Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.413
Filtrar
1.
Front Cell Infect Microbiol ; 13: 1191806, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37424774

RESUMO

Pseudomonas aeruginosa is a common cause of hospital-acquired infections, including central line-associated bloodstream infections and ventilator-associated pneumonia. Unfortunately, effective control of these infections can be difficult, in part due to the prevalence of multi-drug resistant strains of P. aeruginosa. There remains a need for novel therapeutic interventions against P. aeruginosa, and the use of monoclonal antibodies (mAb) is a promising alternative strategy to current standard of care treatments such as antibiotics. To develop mAbs against P. aeruginosa, we utilized ammonium metavanadate, which induces cell envelope stress responses and upregulates polysaccharide expression. Mice were immunized with P. aeruginosa grown with ammonium metavanadate and we developed two IgG2b mAbs, WVDC-0357 and WVDC-0496, directed against the O-antigen lipopolysaccharide of P. aeruginosa. Functional assays revealed that WVDC-0357 and WVDC-0496 directly reduced the viability of P. aeruginosa and mediated bacterial agglutination. In a lethal sepsis model of infection, prophylactic treatment of mice with WVDC-0357 and WVDC-0496 at doses as low as 15 mg/kg conferred 100% survival against challenge. In both sepsis and acute pneumonia models of infection, treatment with WVDC-0357 and WVDC-0496 significantly reduced bacterial burden and inflammatory cytokine production post-challenge. Furthermore, histopathological examination of the lungs revealed that WVDC-0357 and WVDC-0496 reduced inflammatory cell infiltration. Overall, our results indicate that mAbs directed against lipopolysaccharide are a promising therapy for the treatment and prevention of P. aeruginosa infections.


Assuntos
Anticorpos Antibacterianos , Anticorpos Monoclonais , Lipopolissacarídeos , Infecções por Pseudomonas , Pseudomonas aeruginosa , Animais , Feminino , Camundongos , Anticorpos Antibacterianos/imunologia , Anticorpos Monoclonais/imunologia , Aderência Bacteriana , Carga Bacteriana/imunologia , Convalescença , Mediadores da Inflamação/imunologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/imunologia , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/prevenção & controle , Pseudomonas aeruginosa/imunologia , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/prevenção & controle , Sepse/imunologia , Sepse/microbiologia , Sepse/prevenção & controle
2.
Allergol Immunopathol (Madr) ; 51(3): 1-7, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37169553

RESUMO

BACKGROUND: Immune dysfunction is a common and serious complication of sepsis. This study finds key genes linked to immunity in sepsis. METHODS: The "Limma package" was used to analyze GSE154918 datasets for differentially expressed genes. The differentially expressed genes were then enriched for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and interleukin 2 receptor subunit Beta (IL2RB) protein coding gene was chosen for investigation. IL2RB expression in peripheral blood mononuclear cells (PBMC) was assessed by polymerase chain reaction. White blood cells of septic patients and healthy controls were collected from hospitals and linked with acute physiology and chronic health evaluation (APACHE) II, sequential organ failure assessment (SOFA), C-reactive protein (CRP), and procalcitonin (PCT) of septic patients using Pearson's correlation analysis. PBMC cells were transfected with IL2RB, and the effect of transfection was observed on cellular interferon gamma (IFN-γ), interleukin (IL)-12, IL-4, IL-10, and IL-17A. RESULTS: A total of 686 differential genes, comprising 446 upregulated and 240 down regulated genes, were identified. The enrichment of KEGG pathway revealed that the majority of differential genes were enriched in the T helper (Th1)/Th2 cell and Th17 cell differentiation pathways. In patients with sepsis, correlation analysis revealed a negative correlation between IL2RB and APACHE II score, SOFA score, CRP, and PCT. IFN-γ and IL-12 levels were elevated in PBMC of septic patients after IL2RB transfection, but IL-4, IL-10, and IL-17A levels were lowered. CONCLUSION: Sepsis-induced immunological dysfunction is improved by IL2RB, which also balances Th1/Th2 responses and prevents Th17 activation. © 2023 Codon Publications. Published by Codon Publications.


