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Bourial A, Lahlou W, Rghioui M, Louraoui SM, El Azhari A, Guessous F. An Exceptional Case of a Supra-tentorial Streptococcus Salivarius Brain Abscess-A Case Report. CLINICAL MEDICINE INSIGHTS-CASE REPORTS 2025; 18:11795476251325803. [PMID: 40103915 PMCID: PMC11915240 DOI: 10.1177/11795476251325803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 02/19/2025] [Indexed: 03/20/2025]
Abstract
Introduction During the COVID-19 pandemic, incidence of brain abscesses is difficult to assess. Numerous studies reported benign and severe post SARS-CoV-2 vaccine side effects, including rare cases of brain abscesses associated with COVID-19 or Anti-SARS-CoV-2 vaccines. Here in, we report what we believe to be, up to date, the fourth known case in the medical literature of a streptococcus salivarius brain abscess, the first intra parenchymatous or supra-tentorial streptococcus salivarius brain abscess and also the first that occurs following an anti-SARS-CoV-2 vaccine. Case presentation We describe the case of a north african 63-year-old man with an unremarkable medical history except for recent anti-SARS-CoV-2 vaccinations. Following the administration of a third anti-SARS-CoV-2 booster vaccine, the patient developed neurological symptoms, including left hemiparesis, facial palsy, vertigo, and balance issues. Imaging studies revealed a right temporo-parietal lesion consistent with intracranial suppuration. Stereotaxic cerebral biopsy confirmed the presence of purulent content, indicating a brain abscess caused by multi-sensitive streptococcus salivarius. Conclusion Sepsis-induced immunodepression appears to be a consequence of severe inflammatory state, as it dysregulates leukocytes population and results in serious infections. A plausible hypothesis is that a previous stress such as anti-SARS-CoV-2 vaccination could lead to the development of a streptococcus salivarius septicemia. In light of the available evidence and research findings, no definitive conclusion can be drawn regarding any potential link between anti-SARS-CoV-2 vaccines and the physiopathology of sepsis-induced immunodepression.
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Affiliation(s)
- Abderrahim Bourial
- Department of Oto-Laryngology, Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
- Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
| | - Wahib Lahlou
- Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
| | - Mounir Rghioui
- Department of Neurosurgery, Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
| | - Sidi Mamoun Louraoui
- Department of Neurosurgery, Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
| | - Abdessamad El Azhari
- Department of Neurosurgery, Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
| | - Fadila Guessous
- Department of Microbiology, Immunology and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA, USA
- Department of Biological Sciences, Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
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Tie X, Zhao Y, Su J, Liu X, Zou T, Yin W. Genetic associations between autoimmune diseases and the risks of severe sepsis and 28-day mortality: a two-sample Mendelian randomization study. Front Med (Lausanne) 2024; 11:1331950. [PMID: 38343642 PMCID: PMC10853392 DOI: 10.3389/fmed.2024.1331950] [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: 11/02/2023] [Accepted: 01/08/2024] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Autoimmune diseases exhibit heterogenous dysregulation of pro-inflammatory or anti-inflammatory cytokine expression, akin to the pathophysiology of sepsis. It is speculated that individuals with autoimmune diseases may have an increased likelihood of developing sepsis and face elevated mortality risks following septic events. However, current observational studies have not yielded consistent conclusions. This study aims to explore the causal relationship between autoimmune diseases and the risks of sepsis and mortality using Mendelian randomization (MR) analysis. METHODS We conducted a two-sample MR study involving a European population, with 30 autoimmune diseases as the exposure factors. To assess causal relationships, we employed the inverse variance-weighted (IVW) method and used Cochran's Q test for heterogeneity, as well as the MR pleiotropy residual sum and outlier (MR-PRESSO) global test for potential horizontal pleiotropy. RESULTS Genetically predicted Crohn's disease (β = 0.067, se = 0.034, p = 0.046, OR = 1.069, 95% CI = 1.001-1.141) and idiopathic thrombocytopenic (β = 0.069, se = 0.031, p = 0.023, OR = 1.071, 95% CI = 1.009-1.136) were positively associated with an increased risk of sepsis in critical care. Conversely, rheumatoid arthritis (β = -0.104, se = 0.047, p = 0.025, OR = 0.901, 95% CI = 0.823-0.987), ulcerative colitis (β = -0.208, se = 0.084, p = 0.013, OR = 0.812, 95% CI = 0.690-0.957), and narcolepsy (β = -0.202, se = 0.092, p = 0.028, OR = 0.818, 95% CI = 0.684-0.978) were associated with a reduced risk of sepsis in critical care. Moreover, Crohn's disease (β = 0.234, se = 0.067, p = 0.001, OR = 1.263, 95% CI = 1.108-1.440) and idiopathic thrombocytopenic (β = 0.158, se = 0.061, p = 0.009, OR = 1.171, 95% CI = 1.041-1.317) were also linked to an increased risk of 28-day mortality of sepsis in critical care. In contrast, multiple sclerosis (β = -0.261, se = 0.112, p = 0.020, OR = 0.771, 95% CI = 0.619-0.960) and narcolepsy (β = -0.536, se = 0.184, p = 0.003, OR = 0.585, 95% CI = 0.408-0.838) were linked to a decreased risk of 28-day mortality of sepsis in critical care. CONCLUSION This MR study identified causal associations between certain autoimmune diseases and risks of sepsis in critical care, and 28-day mortality in the European population. These findings suggest that exploring the mechanisms underlying autoimmune diseases may offer new diagnostic and therapeutic strategies for sepsis prevention and treatment.
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Affiliation(s)
- Xin Tie
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yanjie Zhao
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jing Su
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xing Liu
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tongjuan Zou
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Wanhong Yin
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
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Ansari MA, Das S, Rai G, Singh PK, Lahan S, Tyagi A, Alamer E, Dar SA. Low monocytic HLA-DR expression in critically ill patients of sepsis: An indicator for antimicrobial and/or immunomodulatory intervention. Transpl Immunol 2023; 81:101942. [PMID: 37866671 DOI: 10.1016/j.trim.2023.101942] [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: 08/26/2023] [Revised: 10/10/2023] [Accepted: 10/19/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND Sepsis is a result of suppressed host immune response which leads to fatal multi-organ dysfunctionality. Low frequency of active monocytes or reduced expression of human leukocyte antigen (HLA)-DR on monocytes shows the suppressed immune response in sepsis patients. One of the well-studied markers in patients with sepsis is procalcitonin (PCT). The role of monocytic (m) HLA-DR expression has been monitored in sepsis and is being considered a marker of the severity of interim immuno-depression in these patients. The study describes the impact of HLA-DR expression on monocytes quantitatively using flow cytometry. METHODS In this prospective study, we quantified monocytes and their HLA-DR expression in 20 patients of sepsis admitted to the Intensive Care Unit (ICU). Serum levels of PCT and interleukin (IL)-6 production were also measured in these patients, and the results were compared with those in healthy controls. RESULTS Monocyte frequency calculated was higher in sepsis patients as compared to healthy controls, however, HLA-DR expressing monocytes were significantly reduced as was the mean fluorescence intensity (MFI) of HLA-DR. Contrastingly, IL-6 and PCT levels were significantly high in sepsis than controls. The results suggest that low HLA-DR expression, combined with PCT, is a better prognostic parameter in the early phase of sepsis. CONCLUSION Poor recovery of mHLA-DR may serve as an early guide for clinicians to assess the prognosis of sepsis patients and consider immunomodulatory therapy in its management.
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Affiliation(s)
- Mohammad Ahmad Ansari
- Department of Microbiology, University College of Medical Sciences (University of Delhi) & GTB Hospital, Delhi 110095, India
| | - Shukla Das
- Department of Microbiology, University College of Medical Sciences (University of Delhi) & GTB Hospital, Delhi 110095, India.
| | - Gargi Rai
- Department of Microbiology, University College of Medical Sciences (University of Delhi) & GTB Hospital, Delhi 110095, India
| | - Praveen Kumar Singh
- Department of Microbiology, University College of Medical Sciences (University of Delhi) & GTB Hospital, Delhi 110095, India
| | - Shubham Lahan
- University College of Medical Sciences (University of Delhi) & GTB Hospital, Delhi 110095, India
| | - Asha Tyagi
- Department of Anesthesiology and Critical Care, University College of Medical Sciences (University of Delhi) & GTB Hospital, Delhi 110095, India
| | - Edrous Alamer
- Department of Medical Laboratory Technology, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Sajad Ahmad Dar
- Department of Microbiology, University College of Medical Sciences (University of Delhi) & GTB Hospital, Delhi 110095, India; Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan 45142, Saudi Arabia.
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Cavaillon JM. During Sepsis and COVID-19, the Pro-Inflammatory and Anti-Inflammatory Responses Are Concomitant. Clin Rev Allergy Immunol 2023; 65:183-187. [PMID: 37395985 DOI: 10.1007/s12016-023-08965-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2023] [Indexed: 07/04/2023]
Abstract
The most severe forms of COVID-19 share many features with bacterial sepsis and have thus been considered to be a viral sepsis. Innate immunity and inflammation are closely linked. While the immune response aims to get rid of the infectious agent, the pro-inflammatory host response can result in organ injury including acute respiratory distress syndrome. On its side, a compensatory anti-inflammatory response, aimed to dampen the inflammatory reaction, can lead to immunosuppression. Whether these two key events of the host inflammatory response are consecutive or concomitant has been regularly depicted in schemes. Initially proposed from 2001 to 2013 to be two consecutive steps, the concomitant occurrence has been supported since 2013, although it was proposed for the first time in 2001. Despite a consensus was reached, the two consecutive steps were still recently proposed for COVID-19. We discuss why the concomitance view could have been initiated as early as 1995.
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Soubani AO, Sharma A, Soubani O, Mishra T. Septic Shock Short-Term Outcomes in Patients With Psychiatric Disorders: Analysis From the National Inpatient Sample Database. J Acad Consult Liaison Psychiatry 2023; 64:436-443. [PMID: 36972754 DOI: 10.1016/j.jaclp.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND Major psychiatric disorders are associated with lower life expectancy primarily due to comorbid illnesses and suboptimal access to health care. Large-scale contemporary data in the United States on in-hospital mortality of patients with major psychiatric disorder and sepsis are lacking. OBJECTIVE To describe the short-term outcomes of hospitalized patients with major psychiatric disorders and septic shock. METHODS We performed a retrospective cohort study using the National Inpatient Sample database from 2016 to 2019 to identify septic shock hospitalizations in patients with versus without major psychiatric disorder (defined as schizophrenia and affective disorders). Baseline variables and in-hospital mortality trends were compared between the 2 groups. RESULTS Out of 1,653,255 hospitalizations with septic shock identified between 2016 and 2019, 16.2% had a diagnosis of major psychiatric disorder as defined above. After adjusting for various patient-level and hospital-level demographics and coexisting clinical conditions in a multivariable logistic regression, the odds of in-hospital mortality in patients with any major psychiatric disorder were 0.71 times that of those without a diagnosis of psychiatric illness (95% confidence interval [CI], 0.69-0.73; P < 0.001). Similarly, when the disorders were divided into 2 categories for subanalysis, those with schizophrenia had 38% lower odds of dying compared to those without schizophrenia (adjusted odds ratio, 0.62; 95% CI, 0.58-0.66; P < 0.001). Those with affective disorders had 25% lower odds of in-hospital mortality than those without a diagnosis of an affective disorder (adjusted odds ratio, 0.75; 95% CI, 0.73-0.77; P < 0.001). The adjusted mean length of stay for those diagnosed with major psychiatric disorder was 0.38 days longer than those without significant psychiatric illness (95% CI, 0.28-0.49; P < 0.001). On the other hand, the mean hospitalization charges were $10,516 less for patients with a major psychiatric disorder compared to those without (95% CI, -$11,830 to -$9,201; P < 0.001). CONCLUSIONS Hospitalized patients with major psychiatric disorder and septic shock had lower risk of short-term mortality. Further studies are needed to examine the reasons behind this lower in-hospital mortality risk.
