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Cell-free hemoglobin increases inflammation, lung apoptosis, and microvascular permeability in murine polymicrobial sepsis.
Meegan JE, Shaver CM, Putz ND, Jesse JJ, Landstreet SR, Lee HNR, Sidorova TN, McNeil JB, Wynn JL, Cheung-Flynn J, Komalavilas P, Brophy CM, Ware LB, Bastarache JA
(2020) PLoS One 15: e0228727
MeSH Terms: Animals, Apoptosis, Capillary Permeability, Endothelial Cells, Female, Hemoglobins, Humans, Inflammation, Lung, Mice, Mice, Inbred C57BL, Oxidative Stress, Sepsis
Show Abstract · Added March 3, 2020
Increased endothelial permeability is central to the pathogenesis of sepsis and leads to organ dysfunction and death but the endogenous mechanisms that drive increased endothelial permeability are not completely understood. We previously reported that cell-free hemoglobin (CFH), elevated in 80% of patients with sepsis, increases lung microvascular permeability in an ex vivo human lung model and cultured endothelial cells. In this study, we augmented a murine model of polymicrobial sepsis with elevated circulating CFH to test the hypothesis that CFH increases microvascular endothelial permeability by inducing endothelial apoptosis. Mice were treated with an intraperitoneal injection of cecal slurry with or without a single intravenous injection of CFH. Severity of illness, mortality, systemic and lung inflammation, endothelial injury and dysfunction and lung apoptosis were measured at selected time points. We found that CFH added to CS increased sepsis mortality, plasma inflammatory cytokines as well as lung apoptosis, edema and inflammation without affecting large vessel reactivity or vascular injury marker concentrations. These results suggest that CFH is an endogenous mediator of increased endothelial permeability and apoptosis in sepsis and may be a promising therapeutic target.
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13 MeSH Terms
Cell-free hemoglobin augments acute kidney injury during experimental sepsis.
Shaver CM, Paul MG, Putz ND, Landstreet SR, Kuck JL, Scarfe L, Skrypnyk N, Yang H, Harrison FE, de Caestecker MP, Bastarache JA, Ware LB
(2019) Am J Physiol Renal Physiol 317: F922-F929
MeSH Terms: Acute Kidney Injury, Animals, Cell Line, Cell Survival, Cell-Free System, Cytokines, Female, Glomerular Filtration Rate, Hemoglobins, Hepatitis A Virus Cellular Receptor 1, Kidney Tubules, Lipocalin-2, Male, Mice, Mice, Inbred C57BL, Sepsis, Survival Analysis
Show Abstract · Added May 10, 2020
Acute kidney injury is a common complication of severe sepsis and contributes to high mortality. The molecular mechanisms of acute kidney injury during sepsis are not fully understood. Because hemoproteins, including myoglobin and hemoglobin, are known to mediate kidney injury during rhabdomyolysis, we hypothesized that cell-free hemoglobin (CFH) would exacerbate acute kidney injury during sepsis. Sepsis was induced in mice by intraperitoneal injection of cecal slurry (CS). To mimic elevated levels of CFH observed during human sepsis, mice also received a retroorbital injection of CFH or dextrose control. Four groups of mice were analyzed: sham treated (sham), CFH alone, CS alone, and CS + CFH. The addition of CFH to CS reduced 48-h survival compared with CS alone (67% vs. 97%, = 0.001) and increased the severity of illness. After 24 and 48 h, CS + CFH mice had a reduced glomerular filtration rate from baseline, whereas sham, CFH, and CS mice maintained baseline glomerular filtration rate. Biomarkers of acute kidney injury, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), were markedly elevated in CS+CFH compared with CS (8-fold for NGAL and 2.4-fold for KIM-1, < 0.002 for each) after 48 h. Histological examination showed a trend toward increased tubular injury in CS + CFH-exposed kidneys compared with CS-exposed kidneys. However, there were similar levels of renal oxidative injury and apoptosis in the CS + CFH group compared with the CS group. Kidney levels of multiple proinflammatory cytokines were similar between CS and CS + CFH groups. Human renal tubule cells (HK-2) exposed to CFH demonstrated increased cytotoxicity. Together, these results show that CFH exacerbates acute kidney injury in a mouse model of experimental sepsis, potentially through increased renal tubular injury.
