matsumoto P, Perez EM, Rosenstein Y, Limón-Rojas AE, Ortiz-Ibarra FJ, Madrid-Marina V. Serum concentrations of apoptosis-associated molecules in septic children with leukemia, neutropenia and fever. Int J Hematol 2017; 105:668-675. [PMID: 28144786 DOI: 10.1007/s12185-016-2175-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 12/21/2016] [Accepted: 12/21/2016] [Indexed: 01/10/2023]
Abstract
It has been shown that Fas, Fas-L, TNF and TNFR-1 display high serum concentrations in subjects with sepsis. This suggests that these are potential severity markers. However, the serum concentration of these molecules in children with leukemia and suspected sepsis has to be established before proposing their use as diagnostic biomarkers. We included children <17 years of age diagnosed with acute lymphoblastic leukemia with neutropenia and fever (NF). The subjects were divided into two groups: (1) leukemia and NF with sepsis, (2) leukemia and NF without sepsis. Determination of serum levels of TNF-α, TNFR-1, Fas and Fas-L was performed using ELISA tests, and apoptosis percentage using flow cytometry. Seventy-two subjects with ALL and NF were included in the two groups. The highest serum levels of TNF-α (35.2 ± 7.6 pg/ml) and TNF-R1 (4102 ± 2440) and the lowest levels of Fas-L (19.4 ± 7.3 pg/ml) were found in group 2: however, the difference in comparison with patients without sepsis was not statistically significant. Low levels of Fas-L and low percentage of apoptotic cells are observed in septic subjects. This pattern may reflect the presence of sepsis among subjects with NF secondary to leukemia.
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Affiliation(s)
- Jesus Reyna-Figueroa
- Pediatrics Service, South Central Hospital of High Specialty of Petroleos Mexicanos, Health Services of Petroleos Mexicanos, Dirección: Blvd. Adolfo Ruiz Cortines 4091, Tlalpan, Fuentes del Pedregal, 14140, Mexico City, DF, Mexico. .,Centre for Research on Infectious Diseases, National Institute of Public Health, Secretary of Health, Cuernavaca, Morelos, Mexico.
| | - Alfredo Lagunas-Martínez
- Centre for Research on Infectious Diseases, National Institute of Public Health, Secretary of Health, Cuernavaca, Morelos, Mexico
| | - Patricia Galindo-Delgado
- Pediatrics Service, South Central Hospital of High Specialty of Petroleos Mexicanos, Health Services of Petroleos Mexicanos, Dirección: Blvd. Adolfo Ruiz Cortines 4091, Tlalpan, Fuentes del Pedregal, 14140, Mexico City, DF, Mexico
| | - María Fernanda Fernández-Bautista
- Pediatrics Service, South Central Hospital of High Specialty of Petroleos Mexicanos, Health Services of Petroleos Mexicanos, Dirección: Blvd. Adolfo Ruiz Cortines 4091, Tlalpan, Fuentes del Pedregal, 14140, Mexico City, DF, Mexico
| | - Paola Guadalupe Castro-Oteo
- Pediatrics Service, South Central Hospital of High Specialty of Petroleos Mexicanos, Health Services of Petroleos Mexicanos, Dirección: Blvd. Adolfo Ruiz Cortines 4091, Tlalpan, Fuentes del Pedregal, 14140, Mexico City, DF, Mexico
| | - Pilar Martínez-Matsumoto
- Pediatrics Service, South Central Hospital of High Specialty of Petroleos Mexicanos, Health Services of Petroleos Mexicanos, Dirección: Blvd. Adolfo Ruiz Cortines 4091, Tlalpan, Fuentes del Pedregal, 14140, Mexico City, DF, Mexico
| | - Erika Melchy Perez
- Department of Molecular Medicine and Bioprocesses, Institute of Biotechnology, National Autonomous University of Mexico, Mexico City, Mexico
| | - Yvonne Rosenstein
- Department of Molecular Medicine and Bioprocesses, Institute of Biotechnology, National Autonomous University of Mexico, Mexico City, Mexico
| | - Ana Elena Limón-Rojas
- Pediatrics Service, South Central Hospital of High Specialty of Petroleos Mexicanos, Health Services of Petroleos Mexicanos, Dirección: Blvd. Adolfo Ruiz Cortines 4091, Tlalpan, Fuentes del Pedregal, 14140, Mexico City, DF, Mexico
| | | | - Vicente Madrid-Marina
- Centre for Research on Infectious Diseases, National Institute of Public Health, Secretary of Health, Cuernavaca, Morelos, Mexico
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12
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Li MX, Liu JF, Lu JD, Zhu Y, Kuang DW, Xiang JB, Sun P, Wang W, Xue J, Gu Y, Hao CM. Plasmadiafiltration ameliorating gut mucosal barrier dysfunction and improving survival in porcine sepsis models. Intensive Care Med Exp 2016; 4:31. [PMID: 27682607 PMCID: PMC5040657 DOI: 10.1186/s40635-016-0105-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 09/20/2016] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The object of this study is to explore whether the plasmadiafiltration (PDF) is more effective in improving the intestinal mucosal barrier function by removing more key large molecular inflammatory mediators and then prolonging the survival time. METHODS Totally, 24 porcine sepsis models induced by cecal ligation and puncture (CLP) operation were randomly divided into three groups: PDF group, high-volume hemofiltration (HVHF) group, and control group, and received 8 h treatment, respectively. The expression of ZO-1 and occludin in intestinal mucosal epithelial cells were detected by immunohistochemistry, and apoptotic protein caspase-3-positive lymphocytes were signed in mesenteric lymph nodes by TUNEL staining. The hemodynamic parameters were measured by invasive cavity detection. The tumor necrosis factor alpha (TNFα) and high-mobility group protein 1 (HMGB1) were tested by ELISA method. And then, the survival curves with all-cause death were compared with three groups. RESULTS PDF led to a superior reversal of sepsis-related hemodynamic impairment and serum biochemistry abnormalities and resulted in longer survival time compared with HVHF and control (p < 0.01). Definitive protection from excessive TNF-α and HMGB1 response were only achieved by PDF. A more regular distribution pattern of ZO-1 and occludin along the epithelium was found in PDF animals (p < 0.01). The presence of apoptotic lymphocytes was significantly reduced in the PDF animals (p < 0.01). CONCLUSIONS PDF can effectively eliminate more pivotal inflammatory mediators of TNFα and HMGB1 and reduce the inflammation damage of the intestinal mucosal barrier and apoptosis of lymphocyte then improve the circulation function and prolong the survival time.
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Affiliation(s)
- Ming Xin Li
- Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Jun Feng Liu
- Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Jian Da Lu
- Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Ying Zhu
- Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Ding Wei Kuang
- Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Jian Bing Xiang
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Peng Sun
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Wei Wang
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Jun Xue
- Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.
| | - Yong Gu
- Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Chuan Ming Hao
- Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
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Wesche-Soldato DE, Lomas-Neira JL, Perl M, Jones L, Chung CS, Ayala A. The role and regulation of apoptosis in sepsis. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519050110060101] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Today, sepsis continues to be a growing problem in the critically ill patient population. A number of laboratories have been interested in understanding how changes in immune cell apoptosis during sepsis appear to contribute to septic morbidity. Consistently, it has been found that immune cell apoptosis is altered in a variety of tissue sites and cell populations both in experimental animals and humans. While divergent mediators, such as steroids and TNF, contribute to some of these apoptotic changes, their effects are tissue and cell population selective. Inhibition of FasL—Fas signaling (by either FasL gene deficiency, in vivo gene silencing [siRNA] or with FasL binding protein) protects septic mice from the onset of marked apoptosis and the morbidity/mortality seen in sepsis. Further, this extrinsic apoptosis response appears to utilize aspects of the Bid-induced mitochondrial pathway. This is in keeping with the findings that pan-specific caspase inhibition or the overexpression of Bcl-2 also protect these animals from the sequellae of sepsis.