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Affiliation(s)
- Ayman O Soubani
- Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI.
| | - Aditi Sharma
- Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI
| | - Omar Soubani
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI
| | - Tushar Mishra
- Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI
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Oud L, Garza J. The association of systemic lupus erythematosus with short-term mortality in sepsis: a population-level analysis. J Investig Med 2023; 71:419-428. [PMID: 36655787 DOI: 10.1177/10815589221150641] [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] [Indexed: 01/20/2023]
Abstract
Systemic lupus erythematosus (SLE) is associated with higher risks of sepsis and sepsis-related mortality compared to the general population. However, the prognostic impact of SLE in sepsis is uncertain. We used statewide data to identify hospitalizations aged ≥18 years in Texas with sepsis, with and without SLE during 2014-2017. Multilevel logistic regression with propensity adjustment (primary model), propensity score matching, and multivariable logistic regression without propensity adjustment were used to estimate the association of SLE with short-term mortality (defined as in-hospital mortality or discharge to hospice) among sepsis hospitalizations. Among 283,025 sepsis hospitalizations, 2933 (1.0%) had SLE. Compared to sepsis hospitalizations without SLE, those with SLE were younger (aged ≥65 years, 25.0% vs 57.0%) and had higher burden of comorbidities (mean Deyo comorbidity index 3.0 vs 2.6). Short-term mortality of sepsis hospitalizations with and without SLE was 22.9% vs 31.3%. SLE remained associated with lower short-term mortality on the secondary models, but not on the primary one (adjusted odds ratio: 0.905; 95% confidence interval: 0.817-1.001). When in-hospital mortality was used as secondary outcome, SLE was associated with mortality only on propensity score matching. The increased sepsis-related mortality in SLE is driven by higher risk of sepsis, but not by higher case fatality among septic patients. SLE may be associated with lower risk of mortality among septic patients, but further studies are needed due to heterogeneity of the prognostic associations across models.
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Affiliation(s)
- Lavi Oud
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Texas Tech University Health Sciences Center at the Permian Basin, Odessa, TX, USA
| | - John Garza
- Texas Tech University Health Sciences Center at the Permian Basin, Odessa, TX, USA
- Department of Mathematics, The University of Texas of the Permian Basin, Odessa, TX, USA
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Lindell RB, Meyer NJ. Interrogating the sepsis host immune response using cytomics. Crit Care 2023; 27:93. [PMID: 36941659 PMCID: PMC10027588 DOI: 10.1186/s13054-023-04366-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023] Open
Abstract
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2023. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2023 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .
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Affiliation(s)
- Robert B Lindell
- Division of Critical Care Medicine, Department of Anesthesia and Critical Care Medicine, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Pediatric Sepsis Program, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Nuala J Meyer
- Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- Center for Translational Lung Biology and Lung Biology Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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Oud L, Garza J. Association of multiple sclerosis with mortality in sepsis: a population-level analysis. J Intensive Care 2022; 10:36. [PMID: 35879778 PMCID: PMC9310428 DOI: 10.1186/s40560-022-00628-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 07/17/2022] [Indexed: 11/21/2022] Open
Abstract
Background Multiple sclerosis (MS) is associated with increased risk of sepsis and higher sepsis-related mortality, compared to the general population. However, the evidence on the prognostic impact of MS in sepsis has been scarce. We aimed to evaluate the population-level association of MS with short-term mortality in sepsis. Methods We performed a retrospective population-based cohort study using a statewide data set to identify hospitalizations aged ≥ 18 years in Texas with sepsis, with and without MS during 2010–2017. Multilevel logistic models were fit to estimate the association of MS with short-term mortality among all sepsis hospitalizations, and for sensitivity analyses among hospitalizations with septic shock and those admitted to ICU. Results Among 283,025 sepsis hospitalizations, 1687 (0.6%) had MS. Compared to sepsis hospitalizations without MS, those with MS were younger (aged ≥ 65 years 35.0% vs 56.8%), less commonly racial/ethnic minority (36.2% vs 48.1%), and had lower mean Deyo comorbidity index (1.6 vs 2.7). The rates of septic shock and ICU admission were similar for sepsis hospitalizations with and without MS (58.7% vs 59.6% and 46.7% vs 46.0%, respectively). The unadjusted short-term mortality among sepsis hospitalizations with and without MS for the whole cohort, among those with septic shock, and among ICU admissions were 20.2% vs 31.3%, 25.6% vs 40.0%, and 24.0% vs 34.8%, respectively. On adjusted analyses, MS was associated with 17% lower odds of short-term mortality (adjusted odds ratio [aOR] 0.828 [95% CI 0.723–0.947]). Similar findings were observed on sensitivity analyses of patients with septic shock (aOR 0.764 [95% CI 0.651–0.896]), but MS was not associated with mortality among sepsis hospitalizations admitted to ICU (aOR 0.914 [95% CI 0.759–1.101]). Conclusions MS was associated with lower short-term mortality among septic patients, with findings consistent among the subset with septic shock. Among septic patients admitted to ICU, MS was not associated with mortality. Supplementary Information The online version contains supplementary material available at 10.1186/s40560-022-00628-1.
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Oud L, Garza J. Impact of history of mental disorders on short-term mortality among hospitalized patients with sepsis: A population-based cohort study. PLoS One 2022; 17:e0265240. [PMID: 35271683 PMCID: PMC8912146 DOI: 10.1371/journal.pone.0265240] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 02/24/2022] [Indexed: 11/26/2022] Open
Abstract
Background Mental disorders are associated with markedly reduced life expectancy, in part due to an increased risk of death due to infection, likely reflecting sepsis-associated mortality. Patients with mental disorders are at an increased risk of sepsis, but data on the prognostic impact of mental disorders in sepsis are sparse, showing conflicting findings. Methods We used statewide data to identify hospitalizations aged ≥18 years with sepsis in Texas during 2014–2017. Mental disorders, including mood, anxiety, psychosis, and personality disorders were identified using Clinical Classification Software codes. Multilevel, multivariable logistic regression with propensity adjustment (primary model), with propensity score matching, and multivariable logistic regression as alternative models, were used to estimate the association between mental disorders and short-term mortality (defined as in-hospital mortality or discharge to hospice). Additional models were fitted for sensitivity analyses and to estimate the prognostic associations of individual categories of mental disorders. Results Among 283,025 hospitalizations with sepsis, 56,904 (20.1%) had mental disorders. Hospitalizations with vs without mental disorders were younger (age 18–44 years 12.2% vs 10.6%), more commonly white (61.0% vs 49.8%), with lower burden of comorbidities (mean [SD] Deyo comorbidity index 2.53 [2.27] vs 2.73 [2.47]), and with lower need for organ support (mechanical ventilation 32.8% vs 36.0%); p<0.0001 for all comparisons. Crude short-term mortality among sepsis hospitalizations with and without mental disorders was 25.0% vs 32.8%, respectively. On adjusted analyses, mental disorders remained associated with lower odds of short-term mortality (adjusted odds ratio 0.792 [95% CI 0.772–0.812]). This finding was consistent on the alternative modeling approaches, sensitivity analyses, and examination of individual categories of mental disorders. Conclusions Mental disorders were associated, unexpectedly, with markedly lower risk of short-term mortality in sepsis. Further studies to examine the mechanisms underlying these findings may inform future efforts to improve sepsis outcomes.
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Affiliation(s)
- Lavi Oud
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Texas Tech University Health Sciences Center at the Permian Basin, Odessa, Texas, United States of America
- * E-mail:
| | - John Garza
- Department of Mathematics, The University of Texas Permian Basin, Odessa, Texas, United States of America
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Abstract
Changing demographic trends have led to an increase in the overall geriatric trauma patient volume. Furthermore, the intersection of aging and injury can be problematic because geriatric patients have multiple comorbidities, geriatric-specific syndromes, and reduced physiological reserve. Despite mounting evidence that frail geriatric patients have inferior outcomes following trauma, very few studies have examined the effect of aging on the biological response to injury. In the present article, we review the current literature and explore the pathophysiological rationale underlying observed data, available evidence, and future directions on this topic.
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Pravda J. Sepsis: Evidence-based pathogenesis and treatment. World J Crit Care Med 2021; 10:66-80. [PMID: 34316443 PMCID: PMC8291008 DOI: 10.5492/wjccm.v10.i4.66] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/13/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023] Open
Abstract
Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure, irreversible shock, and death. Sepsis has been vexing health care providers for centuries due to its insidious onset, generalized metabolic dysfunction, and lack of specific therapy. A common factor underlying sepsis is the characteristic hypermetabolic response as the body ramps up every physiological system in its fight against the underlying critical illness. A hypermetabolic response requires supraphysiological amounts of energy, which is mostly supplied via oxidative phosphorylation generated ATP. A by-product of oxidative phosphorylation is hydrogen peroxide (H2O2), a toxic, membrane-permeable oxidizing agent that is produced in far greater amounts during a hypermetabolic state. Continued production of mitochondrial H2O2 can overwhelm cellular reductive (antioxidant) capacity leading to a build-up within cells and eventual diffusion into the bloodstream. H2O2 is a metabolic poison that can inhibit enzyme systems leading to organ failure, microangiopathic dysfunction, and irreversible septic shock. The toxic effects of H2O2 mirror the clinical and laboratory abnormalities observed in sepsis, and toxic levels of blood H2O2 have been reported in patients with septic shock. This review provides evidence to support a causal role for H2O2 in the pathogenesis of sepsis, and an evidence-based therapeutic intervention to reduce H2O2 levels in the body and restore redox homeostasis, which is necessary for normal organ function and vascular responsiveness.
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Affiliation(s)
- Jay Pravda
- Inflammatory Disease Research Centre, Therashock LLC, Palm Beach Gardens, FL 33410, United States
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Chen F, Yao C, Feng Y, Yu Y, Guo H, Yan J, Chen J. The identification of neutrophils-mediated mechanisms and potential therapeutic targets for the management of sepsis-induced acute immunosuppression using bioinformatics. Medicine (Baltimore) 2021; 100:e24669. [PMID: 33761636 PMCID: PMC9282053 DOI: 10.1097/md.0000000000024669] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 01/18/2021] [Indexed: 01/05/2023] Open
Abstract
Neutrophils have crucial roles in defensing against infection and adaptive immune responses. This study aimed to investigate the genetic mechanism in neutrophils in response to sepsis-induced immunosuppression.The GSE64457 dataset was downloaded from the Gene Expression Omnibus database and the neutrophil samples (D3-4 and D6-8 post sepsis shock) were assigned into two groups. The differentially expressed genes (DEGs) were identified. The Short Time-series Expression Miner (STEM) clustering analysis was conducted to select the consistently changed DEGs post sepsis shock. The overlapping genes between the DEGs and the deposited genes associated with immune, sepsis, and immunosuppression in the AmiGO2 and Comparative Toxicogenomics Database were screened out and used for the construction of the protein-protein interaction (PPI) network. The expression of several hub genes in sepsis patients was validated using the PCR analysis. The drugs targeting the hub genes and the therapy strategies for sepsis or immunosuppression were reviewed and used to construct the drug-gene-therapy-cell network to illustrate the potential therapeutic roles of the hub genes.A total of 357 overlapping DEGs between the two groups were identified and were used for the STEM clustering analysis, which generated four significant profiles with 195 upregulated (including annexin A1, ANXA1; matrix metallopeptidase 9, MMP9; and interleukin 15, IL-15) and 151 downregulated DEGs (including, AKT1, IFN-related genes, and HLA antigen genes). Then, a total of 34 of the 151 downregulated DEGs and 39 of the 195 upregulated DEGs were shared between the databases and above DEGs, respectively. The PPI network analysis identified a downregulated module including IFN-related genes. The deregulation of DEGs including AKT1 (down), IFN-inducible protein 6 (IFI6, down), IL-15 (up), and ANXA1 (up) was verified in the neutrophils from patients with sepsis-induced immunosuppression as compared with controls. Literature review focusing on the therapy showed that the upregulation of IL-15, IFN, and HLA antigens are the management targets. Besides, the AKT1 gene was targeted by gemcitabine.These findings provided additional clues for understanding the mechanisms of sepsis-induced immunosuppression. The drugs targeting AKT1 might provide now clues for the management strategy of immunosuppression with the intention to prevent neutrophil infiltration.