Assuntos
Leucócitos Mononucleares , Sepse , Humanos , Proteína C-Reativa , Interleucina-10 , Interleucina-12 , Interleucina-17 , Subunidade beta de Receptor de Interleucina-2 , Interleucina-4 , Sepse/genética , Sepse/imunologia , Células Th1 , Células Th17 , Células Th2
3.
J Intensive Care Med ; 38(11): 997-1002, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37211665

RESUMO

BACKGROUND: Although the role of oxytocin in the pathophysiology of sepsis is still unknown, rising preclinical evidence suggests that oxytocin is possibly involved. However, no direct clinical studies have measured the levels of oxytocin during sepsis. In this preliminary study, the serum oxytocin levels were evaluated throughout the duration of sepsis. METHOD: Twenty-two male patients over 18 years of age with a SOFA score of 2 points or more who were admitted to the ICU were included. Patients with a history of neuroendocrine, psychiatric, and neurologic disorders, cancer, an infection caused by COVID-19, shock due to reasons other than sepsis, a history of psychiatric or neurologic medication use, and those who died during the study were excluded. The main endpoint included the measurement of serum oxytocin levels using radioimmunoassay at 6, 24, and 48 h of the ICU admission. RESULTS: Mean serum oxytocin level was higher at 6 h of ICU admission (41.27 ± 13.14 ng/L) than after 24 and 48 h of ICU admission (22.63 ± 5.75 and 20.97 ± 7.61 ng/L respectively) (P-value < .001). CONCLUSION: Our study, while reporting increased serum oxytocin levels in the initial phase of sepsis and decline afterward, supports the possible contribution of oxytocin in the pathophysiology of sepsis. Given that oxytocin seems to modulate the innate immune system, future investigations are necessary to assess the potential role of oxytocin in the pathophysiology of sepsis.


Assuntos
Ocitocina , Sepse , Adolescente , Adulto , Humanos , Masculino , COVID-19 , Hospitalização , Unidades de Terapia Intensiva , Ocitocina/sangue , Ocitocina/imunologia , Prognóstico , Estudos Retrospectivos , Sepse/sangue , Sepse/imunologia , Sepse/fisiopatologia , Imunidade Inata/imunologia
4.
Allergol. immunopatol ; 51(3): 1-7, 01 mayo 2023. tab
Artigo em Inglês | IBECS | ID: ibc-219807

RESUMO

Background: Immune dysfunction is a common and serious complication of sepsis. This study finds key genes linked to immunity in sepsis. Methods: The “Limma package” was used to analyze GSE154918 datasets for differentially expressed genes. The differentially expressed genes were then enriched for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and interleukin 2 receptor subunit Beta (IL2RB) protein coding gene was chosen for investigation. IL2RB expression in peripheral blood mononuclear cells (PBMC) was assessed by polymerase chain reaction. White blood cells of septic patients and healthy controls were collected from hospitals and linked with acute physiology and chronic health evaluation (APACHE) II, sequential organ failure assessment (SOFA), C-reactive protein (CRP), and procalcitonin (PCT) of septic patients using Pearson’s correlation analysis. PBMC cells were transfected with IL2RB, and the effect of transfection was observed on cellular interferon gamma (IFN-γ), interleukin (IL)-12, IL-4, IL-10, and IL-17A. Results: A total of 686 differential genes, comprising 446 upregulated and 240 down regulated genes, were identified. The enrichment of KEGG pathway revealed that the majority of differential genes were enriched in the T helper (Th1)/Th2 cell and Th17 cell differentiation pathways. In patients with sepsis, correlation analysis revealed a negative correlation between IL2RB and APACHE II score, SOFA score, CRP, and PCT. IFN-γ and IL-12 levels were elevated in PBMC of septic patients after IL2RB transfection, but IL-4, IL-10, and IL-17A levels were lowered. Conclusion: Sepsis-induced immunological dysfunction is improved by IL2RB, which also balances Th1/Th2 responses and prevents Th17 activation. © 2023 Codon Publications. Published by Codon Publications (AU)


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Receptores de Interleucina-2/imunologia , Células Th1/imunologia , Células Th2/imunologia , Sepse/imunologia , Biologia Computacional
5.
Ren Fail ; 45(1): 2187229, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36883358