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Affiliation(s)
- Doreen E. Wesche-Soldato
- Division of Surgical Research, Department of Surgery, RI Hospital/Brown University School of Medicine, Providence, Rhode Island, USA
| | - Joanne L. Lomas-Neira
- Division of Surgical Research, Department of Surgery, RI Hospital/Brown University School of Medicine, Providence, Rhode Island, USA
| | - Mario Perl
- Division of Surgical Research, Department of Surgery, RI Hospital/Brown University School of Medicine, Providence, Rhode Island, USA
| | - Leslie Jones
- Division of Surgical Research, Department of Surgery, RI Hospital/Brown University School of Medicine, Providence, Rhode Island, USA
| | - Chun-Shiang Chung
- Division of Surgical Research, Department of Surgery, RI Hospital/Brown University School of Medicine, Providence, Rhode Island, USA
| | - Alfred Ayala
- Division of Surgical Research, Department of Surgery, RI Hospital/Brown University School of Medicine, Providence, Rhode Island, USA,
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14
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Serum Levels of TNF Receptor Ligands Are Dysregulated in Sepsis and Predict Mortality in Critically Ill Patients. PLoS One 2016; 11:e0153765. [PMID: 27124414 PMCID: PMC4849634 DOI: 10.1371/journal.pone.0153765] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 04/04/2016] [Indexed: 12/13/2022] Open
Abstract
Introduction TNF superfamily members, including TNF-related weak inducer of apoptosis (TWEAK) and Glucocorticoid-Induced TNFR-Related Protein Ligand (GITRL) have been described as serum based biomarkers for inflammatory and immune mediated diseases. However, up to now the role of TWEAK and GITRL has not been analyzed in critical illness and sepsis. Methods GITRL and TWEAK serum concentrations were measured in 121 critically ill patients (84 fulfilled with septic disease), in comparison to 50 healthy controls. Results were correlated with clinical data. Results Serum levels of TWEAK and GITRL were strongly decreased in critically ill patients compared with healthy controls. Concentrations of TWEAK (but not GITRL) were further decreased in patients with sepsis and correlated with routinely used markers of inflammation and bacterial infection such as C-reactive protein, procalcitonin and Interleukin-6. Notably, we failed to detect a correlation to other TNFR ligands such as TNF or APRIL. Finally, TWEAK levels of the upper quartile of the cohort were prognostic for mortality during ICU treatment. Conclusion TWEAK and GITRL levels were lower in intensive care unit medical patients. Levels of TWEAK were further decreased in septic patients, and alterations in TWEAK concentrations were linked to an unfavorable outcome. Together with recently published results on other TNFR ligands, these data indicate specific functions of the different TNFR ligands in septic diseases.
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15
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Hahn WO, Mikacenic C, Price BL, Harju-Baker S, Katz R, Himmelfarb J, Wurfel MM, Liles WC. Host derived biomarkers of inflammation, apoptosis, and endothelial activation are associated with clinical outcomes in patients with bacteremia and sepsis regardless of microbial etiology. Virulence 2016; 7:387-94. [PMID: 26818467 DOI: 10.1080/21505594.2016.1144003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- William O Hahn
- a Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington , Seattle , WA , USA
| | - Carmen Mikacenic
- b Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington , Seattle , WA , USA
| | - Brenda L Price
- c Department of Biostatistics , University of Washington , Seattle , WA , USA
| | - Susanna Harju-Baker
- b Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington , Seattle , WA , USA
| | - Ronit Katz
- d Kidney Research Institute, University of Washington , Seattle , WA , USA
| | | | - Mark M Wurfel
- b Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington , Seattle , WA , USA
| | - W Conrad Liles
- a Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington , Seattle , WA , USA
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16
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Vinther AML, Skovgaard K, Heegaard PMH, Andersen PH. Dynamic expression of leukocyte innate immune genes in whole blood from horses with lipopolysaccharide-induced acute systemic inflammation. BMC Vet Res 2015; 11:134. [PMID: 26076814 PMCID: PMC4467047 DOI: 10.1186/s12917-015-0450-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 06/02/2015] [Indexed: 01/05/2023] Open
Abstract
Background In horses, insights into the innate immune processes in acute systemic inflammation are limited even though these processes may be highly important for future diagnostic and therapeutic advances in high-mortality disease conditions as the systemic inflammatory response syndrome (SIRS) and sepsis. Therefore, the aim of this study was to investigate the expression of 31 selected blood leukocyte immune genes in an equine model of acute systemic inflammation to identify significantly regulated genes and to describe their expression dynamics during a 24-h experimental period. Systemic inflammation was induced in 6 adult horses by the intravenous injection of 1 μg lipopolysaccharide (LPS) per kg btw. Sixteen blood samples were collected for each horse at predetermined intervals and analyzed by reverse transcription quantitative real-time PCR. Post-induction expression levels for each gene were compared with baseline levels. Results Systemic inflammation was confirmed by the presence of clinical and hematological changes which were consistent with SIRS. The clinical response to LPS was transient and brief as all horses except one showed unaltered general demeanor after 24 h. Twenty-two leukocyte genes were significantly regulated at at least one time point during the experimental period. By close inspection of the temporal responses the dynamic changes in mRNA abundance revealed a very rapid onset of both pro- and anti-inflammatory mediators and a substantial variation in both expression magnitudes and duration of changes between genes. A majority of the 22 significantly regulated genes peaked within the first 8 h after induction, and an on-going, albeit tightly controlled, regulation was seen after 24 h despite approximate clinical recovery. Conclusions This first broad study of gene expressions in blood leukocytes during equine acute LPS-induced systemic inflammation thoroughly characterized a highly regulated and dynamic innate immune response. These results provide new insights into the molecular mechanisms of equine systemic inflammation. Electronic supplementary material The online version of this article (doi:10.1186/s12917-015-0450-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Anne Mette L Vinther
- Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
| | - Kerstin Skovgaard
- Innate Immunology Group, Section for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Frederiksberg, Denmark.
| | - Peter M H Heegaard
- Innate Immunology Group, Section for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Frederiksberg, Denmark.
| | - Pia H Andersen
- Department of Clinical Sciences, Faculty of Veterinary and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden.
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17
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Parlato M, Cavaillon JM. Host response biomarkers in the diagnosis of sepsis: a general overview. Methods Mol Biol 2015; 1237:149-211. [PMID: 25319788 DOI: 10.1007/978-1-4939-1776-1_15] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Critically ill patients who display a systemic inflammatory response syndrome (SIRS) are prone to develop nosocomial infections. The challenge remains to distinguish as early as possible among SIRS patients those who are developing sepsis. Following a sterile insult, damage-associated molecular patterns (DAMPs) released by damaged tissues and necrotic cells initiate an inflammatory response close to that observed during sepsis. During sepsis, pathogen-associated molecular patterns (PAMPs) trigger the release of host mediators involved in innate immunity and inflammation through identical receptors as DAMPs. In both clinical settings, a compensatory anti-inflammatory response syndrome (CARS) is concomitantly initiated. The exacerbated production of pro- or anti-inflammatory mediators allows their detection in biological fluids and particularly within the bloodstream. Some of these mediators can be used as biomarkers to decipher among the patients those who developed sepsis, and eventually they can be used as prognosis markers. In addition to plasma biomarkers, the analysis of some surface markers on circulating leukocytes or the study of mRNA and miRNA can be helpful. While there is no magic marker, a combination of few biomarkers might offer a high accuracy for diagnosis.
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Affiliation(s)
- Marianna Parlato
- Unit of Cytokines and Inflammation, Institut Pasteur, 28 rue du Dr Roux, 75724, Paris Cedex 15, France
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18
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Serum concentrations of A Proliferation-Inducing Ligand (APRIL) are elevated in sepsis and predict mortality in critically ill patients. J Crit Care 2013; 28:882.e1-11. [PMID: 23337484 DOI: 10.1016/j.jcrc.2012.11.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Revised: 11/12/2012] [Accepted: 11/15/2012] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Inflammatory and autoimmune diseases have been associated with the tumor necrosis factor superfamily member "A PRoliferation Inducing Ligand" (APRIL). However, up to now, APRIL has not been investigated in critical illness or sepsis. We therefore analyzed APRIL serum concentrations in a large cohort of well-characterized intensive care unit patients. METHODS Serum concentrations of APRIL were measured in 246 critically ill patients, of which 157 fulfilled sepsis criteria in comparison with 81 healthy controls. Clinical data were recorded and correlated with APRIL serum levels. RESULTS We detected strongly elevated serum levels of APRIL in critically ill patients compared with healthy controls. Levels of APRIL were further elevated in sepsis and significantly correlated with classical markers of inflammation, bacterial infection, or multiorgan failure. Consequently, high APRIL levels were associated with an unfavorable prognosis and predicted mortality with higher diagnostic accuracy than established prognostic scoring systems such as the Acute Physiology and Chronic Health Evaluation II score. CONCLUSION Serum levels of APRIL were significantly elevated in intensive care unit patients, with the highest concentrations in septic patients, and associated with unfavorable outcome. Besides being used as a single marker, APRIL may be implemented into established scoring systems to further improve their sensitivity and specificity in predicting patient's prognosis.