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Affiliation(s)
- Fang Chen
- Nursing Department, Zhejiang Hospital
| | - Chunyan Yao
- Institute of Health Food, Zhejiang Academy of Medical Sciences
| | - Yue Feng
- Radiology Department, Zhejiang Hospital
| | - Ying Yu
- Institute of Health Food, Zhejiang Academy of Medical Sciences
| | - Honggang Guo
- Zhejiang Experimental Animal Center, Zhejiang Academy of Medical Sciences
| | - Jing Yan
- Intensive Care Unit, Zhejiang Hospital
| | - Jin Chen
- General Practice Department, Zhejiang Hospital, Hangzhou, Zhejiang, China
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Cao L, Zhu T, Lang X, Jia S, Yang Y, Zhu C, Wang Y, Feng S, Wang C, Zhang P, Chen J, Jiang H. Inhibiting DNA Methylation Improves Survival in Severe Sepsis by Regulating NF-κB Pathway. Front Immunol 2020; 11:1360. [PMID: 32714333 PMCID: PMC7343767 DOI: 10.3389/fimmu.2020.01360] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 05/28/2020] [Indexed: 12/17/2022] Open
Abstract
Organ dysfunction caused by sepsis is life-threatening and results in high mortality. Therapeutic options for sepsis are limited. Pathogenic factors are considered as components of environmental pressure that modify DNA methylation patterns thereby enhancing disease progression. Here, we found that sepsis patients exhibited higher levels of genomic DNA methylation patterns and hypermethylated genes associated with the NF-kB signaling pathway. Therefore, we hypothesized that a DNA methyl transferase inhibitor, Decitabine, may mitigate inflammation and improve survival by inhibiting the NF-κB signaling pathway. To test the hypothesis, mice challenged with caecal ligation and puncture (CLP) were subcutaneously injected with Decitabine solution (0.5, 1, and 1.5 mg/kg) 2 h following operation. Our results indicated that Decitabine reduces DNA methyltransferases (DNMTs), attenuates NF-κB activation, downregulates inflammatory cytokine levels, and inhibits the progression of sepsis. Thus, DNA methylation may be indispensable for sepsis and serve as a predicting factor. The use of Decitabine could represent a novel strategy in the treatment of sepsis.
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Affiliation(s)
- Luxi Cao
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Tingting Zhu
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Xiabing Lang
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Sha Jia
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Yi Yang
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Chaohong Zhu
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Yucheng Wang
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Shi Feng
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Cuili Wang
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Ping Zhang
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Hong Jiang
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Beijing, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
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14
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Cardoso-Sousa L, Aguiar EMG, Caixeta DC, Vilela DD, da Costa DP, Silva TL, Cunha TM, Faria PR, Espindola FS, Jardim AC, Vieira AA, Oliveira TL, Goulart LR, Sabino-Silva R. Effects of salbutamol and phlorizin on acute pulmonary inflammation and disease severity in experimental sepsis. PLoS One 2019; 14:e0222575. [PMID: 31536570 PMCID: PMC6752759 DOI: 10.1371/journal.pone.0222575] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 09/03/2019] [Indexed: 02/05/2023] Open
Abstract
Respiratory infection can be exacerbated by the high glucose concentration in the airway surface liquid (ASL). We investigated the effects of salbutamol and phlorizin on the pulmonary function, oxidative stress levels and SGLT1 activity in lung, pulmonary histopathological damages and survival rates of rats with sepsis. Sepsis was induced by cecal ligation and puncture surgery (CLP). Twenty-four hours after surgery, CLP rats were intranasally treated with saline, salbutamol or phlorizin. After 2 hours, animals were anesthetized and sacrificed. Sepsis promoted atelectasis and bronchial inflammation, and led to increased expression of SGLT1 on cytoplasm of pneumocytes. Salbutamol treatment reduced bronchial inflammation and promoted hyperinsuflation in CLP rats. The interferon-ɤ and Interleucin-1β concentrations in bronchoalveolar lavage (BAL) were closely related to the bronchial inflammation regulation. Salbutamol stimulated SGLT1 in plasma membrane; whereas, phlorizin promoted the increase of SGLT1 in cytoplasm. Phlorizin reduced catalase activity and induced a significant decrease in the survival rate of CLP rats. Taken together, sepsis promoted atelectasis and lung inflammation, which can be associated with SGLT1 inhibition. The loss of function of SGLT1 by phlorizin are related to the augmented disease severity, increased atelectasis, bronchial inflammation and a significant reduction of survival rate of CLP rats. Alternatively salbutamol reduced BAL inflammatory cytokines, bronchial inflammation, atelectasis, and airway damage in sepsis. These data suggest that this selective β2-adrenergic agonist may protect lung of septic acute effects.
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Affiliation(s)
- Léia Cardoso-Sousa
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Emilia Maria Gomes Aguiar
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | | | | | - Danilo Pereira da Costa
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Tamires Lopes Silva
- Institute of Biomedical Sciences, Laboratory of Immunoparasitology "Dr. Mario Endsfeldz Camargo", Federal University of Uberlandia, Minas Gerais, Brazil
| | - Thúlio Marquez Cunha
- Department of Pulmonology, School of Medicine, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Paulo Rogério Faria
- Department of Morphology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | | | - Ana Carolina Jardim
- Laboratory of Virology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Alexandre Antônio Vieira
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Tales Lyra Oliveira
- Faculty of Medicine, Municipal University of Sao Caetano do Sul, Sao Paulo, Brazil
| | - Luiz Ricardo Goulart
- Institute of Biotechnology, Federal University of Uberlandia, Minas Gerais, Brazil
- Department of Medical Microbiology and Immunology, University of California Davis, California, United States of America
| | - Robinson Sabino-Silva
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
- * E-mail:
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15
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Wisler JR, Singh K, Mccarty AR, Abouhashem ASE, Christman JW, Sen CK. Proteomic Pathway Analysis of Monocyte-Derived Exosomes during Surgical Sepsis Identifies Immunoregulatory Functions. Surg Infect (Larchmt) 2019; 21:101-111. [PMID: 31478785 DOI: 10.1089/sur.2019.051] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Background: Patients with sepsis exhibit significant long-term immunosuppressive sequelae. Monocyte dysfunction is a hallmark of this damage. Circulating exosomes are an important mediator of the systemic signaling events that occur during the septic response; thus, we sought to characterize the contribution of circulating exosomes to the inflammatory process induced during sepsis Methods: Monocyte-derived exosomes were isolated from cultured monocytes from healthy adult donors via stimulation with lipopolysaccharide (LPS) or phosphate-buffered saline (PBS). The proteome was determined by capillary-liquid chromatography-nanospray tandem mass spectrometry (capillary-LC/NT/MS). Using pathway analysis, proteomic networks of exosomes derived from LPS-stimulated monocytes were compared with those isolated from patients with surgical sepsis. Naïve monocytes were then treated with these exosomes and stimulated with LPS to determine the effects on recipient-cell immune function. Results: Proteomic analysis demonstrated 18 differentially expressed proteins (17 down-regulated, one up-regulated) in sepsis-derived exosomes, with 15 differentially expressed proteins (14 down-regulated, one up-regulated) in the LPS-stimulated exosomes. Functional enrichment analysis demonstrated several down-regulated processes, including localization, biogenesis, and metabolic and cellular processes in addition to immune system processes. In LPS-stimulated macrophages, similar down-regulated processes were seen, including metabolic and cellular processes, as well as the response to stimulus. Cells treated with sepsis-derived exosomes or exosomes from LPS-stimulated monocytes demonstrated significant reductions in tumor necrosis factor (TNF)-α generation in response to LPS stimulation. Conclusions: Proteomic analysis of sepsis-derived exosomes and LPS-stimulated, macrophage-derived exosomes exhibited down-regulation of several important protein networks, including the immune response. In addition, human monocytes treated with exosomes from patients with sepsis or LPS-stimulated monocytes demonstrated significant reductions in TNF-α generation in response to LPS stimulation. These data suggest the contribution of circulating exosomes to systemic signaling and immunomodulation during sepsis.
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Affiliation(s)
- Jon R Wisler
- Divison of Trauma and Critical Care, Department of Surgery, Ohio State University, Columbus, Ohio
| | - Kanhaiya Singh
- Indiana Center for Regenerative Medicine & Engineering, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Adara R Mccarty
- Divison of Trauma and Critical Care, Department of Surgery, Ohio State University, Columbus, Ohio
| | - Ahmed Safwat Elsayed Abouhashem
- Indiana Center for Regenerative Medicine & Engineering, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - John W Christman
- Division of Pulmonary, Critical Care and Sleep, Department of Medicine, Ohio State University, Columbus, Ohio
| | - Chandan K Sen
- Indiana Center for Regenerative Medicine & Engineering, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
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16
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Toni Ho GG, Heinen F, Stieglitz F, Blasczyk R, Bade-Döding C. Dynamic Interaction between Immune Escape Mechanism and HLA-Ib Regulation. Immunogenetics 2019. [DOI: 10.5772/intechopen.80731] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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17
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Sheth M, Benedum CM, Celi LA, Mark RG, Markuzon N. The association between autoimmune disease and 30-day mortality among sepsis ICU patients: a cohort study. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2019; 23:93. [PMID: 30885252 PMCID: PMC6423870 DOI: 10.1186/s13054-019-2357-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 02/13/2019] [Indexed: 12/12/2022]
Abstract
Introduction Sepsis results from a dysregulated host response to an infection that is associated with an imbalance between pro- and anti-inflammatory cytokines. This imbalance is hypothesized to be a driver of patient mortality. Certain autoimmune diseases modulate the expression of cytokines involved in the pathophysiology of sepsis. However, the outcomes of patients with autoimmune disease who develop sepsis have not been studied in detail. The objective of this study is to determine whether patients with autoimmune diseases have different sepsis outcomes than patients without these comorbidities. Methods Using the Multiparameter Intelligent Monitoring in Intensive Care III database (v. 1.4) which contains retrospective clinical data for over 50,000 adult ICU stays, we compared 30-day mortality risk for sepsis patients with and without autoimmune disease. We used logistic regression models to control for known confounders, including demographics, disease severity, and immunomodulation medications. We used mediation analysis to evaluate how the chronic use of immunomodulation medications affects the relationship between autoimmune disease and 30-day mortality. Results Our study found a statistically significant 27.00% reduction in the 30-day mortality risk associated with autoimmune disease presence. This association was found to be the strongest (OR 0.71, 95% CI 0.54–0.93, P = 0.014) among patients with septic shock. The autoimmune disease-30-day mortality association was not mediated through the chronic use of immunomodulation medications (indirect effect OR 1.07, 95% CI 1.01–1.13, P = 0.020). Conclusions We demonstrated that autoimmune diseases are associated with a lower 30-day mortality risk in sepsis. Our findings suggest that autoimmune diseases affect 30-day mortality through a mechanism unrelated to the chronic use of immunomodulation medications. Since this study was conducted within a single study center, research using data from other medical centers will provide further validation. Electronic supplementary material The online version of this article (10.1186/s13054-019-2357-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mallory Sheth
- MIT Operations Research Center, Cambridge, MA, USA.,The Charles Stark Draper Laboratory, Cambridge, MA, USA
| | - Corey M Benedum
- The Charles Stark Draper Laboratory, Cambridge, MA, USA.,Boston University School of Public Health, Boston, MA, USA
| | - Leo Anthony Celi
- Harvard-MIT Division of Health Science and Technology, Boston, MA, USA.,Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Roger G Mark
- Harvard-MIT Division of Health Science and Technology, Boston, MA, USA.,Beth Israel Deaconess Medical Center, Boston, MA, USA
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18
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Eliwan HO, Watson WRG, Regan I, Philbin B, O'Hare FM, Strickland T, O'Neill A, O'Rourke M, Blanco A, Healy M, Nolan B, Smith O, Molloy EJ. Pediatric Intensive Care: Immunomodulation With Activated Protein C ex vivo. Front Pediatr 2019; 7:386. [PMID: 31612119 PMCID: PMC6776988 DOI: 10.3389/fped.2019.00386] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 09/06/2019] [Indexed: 11/21/2022] Open
Abstract
Objective: Sepsis is major cause of morbidity and mortality in the Pediatric Intensive Care Unit (PICU). PICU patients may develop transient immune deficiency during sepsis. Activated Protein C (APC) has significant anti-inflammatory and cytoprotective effects. Clinical trials of APC in adult sepsis initially showed improved outcome but recent trials showed no benefit in adults or children. We aimed to assess the effects of APC treatment on innate immune responses in children. Design and Subjects: We compared neutrophil and monocyte responses to lipopolysaccharide (LPS) with and without APC treatment in PICU patients at the time of evaluation for sepsis compared with healthy adults and age-matched pediatric controls. We used flow cytometry to examine cell activation (CD11b expression), function [intracellular reactive oxygen intermediate (ROI) release] and LPS recognition [Toll like Receptor 4 (TLR4) expression]. Results: PICU patients had significantly decreased protein c levels and LPS responses compared with adult and pediatric controls for all parameters. APC reduced LPS-induced neutrophil PICU TLR4 and adult ROI (p < 0.05). PICU non-survivors had increased LPS induced neutrophil and monocyte ROI production vs. survivors which was significantly reduced by APC. Conclusion: PICU patients demonstrate significantly reduced endotoxin reactivity which may predispose them to sepsis and alter effective antibacterial responses. APC reduces LPS-induced ROI production in adults and may have a role in treating severely compromised PICU patients especially given that newer APC forms are associated with decreased bleeding risk and enhanced anti-inflammatory effects.
