Correction: Chronic Alcohol Ingestion Increases Mortality and Organ Injury in a Murine Model of Septic Peritonitis.
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ABSTRACT:
SUBMITTER: Yoseph BP
PROVIDER: S-EPMC7498101 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Correction: Chronic Alcohol Ingestion Increases Mortality and Organ Injury in a Murine Model of Septic Peritonitis.
Yoseph Benyam P BP Breed Elise E Overgaard Christian E CE Ward Christina J CJ Liang Zhe Z Wagener Maylene E ME Lexcen Daniel R DR Lusczek Elizabeth R ER Beilman Greg J GJ Burd Eileen M EM Farris Alton B AB Guidot David M DM Koval Michael M Ford Mandy L ML Coopersmith Craig M CM
PloS one 20200917 9
[This corrects the article DOI: 10.1371/journal.pone.0062792.]. ...[more]
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Project description:BackgroundPatients admitted to the intensive care unit with alcohol use disorders have increased morbidity and mortality. The purpose of this study was to determine how chronic alcohol ingestion alters the host response to sepsis in mice.MethodsMice were randomized to receive either alcohol or water for 12 weeks and then subjected to cecal ligation and puncture. Mice were sacrificed 24 hours post-operatively or followed seven days for survival.ResultsSeptic alcohol-fed mice had a significantly higher mortality than septic water-fed mice (74% vs. 41%, p = 0.01). This was associated with worsened gut integrity in alcohol-fed mice with elevated intestinal epithelial apoptosis, decreased crypt proliferation and shortened villus length. Further, alcohol-fed mice had higher intestinal permeability with decreased ZO-1 and occludin protein expression in the intestinal tight junction. The frequency of splenic and bone marrow CD4+ T cells was similar between groups; however, splenic CD4+ T cells in septic alcohol-fed mice had a marked increase in both TNF and IFN-γ production following ex vivo stimulation. Neither the frequency nor function of CD8+ T cells differed between alcohol-fed and water-fed septic mice. NK cells were decreased in both the spleen and bone marrow of alcohol-fed septic mice. Pulmonary myeloperoxidase levels and BAL levels of G-CSF and TFG-β were higher in alcohol-fed mice. Pancreatic metabolomics demonstrated increased acetate, adenosine, xanthine, acetoacetate, 3-hydroxybutyrate and betaine in alcohol-fed mice and decreased cytidine, uracil, fumarate, creatine phosphate, creatine, and choline. Serum and peritoneal cytokines were generally similar between alcohol-fed and water-fed mice, and there were no differences in bacteremia, lung wet to dry weight, or pulmonary, liver or splenic histology.ConclusionsWhen subjected to the same septic insult, mice with chronic alcohol ingestion have increased mortality. Alterations in intestinal integrity, the host immune response, and pancreatic metabolomics may help explain this differential response.
| S-EPMC3661585 | biostudies-literature
Project description:Selegiline, an anti-Parkinson drug, has antioxidant and anti-apoptotic effects. To explore the effect of selegiline on sepsis, we used a clinically relevant animal model of polymicrobial sepsis. Cecal ligation and puncture (CLP) or sham operation was performed in male rats under anesthesia. Three hours after surgery, animals were randomized to receive intravenously selegiline (3 mg/kg) or an equivalent volume of saline. The administration of CLP rats with selegiline (i) increased arterial blood pressure and vascular responsiveness to norepinephrine, (ii) reduced plasma liver and kidney dysfunction, (iii) attenuated metabolic acidosis, (iv) decreased neutrophil infiltration in liver and lung, and (v) improved survival rate (from 44% to 65%), compared to those in the CLP alone rats. The CLP-induced increases of plasma interleukin-6, organ superoxide levels, and liver inducible nitric oxide synthase and caspase-3 expressions were ameliorated by selegiline treatment. In addition, the histological changes in liver and lung were significantly attenuated in the selegiline -treated CLP group compared to those in the CLP group. The improvement of organ dysfunction and survival through reducing inflammation, oxidative stress and apoptosis in peritonitis-induced sepsis by selegiline has potential as an adjuvant agent for critical ill.
