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1.
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
2.
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
4.
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
5.
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
6.
Int J Mol Sci ; 23(3)2022 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-35163830

RESUMO

Although bacteria-free DNA in blood during systemic infection is mainly derived from bacterial death, translocation of the DNA from the gut into the blood circulation (gut translocation) is also possible. Hence, several mouse models with experiments on macrophages were conducted to explore the sources, influences, and impacts of bacteria-free DNA in sepsis. First, bacteria-free DNA and bacteriome in blood were demonstrated in cecal ligation and puncture (CLP) sepsis mice. Second, administration of bacterial lysate (a source of bacterial DNA) in dextran sulfate solution (DSS)-induced mucositis mice elevated blood bacteria-free DNA without bacteremia supported gut translocation of free DNA. The absence of blood bacteria-free DNA in DSS mice without bacterial lysate implies an impact of the abundance of bacterial DNA in intestinal contents on the translocation of free DNA. Third, higher serum cytokines in mice after injection of combined bacterial DNA with lipopolysaccharide (LPS), when compared to LPS injection alone, supported an influence of blood bacteria-free DNA on systemic inflammation. The synergistic effects of free DNA and LPS on macrophage pro-inflammatory responses, as indicated by supernatant cytokines (TNF-α, IL-6, and IL-10), pro-inflammatory genes (NFκB, iNOS, and IL-1ß), and profound energy alteration (enhanced glycolysis with reduced mitochondrial functions), which was neutralized by TLR-9 inhibition (chloroquine), were demonstrated. In conclusion, the presence of bacteria-free DNA in sepsis mice is partly due to gut translocation of bacteria-free DNA into the systemic circulation, which would enhance sepsis severity. Inhibition of the responses against bacterial DNA by TLR-9 inhibition could attenuate LPS-DNA synergy in macrophages and might help improve sepsis hyper-inflammation in some situations.


Assuntos
Citocinas/sangue , DNA Bacteriano/imunologia , Sulfato de Dextrana/efeitos adversos , Lipopolissacarídeos/imunologia , Mucosite/imunologia , Sepse/imunologia , Animais , Modelos Animais de Doenças , Fezes/microbiologia , Interleucina-10/sangue , Interleucina-6/sangue , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Mucosite/induzido quimicamente , Mucosite/microbiologia , Sepse/induzido quimicamente , Sepse/microbiologia , Fator de Necrose Tumoral alfa/sangue
7.
Indian J Pathol Microbiol ; 65(1): 111-116, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35074974

RESUMO

BACKGROUND: : Many biomarkers have now been studied such as C-reactive Protein (CRP), procalcitonin (PCT), etc., and are widely used for the diagnosis of sepsis in clinical practice which may determine the appropriate antibiotic treatment. A flowcytometric cytokine bead array (CBA) assay has now been used to determine multiple interleukins (IL), simultaneously. The aim of this study was to determine the cytokine (IL2, IL4, IL6, IL10, TNFα, INFγ, and IL17) profiles of interleukins in plasma of sepsis patients by using multiplex Flowcytometric CBA array assay. MATERIALS AND METHOD: s: A total of 99 consecutive patients admitted with the suspected sepsis were studied. PCT concentrations were measured by using the enzyme-linked fluorescent immunoassay (ELFA) technique and flow cytometry-based BD™ CBA Cytokine Kit was used to evaluate levels of 7 cytokines [IL-2, IL-4, IL-6, IL-10, Tumour Necrosis Factor (TNF), Interferon- γ (IFN-γ), and IL-17A]. RESULTS: Microbiologically defined infection (MDI) demonstrated a positive culture report in 79/99 (79.7%) of patients. The IL6 [1873.7 (4-5000)] and IL10 [(154.7 (0-1764)] levels were significantly higher in septic patients than those in the negative MDI IL6 [901 (4-5000)] and IL10 [110.4 (4-1372)] levels. The AUROC value of IL6 [0.66 (0.53-0.79)] was found to be the highest among all followed by IL10 [0.65 (0.51-0.79)], IFNγ [0.63 (0.51-0.77)], PCT [0.61 (0.48-0.75)], and TNFα [0.55 (0.42-0.69)]. CONCLUSION: Our study suggests that that IL6 is substantially more economical and can reduce the investigation cost to half as compared with the procalcitonin assay.