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19
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Girard TD, Ware LB, Bernard GR, Pandharipande PP, Thompson JL, Shintani AK, Jackson JC, Dittus RS, Ely EW. Associations of markers of inflammation and coagulation with delirium during critical illness. Intensive Care Med 2012; 38:1965-73. [PMID: 22903241 DOI: 10.1007/s00134-012-2678-x] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2012] [Accepted: 07/24/2012] [Indexed: 01/11/2023]
Abstract
PURPOSE To assess the associations between a priori-selected markers of inflammation and coagulation and delirium during critical illness. METHODS In this prospective cohort study, we collected blood from mechanically ventilated medical intensive care unit (ICU) patients and measured nine plasma markers of inflammation and coagulation. We assessed patients daily for delirium using the Confusion Assessment Method for the ICU and used multivariable regression to analyze the associations between plasma markers and subsequent delirium, after adjusting for age, severity of illness, and sepsis. RESULTS Among the 138 patients studied, with median age of 66 years and median Acute Physiology and Chronic Health Evaluation (APACHE) II of 27, 107 (78 %) were delirious at some point during the study. Two markers of inflammation and one of coagulation were significantly associated with delirium. After adjusting for covariates, lower plasma concentrations of matrix metalloproteinase-9 (MMP-9) and protein C were associated with increased probability of delirium (p = 0.04 and 0.01, respectively), and higher concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1) were associated with increased probability of delirium (p < 0.01). Concentrations of C-reactive protein (p = 0.82), myeloperoxidase (p = 0.11), neutrophil gelatinase-associated lipocalin (p = 0.70), D-dimer (p = 0.83), plasminogen activator inhibitor type 1 (p = 0.98), and Von Willebrand factor antigen (p = 0.65) were not associated with delirium. CONCLUSIONS In this study, MMP-9, protein C, and sTNFR1 were independently associated with subsequent ICU delirium. These results suggest that specific aspects of inflammation and coagulation may play a role in the evolution of delirium during critical illness and that these markers should be examined in larger studies of ICU patients.
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Affiliation(s)
- Timothy D Girard
- Vanderbilt University School of Medicine, Nashville, TN 37232-8300, USA.
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Lvovschi V, Arnaud L, Parizot C, Freund Y, Juillien G, Ghillani-Dalbin P, Bouberima M, Larsen M, Riou B, Gorochov G, Hausfater P. Cytokine profiles in sepsis have limited relevance for stratifying patients in the emergency department: a prospective observational study. PLoS One 2011; 6:e28870. [PMID: 22220196 PMCID: PMC3248412 DOI: 10.1371/journal.pone.0028870] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Accepted: 11/16/2011] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Morbidity, mortality and social cost of sepsis are high. Previous studies have suggested that individual cytokines levels could be used as sepsis markers. Therefore, we assessed whether the multiplex technology could identify useful cytokine profiles in Emergency Department (ED) patients. METHODS ED patients were included in a single tertiary-care center prospective study. Eligible patients were >18 years and met at least one of the following criteria: fever, suspected systemic infection, ≥ 2 systemic inflammatory response syndrome (SIRS) criteria, hypotension or shock. Multiplex cytokine measurements were performed on serum samples collected at inclusion. Associations between cytokine levels and sepsis were assessed using univariate and multivariate logistic regressions, principal component analysis (PCA) and agglomerative hierarchical clustering (AHC). RESULTS Among the 126 patients (71 men, 55 women; median age: 54 years [19-96 years]) included, 102 had SIRS (81%), 55 (44%) had severe sepsis and 10 (8%) had septic shock. Univariate analysis revealed weak associations between cytokine levels and sepsis. Multivariate analysis revealed independent association between sIL-2R (p = 0.01) and severe sepsis, as well as between sIL-2R (p = 0.04), IL-1β (p = 0.046), IL-8 (p = 0.02) and septic shock. However, neither PCA nor AHC distinguished profiles characteristic of sepsis. CONCLUSIONS Previous non-multiparametric studies might have reached inappropriate conclusions. Indeed, well-defined clinical conditions do not translate into particular cytokine profiles. Additional and larger trials are now required to validate the limited interest of expensive multiplex cytokine profiling for staging septic patients.
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Affiliation(s)
- Virginie Lvovschi
- Emergency Department, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 945, Paris, France
- Department of Immunology, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
| | - Laurent Arnaud
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 945, Paris, France
- Department of Immunology, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
| | - Christophe Parizot
- Department of Immunology, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
| | - Yonathan Freund
- Emergency Department, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
- Université Pierre et Marie Curie, UPMC Univ Paris 06, Paris, France
| | - Gaëlle Juillien
- Emergency Department, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
| | | | - Mohammed Bouberima
- Emergency Biology Laboratory, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
| | - Martin Larsen
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 945, Paris, France
- Department of Immunology, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
- Université Pierre et Marie Curie, UPMC Univ Paris 06, Paris, France
| | - Bruno Riou
- Emergency Department, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
- Université Pierre et Marie Curie, UPMC Univ Paris 06, Paris, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 956, Paris, France
| | - Guy Gorochov
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 945, Paris, France
- Department of Immunology, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
- Université Pierre et Marie Curie, UPMC Univ Paris 06, Paris, France
- * E-mail: (PH); (GG)
| | - Pierre Hausfater
- Emergency Department, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
- Université Pierre et Marie Curie, UPMC Univ Paris 06, Paris, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 956, Paris, France
- * E-mail: (PH); (GG)
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Pandey P, Chaudhary R, Aggarwal A, Kumar R, Khetan D, Verma A. Transfusion-associated immunomodulation: Quantitative changes in cytokines as a measure of immune responsiveness after one time blood transfusion in neurosurgery patients. Asian J Transfus Sci 2011; 4:78-85. [PMID: 20859504 PMCID: PMC2937301 DOI: 10.4103/0973-6247.67021] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Very few studies in humans have investigated the laboratory evidences suggestive of transfusion-associated immunologic changes. In this prospective study, we examined the effects of perioperative blood transfusion on immune response, by measuring various cytokines production, namely, interferon-gamma (IFN-γ), interleukin-10 (IL-10), and Fas Ligand (FasL). A total of 40 patients undergoing neurosurgery were randomly allocated into four groups: (a) no transfusion, (b) allogeneic non-leukofiltered transfusion, (c) prestorage leukofiltered transfusion, (d) autologous transfusion. Samples were collected before operation (day 0) and postoperative days (post-op) 1, 7, and 14. IFN-γ and IL-10 production capacity was measured in supernatant after whole blood culture and serum FasL levels in patients’ sera using commercially available ELISA kits. Change in ratios (cytokine value after PHA stimulation/control value) of IFN-γ and IL-10 and percentage change from baseline for serum FasL levels across different transfusion groups during the sampling period were calculated. There was an increase in IL-10 production in patients receiving allogeneic non-leukofiltered transfusion on days 1 and 7 (mean ratio 2.22 (± 2.16), 4.12 (± 1.71), 4.46 (± 1.97) on days 0, 1, and 7, respectively). Similarly there was a significant (P<0.05) decrease in IFN-γ production in patients who received allogeneic non-leukofiltered red cell transfusion on post-op days 1, 7, and 14 (mean ratio 6.88 (± 4.56), 2.53 (± 0.95), 3.04 (± 1.38) and 2.58 (± 1.48) on day 0, 1, 7, and 14, respectively). Serum FasL production was increased across all patients till 7th day except for ‘no transfusion’ group and this increase was most significant in the non-leukofiltered group. We conclude that one time transfusion leads to quantitative changes in levels of these cytokines largely through interplay of Th2/Th1 pathways in allogeneic nonleukofiltered blood transfusion; however, soluble mediators like FasL which are also present in autologous and leukofiltered blood products may contribute toward minor immunologic effect in these settings.