| S-EPMC4182482 | biostudies-literature
Project description:TLRs are considered important for innate immune responses that combat bacterial infections. Here, the role of TLRs in severe septic peritonitis using the colon ascendens stent peritonitis (CASP) model was examined. We demonstrate that mice deficient for MyD88 and TRIF had markedly reduced bacterial numbers both in peritoneal cavity and peripheral blood, indicating that bacterial clearance in this model is inhibited by TLR signals. Moreover, survival of Myd88-/-;TrifLps2/Lps2 mice was significantly improved. The lack of TLR signals prevented the excessive induction of inflammatory cytokines and of IL 10. Notably, the expression of IFN-gamma, which has an essential protective role in septic peritonitis, and of IFN-regulated genes including several p47 and p65 GTPases as well as IP 10 was independent of TLR signaling. These results provide evidence that, in severe septic peritonitis, TLR deficiency balances the innate immune response in a favorable manner by attenuating deleterious responses such as excessive cytokine release, while leaving intact protective IFN-gamma production.
2011-06-28 | GSE24327 | GEO
Project description:WHAT WE ALREADY KNOW ABOUT THIS TOPIC:Toll-like receptor 7 responds to elevated single-stranded RNA by increasing cytokine production. Sepsis is characterized by elevated plasma levels of tissue damage (and pathogen)-associated molecular patterns, including RNA. WHAT THIS ARTICLE TELLS US THAT IS NEW:Using murine models of bacterial sepsis, knockout of the Toll-like receptor 7 resulted in lower mortality and cytokine levels and less end-organ injury. Therefore, Toll-like receptor 7, which mediates innate immune response, contributes to harm in experimental sepsis. BACKGROUND:Sepsis remains a critical illness with high mortality. The authors have recently reported that mouse plasma RNA concentrations are markedly increased during sepsis and closely associated with its severity. Toll-like receptor 7, originally identified as the sensor for single-stranded RNA virus, also mediates host extracellular RNA-induced innate immune responses in vitro and in vivo. Here, the authors hypothesize that innate immune signaling via Toll-like receptor 7 contributes to inflammatory response, organ injury, and mortality during polymicrobial sepsis. METHODS:Sepsis was created by (1) cecal ligation and puncture or (2) stool slurry peritoneal injection. Wild-type and Toll-like receptor 7 knockout mice, both in C57BL/6J background, were used. The following endpoints were measured: mortality, acute kidney injury biomarkers, plasma and peritoneal cytokines, blood bacterial loading, peritoneal leukocyte counts, and neutrophil phagocytic function. RESULTS:The 11-day overall mortality was 81% in wild-type mice and 48% in Toll-like receptor 7 knockout mice after cecal ligation and puncture (N = 27 per group, P = 0.0031). Compared with wild-type septic mice, Toll-like receptor 7 knockout septic mice also had lower sepsis severity, attenuated plasma cytokine storm (wild-type vs. Toll-like receptor 7 knockout, interleukin-6: 43.2 [24.5, 162.7] vs. 4.4 [3.1, 12.0] ng/ml, P = 0.003) and peritoneal inflammation, alleviated acute kidney injury (wild-type vs. Toll-like receptor 7 knockout, neutrophil gelatinase-associated lipocalin: 307 ± 184 vs.139 ± 41-fold, P = 0.0364; kidney injury molecule-1: 40 [16, 49] vs.13 [4, 223]-fold, P = 0.0704), lower bacterial loading, and enhanced leukocyte peritoneal recruitment and phagocytic activities at 24?h. Moreover, stool slurry from wild-type and Toll-like receptor 7 knockout mice resulted in similar level of sepsis severity, peritoneal cytokines, and leukocyte recruitment in wild-type animals after peritoneal injection. CONCLUSIONS:Toll-like receptor 7 plays an important role in the pathogenesis of polymicrobial sepsis by mediating host innate immune responses and contributes to acute kidney injury and mortality.