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Affiliation(s)
- Hassan O Eliwan
- Neonatology, National Maternity Hospital, Dublin, Ireland.,National Children's Research Centre, Dublin, Ireland.,Paediatrics, Royal College of Surgeons in Ireland, Dublin, Ireland.,University College Dublin School of Medicine and Medical Sciences, Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - William R G Watson
- University College Dublin School of Medicine and Medical Sciences, Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Irene Regan
- Haematology, Our Lady's Children's Hospital, Dublin, Ireland
| | - Brian Philbin
- Haematology, Our Lady's Children's Hospital, Dublin, Ireland
| | - Fiona M O'Hare
- Neonatology, National Maternity Hospital, Dublin, Ireland.,National Children's Research Centre, Dublin, Ireland.,University College Dublin School of Medicine and Medical Sciences, Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Tammy Strickland
- Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland
| | - Amanda O'Neill
- University College Dublin School of Medicine and Medical Sciences, Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | | | - Alfonso Blanco
- University College Dublin School of Medicine and Medical Sciences, Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Martina Healy
- Critical Care, Our Lady's Children's Hospital, Dublin, Ireland
| | - Beatrice Nolan
- Haematology, Our Lady's Children's Hospital, Dublin, Ireland
| | - Owen Smith
- Haematology, Our Lady's Children's Hospital, Dublin, Ireland
| | - Eleanor J Molloy
- Neonatology, National Maternity Hospital, Dublin, Ireland.,National Children's Research Centre, Dublin, Ireland.,Paediatrics, Royal College of Surgeons in Ireland, Dublin, Ireland.,University College Dublin School of Medicine and Medical Sciences, Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.,Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland.,Neonatology, Our Lady's Children's Hospital, Dublin, Ireland.,Paediatrics, Coombe Women's and Infant's University Hospital, Dublin, Ireland
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19
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Dadkhah A, Fatemi F, Rasooli A, Mohammadi Malayeri MR, Torabi F. Assessing the effect of Mentha longifolia essential oils on COX-2 expression in animal model of sepsis induced by caecal ligation and puncture. PHARMACEUTICAL BIOLOGY 2018; 56:495-504. [PMID: 31070531 PMCID: PMC6282450 DOI: 10.1080/13880209.2018.1510972] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 06/15/2018] [Accepted: 08/03/2018] [Indexed: 05/16/2023]
Abstract
CONTEXT Mentha longifolia L. (Lamiaceae), a traditional Iranian plant, possesses antimicrobial and antioxidant activities. OBJECTIVE We investigated the potential protective effects of M. longifolia essential oils (E.Os) on caecal ligation and puncture (CLP) induced liver injury. MATERIALS AND METHODS Wistar Albino rats (n = 50) were grouped as follows: (1) a laparotomy group (LAP); (2) a CLP group (CLP); (3) the treatment groups received orally the E.Os (50 and 100 mg/kg b.w) and indomethacin (2 mg/kg b.w) for 2 weeks. The oxidative stress parameters, liver enzymes and prostaglandin E2 (PGE2) level were measured in liver and plasma tissues. The liver was also harvested for the real time PCR of cyclooxygenase (COX-2) expression following histopathological examinations. RESULTS The results indicated that the CLP operation significantly increased lipid peroxidation (LP) [1.79-fold], myeloperoxidase (MPO) [2.76-fold], PGE2 [1.56-fold] besides plasma aspartate aminotransferase (AST) [2.4-fold] and alanine aminotransferase (ALT) activities [2.22-fold], while, markedly reduced glutathione (GSH) [0.63-fold] and ferric reducing ability of plasma (FRAP) levels [0.63-fold]. Even COX2 expression significantly increased in the CLP group as compared to the LAP group. Treatments of rats with the E.Os could return all the hepatic and plasma biomarkers to the normal levels. These results were further confirmed by pathological examination on liver indicating that E.Os could successfully improve the CLP-induced liver injuries. DISCUSSION AND CONCLUSIONS Our findings suggest that E.Os is able to protect liver injuries against sepsis via modulating the oxidative stress parameters concomitant with the suppression of inflammatory reactions such as PGE2 and COX-2.
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Affiliation(s)
- Abolfazl Dadkhah
- Department of Medicine, Faculty of Medicine, Qom Branch, Islamic Azad University, Qom, Iran
| | - Faezeh Fatemi
- Materials and Nuclear Fuel Research School, Nuclear Science and Technology Research Institute, Tehran, Iran
| | - Azadeh Rasooli
- Department of Biochemistry, Faculty of Science, Payame-e-Noor University, Tehran, Iran
| | | | - Fatemeh Torabi
- Department of Physiology, Faculty of Science, Qom Branch, Islamic Azad University, Qom, Iran
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20
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Niederwanger C, Bachler M, Hell T, Linhart C, Entenmann A, Balog A, Auer K, Innerhofer P. Inflammatory and coagulatory parameters linked to survival in critically ill children with sepsis. Ann Intensive Care 2018; 8:111. [PMID: 30446841 PMCID: PMC6240023 DOI: 10.1186/s13613-018-0457-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 11/09/2018] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Sepsis is associated with a deflection of inflammatory and coagulative parameters, since some clotting factors are known to be involved in the host's defense against infection and inflammation. These parameters could play a crucial role in the course of sepsis and be used as prognostic markers in critically ill children. METHODS A total of 250 critically ill pediatric patients diagnosed with sepsis were retrospectively analyzed to identify routinely measured predictors for in-hospital mortality at the peak level of C-reactive protein. Those parameters entered multivariate logistic regression analysis as well as a decision tree for survival. RESULTS Multivariate logistic regression analysis revealed fibrinogen, platelets and activated partial thromboplastin time (aPTT) at the peak level of C-reactive protein to be predictors for survival (p = 0.03, p = 0.01 and p = 0.02, respectively). An increase in fibrinogen and platelets is linked to survival, whereas an aPTT prolongation is associated with higher mortality; adjusted odds ratios (95% CI) for an increase of 100 mg/dl in fibrinogen are 1.35 (1.04-1.82) per 50 G/l platelets 1.94 (1.3-3.29) and 0.83 (0.69-0.96) for an aPTT prolongation of 10 s. Decision tree analysis shows that a fibrinogen level below 192 mg/dl (90.9% vs. 13% mortality) is most distinctive in non-survivors. CONCLUSIONS High levels of fibrinogen and platelets as well as a non-overshooting aPTT are associated with a higher survival rate in pediatric patients with diagnosed sepsis. In particular, hypofibrinogenemia is distinctive for a high mortality rate in septic critically ill children.
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Affiliation(s)
- Christian Niederwanger
- Department of Pediatrics, Pediatrics I, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Mirjam Bachler
- Institute for Sports Medicine, Alpine Medicine and Health Tourism, UMIT - University for Health Sciences, Medical Informatics and Technology, Eduard Wallnöfer Zentrum 1, 6060, Hall in Tirol, Austria.
| | - Tobias Hell
- Department of Mathematics, Faculty of Mathematics, Computer Science and Physics, University of Innsbruck, Technikerstraße 13, 6020, Innsbruck, Austria
| | - Caroline Linhart
- Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Andreas Entenmann
- Department of Pediatrics, Pediatrics I, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Agnes Balog
- Department of Pediatrics, Pediatrics I, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Katharina Auer
- Department of General and Surgical Critical Care Medicine, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Petra Innerhofer
- Department of Anaesthesiology and Critical Care Medicine, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
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21
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Chronic Critical Illness and Persistent Inflammation: What can we Learn from the Elderly, Injured, Septic, and Malnourished? Shock 2018; 49:4-14. [PMID: 28682945 DOI: 10.1097/shk.0000000000000939] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Patients in the intensive care unit (ICU) who develop chronic critical illness significantly stress the clinical capacity and financial resources of healthcare systems. Although vast improvements have been made in critical care management, outcomes for this ICU subset remain poor. A hallmark for patients who progress to chronic critical illness is the development of persistent inflammation and immunosuppression. The risk factors associated with the development of chronic critical illness include increased age, medical comorbidities, severe injury, septic shock, and malnutrition. Interestingly, each of these clinical states bears strikingly similar immune defects, often resulting in the activation of a persistent inflammatory state. Strategies aimed at the prevention or early recognition of this state of immune compromise may help improve outcomes for these individuals and minimize the number who progress to chronic critical illness. This review explores the current knowledge regarding the immune defects associated with the development of persistent inflammation, the ways in which it can manifest clinically, attempted therapeutic interventions to date, and future insights into improving outcomes for this patient population.
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22
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Schmoeckel K, Mrochen DM, Hühn J, Pötschke C, Bröker BM. Polymicrobial sepsis and non-specific immunization induce adaptive immunosuppression to a similar degree. PLoS One 2018; 13:e0192197. [PMID: 29415028 PMCID: PMC5802895 DOI: 10.1371/journal.pone.0192197] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 01/19/2018] [Indexed: 11/18/2022] Open
Abstract
Sepsis is frequently complicated by a state of profound immunosuppression, in its extreme form known as immunoparalysis. We have studied the role of the adaptive immune system in the murine acute peritonitis model. To read out adaptive immunosuppression, we primed post-septic and control animals by immunization with the model antigen TNP-ovalbumin in alum, and measured the specific antibody-responses via ELISA and ELISpot assay as well as T-cell responses in a proliferation assay after restimulation. Specific antibody titers, antibody affinity and plasma cell counts in the bone marrow were reduced in post-septic animals. The antigen-induced splenic proliferation was also impaired. The adaptive immunosuppression was positively correlated with an overwhelming general antibody response to the septic insult. Remarkably, antigen “overload” by non-specific immunization induced a similar degree of adaptive immunosuppression in the absence of sepsis. In both settings, depletion of regulatory T cells before priming reversed some parameters of the immunosuppression. In conclusion, our data show that adaptive immunosuppression occurs independent of profound systemic inflammation and life-threatening illness.