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Affiliation(s)
- Prashant Pandey
- Department of Transfusion Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Paunel-Görgülü A, Flohé S, Scholz M, Windolf J, Lögters T. Increased serum soluble Fas after major trauma is associated with delayed neutrophil apoptosis and development of sepsis. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2011; 15:R20. [PMID: 21232130 PMCID: PMC3222054 DOI: 10.1186/cc9965] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2010] [Revised: 12/14/2010] [Accepted: 01/13/2011] [Indexed: 12/14/2022]
Abstract
Introduction Deregulated apoptosis and overshooting neutrophil functions contribute to immune and organ dysfunction in sepsis and multiple organ failure (MOF). In the present study, we determined the role of soluble Fas (sFas) in the regulation of posttraumatic neutrophil extrinsic apoptosis and the development of sepsis. Methods Forty-seven major trauma patients, 18 with and 29 without sepsis development during the first 10 days after trauma, were enrolled in this prospective study. Seventeen healthy volunteers served as controls. Blood samples from severely injured patients were analyzed at day 1, day 5 and day 9 after major trauma. sFas levels, plasma levels of neutrophil elastase (PMNE) and levels of interleukin (IL)-6 were quantified by enzyme-linked immunosorbent assay and related to patients' Sequential Organ Failure Assessment (SOFA) score and Multiple Organ Dysfunction Score (MODS). Neutrophil apoptosis was determined by propidium iodide staining of fragmented DNA and flow cytometry. sFas-mediated effects on neutrophil apoptosis were investigated in cells cultured with agonistic anti-Fas antibodies in the presence of recombinant sFas, sFas-depleted serum or untreated serum from septic patients. Results Serum levels of sFas in patients who later developed sepsis were significantly increased at day 5 (P < 0.01) and day 9 (P < 0.05) after trauma compared with patients with uneventful recovery. Apoptosis of patient neutrophils was significantly decreased during the observation period compared with control cells. Moreover, Fas-mediated apoptosis of control neutrophils was efficiently inhibited by recombinant sFas and serum from septic patients. Depletion of sFas from septic patient sera diminished the antiapoptotic effects. In septic patients, sFas levels were positively correlated with SOFA at day 1 (r = 0.7, P < 0.001), day 5 (r = 0.62, P < 0.01) and day 9 (r = 0.58, P < 0.01) and with PMNE and leukocyte counts (r = 0.49, P < 0.05 for both) as well as MODS at day 5 (r = 0.56, P < 0.01) after trauma. Conclusions Increased sFas in patients with sepsis development impairs neutrophil extrinsic apoptosis and shows a positive correlation with the organ dysfunction scores and PMNE. Therefore, sFas might be a therapeutic target to prevent posttrauma hyperinflammation and sepsis.
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Affiliation(s)
- Adnana Paunel-Görgülü
- Department of Trauma and Hand Surgery, University Hospital Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
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Chana F, Guisasola MC, Villanueva MJ, de las Heras J, Calvo JA, Vaquero J. Heat shock proteins in total knee arthroplasty. A pilot study. ACTA ACUST UNITED AC 2010. [DOI: 10.1007/s12570-010-0026-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Moreira VG, Prieto B, Rodríguez JSM, Alvarez FV. Usefulness of cell-free plasma DNA, procalcitonin and C-reactive protein as markers of infection in febrile patients. Ann Clin Biochem 2010; 47:253-8. [PMID: 20421309 DOI: 10.1258/acb.2010.009173] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Circulating nucleic acids were discovered more than 60 y ago. With the recent developments in the study of circulating nucleic acids, its application in the diagnostic field has increased. The objective of this study was to assess the usefulness of the quantification of cell-free plasma DNA (CF-DNA) concentration in the diagnosis of infections in febrile patients and as a prognostic marker in septic patients. METHODS Concentrations of CF-DNA, procalcitonin (PCT) and C-reactive protein (CRP) were measured in 110 febrile patients who were clinically diagnosed with fever of unknown origin, localized infection, sepsis or septic shock. RESULTS Concentrations of CF-DNA increase according to the severity of the infection. The best cut-off point for predicting infection was 2800 GE (genome equivalents)/mL (sensitivity: 95.0%; specificity: 96.7%) and 14,000 GE/mL for sepsis prediction (sensitivity: 77.8%; specificity: 94.6%). Higher concentrations of CF-DNA were found in exitus septic patients than in survivors. The diagnostic efficiency of CF-DNA was similar to PCT and higher than CRP in infectious processes. CONCLUSIONS Normal concentrations of CF-DNA can exclude the presence of an infection in febrile patients, and very high concentrations (>10-fold over the normal reference range) stratify the severity of infections, showing a high prognostic value to predict mortality in the absence of other causes for elevated CF-DNA.
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Affiliation(s)
- Vanessa García Moreira
- Servicio de Bioquímica Clínica, Hospital Universitario Central de Asturias, Oviedo 33006, Spain
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Pierrakos C, Vincent JL. Sepsis biomarkers: a review. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2010; 14:R15. [PMID: 20144219 PMCID: PMC2875530 DOI: 10.1186/cc8872] [Citation(s) in RCA: 876] [Impact Index Per Article: 58.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/10/2009] [Revised: 12/28/2009] [Accepted: 02/09/2010] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Biomarkers can be useful for identifying or ruling out sepsis, identifying patients who may benefit from specific therapies or assessing the response to therapy. METHODS We used an electronic search of the PubMed database using the key words "sepsis" and "biomarker" to identify clinical and experimental studies which evaluated a biomarker in sepsis. RESULTS The search retrieved 3370 references covering 178 different biomarkers. CONCLUSIONS Many biomarkers have been evaluated for use in sepsis. Most of the biomarkers had been tested clinically, primarily as prognostic markers in sepsis; relatively few have been used for diagnosis. None has sufficient specificity or sensitivity to be routinely employed in clinical practice. PCT and CRP have been most widely used, but even these have limited ability to distinguish sepsis from other inflammatory conditions or to predict outcome.
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Affiliation(s)
- Charalampos Pierrakos
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, route de Lennik 808, 1070 Brussels, Belgium.
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Hsu HY, Joos TO, Koga H. Multiplex microsphere-based flow cytometric platforms for protein analysis and their application in clinical proteomics â from assays to results. Electrophoresis 2009; 30:4008-19. [DOI: 10.1002/elps.200900211] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Stromberg PE, Woolsey CA, Clark AT, Clark JA, Turnbull IR, McConnell KW, Chang KC, Chung CS, Ayala A, Buchman TG, Hotchkiss RS, Coopersmith CM. CD4+ lymphocytes control gut epithelial apoptosis and mediate survival in sepsis. FASEB J 2009; 23:1817-25. [PMID: 19158156 PMCID: PMC2698654 DOI: 10.1096/fj.08-119024] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2008] [Accepted: 12/23/2008] [Indexed: 12/30/2022]
Abstract
Lymphocytes help determine whether gut epithelial cells proliferate or differentiate but are not known to affect whether they live or die. Here, we report that lymphocytes play a controlling role in mediating gut epithelial apoptosis in sepsis but not under basal conditions. Gut epithelial apoptosis is similar in unmanipulated Rag-1(-/-) and wild-type (WT) mice. However, Rag-1(-/-) animals have a 5-fold augmentation in gut epithelial apoptosis following cecal ligation and puncture (CLP) compared to septic WT mice. Reconstitution of lymphocytes in Rag-1(-/-) mice via adoptive transfer decreases intestinal apoptosis to levels seen in WT animals. Subset analysis indicates that CD4(+) but not CD8(+), gammadelta, or B cells are responsible for the antiapoptotic effect of lymphocytes on the gut epithelium. Gut-specific overexpression of Bcl-2 in transgenic mice decreases mortality following CLP. This survival benefit is lymphocyte dependent since gut-specific overexpression of Bcl-2 fails to alter survival when the transgene is overexpressed in Rag-1(-/-) mice. Further, adoptively transferring lymphocytes to Rag-1(-/-) mice that simultaneously overexpress gut-specific Bcl-2 results in improved mortality following sepsis. Thus, sepsis unmasks CD4(+) lymphocyte control of gut apoptosis that is not present under homeostatic conditions, which acts as a key determinant of both cellular survival and host mortality.