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Mitochondrial DNA Haplogroups and Delirium During Sepsis.
Samuels DC, Hulgan T, Fessel JP, Billings FT, Thompson JL, Chandrasekhar R, Girard TD
(2019) Crit Care Med 47: 1065-1071
MeSH Terms: Adult, African Americans, Critical Illness, DNA, Mitochondrial, European Continental Ancestry Group, Female, Haplotypes, Humans, Male, Middle Aged, Polymerase Chain Reaction, Retrospective Studies, Sepsis-Associated Encephalopathy, Sequence Analysis, DNA
Show Abstract · Added December 11, 2019
OBJECTIVES - Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis.
DESIGN - Retrospective cohort study.
SETTING - Medical and surgical ICUs at a large tertiary care center.
PATIENTS - Caucasian and African American adults with sepsis.
MEASUREMENTS AND MAIN RESULTS - We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03).
CONCLUSIONS - Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.
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14 MeSH Terms
Sepsis-Associated Acute Kidney Injury: A Problem Deserving of New Solutions.
Kellum JA, Wen X, de Caestecker MP, Hukriede NA
(2019) Nephron 143: 174-178
MeSH Terms: Acute Kidney Injury, Animals, Histone Deacetylase Inhibitors, Humans, Kidney, Regeneration, Sepsis
Show Abstract · Added May 10, 2020
Sepsis-associated acute kidney injury (S-AKI) significantly worsens patient prognosis, and recent evidence suggests that the injury process begins early and may be sustained by therapies used to treat the sepsis (e.g., fluids resuscitation, antibiotics). While efforts to develop less-injurious treatments are making progress, some degree of secondary injury is to be expected. So too is the inevitable nature of organ injury, which is often present at the time the patient seeks medical attention. We recently found that most patients presenting with septic shock and developing AKI had evidence of kidney damage at the time of, or within 24 h of their admission. In such patients, prevention is not a viable option, as injury has already occurred by the time of presentation. Since S-AKI patients are at increased risk of developing chronic kidney disease, a fundamental target for interventions in S-AKI is to prevent fibrosis (maladaptive repair) while stimulating regeneration (proliferation of viable epithelial cells). Using a pathway-agnostic, proliferation-based phenotypic assay, we discovered phenylthiobutanoic acid, a small molecule histone deacetylase inhibitor, that enhances renal recovery and reduces fibrosis in both zebrafish and mouse models of AKI.
© 2019 S. Karger AG, Basel.
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Rapid changes in the microvascular circulation of skeletal muscle impair insulin delivery during sepsis.