RESUMO

OBJECTIVE: The present study investigated the specific mechanism by which mesenchymal stem cells (MSCs) protect against sepsis-associated acute kidney injury (SA-AKI). METHODS: Male C57BL/6 mice underwent cecal ligation and puncture surgery to induce sepsis and then received either normal IgG or MSCs (1 × 106 cells, intravenously) plus Gal-9 or soluble Tim-3 3 h after surgery. RESULTS: After cecal ligation and puncture surgery, the mice injected with Gal-9 or MSCs plus Gal-9 had a higher survival rate than the mice in the IgG treatment group. Treatment with MSCs plus Gal-9 decreased serum creatinine and blood urea nitrogen levels, improved tubular function recovery, reduced IL-17 and RORγt levels and induced IL-10 and FOXP3 expression. Additionally, the Th17/Treg cell balance was altered. However, when soluble Tim-3 was used to block the Gal-9/Tim-3 pathway, the septic mice developed kidney injury and exhibited increased mortality. Treatment with MSCs plus soluble Tim-3 blunted the therapeutic effect of MSCs, inhibited the induction of Tregs, and suppressed the inhibition of differentiation into Th17 cells. CONCLUSION: Treatment with MSCs significantly reversed the Th1/Th2 balance. Thus, the Gal-9/Tim-3 pathway may be an important mechanism of MSC-mediated protection against SA-AKI.


Assuntos
Injúria Renal Aguda , Homeostase , Células-Tronco Mesenquimais , Sepse , Animais , Masculino , Camundongos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/terapia , Receptor Celular 2 do Vírus da Hepatite A , Homeostase/imunologia , Imunoglobulina G/uso terapêutico , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Sepse/complicações , Sepse/imunologia
6.
J Transl Med ; 21(1): 141, 2023 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-36823620

RESUMO

BACKGROUND: Sepsis is a frequent complication in critically ill patients, is highly heterogeneous and is associated with high morbidity and mortality rates, especially in the elderly population. Utilizing RNA sequencing (RNA-Seq) to analyze biological pathways is widely used in clinical and molecular genetic studies, but studies in elderly patients with sepsis are still lacking. Hence, we investigated the mortality-relevant biological features and transcriptomic features in elderly patients who were admitted to the intensive care unit (ICU) for sepsis. METHODS: We enrolled 37 elderly patients with sepsis from the ICU at Taichung Veterans General Hospital. On day-1 and day-8, clinical and laboratory data, as well as blood samples, were collected for RNA-Seq analysis. We identified the dynamic transcriptome and enriched pathways of differentially expressed genes between day-8 and day-1 through DVID enrichment analysis and Gene Set Enrichment Analysis. Then, the diversity of the T cell repertoire was analyzed with MiXCR. RESULTS: Overall, 37 patients had sepsis, and responders and non-responders were grouped through principal component analysis. Significantly higher SOFA scores at day-7, longer ventilator days, ICU lengths of stay and hospital mortality were found in the non-responder group, than in the responder group. On day-8 in elderly ICU patients with sepsis, genes related to innate immunity and inflammation, such as ZDHCC19, ALOX15, FCER1A, HDC, PRSS33, and PCSK9, were upregulated. The differentially expressed genes (DEGs) were enriched in the regulation of transcription, adaptive immune response, immunoglobulin production, negative regulation of transcription, and immune response. Moreover, there was a higher diversity of T-cell receptors on day-8 in the responder group, than on day-1, indicating that they had better regulated recovery from sepsis compared with the non-response patients. CONCLUSION: Sepsis mortality and incidence were both high in elderly individuals. We identified mortality-relevant biological features and transcriptomic features with functional pathway and MiXCR analyses based on RNA-Seq data; and found that the responder group had upregulated innate immunity and increased T cell diversity; compared with the non-responder group. RNA-Seq may be able to offer additional complementary information for the accurate and early prediction of treatment outcome.


Assuntos
Sepse , Transcriptoma , Idoso , Humanos , Estado Terminal , Perfilação da Expressão Gênica , Prognóstico , Sepse/imunologia , Sepse/metabolismo
7.
FEBS J ; 290(6): 1549-1562, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36181338

RESUMO

Sepsis often causes cell death via pyroptosis and hence results in septic cardiomyopathy. Triggering receptors expressed in myeloid cells-1 (TREM-1) may initiate cellular cascade pathways and, in turn, induce cell death and vital organ dysfunction in sepsis, but the evidence is limited. We set to investigate the role of TREM-1 on nucleotide-binding oligomerization domain-like receptors with pyrin domain-3 (NLRP3) inflammasome activation and cardiomyocyte pyroptosis in sepsis models using cardiac cell line (HL-1) and mice. In this study, TREM-1 was found to be significantly increased in HL-1 cells challenged with lipopolysaccharide (LPS). Pyroptosis was also significantly increased in the HL-1 cells challenged with lipopolysaccharide and an NLRP3 inflammasome activator, nigericin. The close interaction between TREM-1 and structural maintenance of chromosome 4 (SMC4) was also identified. Furthermore, inhibition of TREM-1 or SMC4 prevented the upregulation of NLRP3 and decreased Gasdermin-D, IL-1ß and caspase-1 cleavage. In mice subjected to caecal ligation and puncture, the TREM-1 inhibitor LR12 decreased the expression of NLRP3 and attenuated cardiomyocyte pyroptosis, leading to improved cardiac function and prolonged survival of septic mice. Our work demonstrates that, under septic conditions, TREM-1 plays a critical role in cardiomyocyte pyroptosis. Targeting TREM-1 and its associated molecules may therefore lead to novel therapeutic treatments for septic cardiomyopathy.


