Heart transcriptome of different subtype of sepsis induced myocardium dysfunction according to ejection fraction
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE229925 | GEO | 2023/08/28
REPOSITORIES: GEO
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Project description:Dysregulated cardiac function after sepsis is common in intensive care unit (ICU) and known to predict poor long-term outcome and increase mortality. Effective therapeutic strategies are largely lacking. Moreover, the pathological feature and the molecular mechanism underlying cardiac dysfunction induced by sepsis remain unclear. Here, by performing echocardiograms on rodents after induction of polymicrobial sepsis with cecum ligation and puncture (CLP), we assessed the temporal dynamics of left ventricular ejection fraction (LVEF) and a serial of hemodynamics parameters on animals at different time point after CLP. Intriguingly, the mean LVEF is comparable in mice induced by CLP and sham, whereas survivors post CLP had stable LVEF and non-survivors had markedly fluctuated LVEF at early phase of CLP induction, suggesting LVEF away from normal range is highly associated with mortality. Consistent with clinical observations of depressed, preserved or hyperdynamic LVEF in septic patients from data compiled using our ICU cohort and from other studies, CLP-induced mice fall into three groups based on LVEF measured at 24 hours after surgery: high LVEF (HEF, LVEF>=90%), low LVEF (LEF, LVEF<65%), and normal LVEF (NEF, 65%=<LVEF<90%). We performed genome-wide transcriptomic and proteomic profiling on left ventricle samples collected from three CLP groups and sham mice. By implementing pathway analysis, gene set enrichment and coexpression network analysis, we identified jointly and distinctively changed genes, proteins and biologically-essential processes and pathways in three CLP groups with different LVEF. Notably, transmission electron microscopy examination shows remarkable mitochondrial and sarcomere defects in three CLP groups with different phenotypes associated with LVEF variances. Together, this study systematically characterizes the molecular, morphological, and functional alterations in CLP-induced cardiac injury, serving as a framework for future research into pathology and molecular mechanism of sepsis-induced cardiomyopathy.
2023-04-14 | PXD041530 | iProX
Project description:Because the immune regulation in survivor after sepsis (an immune dysregulation from severe infection) might be applied for treatment, survivors and moribund mice after cecal liga-tion and puncture (CLP) and in vitro experiments on macrophages were explored. Most of the parameters in survivors (5-days post-CLP) were normalized, except for the slightly increase in alanine transaminase, IL-10, lipopolysaccharide (LPS) and gut leakage (FITC-dextran assay), with the enhanced adaptive immunity; serum immunoglobulin (using serum protein electrophoresis) and activated immune cells in spleens (flow cytometry analysis). Then, a clue to surviving sepsis may be effective innate immunity regulation by adaptive immune responses. Indeed, soluble heat aggregated immunoglobulin (sHA-Ig, a representative of immune complex) in LPS-activated macrophages reduced supernatant cytokines and down-regulated proteins in sev-eral processes (using proteomic analysis). As a proof of concept, intravenous immunoglobulin (IVIG) attenuated sepsis severity in CLP mice as evaluated by serum creatinine, ALT, serum cy-tokines, spleen apoptosis (24 h post-CLP) and 48 h survival analysis. In conclusion, immuno-globulin may play a role in sepsis immune hyper-responsiveness. Despite the debate over IVIG's use in sepsis, adequate selection criteria for sepsis patients who may benefit the most from IVIG could lead to an increase use of this clinically viable treatment.
2022-02-22 | PXD027471 | Pride
Project description:Millions of sepsis survivors annually face long-term neuropsychiatric sequelae of their illness. Corticosteroids are frequently administered in sepsis, and their use affects neuropsychiatric outcomes, but the mechanisms are unknown. We used the cecal ligation and puncture method to induce acute infection in mice and test the hypothesis that corticosteroid treatment during illness has long-term effects on hippocampal function. Functional phenotyping and hippocampal RNA-sequencing were performed in the same survivor mice to identify underlying mechanisms of behavioral and neuroendocrine outcomes. Long-term CLP survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal (HPA) axis activity, and persistent systemic and neuro-inflammation. The relationship between gene expression and behavior suggested a protective role for inflammation and oxidative metabolism after CLP. Corticosterone treatment during illness had distinct effects on hippocampal function in survivors, including object memory impairment. The long-term behavioral effects of corticosterone treatment were associated with persistent downregulation of activity-dependent gene expression in the hippocampus. The results suggest that corticosteroid treatment for sepsis influences hippocampal function in survivors via long-lasting changes to basal hippocampal activity. Neural activity, inflammation, and oxidative metabolism should be explored as future treatment targets to modify neuropsychiatric outcomes in sepsis survivors.