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Affiliation(s)
- Paul E Stromberg
- Department of Surgery, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110, USA
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Abstract
Prompt diagnosis, intervention, and risk assessment are critical in caring for septic patient but remain difficult with currently available methods. Biomarkers may become useful adjuncts to clinicians and ultimately serve as targets for future therapeutic trials in sepsis. The most relevant markers are reviewed in this article, including interleukin-6, C-reactive protein, procalcitonin, triggering receptor expressed on myeloid cells-1, and biomarker panels.
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Affiliation(s)
- Corey E Ventetuolo
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, College of Physicians and Surgeons, Columbia University, PH 8, Room 101, 622 W. 168th Street, New York City, NY 10032, USA
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Weber S, Baessler B, Schroeder S. Lymphocyte Apoptosis in Sepsis and Potential Anti-apoptotic Strategies. Intensive Care Med 2009. [DOI: 10.1007/978-0-387-92278-2_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Presymptomatic prediction of sepsis in intensive care unit patients. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2008; 15:1089-94. [PMID: 18480235 DOI: 10.1128/cvi.00486-07] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Postoperative or posttraumatic sepsis remains one of the leading causes of morbidity and mortality in hospital populations, especially in populations in intensive care units (ICUs). Central to the successful control of sepsis-associated infections is the ability to rapidly diagnose and treat disease. The ability to identify sepsis patients before they show any symptoms would have major benefits for the health care of ICU patients. For this study, 92 ICU patients who had undergone procedures that increased the risk of developing sepsis were recruited upon admission. Blood samples were taken daily until either a clinical diagnosis of sepsis was made or until the patient was discharged from the ICU. In addition to standard clinical and laboratory parameter testing, the levels of expression of interleukin-1beta (IL-1beta), IL-6, IL-8, and IL-10, tumor necrosis factor-alpha, FasL, and CCL2 mRNA were also measured by real-time reverse transcriptase PCR. The results of the analysis of the data using a nonlinear technique (neural network analysis) demonstrated discernible differences prior to the onset of overt sepsis. Neural networks using cytokine and chemokine data were able to correctly predict patient outcomes in an average of 83.09% of patient cases between 4 and 1 days before clinical diagnosis with high sensitivity and selectivity (91.43% and 80.20%, respectively). The neural network also had a predictive accuracy of 94.55% when data from 22 healthy volunteers was analyzed in conjunction with the ICU patient data. Our observations from this pilot study indicate that it may be possible to predict the onset of sepsis in a mixed patient population by using a panel of just seven biomarkers.
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Hsu HY, Wittemann S, Schneider EM, Weiss M, Joos TO. Suspension microarrays for the identification of the response patterns in hyperinflammatory diseases. Med Eng Phys 2008; 30:976-83. [PMID: 18313970 DOI: 10.1016/j.medengphy.2008.01.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2007] [Revised: 11/27/2007] [Accepted: 01/11/2008] [Indexed: 12/11/2022]
Abstract
Miniaturized and parallelized sandwich immunoassays allow the simultaneous analysis of a variety of parameters in a single experiment. Bead-based protein array systems or suspension microarrays are well-established multiplex sandwich immunoassay formats. To study inflammatory diseases, protein arrays can be used to analyze changes in plasma protein levels, such as cytokines, chemokines, soluble receptors, and matrix metalloproteinases. Using the bead-based Luminex system, multiplexed sandwich immunoassays have been developed to analyze the plasma concentrations of soluble receptors: sTNF-RI, sTNF-RII, sIL-2R, sgp130, sFas, sRAGE, sE-selectin, sICAM-1, sVCAM-1, sMIF-1 and sFasL. This newly established 11-plex soluble receptors assay demonstrated acceptable intra-assay and inter-assay precision, appropriate accuracy, and no crossreactivity between analytes. Using this assay, 100 plasma samples derived from 36 critically ill intensive care unit (ICU) patients with trauma or sepsis were analyzed for their soluble receptor plasma concentrations. Results obtained allowed grouping of patients' samples into a trauma and a sepsis group. Four candidate molecules: sFas, sICAM-1, sTNF-RI, and sTNF-RII had higher concentrations in patients with sepsis than in those with trauma, contributing the highest discriminatory values to define the nature of the inflammatory disease originating from pathogen-involved (sepsis) or pathogen-independent inflammation.
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Affiliation(s)
- Hsin-Yun Hsu
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
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Falasca L, Farrace MG, Rinaldi A, Tuosto L, Melino G, Piacentini M. Transglutaminase type II is involved in the pathogenesis of endotoxic shock. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2008; 180:2616-24. [PMID: 18250473 DOI: 10.4049/jimmunol.180.4.2616] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The pathogenesis of sepsis is characterized by the inability of the host to regulate the inflammatory response, and as a consequence, dysregulated inflammatory processes induce organ dysfunctions and death. Altered transglutaminase type II (TG2) expression is associated with the development of many inflammatory diseases. Therefore, in this study, we questioned whether TG2 could also contribute to the pathological inflammatory dysregulation occurring in septic shock in vivo. To this aim, we used as an experimental model the TG2 knockout mice, in which the process of septic shock was elicited by treatment with LPS. Interestingly, our results demonstrated that TG2 ablation leads to partial resistance to experimental sepsis. The increased survival of TG2(-/-) mice was reflected in a drastic reduction of organ injury, highlighted by a limited infiltration of neutrophils in kidney and peritoneum and by a better homeostasis of the proinflammatory mediators as well as mitochondrial function. We also showed that in wild-type mice, the TG2 expression is increased during endotoxemia and, being directly involved in the mechanisms of NF-kappaB activation, it may cause a continuous activation cycle in the inflammatory process, thus contributing to development of sepsis pathogenesis. We propose that the inhibition of TG2 could represent a novel approach in the treatment of inflammatory processes associated with sepsis.
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Affiliation(s)
- Laura Falasca
- Laboratory of Electron Microscopy, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy
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Monneret G, Venet F, Pachot A, Lepape A. Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol Med 2008; 14:64-78. [PMID: 18026569 PMCID: PMC2078557 DOI: 10.2119/2007-00102.monneret] [Citation(s) in RCA: 253] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2007] [Accepted: 11/06/2007] [Indexed: 12/16/2022] Open
Abstract
Septic syndromes represent a major although largely underrecognized healthcare problem worldwide, accounting for thousands of deaths every year. It is now agreed that sepsis deeply perturbs immune homeostasis by inducing an initial tremendous systemic inflammatory response which is accompanied by an antiinflammatory process, acting as negative feedback. This compensatory inhibitory response secondly becomes deleterious as nearly all immune functions are compromised. These alterations might be directly responsible for worsening outcome, as they may play a major role in the decreased resistance to nosocomial infections in patients who survived initial resuscitation. Consequently, immunostimulatory therapies may now be assessed for the treatment of sepsis. This review focuses on immune dysfunctions described in septic patients and on their potential use as markers on a routine standardized basis for prediction of adverse outcome or of occurrence of secondary nosocomial infections. This constitutes a prerequisite to a staging system for individualized treatment for these hitherto deadly syndromes.
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Affiliation(s)
- Guillaume Monneret
- Hospices civils de Lyon, Immunology laboratory, Hopital E. Herriot, Lyon, France.
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Abstract
Sepsis, the systemic inflammatory response to infection, is considered the major cause of death among critically ill patients in the developed world. While there is a general view that this reflects contributions from both the pathogen and the host with respect to an inappropriate inflammatory response, there is a lack of agreement as to the key immune mechanisms. This has been reflected in the diverse range of immunotherapies tested in clinical trials, often with rather marginal effects. The case has been made for a pathogenic role of excessive immunity, the so-called 'cytokine storm', and for a role of too little immunity through immune paralysis. Apoptosis is implicated as a key mechanism in both this immune paralysis and the multi-organ failure that is a feature of severe sepsis. A number of polymorphisms have been implicated in susceptibility to sepsis, including cytokine genes, HLA class II and caspase-12. In this review we focus in particular on the role of group A streptococci in severe sepsis. Here the effect of bacterial superantigens appears to be a correlate of inflammatory activation, although the precise evolutionary role of the superantigens remains unclear.