Assuntos
Inflamassomos , Miócitos Cardíacos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Sepse , Receptor Gatilho 1 Expresso em Células Mieloides , Animais , Humanos , Camundongos , Adenosina Trifosfatases/imunologia , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/imunologia , Caspase 1/genética , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/imunologia , Cromossomos Humanos Par 4/imunologia , Inflamassomos/agonistas , Inflamassomos/genética , Inflamassomos/imunologia , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/farmacologia , Células Mieloides/imunologia , Miócitos Cardíacos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/agonistas , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Piroptose/genética , Piroptose/imunologia , Sepse/complicações , Sepse/genética , Sepse/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Receptor Gatilho 1 Expresso em Células Mieloides/imunologia
8.
Thorax ; 78(4): 383-393, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-35354645

RESUMO

BACKGROUND: One hallmark of sepsis is the reduced number of lymphocytes, termed lymphopenia, that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by their epigenetic and non-epigenetic functions; however, the role of these enzymes in lymphopenia remains elusive. METHODS: We used molecular biological approaches to investigate the high expression and function of a chromatin modulator protein arginine N-methyltransferase 4 (PRMT4)/coactivator-associated arginine methyltransferase 1 in human samples from septic patients and cellular and animal septic models. RESULTS: We identified that PRMT4 is elevated systemically in septic patients and experimental sepsis. Gram-negative bacteria and their derived endotoxin lipopolysaccharide (LPS) increased PRMT4 in B and T lymphocytes and THP-1 monocytes. Single-cell RNA sequencing results indicate an increase of PRMT4 gene expression in activated T lymphocytes. Augmented PRMT4 is crucial for inducing lymphocyte apoptosis but not monocyte THP-1 cells. Ectopic expression of PRMT4 protein caused substantial lymphocyte death via caspase 3-mediated cell death signalling, and knockout of PRMT4 abolished LPS-mediated lymphocyte death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis. CONCLUSIONS: These findings demonstrate a previously uncharacterised role of a key chromatin modulator in lymphocyte survival that may shed light on devising therapeutic modalities to lessen the severity of septic immunosuppression.


Assuntos
Linfopenia , Proteína-Arginina N-Metiltransferases , Sepse , Animais , Humanos , Arginina/genética , Caspase 3/genética , Caspase 3/imunologia , Cromatina , Lipopolissacarídeos/farmacologia , Linfopenia/etiologia , Linfopenia/genética , Linfopenia/imunologia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Sepse/complicações , Sepse/genética , Sepse/imunologia
9.
Mol Ther ; 31(1): 154-173, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36068919

RESUMO

Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets.


Assuntos
Tolerância Imunológica , Peptídeos e Proteínas de Sinalização Intercelular , Macrófagos , NF-kappa B , Sepse , Fatores de Transcrição , Animais , Camundongos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/imunologia , NF-kappa B/metabolismo , Sepse/imunologia , Sepse/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Hospedeiro Imunocomprometido
10.
Neonatology ; 120(1): 40-48, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36549285