Mignemi NA, McClatchey PM, Kilchrist KV, Williams IM, Millis BA, Syring KE, Duvall CL, Wasserman DH, McGuinness OP
(2019) Am J Physiol Endocrinol Metab 316: E1012-E1023
MeSH Terms: Animals, Capillaries, Capillary Permeability, Disease Models, Animal, Echocardiography, Hyperglycemia, Insulin, Insulin Resistance, Lipopolysaccharides, Mice, Microcirculation, Microvessels, Muscle Fibers, Skeletal, Muscle, Skeletal, Sepsis
Show Abstract · Added March 26, 2019
Sepsis costs the healthcare system $23 billion annually and has a mortality rate between 10 and 40%. An early indication of sepsis is the onset of hyperglycemia, which is the result of sepsis-induced insulin resistance in skeletal muscle. Previous investigations have focused on events in the myocyte (e.g., insulin signaling and glucose transport and subsequent metabolism) as the causes for this insulin-resistant state. However, the delivery of insulin to the skeletal muscle is also an important determinant of insulin action. Skeletal muscle microvascular blood flow, which delivers the insulin to the muscle, is known to be decreased during sepsis. Here we test whether the reduced capillary blood flow to skeletal muscle belies the sepsis-induced insulin resistance by reducing insulin delivery to the myocyte. We hypothesize that decreased capillary flow and consequent decrease in insulin delivery is an early event that precedes gross cardiovascular alterations seen with sepsis. This hypothesis was examined in mice treated with either lipopolysaccharide (LPS) or polymicrobial sepsis followed by intravital microscopy of the skeletal muscle microcirculation. We calculated insulin delivery to the myocyte using two independent methods and found that LPS and sepsis rapidly reduce insulin delivery to the skeletal muscle by ~50%; this was driven by decreases in capillary flow velocity and the number of perfused capillaries. Furthermore, the changes in skeletal muscle microcirculation occur before changes in both cardiac output and arterial blood pressure. These data suggest that a rapid reduction in skeletal muscle insulin delivery contributes to the induction of insulin resistance during sepsis.
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15 MeSH Terms
Association Between Low-Density Lipoprotein Cholesterol Levels and Risk for Sepsis Among Patients Admitted to the Hospital With Infection.
Feng Q, Wei WQ, Chaugai S, Leon BGC, Mosley JD, Leon DAC, Jiang L, Ihegword A, Shaffer CM, Linton MF, Chung CP, Stein CM
(2019) JAMA Netw Open 2: e187223
MeSH Terms: Aged, Cholesterol, LDL, Female, Hospital Mortality, Hospitalization, Humans, Infections, Intensive Care Units, Male, Middle Aged, Risk Factors, Sepsis
Show Abstract · Added April 10, 2019
Importance - Whether low levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of sepsis and poorer outcomes is unknown.
Objective - To examine the association between LDL-C levels and risk of sepsis among patients admitted to the hospital with infection.
Design, Setting, and Participants - Cohort study in which deidentified electronic health records were used to define a cohort of patients admitted to Vanderbilt University Medical Center, Nashville, Tennessee, with infection. Patients were white adults, had a code indicating infection from the International Classification of Diseases, Ninth Revision, Clinical Modification, and received an antibiotic within 1 day of hospital admission (N = 61 502). Data were collected from January 1, 1993, through December 31, 2017, and analyzed from January 24 through October 31, 2018.
Interventions - Clinically measured LDL-C levels (excluding measurements <1 year before hospital admission and those associated with acute illness) and a genetic risk score (GRS).
Main Outcomes and Measures - The primary outcome was sepsis; secondary outcomes included admission to an intensive care unit (ICU) and in-hospital death.
Results - Among the 3961 patients with clinically measured LDL-C levels (57.8% women; mean [SD] age, 64.1 [15.9] years) and the 7804 with a GRS for LDL-C (54.0% men; mean [SD] age, 59.8 [15.2] years), lower measured LDL-C levels were significantly associated with increased risk of sepsis (odds ratio [OR], 0.86; 95% CI, 0.79-0.94; P = .001) and ICU admission (OR, 0.85; 95% CI, 0.76-0.96; P = .008), but not in-hospital mortality (OR, 0.80; 95% CI, 0.63-1.00; P = .06); however, none of these associations were statistically significant after adjustment for age, sex, and comorbidity variables (OR for risk of sepsis, 0.96 [95% CI, 0.88-1.06]; OR for ICU admission, 0.94 [95% CI, 0.83-1.06]; OR for in-hospital death, 0.97 [95% CI, 0.76-1.22]; P > .05 for all). The LDL-C GRS correlated with measured LDL-C levels (r = 0.24; P < 2.2 × 10-16) but was not significantly associated with any of the outcomes.