| S-EPMC6822621 | biostudies-literature
Project description:IntroductionMethanol poisoning is an uncommon life-threatening ingestion associated with significant morbidity and requires prompt diagnosis and management for the best possible outcome. We created a simulation case that challenges learners to analyze case information, construct a differential diagnosis of an anion gap metabolic acidosis, narrow the differential based on reasoning, and empirically initiate management.MethodsThe simulation case was designed for emergency medicine residents and pediatric emergency medicine fellows. The activity began with a brief overview of the monitors, equipment, and simulation experience. First-year residents managed the case as a team of two. Second- and third-year residents and fellows managed the case alone. The learners had 15 minutes to complete a focused history and physical exam, request and interpret labs and studies, provide stabilization of life threats, and initiate specific interventions based on a presumptive diagnosis. The simulation was followed by a 20-minute facilitated debrief session that reviewed key learning points and learner performance based on an evaluation checklist.ResultsResidents completed a six-question, 5-point Likert-scale postparticipation questionnaire. Overall, residents reported a high degree of satisfaction with the simulation experience. The case and debrief were effective in meeting the educational objectives and proved to be an effective modality to fill this educational gap.DiscussionThis simulation experience successfully exposed residents to the uncommon presentation of methanol poisoning. The simulation experience effectively closed the identified educational gap and provided an experiential learning opportunity that accomplished the targeted learning objectives.
| S-EPMC6342378 | biostudies-literature
Project description:TLRs are considered important for innate immune responses that combat bacterial infections. Here, the role of TLRs in severe septic peritonitis using the colon ascendens stent peritonitis (CASP) model was examined. We demonstrate that mice deficient for MyD88 and TRIF had markedly reduced bacterial numbers both in peritoneal cavity and peripheral blood, indicating that bacterial clearance in this model is inhibited by TLR signals. Moreover, survival of Myd88-/-;TrifLps2/Lps2 mice was significantly improved. The lack of TLR signals prevented the excessive induction of inflammatory cytokines and of IL 10. Notably, the expression of IFN-gamma, which has an essential protective role in septic peritonitis, and of IFN-regulated genes including several p47 and p65 GTPases as well as IP 10 was independent of TLR signaling. These results provide evidence that, in severe septic peritonitis, TLR deficiency balances the innate immune response in a favorable manner by attenuating deleterious responses such as excessive cytokine release, while leaving intact protective IFN-gamma production. In this dataset, expression data of genes induced by septic peritonitis in spleens from TLR-deficient and wildtype mice are included. 3 groups (septic TLR-deficient mice, septic wildtype mice, and untreated wildtype mice) with 4 replicates each.
2011-06-27 | E-GEOD-24327 | biostudies-arrayexpress
Project description:BackgroundLeft ventricular ejection fraction (LVEF) is inconsistently associated with poor outcomes in patients with sepsis. Newer parameters such as LV longitudinal strain (LVLS), mitral annular plane systolic excursion (MAPSE) and LV longitudinal wall fractional shortening (LV-LWFS) may be more sensitive indicators of LV dysfunction, but are sparsely investigated. Our objective was to evaluate the association between five traditional and novel echocardiographic parameters of LV systolic function (LVEF, peak tissue Doppler velocity at the mitral valve (s´), LVLS, MAPSE and LV-LWFS) and outcomes in patients admitted to the Intensive Care Unit (ICU) with septic shock.MethodsA total of 152 patients admitted to the ICU with septic shock from two data repositories were included. Transthoracic echocardiograms were performed within 24 h of ICU admission. The primary outcome was myocardial injury, defined as high-sensitivity troponin T ≥ 45 ng/L on ICU admission. Secondary outcomes were organ support-free days (OSFD) and 30-day mortality. We also tested for the prognostic value of the systolic function parameters using multivariable analysis.ResultsLVLS, MAPSE and LV-LWFS, but not LVEF and s´, differed between patients with and without myocardial injury. After adjustment for age, pre-existing cardiac disease, Simplified Acute Physiology (SAPS3) score, Sequential Organ Failure Assessment (SOFA) score, plasma creatinine and presence of right ventricular dysfunction, only MAPSE and LV-LWFS were independently associated with myocardial injury. None of the systolic function parameters were associated with OSFD or 30-day mortality.ConclusionsMAPSE and LV-LWFS are independently associated with myocardial injury and outperform LVEF, s´ and LVLS. Whether these parameters are associated with clinical outcomes such as the need for organ support and short-term mortality is still unclear. Trial registration NCT01747187 and NCT04695119.