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Affiliation(s)
- S Sriskandan
- Department of Infectious Diseases and Immunity, Imperial College, London, UK
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Koch L, Linderkamp O, Ittrich C, Benner A, Poeschl J. Gene expression profiles of adult peripheral and cord blood mononuclear cells altered by lipopolysaccharide. Neonatology 2008; 93:87-100. [PMID: 17700033 DOI: 10.1159/000107350] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2007] [Accepted: 05/14/2007] [Indexed: 11/19/2022]
Abstract
BACKGROUND Neonatal Gram-negative sepsis is often characterized by a fulminant clinical course, compared to adults, resulting in higher morbidity and mortality. Genome-wide gene expression analysis can provide insights into the molecular alterations in sepsis. OBJECTIVES To evaluate in vitro activation of the neonatal and adult immune system, gene expression patterns were compared in mononuclear cells from cord (CBMNC) and adult peripheral blood (APBMNC). METHODS To better understand the influence of early molecular signals on the effects of sepsis, Affymetrix gene profiling (8,475 genes) was done on RNA isolated from CBMNC and APBMNC without and after incubation with 100 ng/ml lipopolysaccharide (LPS). RESULTS We demonstrated significant alterations in the expression of 108 CBMNC and APBMNC genes compared with basal levels, 188 significant changes in CBMNC and 97 in APBMNC, including cytokines, chemokines and immunoregulatory genes. Furthermore, we found 5 genes showing a significant interaction effect between cell type and LPS stimulation, including tumor necrosis factor receptor superfamily, member 6 (FAS), absent in melanoma 2, malic enzyme 1, hemoglobin epsilon 1, and trans-prenyltransferase. CONCLUSIONS These results provide further support for a marked difference in the pathogenesis of neonatal and adult sepsis and may stimulate additional studies to investigate some of the altered genes as potential new targets for diagnostic tools and therapeutic strategies.
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Affiliation(s)
- Lutz Koch
- Division of Neonatology, Department of Pediatrics, University of Heidelberg Medical School, Heidelberg, Germany.
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O'Mahony DS, Liles WC, Altemeier WA, Dhanireddy S, Frevert CW, Liggitt D, Martin TR, Matute-Bello G. Mechanical ventilation interacts with endotoxemia to induce extrapulmonary organ dysfunction. Crit Care 2007; 10:R136. [PMID: 16995930 PMCID: PMC1751060 DOI: 10.1186/cc5050] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2006] [Revised: 09/09/2006] [Accepted: 09/22/2006] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION Multiple organ dysfunction syndrome (MODS) is a common complication of sepsis in mechanically ventilated patients with acute respiratory distress syndrome, but the links between mechanical ventilation and MODS are unclear. Our goal was to determine whether a minimally injurious mechanical ventilation strategy synergizes with low-dose endotoxemia to induce the activation of pro-inflammatory pathways in the lungs and in the systemic circulation, resulting in distal organ dysfunction and/or injury. METHODS We administered intraperitoneal Escherichia coli lipopolysaccharide (LPS; 1 microg/g) to C57BL/6 mice, and 14 hours later subjected the mice to 6 hours of mechanical ventilation with tidal volumes of 10 ml/kg (LPS + MV). Comparison groups received ventilation but no LPS (MV), LPS but no ventilation (LPS), or neither LPS nor ventilation (phosphate-buffered saline; PBS). RESULTS Myeloperoxidase activity and the concentrations of the chemokines macrophage inflammatory protein-2 (MIP-2) and KC were significantly increased in the lungs of mice in the LPS + MV group, in comparison with mice in the PBS group. Interestingly, permeability changes across the alveolar epithelium and histological changes suggestive of lung injury were minimal in mice in the LPS + MV group. However, despite the minimal lung injury, the combination of mechanical ventilation and LPS resulted in chemical and histological evidence of liver and kidney injury, and this was associated with increases in the plasma concentrations of KC, MIP-2, IL-6, and TNF-alpha. CONCLUSION Non-injurious mechanical ventilation strategies interact with endotoxemia in mice to enhance pro-inflammatory mechanisms in the lungs and promote extra-pulmonary end-organ injury, even in the absence of demonstrable acute lung injury.
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Affiliation(s)
- D Shane O'Mahony
- Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, WA 98195
- Medical Research Service, VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108
| | - W Conrad Liles
- Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WA 98195
| | - William A Altemeier
- Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, WA 98195
| | - Shireesha Dhanireddy
- Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WA 98195
| | - Charles W Frevert
- Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, WA 98195
- Medical Research Service, VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108
| | - Denny Liggitt
- Department of Comparative Medicine, University of Washington School of Medicine, Seattle WA 9815
| | - Thomas R Martin
- Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, WA 98195
- Medical Research Service, VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108
| | - Gustavo Matute-Bello
- Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, WA 98195
- Medical Research Service, VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108
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Venet F, Pachot A, Debard AL, Bohe J, Bienvenu J, Lepape A, Powell WS, Monneret G. Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. THE JOURNAL OF IMMUNOLOGY 2006; 177:6540-7. [PMID: 17056586 DOI: 10.4049/jimmunol.177.9.6540] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Although it is known that septic shock induces immunosuppression, the mechanism for this phenomenon is not well understood. Monocytes play a central role in septic shock pathophysiology, which is also characterized by an increased proportion of natural regulatory T (Treg) cells. We therefore investigated whether Treg could be involved in the decreased monocyte expression of CD14 and HLA-DR observed during septic shock. We demonstrated that human Treg inhibit LPS-induced retention of monocyte CD14. Because loss of CD14 is a hallmark of monocyte apoptosis, this suggests that Treg inhibit monocyte survival. This effect was largely mediated through the release of a soluble mediator that was not identical with either IL-10 or IL-4. The Fas/FasL pathway participated in the effect as it was blocked by anti-FasL Abs and reproduced by Fas agonist and recombinant soluble FasL. Furthermore, expression of FasL was much higher on Treg than on their CD25(-) counterparts. Collectively, these results indicate that Treg act on monocytes by inhibiting their LPS-induced survival through a proapoptotic mechanism involving the Fas/FasL pathway. This may be an important mechanism for septic shock-induced immunosuppression and may offer new perspectives for the treatment of this deadly disease.
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Affiliation(s)
- Fabienne Venet
- Immunology Laboratory, Hôpital Neurologique, Hospices Civils de Lyon, 59 Boulevard Pinel, 69677 Lyon Cedex, France
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Regulation of sepsis-induced apoptosis of pulmonary cells by posttreatment of erdosteine and N-aceylcysteine. Toxicology 2006; 228:151-61. [DOI: 10.1016/j.tox.2006.08.027] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2006] [Revised: 08/17/2006] [Accepted: 08/18/2006] [Indexed: 11/19/2022]
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Kriebel F, Wittemann S, Hsu HY, Joos T, Weiss M, Schneider EM. Caspase-3 Activation, Bcl-2 Contents, and Soluble FAS-Ligand Are Not Related to the Inflammatory Marker Profile in Patients with Sepsis and Septic Shock. Ann N Y Acad Sci 2006; 1090:168-76. [PMID: 17384259 DOI: 10.1196/annals.1378.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The current comparative investigation analyses markers of inflammation and apoptosis in peripheral blood of intensive care unit (ICU) patients with postoperative/posttraumatic SIRS (systemic inflammatory response syndrome), sepsis, severe sepsis, or septic shock. Inflammatory markers (C-reactive protein [CRP], cytokines, metalloproteinases [MMPs]) and soluble FAS-Ligand (sCD178) were determined in plasma, and apoptosis-relevant antigens such as active caspase-3, Bcl-2, and sCD178 were quantified in whole-blood cell lysates. These parameters were analyzed daily in 20 postoperative/posttraumatic patients: 2 patients had SIRS, 5 suffered from sepsis (2 died), and 13 had septic shock (5 died). Active caspase-3, Bcl-2, and sCD178 were determined by ELISA and by fluorescence-activated cell sorting (FACS)-array kits using bead-assisted flow cytometry. Cytokines and MMPs were quantified by Luminex-assisted Beadlyte assays. Active caspase-3 was identified in defined samples of whole-blood lysates covering, for example, 5/7, 8/18, and 6/11 consecutive days during the patients' stay on the ICU. Also, sCD178 was detected on successive days. Peaks of active caspase-3 antigen contents in whole blood occurred independently of CRP and inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and IL-6. In addition, high MMPs 1-3, 7-10, and 13 concentrations were detected. Interestingly, active caspase-3 and cell-associated sCD178 were either elevated simultaneously or in a close time window. The same was true for Bcl-2. In conclusion, activation of apoptosis can be determined in whole blood of postoperative/posttraumatic patients by active caspase-3 and by Bcl-2. Pro- and antiapoptotic effects during sepsis may occur independently of peaks in inflammatory markers. Apoptosis could explain modeling and remodeling of leukocyte subpopulations.