Conclusions and Relevance - Results of this study suggest that lower measured LDL-C levels were significantly associated with increased risk of sepsis and admission to ICU in patients admitted to the hospital with infection; however, this association was due to comorbidities because both clinical models adjusted for confounders, and the genetic model showed no increased risk. Levels of LDL-C do not appear to directly alter the risk of sepsis or poor outcomes in patients hospitalized with infection.
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Cutting Edge: IL-1α and Not IL-1β Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality.
Benjamin JT, Moore DJ, Bennett C, van der Meer R, Royce A, Loveland R, Wynn JL
(2018) J Immunol 201: 2873-2878
MeSH Terms: Animals, Animals, Newborn, Female, Humans, Infant, Newborn, Inflammation, Interleukin-1alpha, Interleukin-1beta, Male, Mice, Mice, Inbred C57BL, Receptors, Interleukin-1 Type I, Sepsis, Signal Transduction
Show Abstract · Added October 12, 2018
Sepsis disproportionately affects the very old and the very young. IL-1 signaling is important in innate host defense but may also play a deleterious role in acute inflammatory conditions (including sepsis) by promulgating life-threatening inflammation. IL-1 signaling is mediated by two distinct ligands: IL-1α and IL-1β, both acting on a common receptor (IL-1R1). IL-1R1 targeting has not reduced adult human sepsis mortality despite biologic plausibility. Because the specific role of IL-1α or IL-1β in sepsis survival is unknown in any age group and the role of IL-1 signaling remains unknown in neonates, we studied the role of IL-1 signaling, including the impact of IL-1α and IL-1β, on neonatal murine sepsis survival. IL-1 signaling augments the late plasma inflammatory response to sepsis. IL-1α and not IL-1β is the critical mediator of sepsis mortality, likely because of paracrine actions within the tissue. These data do not support targeting IL-1 signaling in neonates.
Copyright © 2018 by The American Association of Immunologists, Inc.
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14 MeSH Terms
Prophylactic Treatment With Simvastatin Modulates the Immune Response and Increases Animal Survival Following Lethal Sepsis Infection.
Braga Filho JAF, Abreu AG, Rios CEP, Trovão LO, Silva DLF, Cysne DN, Nascimento JR, Fortes TS, Silva LA, Guerra RNM, Maciel MCG, Serezani CH, Nascimento FRF
(2018) Front Immunol 9: 2137
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, Cytokines, Disease Models, Animal, Hydrogen Peroxide, Male, Mice, Sepsis, Simvastatin
Show Abstract · Added March 18, 2020
Chronic use of statins may have anti-inflammatory action, promoting immunomodulation and survival in patients with sepsis. This study aimed to analyze the effects of pretreatment with simvastatin in lethal sepsis induced by cecal ligation and puncture (CLP). Male mice received prophylactic treatment with simvastatin or pyrogen-free water orally in a single daily dose for 30 days. After this period, the CLP was performed. Naïve and Sham groups were performed as non-infected controls. Animal survival was monitored for 60 h after the CLP. Half of mice were euthanized after 12 h to analyze colony-forming units (CFUs); hematological parameters; production of IL-10, IL-12, IL-6, TNF-α, IFN-γ, and MCP-1; cell counts on peritoneum, bronchoalveolar lavage (BAL), bone marrow, spleen, and mesenteric lymph node; immunephenotyping of T cells and antigen presenting cells and production of hydrogen peroxide (HO). Simvastatin induced an increase in survival and a decrease in the CFU count on peritoneum and on BAL cells number, especially lymphocytes. There was an increase in the platelets and lymphocytes number in the Simvastatin group when compared to the CLP group. Simvastatin induced a greater activation and proliferation of CD4+ T cells, as well as an increase in IL-6 and MCP-1 production, in chemotaxis to the peritoneum and in HO secretion at this site. These data suggest that simvastatin has an impact on the survival of animals, as well as immunomodulatory effects in sepsis induced by CLP in mice.
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Graphene oxide polarizes iNKT cells for production of TGFβ and attenuates inflammation in an iNKT cell-mediated sepsis model.