| S-EPMC10796855 | biostudies-literature
Project description:This review summarizes the American Physiological Society (APS) Presidential Symposium 1 entitled "Physiological Processes Underlying Organ Injury in Alcohol Abuse" at the 2016 Experimental Biology meeting. The symposium was organized by Dr. Patricia Molina, past president of the APS, was held on April 3 at the Convention Center in San Diego, CA, and was funded by the National Institute on Alcohol Abuse and Alcoholism. The "Physiological Processes Underlying Organ Injury in Alcohol Abuse Symposium" assembled experts and leaders in the field and served as a platform to discuss and share knowledge on the latest developments and scientific advances on the mechanisms underlying organ injury in alcohol abuse. This symposium provided unique, interdisciplinary alcohol research, including several organs, liver, muscle, adipose, and brain, affected by excessive alcohol use.
| S-EPMC5142006 | biostudies-literature
Project description:Septic peritonitis (SP) is common in dogs and is associated with high mortality. Early recognition is essential to maximizing survival and may be aided by biomarker measurement. The present study aimed to evaluate the ability of biomarkers to discriminate septic peritonitis from non-septic ascites (NSA). Eighteen dogs with SP and 19 age-matched controls with NSA were enrolled. Contemporaneous blood and peritoneal effusion samples were obtained. Concentrations of cell-free DNA (cfDNA), cytokines, glucose, lactate, N-terminal pro-C-type natriuretic peptide (NT-proCNP), nucleosomes, and procalcitonin (PCT) were measured using commercial reagents and assays. Paired biomarker concentrations were compared with the Wilcoxon matched-pairs signed rank test, and biomarker concentrations between groups were compared with the Mann-Whitney U-test. P-values were adjusted for multiple comparisons using the Bonferroni correction. Receiver operating characteristic curves were generated to assess the ability of the above biomarkers to discriminate SP from NSA. Dogs with SP had significantly greater blood CCL2 concentrations than dogs with NSA (P = 0.032). Dogs with SP had significantly greater effusion CCL2, IL-6, IL-10, and lactate concentrations than dogs with NSA (P ≤ 0.0121). Blood-effusion concentration gradients of CCL2, glucose, IL-6, IL-10, and lactate were significantly different in dogs with SP compared to dogs with NSA (P ≤ 0.0165). Effusion lactate concentration had the highest AUROC value (0.866, 95% CI 0.751-0.980, P = 0.0001), although other biomarkers performed similarly. An effusion lactate concentration of 4.2 mmol/L was 72.2% (95% CI 46.5-90.3%) sensitive and 84.2% (95% CI 60.4-96.6%) specific for the diagnosis of SP.
| S-EPMC6610427 | biostudies-literature
Project description:BackgroundSepsis is a serious syndrome that is caused by an unbalanced host inflammatory response to an infection. The cytokine network plays a pivotal role in the orchestration of inflammatory response during sepsis. IL-26 is an emerging proinflammatory member of the IL-10 cytokine family with multifaceted actions in inflammatory disorders. However, its role in the pathogenesis of sepsis remains unknown.MethodsSerum IL-26 level was measured and analyzed in 52 septic patients sampled on the day of intensive care unit (ICU) admission, 18 non-septic ICU patient controls, and 30 healthy volunteers. In addition, the effects of recombinant human IL-26 on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis were determined.ResultsOn the day of ICU admission, the patients with sepsis showed a significant increase in serum IL-26 levels compared with ICU patient controls and healthy volunteers, and the serum IL-26 levels were related to the severity of sepsis. Nonsurvivors of septic patients displayed significantly higher serum IL-26 levels compared with survivors. A high serum IL-26 level on ICU admission was associated with 28-day mortality, and IL-26 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, administration of recombinant human IL-26 increased lethality in CLP-induced polymicrobial sepsis. Despite a lower bacterial load, septic mice treated with recombinant IL-26 had higher concentrations of IL-1β, IL-4, IL-6, IL-10, IL-17A, TNF-α, CXCL1, and CCL2 in peritoneal lavage fluid and blood and demonstrated more severe multiple organ injury (including lung, liver and kidney) as indicated by clinical chemistry and histopathology. Furthermore, septic mice treated with recombinant human IL-26 showed an increased neutrophil recruitment to the peritoneal cavity.ConclusionsSeptic patients had elevated serum IL-26 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-26 in increasing lethality despite promoting antibacterial host responses.
| S-EPMC6716900 | biostudies-literature