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Affiliation(s)
- Fabian Kriebel
- Department of Experimental Anesthesiology, University Clinic Ulm, Steinhoevelstrasse 9, 89075 Ulm, Germany
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Abstract
BACKGROUND Orderly cell death, termed apoptosis, features a morphology that is distinct from necrotic, or accidental, cell death. As the body of literature on apoptotic cell death grows, it is difficult for practicing surgeons to stay current with the involved mechanisms and their biologic significance. METHODS A MEDLINE/PubMed literature search was conducted, followed by manual crossreferencing, to identify relevant articles published in the English language between 1972 and 2004. RESULTS Apoptosis is now known to be involved in numerous disease states. Ischemia-reperfusion injury and acute pancreatitis are but two surgical entities in which the balance of apoptotic and necrotic cell death has a profound effect on clinical outcome. Similarly, the timing and extent of apoptosis in immune cells are important factors that determine the outcome of septic patients. CONCLUSIONS As already demonstrated in animal models, further research in this field will target opportunities for therapeutic intervention, making it increasingly important for clinicians to be familiar with apoptosis and necrosis, and their roles in normal and pathologic states.
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Affiliation(s)
- Patrick McHugh
- Department of Surgery, the Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA
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Tschoeke SK, Oberholzer A, Moldawer LL. Interleukin-18: a novel prognostic cytokine in bacteria-induced sepsis. Crit Care Med 2006; 34:1225-33. [PMID: 16540967 DOI: 10.1097/01.ccm.0000208356.05575.16] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Severe inflammation and sepsis remain a serious clinical challenge worldwide. Despite modern supportive medicine and an improved understanding of the underlying pathophysiology, mortality rates remain high in patients suffering from this severe inflammatory process. The often excess production of pro- and anti-inflammatory cytokines frequently found in the circulation of septic patients has stimulated the search for reliable inflammatory mediators that can be used for the diagnosis and prediction of clinical outcome. Interleukin (IL)-18, formerly termed interferon-gamma inducing factor, is a pro-inflammatory and Th1 cytokine suggested to play a significant role in the pathogenesis of this disease. This review focuses on our current understanding of the pro-inflammatory cytokine, IL-18, and its potentially unique role in sepsis. METHODS Bibliographic search of the most recent literature (1995-2005) relating to IL-18 and its role in inflammatory diseases, with emphasis on its pathophysiological importance in sepsis. In addition, a summary of the author's own experimental data from this particular field of research set in the context of current knowledge regarding IL-18. RESULTS AND CONCLUSIONS Several studies have shown elevated plasma IL-18 concentrations to be associated with poor clinical outcome in severe inflammatory and septic conditions. Moreover, a significant increase in IL-18 concentrations has been shown to discriminate between Gram-positive and Gram-negative related sepsis, and, thus, may potentially augment existing diagnostic tools. Biological neutralization of IL-18 via caspase-1 intervention or through the administration of IL-18-binding protein has been promulgated as a promising therapeutic approach, but additional studies are required to evaluate its full potential in acute inflammatory diseases.
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Affiliation(s)
- Sven K Tschoeke
- Department of Trauma and Reconstructive Surgery, Charité--University Hospitals Berlin, Campus Benjamin Franklin, Germany
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Knotzer H, Pajk W, Dünser MW, Maier S, Mayr AJ, Ritsch N, Friesenecker B, Hasibeder WR. Regional microvascular function and vascular reactivity in patients with different degrees of multiple organ dysfunction syndrome. Anesth Analg 2006; 102:1187-93. [PMID: 16551922 DOI: 10.1213/01.ane.0000198587.10553.c1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The pathophysiology of multiple organ dysfunction syndrome (MODS) is believed to be related to that of microcirculatory dysfunction. We hypothesized that the severity of MODS is determined by measuring regional variables of microvascular function and vascular reactivity in critically ill patients. Therefore, we compared (a) reactive hyperemia response in the forearm using transcutaneous Po2/Pco2 electrodes and laser Doppler velocimetry, (b) microvascular permeability assessed by strain-gauge plethysmography in legs, and (c) variables derived from gastric tonometry in hemodynamically stable patients with moderate (n = 15) and severe (n = 15) MODS. There were no differences in systemic oxygen delivery, consumption, and oxygen extraction ratio between the groups. Mortality was 20% in patients with moderate MODS and 60% in patients with severe MODS (P = 0.025). Patients with a high MODS score had significantly larger arterial lactate concentrations (3.81 +/- 2.7 mmol/L) than patients with moderate MODS (1.66 +/- 0.82 mmol/L; P = 0.006). No significant differences in gastric pHi, gastric regional-to-arterial Pco2 difference, capillary filtration coefficient, isovolumetric venous pressure, and skin reactive hyperemia response were observed between patients with moderate and severe MODS. Once MODS is established, regional variables of microvascular function and vascular reactivity measured in this study do not reflect severity of organ dysfunction.
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Affiliation(s)
- Hans Knotzer
- Department of Anesthesia and Critical Care Medicine, Medical University Innsbruck, Innsbruck, Austria.
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Ashare A, Monick MM, Powers LS, Yarovinsky T, Hunninghake GW. Severe bacteremia results in a loss of hepatic bacterial clearance. Am J Respir Crit Care Med 2006; 173:644-52. [PMID: 16399991 PMCID: PMC2662948 DOI: 10.1164/rccm.200509-1470oc] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
RATIONALE Although it has been postulated that liver injury results in impaired clearance of bacteria from the blood, no prior study has evaluated hepatic bacterial clearance during sepsis. OBJECTIVES We hypothesized that liver injury during the evolution of sepsis would result in impaired hepatic bacterial clearance. METHODS Mild and severe bacteremia were generated in C57BL/6 mice by low- and high-dose intratracheal inoculation with Pseudomonas aeruginosa. MEASUREMENTS AND MAIN RESULTS The mortality rates with mild and severe bacteremia were 20% and 60%, respectively. Hepatic bacterial clearance was preserved throughout the evolution of mild bacteremia but was lost late with severe bacteremia. The loss of hepatic bacterial clearance resulted in increased systemic bacteremia and mortality. Pretreatment with a caspase inhibitor resulted in preservation of hepatic bacterial clearance with severe bacteremia and eventual control of the bacteremia. When Kupffer cells were ablated before the onset of bacteremia, there was a loss of hepatic bacterial clearance. This converted an initially mild bacteremia into severe bacteremia with increased organ injury and mortality. CONCLUSIONS These observations suggest that hepatic bacterial clearance may be lost during the evolution of sepsis, resulting in a failure to control bacteremia. Thus, the capacity of the liver to clear bacteria is an important determinant of the outcome in sepsis.
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Affiliation(s)
- Alix Ashare
- Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa College of Medicine, 200 Hawkins Drive, C-33 GH, Iowa City, IA 52242, USA.
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Abstract
OBJECTIVES To provide a current review of the literature regarding the assessment and management of sepsis during pregnancy. DESIGN A comprehensive review of current English-language literature search was performed with Ovid MEDLINE using the Medical Subject Headings pregnancy and sepsis, with Medical Subject Headings or keywords seeking randomized controlled trials and clinical reports, and by reviewing the bibliographies of clinical practice guidelines. RESULTS Sepsis-related maternal morbidity and mortality is a significant and persistent problem in the modern critical care obstetric unit. The management of sepsis during pregnancy is challenging. The obstetric intensivist must simultaneously discern the effect of maternal physiologic changes on fetal vulnerability and the effect of the fetus on maternal status throughout the various phases of pregnancy. Little direct evidence exists to validate the extrapolation of some sepsis treatment modalities from other nonpregnant patient populations. Nevertheless, early detection, accurate diagnosis, and aggressive appropriate treatment strategies may significantly improve outcome. Approaches like the Surviving Sepsis Campaign guidelines are unproven but seem reasonable and practical. CONCLUSIONS Sepsis during pregnancy is uncommon yet potentially fatal. Diagnostic and therapeutic guidelines should predominantly pattern those currently utilized for nonpregnant patients.