RESUMO

INTRODUCTION: Little is known about the interplay between neutrophil heterogeneity in neonates in health and disease states. Olfactomedin-4 (OLFM4) marks a subset of neutrophils that have been described in adults and pediatric patients but not neonates, and this subset is thought to play a role in modulating the host inflammatory response. METHODS: This is a prospective cohort of neonates who were born between June 2020 and December 2021 at the University of Cincinnati Medical Center NICU. Olfactomedin-4-positive (OLFM4+) neutrophils were identified in the peripheral blood using flow cytometry. RESULTS: OLFM4+ neutrophil percentage was not correlated with gestational age or developmental age. Neonates with sepsis had a higher percentage than those without the condition, 66.9% (IQR 24.3-76.9%) versus 21.5% (IQR 10.6-34.7%), respectively, p = 0.0003. At birth, a high percentage of OLFM4+ neutrophils was associated with severe chorioamnionitis at 49.1% (IQR 28.2-61.5%) compared to those without it at 13.7% (IQR 7.7-26.3%), p < 0.0001. Among neonates without sepsis, the percentages of OLFM4+ neutrophils were lower in the BPD/early death group compared to those without BPD, 11.8% (IQR 6.3-29.0%) versus 32.5% (IQR 18.5-46.1%), p = 0.003, and this retained significance in a multiple logistic regression model that included gestational age, birthweight, and race. CONCLUSION: This is the first study describing OLFM4+ neutrophils in neonates and it shows that this neutrophil subpopulation is not influenced by gestational age but is elevated in inflammatory conditions such as sepsis and severe chorioamnionitis, and lower percentage at birth is associated with developing bronchopulmonary dysplasia.


Assuntos
Displasia Broncopulmonar , Corioamnionite , Neutrófilos , Sepse , Criança , Feminino , Humanos , Recém-Nascido , Gravidez , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/imunologia , Corioamnionite/genética , Corioamnionite/imunologia , Idade Gestacional , Neutrófilos/imunologia , Estudos Prospectivos , Sepse/genética , Sepse/imunologia
11.
Proc Natl Acad Sci U S A ; 119(34): e2211370119, 2022 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-35969740

RESUMO

Sepsis, defined as organ dysfunction caused by a dysregulated host-response to infection, is characterized by immunosuppression. The vasopressor norepinephrine is widely used to treat low blood pressure in sepsis but exacerbates immunosuppression. An alternative vasopressor is angiotensin-II, a peptide hormone of the renin-angiotensin system (RAS), which displays complex immunomodulatory properties that remain unexplored in severe infection. In a murine cecal ligation and puncture (CLP) model of sepsis, we found alterations in the surface levels of RAS proteins on innate leukocytes in peritoneum and spleen. Angiotensin-II treatment induced biphasic, angiotensin-II type 1 receptor (AT1R)-dependent modulation of the systemic inflammatory response and decreased bacterial counts in both the blood and peritoneal compartments, which did not occur with norepinephrine treatment. The effect of angiotensin-II was preserved when treatment was delivered remote from the primary site of infection. At an independent laboratory, angiotensin-II treatment was compared in LysM-Cre AT1aR-/- (Myeloid-AT1a-) mice, which selectively do not express AT1R on myeloid-derived leukocytes, and littermate controls (Myeloid-AT1a+). Angiotensin-II treatment significantly reduced post-CLP bacteremia in Myeloid-AT1a+ mice but not in Myeloid-AT1a- mice, indicating that the AT1R-dependent effect of angiotensin-II on bacterial clearance was mediated through myeloid-lineage cells. Ex vivo, angiotensin-II increased post-CLP monocyte phagocytosis and ROS production after lipopolysaccharide stimulation. These data identify a mechanism by which angiotensin-II enhances the myeloid innate immune response during severe systemic infection and highlight a potential role for angiotensin-II to augment immune responses in sepsis.


Assuntos
Angiotensina II , Bacteriemia/imunologia , Células Mieloides/metabolismo , Sepse/imunologia , Angiotensina II/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Receptor Tipo 1 de Angiotensina , Sepse/metabolismo , Transdução de Sinais
12.
Immunol Res ; 70(5): 698-707, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35732880

RESUMO

Sepsis causes a myriad of immunological reactions that result in life-threatening alterations in the human body. Immunosuppression in sepsis is partly attributed to the programmed death receptor (PD-1) and its associated ligand (PD-L1) via the regulation of lymphocytes and neutrophils. Although the soluble forms of these proteins (i.e., sPD-1 and sPD-L1, respectively) are recognized as possible sepsis biomarkers, their functional implications are yet to be elucidated. Our research assessed the correlation between sPD-1 and sPD-L1 and blood mRNA markers and sepsis outcome. Blood samples of septic patients of urogenital origin versus control patients (both groups: n = 18) were analyzed. Blood serum sPD-1 and sPD-L1 levels were determined using the enzyme-linked immunosorbent assay (ELISA). The whole blood mRNA concentrations of PD-1, PD-L1, neutrophil markers (CEACAM8 and MPO), and T-lymphocyte markers (TCRß, CD4 and CD8) were determined via reverse transcriptase quantitative PCR (RT-qPCR). sPD-L1 levels were significantly increased in septic patients when compared to the controls, whereas sPD-1 levels were unaltered. Patients with high sPD-L1 levels, as dichotomized to the median, had a significantly shorter survival rate than those with low sPD-L1 levels. The sensitivity/specificity characteristics of sPD-L1 proved significant for sepsis detection. Furthermore, sPD-L1 correlated with the mRNA concentrations of PD-L1, CEACAM, and MPO, as well as major inflammatory markers (C-reactive protein and procalcitonin). However, sPD-L1 negatively correlated with TCRß, CD4, and CD8 mRNAs. sPD-L1 was found to be significantly increased in septic patients. Notably, sPD-L1 correlated with PD-L1 mRNA and neutrophil markers and was indicative of adverse outcomes.