2023-07-31 | GSE225868 | GEO
Project description:Sepsis is the most common cause of hospitalization worldwide. Millions of people survive sepsis each year and are at risk for rehospitalization and death. Pulmonary complications such as respiratory failure due to pneumonia and exacerbation of chronic respiratory disease are among the most common reasons for rehospitalization in sepsis survivors. In order to prevent additional morbidity and death in patients surviving sepsis, we must establish biomarkers to identify patients at risk for pulmonary complications and develop treatments. Late complications in sepsis survivors, particularly nosocomial infections, are proposed to occur through persistent immune reprogramming after sepsis known as immunoparalysis. However, pro-inflammatory immune reprogramming in the form of primed or enhanced responses to secondary stimuli has also been described and could directly contribute to tissue injury and death. Primed immune responses and their contribution to long-term sepsis complications remains understudied. We hypothesize that primed immune responses to inflammatory stimuli in the lung after sepsis are associated with pulmonary complications in survivors of sepsis. To this end, we developed a model of antibiotic treated sepsis induced by cecal ligation and puncture followed three weeks later by secondary challenge with intranasal lipopolysaccharide to induce inflammatory lung injury. We find that mice surviving sepsis have enhanced lung injury responses in the setting of an exaggerated proinflammatory immune response, including primed Ly6Chi monocyte Tnf expression. Using RNA sequencing, we identified derangements in lung gene expression after CLP prior to LPS administration which may mediate enhanced lung injury in this model. One potential mediator, S100A8/A9, was also found to be elevated in the circulation of human sepsis survivors for up to 180 days after sepsis. These findings validate our model and identify S100A8/A9 as one of many potential biomarkers and therapeutic targets for patients at risk for long-term pulmonary complications after sepsis. The role of S100A8/A9, monocyte priming, and other factors predisposing to enhanced lung injury responses and pulmonary complications after sepsis warrant further investigation in humans and mice.
2021-06-23 | GSE168796 | GEO
Project description:Although in-hospital mortality rates for sepsis have decreased, survivors often experience lasting physical and cognitive deficits. Moreover, older adults are more vulnerable to long-term complications associated with sepsis. We employed a murine model to examine the influence of age and sex on the brain’s response and recovery following sepsis. Young (~4 months) and old (~20 months) mice (C57BL/6) of both sexes underwent cecal ligation and puncture (CLP) with restraint stress. The hippocampal transcriptome was examined in age and sex-matched controls at 1 and 4 days post-CLP. In general, immune and stress-related genes increased while neuronal, synaptic, and glial genes decreased one day after CLP-induced sepsis. However, specific age and sex differences were observed for the initial responsiveness to sepsis as well as the rate of recovery examined on day 4. Young females exhibited a muted transcriptional response relative to young males and old females. Old females exhibited a robust shift in gene transcription on day 1 and, while most genes recovered, genes linked to neurogenesis and myelination continued to be downregulated by day 4. In contrast, old males exhibited a more delayed or prolonged response to sepsis, such that neuronal and synaptic genes continued to decrease while immune response genes continued to increase on day 4. These results suggest that aging is associated with delayed recovery from sepsis, which is particularly evident in males.
2019-07-22 | GSE128925 | GEO
Project description:ICU acquired weakness (ICUAW) is a complication of critical illness characterized by structural and functional impairment of skeletal muscle that may persist for years after ICU discharge with many survivors developing protracted courses with few regaining functional independence. Elucidating molecular mechanisms underscoring sustained ICUAW is crucial to understanding outcomes linked to different morbidity trajectories as well as for the development of novel therapies. Quadriceps muscle biopsies and functional measures of muscle strength and mass were obtained at 7 days and 6 months post-ICU discharge from a cohort of ICUAW patients. Unsupervised co-expression network analysis of transcriptomic profiles identified discrete modules of co-expressed genes associated with the degree of muscle weakness and atrophy in early and sustained ICUAW. Modules were enriched for genes involved in skeletal muscle regeneration and extracellular matrix deposition. Collagen deposition in persistent ICUAW was confirmed by histochemical stain. Modules were further validated in an independent cohort of critically ill patients with sepsis-induced multi-organ failure and a porcine model of ICUAW, demonstrating disease-associated conservation across species and peripheral muscle type. Our findings provide a pathomolecular basis for sustained ICUAW, implicating aberrant expression of distinct skeletal muscle structural and regenerative genes in early and persistent ICUAW. Total RNA was extracted from approximately 200mg of quadriceps muscle (vastus lateralis) tissue in patients with Intensive care unit (ICU) acquired weakness (ICUAW) at day 7 post-ICU discharge (D7) and month 6 post-ICU discharge (M6), and from healthy controls (C)
2016-07-18 | E-GEOD-78929 | biostudies-arrayexpress