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Affiliation(s)
- Evans R Fernández-Pérez
- Multidisciplinary Critical Care Medicine Fellowship Program, Mayo Foundation, Rochester, MN, USA
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Abstract
Immediate and early trauma deaths are determined by primary brain injuries, or significant blood loss (haemorrhagic shock), while late mortality is caused by secondary brain injuries and host defence failure. First hits (hypoxia, hypotension, organ and soft tissue injuries, fractures), as well as second hits (e.g. ischaemia/reperfusion injuries, compartment syndromes, operative interventions, infections), induce a host defence response. This is characterized by local and systemic release of pro-inflammatory cytokines, arachidonic acid metabolites, proteins of the contact phase and coagulation systems, complement factors and acute phase proteins, as well as hormonal mediators: it is defined as systemic inflammatory response syndrome (SIRS), according to clinical parameters. However, in parallel, anti-inflammatory mediators are produced (compensatory anti-inflammatory response syndrome (CARS). An imbalance of these dual immune responses seems to be responsible for organ dysfunction and increased susceptibility to infections. Endothelial cell damage, accumulation of leukocytes, disseminated intravascular coagulation (DIC) and microcirculatory disturbances lead finally to apoptosis and necrosis of parenchymal cells, with the development of multiple organ dysfunction syndrome (MODS), or multiple organ failure (MOF). Whereas most clinical trials with anti-inflammatory, anti-coagulant, or antioxidant strategies failed, the implementation of pre- and in-hospital trauma protocols and the principle of damage control procedures have reduced post-traumatic complications. However, the development of immunomonitoring will help in the selection of patients at risk of post-traumatic complications and, thereby, the choice of the most appropriate treatment protocols for severely injured patients.
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Affiliation(s)
- Marius Keel
- Division of Trauma Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland.
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Gunn SR, Fink MP, Wallace B. Equipment review: the success of early goal-directed therapy for septic shock prompts evaluation of current approaches for monitoring the adequacy of resuscitation. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2005; 9:349-59. [PMID: 16137384 PMCID: PMC1269450 DOI: 10.1186/cc3725] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
A recent trial utilizing central venous oxygen saturation (SCVO2) as a resuscitation marker in patients with sepsis has resulted in its inclusion in the Surviving Sepsis Campaign guidelines. We review the evidence behind SCVO2 and its relationship to previous trials of goal-directed therapy. We compare SCVO2 to other tools for assessing the adequacy of resuscitation including physical examination, biochemical markers, pulmonary artery catheterization, esophageal Doppler, pulse contour analysis, echocardiography, pulse pressure variation, and tissue capnometry. It is unlikely that any single technology can improve outcome if isolated from an organized pattern of early recognition, algorithmic resuscitation, and frequent reassessment. This article includes a response to the journal's Health Technology Assessment questionnaire by the manufacturer of the SCVO2 catheter.
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Affiliation(s)
- Scott R Gunn
- Departments of Critical Care Medicine and Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mitchell P Fink
- Departments of Critical Care Medicine and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Chen J, Su XS, Jiang YF, Gong GZ, Zheng YH, Li GY. Transfection of apoptosis related gene Fas ligand in human hepatocellular carcinoma cells and its significance in apoptosis. World J Gastroenterol 2005; 11:2653-5. [PMID: 15849828 PMCID: PMC4305760 DOI: 10.3748/wjg.v11.i17.2653] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the expression of apoptosis related gene Fas ligand (FasL) in human hepatocellular carcinoma (HCC) cells HepG2 and its significance in apoptosis.
METHODS: Levels of soluble Fas ligand (sFasL) in a group of patients with hepatitis B virus (HBV)-induced chronic hepatitis, HBV-positive liver cirrhosis and HCC were evaluated. In a further study, the recombinant eukaryotic expression plasmid pcDNA3.1hisB-FasL was transfected into HCC cells HepG2 by lipofection, and then soluble FasL was examined in the supernatant of culture cells by EIA, FasL expression in HepG2 cells was detected by immuohistochemistry. After being stained by annexin V and propidium iodine, cells were passed through a flow cytometer and examined by a fluorescence microscope and a laser scanning microscope.
RESULTS: The sFasL levels were significantly lower in patients with HCC when compared to the patients with hepatitis or liver cirrhosis. In comparison with untransfected cells, the soluble FasL could be detected in the supernatant of transfected cells. FasL was expressed on the membranes and cytoplasm of transfected cells. The apoptotic cell rate was 36.30% in transfected cells, and was 11.53% in untransfected cells. Moreover, the different stage of apoptotic cells could be distinguished by annexin V and propidium iodine staining.
CONCLUSION: Fas ligand is an apoptotic pathway of HCC cells.
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Affiliation(s)
- Jun Chen
- Department of Infectious Diseases, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China.
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Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A. Leukocyte apoptosis and its significance in sepsis and shock. J Leukoc Biol 2005; 78:325-37. [PMID: 15817707 DOI: 10.1189/jlb.0105017] [Citation(s) in RCA: 247] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Sepsis and multiple organ failure continue to be significant problems among trauma, burn, and the critically ill patient population. Thus, a number of laboratories have focused on understanding the role of altered apoptotic cell death in contributing to immune and organ dysfunction seen in sepsis and shock. Immune cells that undergo altered apoptotic changes include neutrophils, macrophages, dendritic cells, as well as various lymphocyte populations. Evidence of epithelial as well as endothelial cell apoptotic changes has also been reported. Although mediators such as steroids, tumor necrosis factor, nitric oxide, C5a, and Fas ligand (FasL) appear to contribute to the apoptotic changes, their effects are tissue- and cell population-selective. As inhibiting Fas-FasL signaling (e.g., gene deficiency, Fas fusion protein, or Fas short interfering RNA administration), caspase inhibition (caspase mimetic peptides), and/or the overexpression of downstream antiapoptotic molecules (e.g., Bcl-2, Akt) improve survival of septic mice, it not only demonstrates the pathological significance of this process but points to novel targets for the treatment of sepsis.
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Affiliation(s)
- Doreen E Wesche
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA
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Cummings J, Ward TH, Ranson M, Dive C. Apoptosis pathway-targeted drugs--from the bench to the clinic. Biochim Biophys Acta Rev Cancer 2005; 1705:53-66. [PMID: 15585173 DOI: 10.1016/j.bbcan.2004.09.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
It is an exciting time for cancer researchers in the field of apoptotic cell death. The avalanche of discoveries over the past decade or so regarding how apoptosis is regulated begins to be exploited for therapeutic benefit as the first apoptosis-targeted drugs enter early clinical trials. This chapter provides a selective review on the development of such drugs. We also outline issues regarding the regulation and design of early clinical trials of this type of molecularly targeted agent. Finally, we discuss the biomarkers and surrogate pharmacodynamic endpoint assays currently available to chart the efficacy of apoptosis-inducing anticancer therapy.
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Affiliation(s)
- Jeff Cummings
- Clinical and Experimental Pharmacology Group, Cancer Research UK Paterson Institute, Wilmslow Road, Manchester M20 4BX, UK
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Chen J, Su XS, Jiang YF. cDNA cloning and expression of human CD95 ligand and its role in apoptosis of HepG2 cell lines. Shijie Huaren Xiaohua Zazhi 2004; 12:1789-1792. [DOI: 10.11569/wcjd.v12.i8.1789] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate CD95 ligand and its physiological function in liver neoplasms.
METHODS: The levels of soluble Fas ligand (sFasL) were evaluated in a group of patients affected by hepatitis B virus (HBV)-induced chronic hepatitis, HBV-positive liver cirrhosis and hepatocellular carcinoma (HCC).To further study, we constructed recombinant eukaryotic expression vector pcDNA3.1 hisB-CD95L, which was then tranfected into human hepatoma cell line HepG2 by lipofection.After stained by annexin V and propidium iodine, HepG2 cells were detected by flow cytometer.
RESULTS: CD95L levels were significantly decreased in patients with HCC when compared to the patients with hepatitis or liver cirrhosis.The correct recombinant pcDNA3.1hisB-CD95L was selected by PCR and restriction endonuclease digestion and confirmed by DNA sequencing respectively.Subsequently a significant proportion of cells became apoptotic, as evidenced by positive annexin staining.
CONCLUSION: CD95-CD95 ligand system can induce apoptosis of hepatoma cells.
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