Assuntos
Antígeno B7-H1 , Linfócitos , Neutrófilos , Sepse , Antígeno B7-H1/sangue , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores/sangue , Proteína C-Reativa , Humanos , Ligantes , Linfócitos/imunologia , Neutrófilos/imunologia , Pró-Calcitonina , Prognóstico , Receptor de Morte Celular Programada 1/genética , RNA Mensageiro/genética , RNA Mensageiro/imunologia , DNA Polimerase Dirigida por RNA , Receptores de Morte Celular , Sepse/sangue , Sepse/genética , Sepse/imunologia
13.
J Clin Lab Anal ; 36(6): e24392, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35441408

RESUMO

BACKGROUND: Sepsis is a highly life-threatening disease. Long non-coding RNA urothelial carcinoma associated 1 (lncRNA UCA1) participates in the processes of inflammation and organ injury in several diseases, whereas its role in sepsis patients is still unclear. The aim was to explore the clinical value of lncRNA UCA1 in sepsis patients. METHODS: One hundred seventy-four sepsis patients and 100 age and gender-matched controls were enrolled. LncRNA UCA1 in peripheral blood mononuclear cell samples was examined, and the level of inflammatory cytokines in serum samples was assessed. RESULTS: LncRNA UCA1 was highly expressed in sepsis patients compared with controls. LncRNA UCA1 was positively correlated with tumor necrosis factor-α, interleukin (IL)-6, IL-17, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in sepsis patients, while it was not correlated with these inflammatory cytokines in controls. lncRNA UCA1 upregulation was related to raised APACHE II score and SOFA score in sepsis patients. Moreover, lncRNA UCA1 was increased in sepsis deaths compared with sepsis survivors and was independently correlated with increased 28-day sepsis mortality risk. Further receiver operating characteristic curves presented that lncRNA UCA1 had a good value to predict 28-motality risk, while its combination with other independent factors (including age, history of chronic kidney disease, G+ bacterial infection, Fungus infection, C-reactive protein, and APACHE II score) exerted a great predictive value for 28-day mortality risk. CONCLUSION: LncRNA UCA1 is upregulated and correlates with multiple pro-inflammatory cytokines, terrible disease severity, and poor prognosis in sepsis patients.


Assuntos
RNA Longo não Codificante , Sepse , Estudos de Casos e Controles , Citocinas/sangue , Citocinas/imunologia , Humanos , Interleucina-6 , Leucócitos Mononucleares/patologia , Prognóstico , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , Sepse/sangue , Sepse/genética , Sepse/imunologia , Regulação para Cima
14.
Diagn Microbiol Infect Dis ; 103(3): 115694, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35427887

RESUMO

Granzyme B could be released from cytotoxic T lymphocytes producing apoptosis activation. The objective of our study was to determine whether an association between septic patient mortality and blood granzyme B concentrations exist. We recruited septic patients admitted in 3 Intensive Care Units. We recorded mortality at 30 days and we determined serum granzyme B concentrations at moment of sepsis diagnosis. We found higher rate of history of diabetes mellitus (P = 0.02), serum granzyme B concentrations (P < 0.001), age (P = 0.001), serum lactic acid levels (P = 0.001) and sepsis-related organ failure assessment (P < 0.001) exhibited non-surviving patients (n = 67) than surviving ones (n = 110). We found in multiple logistic regression analysis an association of serum granzyme B concentrations with mortality (odds ratio = 1.223; 95% confidence interval = 1.104-1.355; P < 0.001) controlling for diabetes mellitus, sepsis-related organ failure assessment, lactic acid and age. That we know, our study is the first reporting the existence of an association of high serum granzyme B concentrations with high septic patients mortality.