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Affiliation(s)
- Katrin Schmoeckel
- Department of Immunology, Institute of Immunology and Transfusion Medicine, University Medicine, Greifswald, Germany
| | - Daniel M. Mrochen
- Department of Immunology, Institute of Immunology and Transfusion Medicine, University Medicine, Greifswald, Germany
| | - Jochen Hühn
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Christian Pötschke
- Department of Immunology, Institute of Immunology and Transfusion Medicine, University Medicine, Greifswald, Germany
| | - Barbara M. Bröker
- Department of Immunology, Institute of Immunology and Transfusion Medicine, University Medicine, Greifswald, Germany
- * E-mail:
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Fang WF, Douglas IS, Chen YM, Lin CY, Kao HC, Fang YT, Huang CH, Chang YT, Huang KT, Wang YH, Wang CC, Lin MC. Development and validation of immune dysfunction score to predict 28-day mortality of sepsis patients. PLoS One 2017; 12:e0187088. [PMID: 29073262 PMCID: PMC5658156 DOI: 10.1371/journal.pone.0187088] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 10/15/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Sepsis-induced immune dysfunction ranging from cytokines storm to immunoparalysis impacts outcomes. Monitoring immune dysfunction enables better risk stratification and mortality prediction and is mandatory before widely application of immunoadjuvant therapies. We aimed to develop and validate a scoring system according to patients' immune dysfunction status for 28-day mortality prediction. METHODS A prospective observational study from a cohort of adult sepsis patients admitted to ICU between August 2013 and June 2016 at Kaohsiung Chang Gung Memorial Hospital in Taiwan. We evaluated immune dysfunction status through measurement of baseline plasma Cytokine levels, Monocyte human leukocyte-DR expression by flow cytometry, and stimulated immune response using post LPS stimulated cytokine elevation ratio. An immune dysfunction score was created for 28-day mortality prediction and was validated. RESULTS A total of 151 patients were enrolled. Data of the first consecutive 106 septic patients comprised the training cohort, and of other 45 patients comprised the validation cohort. Among the 106 patients, 21 died and 85 were still alive on day 28 after ICU admission. (mortality rate, 19.8%). Independent predictive factors revealed via multivariate logistic regression analysis included segmented neutrophil-to-monocyte ratio, granulocyte-colony stimulating factor, interleukin-10, and monocyte human leukocyte antigen-antigen D-related levels, all of which were selected to construct the score, which predicted 28-day mortality with area under the curve of 0.853 and 0.789 in the training and validation cohorts, respectively. CONCLUSIONS The immune dysfunction scoring system developed here included plasma granulocyte-colony stimulating factor level, interleukin-10 level, serum segmented neutrophil-to-monocyte ratio, and monocyte human leukocyte antigen-antigen D-related expression appears valid and reproducible for predicting 28-day mortality.
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Affiliation(s)
- Wen-Feng Fang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan
- * E-mail: (WFF); (MCL)
| | - Ivor S. Douglas
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver and Denver Health Medical Center, Denver, Colorado, United States of America
| | - Yu-Mu Chen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
| | - Chiung-Yu Lin
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
| | - Hsu-Ching Kao
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
| | - Ying-Tang Fang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
| | - Chi-Han Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
| | - Ya-Ting Chang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
| | - Kuo-Tung Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
| | - Yi-His Wang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chin-Chou Wang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan
| | - Meng-Chih Lin
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosung, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- * E-mail: (WFF); (MCL)
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Kumari A, Dash D, Singh R. Curcumin inhibits lipopolysaccharide (LPS)-induced endotoxemia and airway inflammation through modulation of sequential release of inflammatory mediators (TNF-α and TGF-β1) in murine model. Inflammopharmacology 2017; 25:329-341. [PMID: 28289922 DOI: 10.1007/s10787-017-0334-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/23/2017] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Curcumin (diferuloylmethane), a major component of turmeric is well known for its anti-inflammatory potential. Present study investigates sequential release of inflammatory mediators post LPS challenge (10 mg/kg,i.p.) causing lung inflammation and its modulation by curcumin through different routes (20 mg/kg, i.p and 10 mg/kg, i.n.) in murine model. Dexamethasone (1 mg/kg, i.p) was used as standard drug. METHODS Lung Inflammation was evaluated by histopathological analysis, myeloperoxidase (MPO) activity followed by inflammatory cell count and total protein content measurements in bronchoalveolar fluid (BALF). Reactive oxygen species (ROS), nitrite and TNF-α levels were measured as markers of endotoxin shock at different time points (1-72 h). The mRNA expression of transforming growth factors-β1 (TGF-β1), iNOS and Toll-like receptor-4 (TLR-4) were measured followed by Masson's trichrome staining and hydroxyproline levels as collagen deposition marker leading to fibrotic changes in lungs. RESULTS We found that LPS-induced lung inflammation and injury was maximum 24-h post LPS challenge shown by MPO and histological analysis which was further supported by elevated nitrite and ROS levels whereas TNF-α level was highest after 1 h. Endotoxin-induced mortality was significantly reduced in curcumin (i.p) pretreatment groups up to 72-h post LPS challenge. Significant inhibition in mRNA expression of iNOS, TGF-β1 and TNF-α level was noted after curcumin treatment along with lowered MPO activity, inflammatory cell count, ROS, nitrite levels and collagen deposition in lungs. CONCLUSION Our results suggest that higher endotoxin dose causes inflammatory mediator release in chronological order which tend to increase with time and reached maximum after 24-h post-endotoxin (LPS) exposure. Intraperitoneal route of curcumin administration was better in modulating inflammatory mediator release in early phase as compared to intranasal route of administration. It can be used as supplementary therapeutic intervention at early stage of endotoxemia, having fewer side effects.
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Affiliation(s)
- Asha Kumari
- Department of Zoology, MMV, Banaras Hindu University, Varanasi, 221005, India
| | - D Dash
- Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Rashmi Singh
- Department of Zoology, MMV, Banaras Hindu University, Varanasi, 221005, India.
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Mizock BA, DeMichele SJ. The Acute Respiratory Distress Syndrome: Role of Nutritional Modulation of Inflammation Through Dietary Lipids. Nutr Clin Pract 2017; 19:563-74. [PMID: 16215155 DOI: 10.1177/0115426504019006563] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The acute respiratory distress syndrome (ARDS) is the most serious form of acute hypoxic respiratory failure. ARDS represents the expression of an acute, diffuse, inflammatory process in the lungs consequent to a variety of infectious and noninfectious conditions. It is characterized pathologically by damage to pulmonary epithelial and endothelial cells, with subsequent alveolar-capillary leak and exudative pulmonary edema. The main clinical features of ARDS include rapid onset of dyspnea, severe defects in gas exchange, and imaging studies demonstrating diffuse pulmonary infiltrates. The role of nutrition in the management of ARDS has traditionally been supportive. Recent research has demonstrated the potential of certain dietary oils (eg, fish oil, borage oil) to modulate pulmonary inflammation, thereby improving lung compliance and oxygenation, and reducing time on mechanical ventilation. This article reviews the alterations in the immune response that underlie ARDS, discusses the physiology of dietary oils as immunonutrients, summarizes animal and human studies that explore the therapeutic effects of dietary oils, and provides clinical recommendations for their use.
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Affiliation(s)
- Barry A Mizock
- Department of Medicine, Cook County Hospital, 1900 West Polk Street, Chicago, Illinois 60612, USA.
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Philips CA, Sarin SK. Sepsis in cirrhosis: emerging concepts in pathogenesis, diagnosis and management. Hepatol Int 2016; 10:871-882. [PMID: 27422251 DOI: 10.1007/s12072-016-9753-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 06/24/2016] [Indexed: 02/07/2023]
Abstract
Infections and sepsis are more common in cirrhotic than in the general population and constitute the commonest cause of sudden worsening and death. The diagnosis of systemic inflammatory syndrome and sepsis are challenging in cirrhotics due to an underlying a state of hyperdynamic circulation. Further, poor nutritional and bone marrow reserves lead to modest host immune response, the so called immunoparalysis state and the outcome of antibiotic therapy is suboptimal. In this review, a comprehensive description of current and emerging concepts in the pathogenesis and diagnosis of sepsis with importance to current and novel biomarkers for diagnosis of sepsis in cirrhosis is presented. Furthermore, novel treatment options and preventive strategies are discussed to improve the overall survival.
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Affiliation(s)
- Cyriac Abby Philips
- Department of Hepatology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, Delhi, 110070, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, Delhi, 110070, India.
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Low-Dose Steroid Therapy Is Associated with Decreased IL-12 Production in PBMCs of Severe Septic Patients. Mediators Inflamm 2016; 2016:1796094. [PMID: 27555669 PMCID: PMC4983364 DOI: 10.1155/2016/1796094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 06/18/2016] [Accepted: 07/03/2016] [Indexed: 12/29/2022] Open
Abstract
Background. Sepsis-induced immunosuppression may result in higher mortality rates in patients. Methods. We examined the relationship of cytokine responses from stimulated peripheral blood mononuclear cells (PBMCs) and monocyte human leukocyte antigen-DR (HLA-DR) expression (days 1 and 7) with low-dose steroid therapy in 29 septic patients. Patients were treated according to the guidelines. Thirty healthy controls were enrolled for validation. Results. Eighteen patients were prescribed low-dose steroids and 11 were not. Interleukin- (IL-) 12 responses in patients without low-dose steroid therapy on days 1 and 7 were higher than those with low-dose steroid therapy. Compared to day 1, IL-12 responses significantly increased on day 7 in patients without low-dose steroid therapy. After regression analysis, the change in the IL-12 response from day 7 to day 1 was found to be independently associated with the low-dose steroid therapy. There was no difference in monocyte HLA-DR expression between patients treated with and without low-dose steroid on day 1 or 7. No change in monocyte HLA-DR expression from day 7 to day 1 was observed in patients with or without low-dose steroid therapy. Conclusion. Decreased IL-12 response was associated with the low-dose steroid therapy in PBMCs of septic patients.
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28
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Ruiz S, Vardon-Bounes F, Merlet-Dupuy V, Conil JM, Buléon M, Fourcade O, Tack I, Minville V. Sepsis modeling in mice: ligation length is a major severity factor in cecal ligation and puncture. Intensive Care Med Exp 2016; 4:22. [PMID: 27430881 PMCID: PMC4949182 DOI: 10.1186/s40635-016-0096-z] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 07/07/2016] [Indexed: 02/01/2023] Open
Abstract
Background The cecal ligation and puncture (CLP) model, a gold standard in sepsis research, is associated with an important variability in mortality. While the number of punctures and needle size is well described in CLP animal studies, the length of cecal ligation is often not. The relationship between cecal ligation and survival in mice is briefly reported in the literature; therefore, we devised an investigation in mice of the consequences of three standardized cecal ligation lengths on mortality and the severity of the ensued sepsis. Methods Male C57BL/6J mice underwent standardized CLP. The cecum was ligated at 5, 20, or 100 % of its total length and further perforated by a single 20-G puncture. Mortality was analyzed. We assessed blood lactate, serum creatinine levels, and serum cytokines (TNF-α, IL-1β, IL-6, and IL-10) after procedure in a control group and in ligated mice. Results Mortality was directly related to ligation length: median survival was 24 h for the “100 %” group and 44 h for the “20 %” group. Blood lactate increased proportionally with the ligation length. At 6 h post-procedure, pro-inflammatory cytokines significantly increased in the ligated group with significantly higher serum levels of IL-6 in the 100 % group compared to the other ligated groups. The 20 % group exhibited the characteristics of septic shock with hypotension below 65 mmHg, pro-inflammatory balance, organ dysfunction, and hyperlactatemia. Conclusions Cecal ligation length appears to be a major limiting factor in the mouse CLP model. Thus, this experimental model should be performed with high consistency in future protocol designs.