Assuntos
Técnicas de Laboratório Clínico/métodos , Técnicas de Laboratório Clínico/normas , Interleucinas/sangue , Pró-Calcitonina/sangue , Sepse/diagnóstico , Biomarcadores/sangue , Estado Terminal , Humanos , Curva ROC , Sepse/imunologia , Atenção Terciária à Saúde/estatística & dados numéricos
8.
Theranostics ; 12(2): 675-688, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34976207

RESUMO

Background: Innate immune memory, also termed "trained immunity", is thought to protect against experimental models of infection, including sepsis. Trained immunity via reprogramming monocytes/macrophages has been reported to result in enhanced inflammatory status and antimicrobial activity against infection in sepsis. However, a safe and efficient way to induce trained immunity remains unclear. Methods: ß-glucan is a prototypical agonist for inducing trained immunity. Ferumoxytol, superparamagnetic iron oxide (SPIO) with low cytotoxicity, has been approved by FDA for clinical use. We synthesized novel nanoparticles BSNPs by coupling ß-glucan with SPIO. BSNPs were further conjugated with fluorescein for quantitative analysis and trace detection of ß-glucan on BSNPs. Inflammatory cytokine levels were measured by ELISA and qRT-PCR, and the phagocytosis of macrophages was detected by flow cytometry and confocal microscopy. The therapeutic effect of BSNPs was evaluated on the well-established sepsis mouse model induced by both clinical Escherichia coli (E. coli) and cecal ligation and puncture (CLP). Results: BSNPs were synthesized successfully with a 3:20 mass ratio of ß-glucan and SPIO on BSNPs, which were mainly internalized by macrophages and accumulated in the lungs and livers of mice. BSNPs effectively reprogrammed macrophages to enhance the production of trained immunity markers and phagocytosis toward bacteria. BSNP-induced trained immunity protected mice against sepsis caused by E. coli and CLP and also against secondary infection. We found that BSNP treatment elevated Akt, S6, and 4EBP phosphorylation, while mTOR inhibitors decreased the trained immunity markers and phagocytosis enhanced by BSNPs. Furthermore, the PCR Array analysis revealed Igf1, Sesn1, Vegfa, and Rps6ka5 as possible key regulators of mTOR signaling during trained immunity. BSNP-induced trained immunity mainly regulated cellular signal transduction, protein modification, and cell cycle by modulating ATP binding and the kinase activity. Our results indicated that BSNPs induced trained immunity in an mTOR-dependent manner. Conclusion: Our data highlight that the trained immunity of macrophages is an effective strategy against sepsis and suggest that BSNPs are a powerful tool for inducing trained immunity to prevent and treat sepsis and secondary infections.


Assuntos
Infecções por Escherichia coli/imunologia , Óxido Ferroso-Férrico/uso terapêutico , Nanopartículas Magnéticas de Óxido de Ferro , Sepse/imunologia , Animais , Modelos Animais de Doenças , Infecções por Escherichia coli/prevenção & controle , Feminino , Imunidade Inata , Memória Imunológica , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Nanopartículas Magnéticas de Óxido de Ferro/química , Camundongos , Camundongos Endogâmicos ICR , Fagocitose/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Sepse/prevenção & controle , beta-Glucanas/química , beta-Glucanas/uso terapêutico
9.
Int Immunopharmacol ; 104: 108452, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34996010

RESUMO

Sepsis is a serious and menacing organ dysfunction that occur due to dysregulated response of the host towards the infection. This organ dysfunction may lead to sepsis with intense cellular, metabolic and circulatory dysregulation, multiple organ failure and high mortality. Lymphopenia is observed in two-third of sepsis patients and a significant depletion of lymphocytes occurs in non-survivors compared to sepsis survivors. Myeloid derived suppressor cells (MDSCs) gave new insights into sepsis-associated lymphopenia. If MDSC expansion and its tissue-infiltration persist, it can induce significant pathophysiology including lymphopenia, host immunosuppression and immune-paralysis that contributes to worsened patient outcomes. This review focuses on MDSCs and its subsets, the role of MDSCs in infection, sepsis and septic shock.


Assuntos
Células Supressoras Mieloides/imunologia , Sepse/imunologia , Animais , Humanos
10.
Int Immunopharmacol ; 104: 108506, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35008007

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) and cyclooxy-genase-2 (COX-2)/Prostaglandin E2 (PGE2) axis are important contributors to sepsis-induced immune-suppression. The purpose of present study is to explore whether COX-2 inhibitor can improve immunological disorder after sepsis via regulating MDSCs. METHODS: A ''two-hit'' model reflecting clinical sepsis development was performed. Cecal ligation and puncture (CLP) and Legionella pneumophila infection were used as the first and the second hit, respectively. NS398, a selective COX-2 inhibitor, was utilized to treat septic mice. The motality, bacterial counts in the lung, systematic inflammatory reaction and CD4 + T cells response after sepsis were assessed, so as the frequency and function of MDSCs. In some experiments, the number of MDSCs was manipulated by adoptive transfer or neutralizing antibody before induction of secondary infection. RESULTS: Mice surviving CLP showed a marked expansion and activation of MDSCs in spleen, accompanied by suppressed proliferating capability, impaired secreting functionand increased apoptosis of CD4 + T cells. Majority of CLP survivors became succumbed to L. pneumophila invasion, associated with defective bacteria elimination ability. NS398 treatment was found to ameliorate these adverse outcomes significantly. CONCLUSION: MDSCs contribute greatly to the sepsis-induced immune dysfunction. Inhibiting COX-2 may become a promising therapy that targets MDSCs-induced immunosuppression.