Lee SW, Park HJ, Van Kaer L, Hong S, Hong S
(2018) Sci Rep 8: 10081
MeSH Terms: Animals, Antigens, CD1d, Cell Polarity, Dendritic Cells, Disease Models, Animal, Galactosylceramides, Graphite, Humans, Inflammation, Intraepithelial Lymphocytes, Lymphocyte Activation, Mice, Nanotubes, Carbon, Natural Killer T-Cells, Sepsis, Toll-Like Receptor 4, Transforming Growth Factor beta
Show Abstract · Added March 26, 2019
Graphene oxide (GO) modulates the functions of antigen-presenting cells including dendritic cells (DCs). Although carbon nanotubes affect expression of the MHC class I-like CD1d molecule, whether GO can influence immune responses of CD1d-dependent invariant natural killer T (iNKT) cells remains unclear. Here, we investigated the impact of GO on inflammatory responses mediated by α-galactosylceramide (α-GalCer), an iNKT cell agonist. We found that in vivo GO treatment substantially inhibited the capacity of α-GalCer to induce the iNKT cell-mediated trans-activation of and cytokine production by innate and innate-like cells, including DCs, macrophages, NK cells, and γδ T cells. Such effects of GO on α-GalCer-induced inflammatory responses closely correlated with iNKT cell polarization towards TGFβ production, which also explains the capacity of GO to expand regulatory T cells. Interestingly, the absence of TLR4, a receptor for GO, failed to downregulate, and instead partially enhanced the anti-inflammatory activity of GO against α-GalCer-elicited responses, implying negative effects of TLR4 signaling on the anti-inflammatory properties of GO. By employing an α-GalCer-induced sepsis model, we further demonstrated that GO treatment significantly protected mice from α-GalCer-induced lethality. Taken together, we provide strong evidence that GO holds promise as an adjuvant to modulate iNKT cell responses for immunotherapy.
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Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis.
Sisti F, Wang S, Brandt SL, Glosson-Byers N, Mayo LD, Son YM, Sturgeon S, Filgueiras L, Jancar S, Wong H, Dela Cruz CS, Andrews N, Alves-Filho JC, Cunha FQ, Serezani CH
(2018) Sci Signal 11:
MeSH Terms: Animals, Cell Nucleus, Female, Gene Expression Profiling, Humans, Inflammation, Macrophages, Male, Mice, Inbred C57BL, Mice, Knockout, MicroRNAs, Myeloid Differentiation Factor 88, PTEN Phosphohydrolase, Peptides, RNA Interference, Regulon, Sepsis
Show Abstract · Added March 18, 2020
Sepsis-induced organ damage is caused by systemic inflammatory response syndrome (SIRS), which results in substantial comorbidities. Therefore, it is of medical importance to identify molecular brakes that can be exploited to dampen inflammation and prevent the development of SIRS. We investigated the role of phosphatase and tensin homolog (PTEN) in suppressing SIRS, increasing microbial clearance, and preventing lung damage. Septic patients and mice with sepsis exhibited increased expression in leukocytes. Myeloid-specific deletion in an animal model of sepsis increased bacterial loads and cytokine production, which depended on enhanced myeloid differentiation primary response gene 88 (MyD88) abundance and resulted in mortality. PTEN-mediated induction of the microRNAs (miRNAs) miR125b and miR203b reduced the abundance of MyD88. Loss- and gain-of-function assays demonstrated that PTEN induced miRNA production by associating with and facilitating the nuclear localization of Drosha-Dgcr8, part of the miRNA-processing complex. Reconstitution of PTEN-deficient mouse embryonic fibroblasts with a mutant form of PTEN that does not localize to the nucleus resulted in retention of Drosha-Dgcr8 in the cytoplasm and impaired production of mature miRNAs. Thus, we identified a regulatory pathway involving nuclear PTEN-mediated miRNA generation that limits the production of MyD88 and thereby limits sepsis-associated mortality.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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