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Affiliation(s)
- Stéphanie Ruiz
- Department of Anesthesiology and Intensive Care, Rangueil Hospital, University Hospital of Toulouse, 1 Avenue du Professeur Jean Poulhès TSA 50032, 31059, Toulouse, Cedex 9, France. .,Inserm/UPS UMR 1048 - I2MC, Equipe 3, Toulouse, France.
| | - Fanny Vardon-Bounes
- Department of Anesthesiology and Intensive Care, Rangueil Hospital, University Hospital of Toulouse, 1 Avenue du Professeur Jean Poulhès TSA 50032, 31059, Toulouse, Cedex 9, France.,Inserm/UPS UMR 1048 - I2MC, Equipe 3, Toulouse, France
| | - Virginie Merlet-Dupuy
- Department of Anesthesiology and Intensive Care, Rangueil Hospital, University Hospital of Toulouse, 1 Avenue du Professeur Jean Poulhès TSA 50032, 31059, Toulouse, Cedex 9, France
| | - Jean-Marie Conil
- Department of Anesthesiology and Intensive Care, Rangueil Hospital, University Hospital of Toulouse, 1 Avenue du Professeur Jean Poulhès TSA 50032, 31059, Toulouse, Cedex 9, France
| | - Marie Buléon
- Inserm/UPS UMR 1048 - I2MC, Equipe 12, Toulouse, France
| | - Olivier Fourcade
- Department of Anesthesiology and Intensive Care, Rangueil Hospital, University Hospital of Toulouse, 1 Avenue du Professeur Jean Poulhès TSA 50032, 31059, Toulouse, Cedex 9, France.,EA 4564 - MATN - Laboratoire de Modélisation de l'Agression Tissulaire et de la Nociception Toulouse, Institut Louis Bugnard (IFR 150), Toulouse, France
| | - Ivan Tack
- Inserm/UPS UMR 1048 - I2MC, Equipe 12, Toulouse, France.,Department of Physiology, Rangueil Hospital, University Hospital of Toulouse, 1 Avenue du Professeur Jean Poulhès TSA 50032, 31059, Toulouse Cedex 9, France
| | - Vincent Minville
- Department of Anesthesiology and Intensive Care, Rangueil Hospital, University Hospital of Toulouse, 1 Avenue du Professeur Jean Poulhès TSA 50032, 31059, Toulouse, Cedex 9, France.,Inserm/UPS UMR 1048 - I2MC, Equipe 3, Toulouse, France
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Ubags NDJ, Stapleton RD, Vernooy JHJ, Burg E, Bement J, Hayes CM, Ventrone S, Zabeau L, Tavernier J, Poynter ME, Parsons PE, Dixon AE, Wargo MJ, Littenberg B, Wouters EFM, Suratt BT. Hyperleptinemia is associated with impaired pulmonary host defense. JCI Insight 2016; 1. [PMID: 27347561 DOI: 10.1172/jci.insight.82101] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this e_ect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia.
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Affiliation(s)
- Niki D J Ubags
- Department of Respiratory Medicine, Maastricht University Medical Centre+, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands; Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Renee D Stapleton
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Juanita H J Vernooy
- Department of Respiratory Medicine, Maastricht University Medical Centre+, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands
| | - Elianne Burg
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Jenna Bement
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Catherine M Hayes
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Sebastian Ventrone
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Lennart Zabeau
- Flanders Institute for Biotechnology (VIB), Department of Medical Protein Research, Ghent University, Ghent, Belgium
| | - Jan Tavernier
- Flanders Institute for Biotechnology (VIB), Department of Medical Protein Research, Ghent University, Ghent, Belgium
| | - Matthew E Poynter
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Polly E Parsons
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Anne E Dixon
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Matthew J Wargo
- Department of Microbiology & Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Benjamin Littenberg
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Emiel F M Wouters
- Department of Respiratory Medicine, Maastricht University Medical Centre+, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands
| | - Benjamin T Suratt
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
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Wu HP, Shih CC, Chu CM, Huang CY, Hua CC, Liu YC, Chuang DY. Effect of interleukin-17 on in vitro cytokine production in healthy controls and patients with severe sepsis. J Formos Med Assoc 2015; 114:1250-7. [DOI: 10.1016/j.jfma.2014.09.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 08/29/2014] [Accepted: 09/02/2014] [Indexed: 12/23/2022] Open
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Abstract
Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (10(6) CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3(-/-)). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3(-/-) mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3(-/-) mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3(-/-) mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility.
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Drosatos K, Lymperopoulos A, Kennel PJ, Pollak N, Schulze PC, Goldberg IJ. Pathophysiology of sepsis-related cardiac dysfunction: driven by inflammation, energy mismanagement, or both? Curr Heart Fail Rep 2015; 12:130-140. [PMID: 25475180 PMCID: PMC4474734 DOI: 10.1007/s11897-014-0247-z] [Citation(s) in RCA: 158] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Sepsis is a systemic inflammatory response that follows bacterial infection. Cardiac dysfunction is an important consequence of sepsis that affects mortality and has been attributed to either elevated inflammation or suppression of both fatty acid and glucose oxidation and eventual ATP depletion. Moreover, cardiac adrenergic signaling is compromised in septic patients and this aggravates further heart function. While anti-inflammatory therapies are important for the treatment of the disease, administration of anti-inflammatory drugs did not improve survival in septic patients. This review article summarizes findings on inflammatory and other mechanisms that are triggered in sepsis and affect cardiac function and mortality. Particularly, it focuses on the effects of the disease in metabolic pathways, as well as in adrenergic signaling and the potential interplay of the latter with inflammation. It is suggested that therapeutic approaches should include combination of anti-inflammatory treatments, stimulation of energy production, and restoration of adrenergic signaling in the heart.
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Affiliation(s)
- Konstantinos Drosatos
- Metabolic Biology Laboratory, Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, 3500 N. Broad Street, MERB-951, Philadelphia, PA 19140, USA
| | - Anastasios Lymperopoulos
- Neurohormonal Control of the Circulation Lab, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, 3200 S. University Dr., Health Professions Division (Terry) Bldg/Room 1338, Fort Lauderdale, FL 33328, USA
| | - Peter Johannes Kennel
- Division of Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
| | - Nina Pollak
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - P. Christian Schulze
- Division of Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
| | - Ira J. Goldberg
- Division of Endocrinology, Diabetes & Metabolism, NYU-Langone School of Medicine, 522 First Avenue, New York, NY 10016, USA
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Tian G, Lu J, Guo H, Liu Q, Wang H. Protective effect of Flt3L on organ structure during advanced multiorgan dysfunction syndrome in mice. Mol Med Rep 2015; 11:4135-41. [PMID: 25672780 PMCID: PMC4408925 DOI: 10.3892/mmr.2015.3328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 04/10/2014] [Indexed: 11/22/2022] Open
Abstract
The present study aimed to examine whether fms-related tyrosine kinase 3 ligand (Flt3L) protects the organs of mice with multiorgan dysfunction syndrome (MODS). Male C57BL/6 mice were randomly assigned to normal control, MODS and Flt3L treatment groups. The mouse models of MODS were established using intraperitoneal zymosan injections, followed by normal saline injections. The treatment group received 5 μg/kg Flt3L for seven days, beginning on day five following zymosan injection. On day 12, the mortality rates of the Flt3L treatment and the MODS groups were 7 and 18%, respectively. Marked pathological changes were observed in the liver, lungs, kidneys and heart of the mice with MODS, including degeneration and focal necrosis of parenchyma cells. Mild pathological changes were observed in different organs of the Flt3L-treated mice. In the MODS group, the number of CD4+ T lymphocytes was significantly reduced, whereas the number of CD8+ T lymphocytes was significantly increased compared with that in the normal control group; thus, the CD4+/CD8+ ratio was reduced. In the Flt3L treatment group, the average number of CD4+ T lymphocytes was not significantly different to the average number of CD4+ T lymphocytes in the normal group. In conclusion, Flt3L administration improved the immune status and alleviated the organ damage in mice with late-phase MODS.
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Affiliation(s)
- Guang Tian
- Department of Pathology, The First Affiliated Hospital of General Hospital of PLA, Beijing 100048, P.R. China
| | - Jiangyang Lu
- Department of Pathology, The First Affiliated Hospital of General Hospital of PLA, Beijing 100048, P.R. China
| | - Huiqin Guo
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Beijing 100730, P.R. China
| | - Qian Liu
- Department of Pathology, The First Affiliated Hospital of General Hospital of PLA, Beijing 100048, P.R. China
| | - Hongwei Wang
- Department of Pathology, The First Affiliated Hospital of General Hospital of PLA, Beijing 100048, P.R. China
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Chun K, Syndergaard C, Damas C, Trubey R, Mukindaraj A, Qian S, Jin X, Breslow S, Niemz A. Sepsis Pathogen Identification. ACTA ACUST UNITED AC 2015; 20:539-61. [PMID: 25631157 DOI: 10.1177/2211068214567345] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Indexed: 12/29/2022]
Abstract
Sepsis is a rapidly progressing, severe inflammatory response to infection, causing more than 200,000 deaths per year. Rapid, specific pathogen identification is important to guide sepsis treatment. In this review, we describe and compare currently available commercial products for sepsis diagnosis and pathogen identification, based on microbiological, molecular, and mass spectrometric technologies. Microbiological techniques, the current "gold standard" in sepsis pathogen identification, include blood culture followed by subculturing and pathogen identification via biochemical or microscopic means. These methods have been automated but nevertheless require several days to generate results. Alternative technologies, including highly multiplexed PCR-based methods and mass spectrometric approaches, can decrease the required turnaround time. Matrix-assisted laser-desorption ionization time-of-flight-based systems have recently become an attractive option to rapidly identify a broad spectrum of sepsis pathogens with good sensitivity and specificity. Effectively integrating rapid sepsis pathogen identification into the hospital workflow can improve patient outcomes and can reduce the length of hospitalization and cost per patient.
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Affiliation(s)
- Katy Chun
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA, USA
| | - Chas Syndergaard
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA, USA
| | - Carlos Damas
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA, USA
| | - Richard Trubey
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA, USA
| | | | - Shenyu Qian
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA, USA
| | - Xin Jin
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA, USA
| | - Scott Breslow
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA, USA
| | - Angelika Niemz
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA, USA
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The preoperative serum C-reactive protein level is a useful predictor of surgical site infections in patients undergoing appendectomy. Surg Today 2014; 45:1404-10. [PMID: 25480421 DOI: 10.1007/s00595-014-1086-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 10/24/2014] [Indexed: 10/24/2022]
Abstract
PURPOSE Although surgical site infections (SSI) are a major postoperative complication of appendectomy, few studies have focused on the risk factors for SSI. In this study, we investigated the risk factors for SSI in patients who had undergone appendectomy. METHODS Three hundred patients who had undergone open appendectomy were enrolled. The patients were divided into two groups based on the presence or absence of SSI. A statistical analysis was performed to assess the clinical features associated with SSI after appendectomy. RESULTS A multivariate analysis using the results of univariate analyses revealed that the serum C-reactive protein (CRP) level (≤ 65/> 65, mg/l), length of the operation (≤ 80/> 80, min) and pathology (catarrhal, phlegmonous/gangrenous) were associated with SSI. Among these three clinical features, only the CRP level was found to predict the risk of SSI prior to appendectomy (odds ratio 3.797; 95 % confidence intervals 1.305-11.04; P = 0.014). CONCLUSION Preoperative elevation of the serum CRP level (> 65 mg/l) is a valuable predictor of SSI in patients undergoing appendectomy.
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Accumulating evidence for a role of oxidized phospholipids in infectious diseases. Cell Mol Life Sci 2014; 72:1059-71. [PMID: 25410378 PMCID: PMC7079780 DOI: 10.1007/s00018-014-1780-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 11/04/2014] [Accepted: 11/13/2014] [Indexed: 12/14/2022]
Abstract
Oxidized phospholipids (OxPL) were originally discovered as by-products and mediators of chronic inflammation such as in atherosclerosis. Over the last years, an increasing body of evidence led to the notion that OxPL not only contribute to the pathogenesis of chronic inflammatory processes but in addition play an integral role as modulators of inflammation during acute infections. Thereby, host defense mechanisms involve the generation of oxygen radicals that oxidize ubiquitously present phospholipids, which in turn act as danger-associated molecular patterns (DAMPs). These OxPL-derived DAMPs can exhibit both pro- and anti-inflammatory functions that ultimately alter the host response to pathogens. In this review, we summarize the currently available data on the role of OxPL in infectious diseases.