Project description:BACKGROUND: Despite best supportive intensive care, the development of severe sepsis and septic shock after trauma is still associated with a high mortality rate in intensive care units (ICU). Incomplete knowledge of the pathophysiological and biochemical mechanisms that lead to perturbations of the host system is a major cause for this clinical entity. This lack of knowledge is mirrored in a delay in both diagnosis of sepsis and stratification of patients at risk. The current diagnostic and classification methods do not provide an early and reliable evidence for the development of sepsis and consequently lead to uncertainty in the classification and a delay in the initiation of an adequate therapy. Here, we present a prospective study performed with a well-defined patient cohort suffering from severe multiple trauma (n=85), in which we aimed to uncover the biological reasons why patients with multiple trauma can have dramatically different outcomes after suffering similar traumatic insults. METHODS: We used peripheral whole blood obtained with the PaxGene system at the time of admission to the ICU, i.e., 12 hours after trauma, for transcriptome analysis and monitored clinically the sequence of events from the admission to the ICU, to the very onset of sepsis and finally to the full development of multiple organ dysfunction syndrome (MODS). Study protocols and standard operating procedures (SOPs) regarding ethics, patient recruitment, logistics in sample acquisition and storage, microarray experiments, data analysis and data management have been developed and provided for a high feasibility and reproducibility of the investigations. FINDINGS: The transcriptome analysis from peripheral blood revealed a strong host response upon severe injury and demonstrated the suitability of whole blood in the PaxGene system as a surrogate marker in clinical gene expression studies. It was evident that patients who developed sepsis in the course of the disease (3-5 days after admission) showed an imbalance in the TH1/TH2 response towards a pronounced TH2 response, soon after trauma. The imbalanced TH1/TH2 shift along with inactivation of T cells, neutrophils, monocytes and macrophages might be critical factors for the initiation of a septic program seen in these patients 12 hours after trauma. INTERPRETATION: First, in this study, we provide protocols for logistics and infrastructure that can be applied generally to successfully integrate gene expression analysis studies in a clinical routine and demonstrate that by following these protocols, dedicated and reproducible results can be obtained. Second, we showed that peripheral whole blood is a suitable surrogate marker for the host response as it contains lots of “information” and is easily accessible. Third, we identified mechanisms involved in the perturbations of the immune system that lead to sepsis. Keywords: Prospective study 159 consecutive traumatized patients were included in the study upon admission to the intensive care unit (ICU), fulfilling all of the following inclusion criteria: severe injuries to at least two body regions or three major fractures, between 18 and 65 years of age, an estimated Injury Severity Score (ISS) of ?15 points after thorough assessment of injuries, <12 hours between the occurrence of the accident and the time of admission to the ICU, and at least greater than 3 days of survival. None of the patients underwent neuro- or cardiac surgery. We excluded patients with severe intracranial head injuries, coagulation abnormalities known at the day of admission to the ICU, acute renal failure, liver failure, malignant disease, or hemofiltration in the patient`s history. The Patients were divided into two groups depending on their posttraumatic course: Patients not complicatd by sepsis (Group: N) and Patients complicated by sepsis (Group: S). Using the CodeLink UniSet Human 10 K Bioarrays (GE Healthcare, Freiburg, Germany), we searched for early differences in the transcriptome of these two groups. Only whole blood samples drawn upon admission to the ICU were used for this investigation. Microarray results were validated by quantification of mRNA by TaqMan® technology. Each patient sample was hybridized in duplicate or triplicate on microarrays (label-extract technical replicate). A total of 72 arrays (36 group N, 36 group S) were subjected to microarray quality analysis. Of these, 2 arrays (0 group N, 2 group S) were excluded from the data set due to quality reasons and a final set of 70 arrays (36 group N and 34 group S) were subjected to microarray analysis. Since the eliminated 2 arrays belonged to patients with three replicates, they were treated as two replicates in the further analysis. The arrays were designated N_xx_yy_z or S_xx_yy_z, with x for the patient-ID (1,2,3,4..) and z for the technical replicate number (1,2 or 3).
2010-12-22 | E-GEOD-12624 | biostudies-arrayexpress
Project description:Expression data from Total RNA extracted from murine spleen. Sepsis was induced in C57Bl/6J mice by cecal ligation and puncture (CLP), followed 6 hours later by an intravenous injection of Mesenchymal Stem Cell (MSC) or saline. Twenty-eight hours after CLP, plasma, bronchoalveolar lavage (BAL) fluid and tissues were collected for analyses. Total RNA was extracted using Trizol (as per manufactures' instruction) followed by clean-up procedure using Qiagen RNA easy Prep (as per manufactures instructions) In the following study we hypothesized that mesenchymal stem cells (MSCs), which have documented immunomodulatory properties, would reduce sepsis-associated inflammation and organ injury in a clinically relevant model of sepsis. To identify the molecular changes associated with decreased inflammation in CLP-injured mice treated with MSCs, we analyzed the gene expression profiles from spleens collected at 28 hours from 4 animals per group: sham/saline, CLP/saline, and CLP/MSCs.
2010-11-22 | E-GEOD-24357 | biostudies-arrayexpress
Project description:Study of the occurrence of glucocorticoid resistance after CLP induced sepsis in mice
2021-02-01 | GSE161183 | GEO
Project description:Study of the occurrence of glucocorticoid resistance after CLP induced sepsis in mice
2021-02-01 | GSE160830 | GEO