Assuntos
Granzimas , Sepse , Granzimas/sangue , Granzimas/imunologia , Humanos , Unidades de Terapia Intensiva , Ácido Láctico/sangue , Prognóstico , Estudos Prospectivos , Sepse/sangue , Sepse/imunologia , Sepse/mortalidade , Choque Séptico/sangue , Choque Séptico/imunologia , Choque Séptico/mortalidade
15.
J Clin Lab Anal ; 36(5): e24309, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35325494

RESUMO

BACKGROUND: Long noncoding RNA GAS5 (lnc-GAS5) is able to regulate macrophage M1 polarization and Th17 cell differentiation, also engaged in sepsis-induced inflammation and organ injury. This study aimed to further evaluate its linkage with Th1 cells and Th17 cells, as well as its clinical value in sepsis management. METHODS: About 101 sepsis patients were enrolled followed by peripheral blood mononuclear cell (PBMC) and serum samples collection. PBMC lnc-GAS5 was detected by RT-qPCR; Th1 cells and Th17 cells in PBMC CD4+ T cells were detected by flow cytometry; serum IFN-γ and IL-17A were detected by ELISA. Besides, PBMC lnc-GAS5 was also detected in 50 health controls (HCs). RESULTS: Lnc-GAS5 was reduced in sepsis patients than in HCs (p < 0.001), which also well-distinguished sepsis patients from HCs with AUC 0.860. Lnc-GAS5 did not relate to Th1 cells (p = 0.059) or IFN-γ (p = 0.192); while negatively linked with Th17 cells (p = 0.002) and IL-17A (p = 0.019) in sepsis patients. Interestingly, lnc-GAS5 negatively correlated with SOFA score (p = 0.001), SOFA-Respiratory system score (p = 0.001), SOFA-Coagulation score (p = 0.015), and SOFA-Renal system score (p = 0.026), but not SOFA-Liver score (p = 0.080), SOFA-Cardiovascular system score (p = 0.207) or SOFA-Nervous system score (p = 0.182) in sepsis patients. Furthermore, lnc-GAS5 was negatively related to CRP (p = 0.002) and APACHE II score (p = 0.004) in sepsis patients. Finally, lnc-GAS5 was decreased in dead sepsis patients compared to survivors (p = 0.007), which also distinguished sepsis deaths from survivors with AUC 0.713. CONCLUSION: Lnc-GAS5 relates to Th17 cells and serves as a potential biomarker for sepsis severity and mortality risk.


Assuntos
RNA Longo não Codificante , Sepse , Células Th17 , Biomarcadores , Humanos , Inflamação/imunologia , Interleucina-17/imunologia , Leucócitos Mononucleares/imunologia , Insuficiência de Múltiplos Órgãos/imunologia , Prognóstico , RNA Longo não Codificante/imunologia , Sepse/imunologia , Células Th17/imunologia
17.
Comput Math Methods Med ; 2022: 4586648, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35222683

RESUMO

Acute respiratory distress syndrome (ARDS) is recognized as a serious public health issue that results in respiratory failure and high mortality rates. The syndrome is characterized by immune cell aggregation, communication, activation, and alveolar epithelial damage. To elucidate the complex dynamic process of the immune system's response in ARDS, we construct the intercellular communication network of immune cells in ARDS based on a single-cell RNA sequencing dataset (including three sepsis-induced ARDS patients and four sepsis-only patients). The results show that macrophages relayed most of the intercellular signals (ligand-receptor pairs) in both groups. Many genes related to immune response (IFI44L, ISG, and HLA-DQB1) and biological functions (response to virus, negative regulation of viral life cycle, and response to interferon-beta) were detected via differentially expressed gene analysis of macrophages between the two groups. Deep analysis of the intercellular signals related to the macrophage found that sepsis-induced ARDS harbored distinctive intercellular signals related to chemokine-chemokine receptors (CCL3/4/5-CCR1), which mainly are involved in the disturbance of the STAT family transcription factors (TFs), such as STAT2 and STAT3. These signals and downstream TFs might play key roles in macrophage M1/M2 polarization in the process of sepsis-induced ARDS. This study provides a comprehensive view of the intercellular communication landscape between sepsis and sepsis-induced ARDS and identifies key intercellular communications and TFs involved in sepsis-induced ARDS. We believe that our study provides valuable clues for understanding the immune response mechanisms of ARDS.