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Zheng Q, Liu W, Liu Z, Zhao H, Han X, Zhao M. Valproic acid protects septic mice from renal injury by reducing the inflammatory response. J Surg Res 2014; 192:163-9. [DOI: 10.1016/j.jss.2014.05.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 05/05/2014] [Accepted: 05/13/2014] [Indexed: 01/17/2023]
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Li B, Zhang H, Zeng M, He W, Li M, Huang X, Deng DYB, Wu J. Bone marrow mesenchymal stem cells protect alveolar macrophages from lipopolysaccharide-induced apoptosis partially by inhibiting the Wnt/β-catenin pathway. Cell Biol Int 2014; 39:192-200. [PMID: 25229877 DOI: 10.1002/cbin.10359] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 08/01/2014] [Indexed: 12/30/2022]
Abstract
Apoptosis of alveolar macrophages (AMs) plays a pathogenic role in acute lung injury (ALI) and its severe type, acute respiratory distress syndrome (ARDS). Mesenchymal stem cells (MSCs) are promising therapeutic cells for preventing apoptosis and eliminating cellular injury. We investigated the effects of rat bone marrow mesenchymal stem cells (BMSCs) on lipopolysaccharide (LPS)-induced apoptosis in AMs using transwell experiments, and examined the underlying mechanisms LPS induced AMs apoptosis in a dose- and time-dependent fashion, whereas BMSCs reduced AMs apoptosis when co-cultured at appropriate ratios. BMSCs decreased expression of cleaved caspase-3 and the pro-apoptotic protein, Bax, whilst increased levels of the anti-apoptotic protein, Bcl-2, prolonging the lifespan of AMs in vitro. Promotion of AMs survival by BMSCs required down-regulation of p-GSK-3β and β-catenin in AMs. The anti-apoptosis action of BMSCs was reversed by SB216763, a specific inhibitor of GSK-3β that also activates Wnt/β-catenin signaling. In conclusion, BMSCs can attenuate AM apoptosis partially by suppressing the Wnt/β-catenin pathway.
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Affiliation(s)
- Bin Li
- Department of MICU, The First Affiliated Hospital, Sun Yat-Sen University, 58# Zhongshan 2nd Road, Guangzhou, 510080, China
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Circulating Immature Granulocytes With T-Cell Killing Functions Predict Sepsis Deterioration*. Crit Care Med 2014; 42:2007-18. [DOI: 10.1097/ccm.0000000000000344] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Li Y, Wang Z, Ma X, Shao B, Gao X, Zhang B, Xu G, Wei Y. Low-dose cisplatin administration to septic mice improves bacterial clearance and programs peritoneal macrophage polarization to M1 phenotype. Pathog Dis 2014; 72:111-23. [PMID: 24850793 DOI: 10.1111/2049-632x.12189] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/09/2014] [Accepted: 05/09/2014] [Indexed: 02/05/2023] Open
Abstract
Sepsis is a systemic inflammatory response to infection, and early responses of macrophages are vital in controlling the infected microorganisms. We used a cecal ligation and puncture (CLP) model of sepsis to determine the role of cisplatin (0.1, 0.5 and 1 mg kg(-1)) with respect to peritoneal macrophages, controlling peritoneal/blood bacterial infection, and systemic inflammation. We found that mice which received low-dose (0.1 and 0.5 mg kg(-1)) i.p. cisplatin had lower mortality rate and improved clinical scores compared with mice in normal saline-treated group, and the level of IL-6 and TNF-α was significantly reduced after cisplatin administration in peritoneal fluid of mice underwent CLP. Although cisplatin had no directly bactericidal ability, the numbers of bacteria in peritoneal and blood were significantly reduced at 24 and 72 h after the onset of CLP. Besides, in vivo phagocytosis and killing assay showed that the ability of macrophage derived from peritoneum was significantly increased with cisplatin treatment (5, 10, and 15 μM) for both gram-positive (Enterococcus faecalis) and gram-negative (Escherichia coli) bacteria. This was associated with the macrophage phenotype polarization from CD11b(+) F4/80(high) CD206(-) to CD11b(+) F4/80(low) CD206(-) M1 group. These findings underscore the importance of low-dose cisplatin in the treatment of sepsis.
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Affiliation(s)
- Yanyan Li
- The Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Amiot L, Vu N, Samson M. Immunomodulatory properties of HLA-G in infectious diseases. J Immunol Res 2014; 2014:298569. [PMID: 24839609 PMCID: PMC4009271 DOI: 10.1155/2014/298569] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 03/09/2014] [Accepted: 03/10/2014] [Indexed: 12/04/2022] Open
Abstract
HLA-G is a nonclassical major histocompatibility complex molecule first described at the maternal-fetal interface, on extravillous cytotrophoblasts. Its expression is restricted to some tissues in normal conditions but increases strongly in pathological conditions. The expression of this molecule has been studied in detail in cancers and is now also beginning to be described in infectious diseases. The relevance of studies on HLA-G expression lies in the well known inhibitory effect of this molecule on all cell types involved in innate and adaptive immunity, favoring escape from immune control. In this review, we summarize the features of HLA-G expression by type of infections (i.e, bacterial, viral, or parasitic) detailing the state of knowledge for each pathogenic agent. The polymorphism, the interference of viral proteins with HLA-G intracellular trafficking, and various cytokines have been described to modulate HLA-G expression during infections. We also discuss the cellular source of HLA-G, according to the type of infection and the potential role of HLA-G. New therapeutic approaches based on synthetic HLA-G-derived proteins or antibodies are emerging in mouse models of cancer or transplantation, and these new therapeutic tools may eventually prove useful for the treatment of infectious diseases.
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Affiliation(s)
- Laurence Amiot
- Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche sur la Santé, l'Environnement, et le Travail (IRSET), 2 Avenue du Pr. Leon Bernard CS 34317, 35043 Rennes, France
- Université de Rennes 1, 35043 Rennes, France
- Fédération de Recherche BioSit de Rennes UMS 3480, 35043 Rennes, France
- Department of Biology, University Hospital Pontchaillou, CHU Pontchaillou, 35033 Rennes, France
| | - Nicolas Vu
- Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche sur la Santé, l'Environnement, et le Travail (IRSET), 2 Avenue du Pr. Leon Bernard CS 34317, 35043 Rennes, France
- Université de Rennes 1, 35043 Rennes, France
- Fédération de Recherche BioSit de Rennes UMS 3480, 35043 Rennes, France
| | - Michel Samson
- Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche sur la Santé, l'Environnement, et le Travail (IRSET), 2 Avenue du Pr. Leon Bernard CS 34317, 35043 Rennes, France
- Université de Rennes 1, 35043 Rennes, France
- Fédération de Recherche BioSit de Rennes UMS 3480, 35043 Rennes, France
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Teixeira-da-Cunha MGA, Gomes RN, Roehrs N, Bozza FA, Prescott SM, Stafforini D, Zimmerman GA, Bozza PT, Castro-Faria-Neto HC. Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration. PLoS One 2013; 8:e74567. [PMID: 24069320 PMCID: PMC3771912 DOI: 10.1371/journal.pone.0074567] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2012] [Accepted: 08/05/2013] [Indexed: 11/18/2022] Open
Abstract
Current evidence indicates that dysregulation of the host inflammatory response to infectious agents is central to the mortality of patients with sepsis. Strategies to block inflammatory mediators such as PAF have been investigated as adjuvant therapies for sepsis. PAF-AH, the enzyme responsible for PAF degradation, showed positive results in pre-clinical studies and phase II clinical trials, but the results of a phase III study were disappointing. In this study, we investigated the potential protective mechanism of PAF-AH in sepsis using the murine model of cecal ligation and puncture (CLP). Treatment with rPAF-AH increased peritoneal fluid levels of the anti-inflammatory mediators MCP-1/CCL2 after CLP. The numbers of bacteria (CFU) in the peritoneal cavity were decreased in the rPAF-AH-treated group, indicating more efficient bacterial clearance after rPAF-AH treatment. Interestingly, we observed increased levels of nitric oxide (NO) after PAF-AH administration, and rPAF-AH treatment did not decrease CFU numbers either in iNOS-deficient mice or in CCR2-deficient mice. We concluded that administration of exogenous rPAF-AH reduced inflammatory injury, altered cytokine levels and favored bacterial clearance with a clear impact on mortality through modulation of MCP-1/CCL2 and NO levels in a clinically relevant sepsis model.
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Affiliation(s)
| | - Rachel N. Gomes
- Laboratório De Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, RJ, Brazil
- Laboratório de Investigação em Medicina Intensiva, IPEC, Fiocruz, RJ, Brazil
- * E-mail:
| | - Nathassia Roehrs
- Laboratório De Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, RJ, Brazil
| | - Fernando A. Bozza
- Laboratório de Investigação em Medicina Intensiva, IPEC, Fiocruz, RJ, Brazil
| | - Stephen M. Prescott
- Oklahoma Medical Research Foundation, Oklahoma City, United States of America
| | - Diana Stafforini
- Huntsman Cancer Institute, Salt Lake City, Utah, United States of America
| | - Guy A. Zimmerman
- Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, United States of America
| | - Patricia T. Bozza
- Laboratório De Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, RJ, Brazil
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Santiago MB, Vieira AA, Giusti-Paiva A. Impaired chemoreflex sensitivity during septic shock induced by cecal ligation and perforation. Can J Physiol Pharmacol 2013; 91:1107-11. [PMID: 24289082 DOI: 10.1139/cjpp-2013-0219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
In this study, we sought to determine the effects produced by cecal ligation and perforation (CLP) on the autonomic responses to the activation of peripheral chemoreflexes in conscious rats. The peripheral chemoreflex was activated with potassium cyanide (KCN; 40 μg·(0.1 mL)(-1); intravenous injection (i.v.)) in male Wistar rats 3, 6, 12, and 24 h after CLP or sham surgery. The mean arterial pressure (MAP), heart rate (HR), and respiratory frequency (fR) were recorded simultaneously. CLP surgery reduced the baseline MAP when compared with the sham animals. In the animals of the sham group, the autonomic responses to KCN produced increases in MAP and fR as well as a decrease in HR. However, 12 and 24 h after CLP surgery, the autonomic responses to KCN were attenuated. The restoration of MAP by i.v. injected l-NAME or phenylephrine did not restore the autonomic response to KCN in rats subjected to CLP. These data show that septic shock induced by CLP compromised the autonomic responses to peripheral chemoreflex activation in conscious rats, suggesting that an important regulatory mechanism is impaired during the course of this condition.
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Affiliation(s)
- Michael B Santiago
- Department of Physiological Science, Institute of Biomedical Sciences of Federal University of Alfenas (Unifal-MG), Alfenas 37130-000, Minas Gerais, Brazil
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Wu B, Walker JA, Temmermand D, Mian K, Spur B, Rodriguez A, Stein TP, Banerjee P, Yin K. Lipoxin A(4) promotes more complete inflammation resolution in sepsis compared to stable lipoxin A(4) analog. Prostaglandins Leukot Essent Fatty Acids 2013; 89:47-53. [PMID: 23688707 DOI: 10.1016/j.plefa.2013.04.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 04/06/2013] [Accepted: 04/09/2013] [Indexed: 12/23/2022]
Abstract
In sepsis, excessive inflammation may lead to organ injury or a paradoxical immunosuppressed state where the host is unable to clear preexisting infection. Resolution of inflammation is the process which restores tissue homeostasis and ensures that a chronic cycle of infection/inflammation does not occur. Lipoxin A4 (LXA4) is one of a family of lipid mediators with novel inflammation resolution activity. We compared the actions of LXA4 to the stable 15-epi-16-(para-fluorophenoxy)-lipoxin A4 methyl ester (LXA4 analog) in the cecal ligation and puncture (CLP) model of sepsis. Both LXA4 compounds (at 7 μg/kg; i.v.) reduced plasma TNFα and IL-6 concentrations compared to rats given vehicle saline. Neither treatment altered plasma IL-10 compared to CLP given saline, but LXA4 analog, increased plasma IL-10 concentrations compared to rats given LXA4. LXA4 reduced blood bacterial load but the LXA4 analog did not. LXA4 increased 8 day survival and the LXA4 analog did not have a significant effect. To examine possible mechanisms for the differences, we investigated peritoneal leukocyte gene expression of iNOS and macrophage phagocytic ability. Only LXA4 increased the percentage of phagocytic peritoneal macrophages. LXA4 reduced neutrophil gene expression of iNOS compared to CLP rats given vehicle, while the LXA4 analog did not. Our results suggest that at doses which reduced systemic inflammation, only LXA4 inhibited bacterial spread and increased survival. This difference may be due to the shorter-lived compound being able to increase macrophage phagocytosis and reduce neutrophil iNOS expression.