Assuntos
Comunicação Celular/imunologia , Síndrome do Desconforto Respiratório/imunologia , Sepse/imunologia , Comunicação Celular/genética , Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Expressão Gênica , Ontologia Genética , Humanos , Macrófagos/imunologia , RNA-Seq , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/genética , Sepse/complicações , Sepse/genética , Análise de Célula Única
18.
Elife ; 112022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35166205

RESUMO

New therapeutic strategies to reduce sepsis-related mortality are urgently needed, as sepsis accounts for one in five deaths worldwide. Since hematopoietic stem and progenitor cells (HSPCs) are responsible for producing blood and immune cells, including in response to immunological stress, we explored their potential for treating sepsis. In a mouse model of Group A Streptococcus (GAS)-induced sepsis, severe immunological stress was associated with significant depletion of bone marrow HSPCs and mortality within approximately 5-7 days. We hypothesized that the inflammatory environment of GAS infection drives rapid HSPC differentiation and depletion that can be rescued by infusion of donor HSPCs. Indeed, infusion of 10,000 naïve HSPCs into GAS-infected mice resulted in rapid myelopoiesis and a 50-60% increase in overall survival. Surprisingly, mice receiving donor HSPCs displayed a similar pathogen load compared to untreated mice. Flow cytometric analysis revealed a significantly increased number of myeloid-derived suppressor cells in HSPC-infused mice, which correlated with reduced inflammatory cytokine levels and restored HSPC levels. These findings suggest that HSPCs play an essential immunomodulatory role that may translate into new therapeutic strategies for sepsis.


Assuntos
Diferenciação Celular/imunologia , Células-Tronco Hematopoéticas/imunologia , Imunomodulação , Sepse/imunologia , Células-Tronco/imunologia , Infecções Estreptocócicas/sangue , Animais , Citocinas/imunologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/terapia , Transplante de Células-Tronco/métodos , Infecções Estreptocócicas/imunologia , Streptococcus/imunologia , Streptococcus/patogenicidade
19.
Int J Mol Sci ; 23(3)2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35163021

RESUMO

Sepsis has recently been defined as life-threatening organ dysfunction caused by the dysregulated host response to an ongoing or suspected infection. To date, sepsis continues to be a leading cause of morbidity and mortality amongst hospitalized patients. Many risk factors contribute to development of sepsis, including pain-relieving drugs like opioids, which are frequently prescribed post-operatively. In light of the opioid crisis, understanding the interactions between opioid use and the development of sepsis has become extremely relevant, as opioid use is associated with increased risk of infection. Given that the intestinal tract is a major site of origin of sepsis-causing microbes, there has been an increasing focus on how alterations in the gut microbiome may predispose towards sepsis and mediate immune dysregulation. MicroRNAs, in particular, have emerged as key modulators of the inflammatory response during sepsis by tempering the immune response, thereby mediating the interaction between host and microbiome. In this review, we elucidate contributing roles of microRNA 146 in modulating sepsis pathogenesis and end with a discussion of therapeutic targeting of the gut microbiome in controlling immune dysregulation in sepsis.


Assuntos
Analgésicos Opioides/efeitos adversos , Microbioma Gastrointestinal , Imunidade , MicroRNAs/genética , Probióticos/administração & dosagem , Sepse/tratamento farmacológico , Humanos , Sepse/genética , Sepse/imunologia , Sepse/microbiologia
20.
Int J Mol Sci ; 23(3)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35163625

RESUMO

In addition to being a leading cause of morbidity and mortality worldwide, sepsis is also the most common cause of acute kidney injury (AKI). When sepsis leads to the development of AKI, mortality increases dramatically. Since the cardinal feature of sepsis is a dysregulated host response to infection, a disruption of kidney-immune crosstalk is likely to be contributing to worsening prognosis in sepsis with acute kidney injury. Since immune-mediated injury to the kidney could disrupt its protein manufacturing capacity, an investigation of molecules mediating this crosstalk not only helps us understand the sepsis immune response, but also suggests that their supplementation could have a therapeutic effect. Erythropoietin, vitamin D and uromodulin are known to mediate kidney-immune crosstalk and their disrupted production could impact morbidity and mortality in sepsis with acute kidney injury.


Assuntos
Injúria Renal Aguda/etiologia , Sistema Imunitário , Rim , Sepse/complicações , Animais , Eritropoetina , Humanos , Sepse/imunologia , Sepse/fisiopatologia , Uromodulina , Vitamina D
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...