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Affiliation(s)
- B Wu
- Department of Cell Biology, University of Medicine and Dentistry, New Jersey School of Osteopathic Medicine, NJ, USA
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45
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Stampalija T, Romero R, Korzeniewski SJ, Chaemsaithong P, Miranda J, Yeo L, Dong Z, Hassan SS, Chaiworapongsa T. Soluble ST2 in the fetal inflammatory response syndrome: in vivo evidence of activation of the anti-inflammatory limb of the immune response. J Matern Fetal Neonatal Med 2013; 26:1384-93. [PMID: 23488731 DOI: 10.3109/14767058.2013.784258] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Inflammation is a mechanism of host response to infection, which can be harmful when inappropriately modulated. Soluble ST2 (sST2) is a decoy receptor of interleukin (IL)-33, and this complex modulates the balance in the Th1/Th2 immune response. Moreover, sST2 inhibits the production of pro-inflammatory cytokines in cooperation with an anti-inflammatory cytokine, IL-10. The objectives of this study were to: (1) determine whether umbilical cord plasma sST2 concentration differs between preterm neonates with and without funisitis and between those with and without the fetal inflammatory response syndrome (FIRS); and (2) evaluate the relationship between sST2 and IL-10 among neonates with funisitis and/or FIRS. METHODS Umbilical cord plasma was collected from neonates delivered prematurely due to preterm labor or preterm prelabor rupture of membranes with (n = 36), and without funisitis (n = 30). FIRS (umbilical cord IL-6 concentration ≥ 17.5 pg/mL) was identified in 29 neonates. Plasma sST2 and IL-10 concentrations were determined by enzyme linked immune sorbent assay. RESULTS The median umbilical cord plasma sST2 concentration was 6.7-fold higher in neonates with FIRS than in those without FIRS (median 44.6 ng/mL, interquartile range (IQR) 13.8-80.3 ng/mL versus median 6.7 ng/mL, IQR 5.6-20.1 ng/mL; p < 0.0001). Similarly, the median umbilical cord plasma sST2 concentration was 2.7-fold higher in neonates with funisitis than in those without funisitis (median 19.1 ng/mL; IQR 7.1-75.0 ng/mL versus median 7.2 ng/mL; IQR 5.9-23.1 ng/mL; p = 0.008). There was a strong positive correlation between sST2 and IL-10 in neonates with funisitis and/or FIRS (Spearman's Rho = 0.7, p < 0.0001). CONCLUSION FIRS and funisitis are associated with an elevation of umbilical cord plasma concentrations of soluble ST2. This protein represents an important mediator of the immune response in neonates diagnosed with FIRS by promoting an anti-inflammatory effect in association with IL-10.
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Affiliation(s)
- Tamara Stampalija
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD and Detroit, MI 48201, USA
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Lim SJ, Lew D, Song HN, Kim YE, Lee SJ, Cho YJ, Jeong YY, Park MJ, Jeon KN, Kim HC, Lee JD, Hwang YS. Development of Acute Respiratory Failure on Initiation of Anti-Tuberculosis Medication in Patients with Pulmonary Tuberculosis: Clinical and Radiologic Features of 8 Patients and Literature Review. Korean J Crit Care Med 2013. [DOI: 10.4266/kjccm.2013.28.2.108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Affiliation(s)
- Su Jin Lim
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
| | - Donghoon Lew
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
| | - Haa-Na Song
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
| | - You Eun Kim
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
| | - Seung Jun Lee
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
| | - Yu Ji Cho
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
- Gyeongsang Institute of Health Sciences, Gyeongsang National University, Jinju, Korea
| | - Yi Yeong Jeong
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
- Gyeongsang Institute of Health Sciences, Gyeongsang National University, Jinju, Korea
| | - Mi Jung Park
- Department of Diagnostic Radiology, College of Medicine, Gyeongsang National University, Jinju, Korea
- Gyeongsang Institute of Health Sciences, Gyeongsang National University, Jinju, Korea
| | - Kyoung-Nyeo Jeon
- Department of Diagnostic Radiology, College of Medicine, Gyeongsang National University, Jinju, Korea
- Gyeongsang Institute of Health Sciences, Gyeongsang National University, Jinju, Korea
| | - Ho Cheol Kim
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
- Gyeongsang Institute of Health Sciences, Gyeongsang National University, Jinju, Korea
| | - Jong Deog Lee
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
- Gyeongsang Institute of Health Sciences, Gyeongsang National University, Jinju, Korea
| | - Young Sil Hwang
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
- Gyeongsang Institute of Health Sciences, Gyeongsang National University, Jinju, Korea
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Nagata A, Takezako N, Tamemoto H, Ohto-Ozaki H, Ohta S, Tominaga SI, Yanagisawa K. Soluble ST2 protein inhibits LPS stimulation on monocyte-derived dendritic cells. Cell Mol Immunol 2012; 9:399-409. [PMID: 22922442 DOI: 10.1038/cmi.2012.29] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
ST2 protein is a soluble splicing variant of ST2L protein, which is the receptor for interleukin-33 (IL-33). Previously, we reported that soluble ST2 suppressed the signal transduction of lipopolysaccharide (LPS) and cytokine production in monocytic cells. To investigate whether or not this inhibitory effect occurs in dendritic cells, which are the key players in innate and adaptive immunity, human monocyte-derived dendritic cells were pre-treated with soluble ST2 protein before LPS stimulation. Although soluble ST2 did not attenuate the LPS-induced maturation of dendritic cells, pre-treatment with soluble ST2 suppressed cytokine production and inhibited LPS signaling. Moreover, the proliferation of naive T cells was inhibited significantly by soluble ST2 pre-treatment. IL-33 had little effect on the cytokine production of immature monocyte-derived dendritic cells. Furthermore, soluble ST2 protein was internalized into dendritic cells, suggesting that soluble ST2 protein acts by a noncanonical mechanism other than the sequestration of IL-33.
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Affiliation(s)
- Akihisa Nagata
- Department of Biochemistry, School of Medicine, Jichi Medical University, Shimotsuke-shi, Tochigi, Japan
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Savasan ZA, Chaiworapongsa T, Romero R, Hussein Y, Kusanovic JP, Xu Y, Dong Z, Kim CJ, Hassan SS. Interleukin-19 in fetal systemic inflammation. J Matern Fetal Neonatal Med 2012; 25:995-1005. [PMID: 21767236 PMCID: PMC3383927 DOI: 10.3109/14767058.2011.605917] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE The fetal inflammatory response syndrome (FIRS) is considered the fetal counterpart of the systemic inflammatory response syndrome (SIRS), which can be caused by infection and non-infection-related insults. Although the initial response is mediated by pro-inflammatory signals, the control of this response is achieved by anti-inflammatory mediators which are essential for the successful outcome of the affected individual. Interleukin (IL)-19 is capable of stimulating the production of IL-10, a major anti-inflammatory cytokine, and is a potent inducer of the T-helper 2 (Th2) response. The aim of this study was to determine if there is a change in umbilical cord plasma IL-19 and IL-10 concentrations in preterm neonates with and without acute funisitis, the histologic counterpart of FIRS. METHODS A case-control study was conducted including 80 preterm neonates born after spontaneous labor. Neonates were classified according to the presence (n = 40) or absence of funisitis (n = 40), which is the pathologic hallmark of FIRS. Neonates in each group were also matched for gestational age. Umbilical cord plasma IL-19 and IL-10 concentrations were determined by ELISA. RESULTS 1) The median umbilical cord plasma IL-19 concentration was 2.5-fold higher in neonates with funisitis than in those without funisitis (median 87 pg/mL; range 20.6-412.6 pg/mL vs. median 37 pg/mL; range 0-101.7 pg/mL; p < 0.001); 2) newborns with funisitis had a significantly higher median umbilical cord plasma IL-10 concentration than those without funisitis (median 4 pg/mL; range 0-33.5 pg/mL vs. median 2 pg/mL; range 0-13.8 pg/mL; p < 0.001); and 3) the results were similar when we included only patients with funisitis who met the definition of FIRS by umbilical cord plasma IL-6 concentrations ≥ 17.5 pg/mL (p < 0.001). CONCLUSION IL-19 and IL-10 are parts of the immunologic response of FIRS. A subset of fetuses with FIRS had high umbilical cord plasma IL-19 concentrations. In utero exposure to high systemic concentrations of IL-19 may reprogram the immune response.
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Affiliation(s)
- Zeynep Alpay Savasan
- Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
| | - Tinnakorn Chaiworapongsa
- Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
| | - Roberto Romero
- Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, United States
| | - Youssef Hussein
- Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, United States
| | - Juan Pedro Kusanovic
- Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, United States
- Department of Obstetrics and Gynecology, Pontificia Universidad Católica de Chile, Santiago, Chile and Center for Perinatal Research, Sótero del Río Hospital, Santiago, Chile
| | - Yi Xu
- Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, United States
| | - Zhong Dong
- Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, United States
| | - Chong Jai Kim
- Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, United States
- Department of Pathology, Wayne State University, Detroit, MI, United States
| | - Sonia S Hassan
- Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
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El-Ganzoury MM, El-Farrash RA, Saad AA, Mohamed AG, El-Sherbini IG. In vivo effect of recombinant human granulocyte colony-stimulating factor on neutrophilic expression of CD11b in septic neonates: a randomized controlled trial. Pediatr Hematol Oncol 2012; 29:272-84. [PMID: 22475305 DOI: 10.3109/08880018.2011.644880] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Neonates are susceptible to septicemia secondary to quantitative and qualitative neutrophilic defects. Granulocyte colony-stimulating factor (G-CSF) stimulates myeloid progenitor cell proliferation and induces selective neutrophil functions. The authors aimed to evaluate the effect of G-CSF administration in septic neonates on neutrophil production and CD11b expression. Sixty septic neonates were randomized to receive intravenous G-CSF 10 μg/kg/day for 3 days (G-CSF group, n = 30), or not to receive G-CSF (non-G-CSF group, n = 30). Thirty healthy newborns were included as controls. Laboratory investigations included complete blood count, C-reactive protein, blood culture, renal and liver function tests, and assessment of neutrophilic expression of CD11b. Total leukocytes count (TLC), absolute neutrophil count (ANC), and immature myeloid cell count in G-CSF group showed significant difference between post-and pre-G-CSF levels. TLC, ANC, immature myeloid cell count and immature/total myeloid cells ratio were higher in G-CSF group compared to non-G-CSF group on days 1 and 3. Higher neutrophilic expression of CD11b was reported in both septic groups on day 0 compared to control group. On day 5, CD11b was higher in G-CSF group than non-G-CSF group. G-CSF improved CD11b% in neutropenic and non-neutropenic septic neonates. No significant difference was found between pre- and posttreatment renal and liver function tests. Lower duration of antibiotic intake and hospitalization was observed in G-CSF group compared to non-G-CSF group. G-CSF administration as an adjuvant therapy for neonatal septicemia, whether neutropenic or not, improves neutrophilic count and function and contributed to early healing from sepsis.
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Christaki E, Anyfanti P, Opal SM. Immunomodulatory therapy for sepsis: an update. Expert Rev Anti Infect Ther 2012; 9:1013-33. [PMID: 22029521 DOI: 10.1586/eri.11.122] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Currently the treatment mainstay of sepsis is early and appropriate antibiotic therapy, accompanied by aggressive fluid administration, the use of vasopressors when needed and the prompt initiation of measures to support each failing organ. Activated protein C and hydrocortisone, when used accordingly can affect mortality. As the pathophysiologic events that take place during sepsis are being elucidated, new molecules that target each step of those pathways are being tested. However, a lot of those molecules affect various mediators of the sepsis cascade including inflammatory cytokines, cellular receptors, nuclear transcription factors, coagulation activators and apoptosis regulators. Over the last decade, a multitude of clinical trials and animal studies have investigated strategies that aimed to restore immune homeostasis either by reducing inflammation or by stimulating the innate and adaptive immune responses. Antibiotics, statins and other molecules with multipotent immunomodulatory actions have also been studied in the treatment of sepsis.
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Affiliation(s)
- Eirini Christaki
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece.
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