Assuntos
Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Doença dos Legionários/tratamento farmacológico , Células Supressoras Mieloides/efeitos dos fármacos , Nitrobenzenos/uso terapêutico , Sepse/tratamento farmacológico , Sulfonamidas/uso terapêutico , Animais , Linfócitos T CD4-Positivos/imunologia , Ceco/cirurgia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Citocinas/sangue , Modelos Animais de Doenças , Hipersensibilidade Tardia , Tolerância Imunológica/efeitos dos fármacos , Legionella pneumophila , Doença dos Legionários/imunologia , Doença dos Legionários/microbiologia , Lipopolissacarídeos/farmacologia , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Nitrobenzenos/farmacologia , Sepse/imunologia , Sepse/microbiologia , Baço/citologia , Baço/imunologia , Sulfonamidas/farmacologia
11.
Pediatr Res ; 91(2): 464-469, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35022559

RESUMO

The complex physiology and medical requirements of children with sepsis and multiple organ dysfunction syndrome (MODS) challenge traditional care coordination models. While the involvement of multiple clinical subspecialty services is often necessary to support different care processes and individual organ system dysfunctions, it can also delay the diagnostic process, monitoring, and treatment. The logistics of coordinating with many specialty providers for critically ill patients are challenging and time consuming, and often can result in fragmented communication. To address these and other related issues, we developed a new multi-disciplinary consult service focused on streamlining diagnostics, management, and communication for patients with sepsis and MODS-associated immune dysregulation. The service, called the Program in Inflammation, Immunity, and the Microbiome (PrIIMe), is now a hospital-wide clinical consult service at our institution caring for a broad group of patients with immune dysregulation, particularly focusing on patients with sepsis and MODS. In this paper, we summarize the development, structure, and function of the program, as well as the initial impact. This information may be helpful to clinicians and healthcare leaders who are developing multi-disciplinary consult services for children with complex care needs, especially those with sepsis and MODS-associated immune dysregulation. IMPACT: The care of children with sepsis and multiple organ dysfunction-associated immune dysregulation requires rapid and flexible involvement of multiple clinical subspecialists that is difficult to achieve without fragmented care and delayed decision making. In this narrative review we describe the development, structure, and function of a multi-disciplinary consult service at a children's hospital dedicated to helping coordinate management and provide continuity of care for patients with sepsis and multiple organ dysfunction-associated immune dysregulation. This information may be helpful to clinicians and healthcare leaders who are developing multi-disciplinary consult services for children with complex care needs, especially those with sepsis and MODS-associated immune dysregulation.


Assuntos
Insuficiência de Múltiplos Órgãos/terapia , Sepse/terapia , Criança , Humanos , Insuficiência de Múltiplos Órgãos/complicações , Insuficiência de Múltiplos Órgãos/imunologia , Sepse/complicações , Sepse/imunologia
12.
J Immunol ; 208(3): 618-632, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35022270

RESUMO

Sepsis is an acute life-threatening disorder associated with multiorgan dysfunction that remains the leading cause of death in intensive care units. As sepsis progresses, it causes prolonged immunosuppression, which results in sustained mortality, morbidity, and susceptibility to secondary infections. Using a mouse model of sepsis, we found that the long noncoding RNA HOTAIRM1 (HOXA transcript antisense RNA myeloid-specific 1) was highly expressed in mice during the late phase of sepsis. The upregulation of HOTAIRM1 was induced by Notch/Hes1 activation and, moreover, was critical for the formation of an immunosuppressive microenvironment. HOTAIRM1 induced T cell exhaustion by increasing the percentage of PD-1+ T cells and regulatory T cells, accompanied by elevated PD-L1. Blockade of either Notch/Hes1 signaling or HOTAIRM1 inhibited T cell exhaustion in late sepsis, having alleviated lung injury and improved survival of mice. Further mechanistic studies identified HOXA1 as a key transcription factor targeted by HOTAIRM1 to regulate PD-L1 expression in lung alveolar epithelial cells. These results implicated that the Notch/Hes1/HOTAIRM1/HOXA1/PD-L1 axis was critical for sepsis-induced immunosuppression and could be a potential target for sepsis therapies.


Assuntos
Tolerância Imunológica/imunologia , MicroRNAs/genética , Sepse/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Sepse/microbiologia , Fatores de Transcrição HES-1/metabolismo , Fatores de Transcrição/metabolismo
13.
BMC Anesthesiol ; 22(1): 16, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996374

RESUMO

BACKGROUND: Sepsis is a highly heterogeneous syndrome with stratified severity levels and immune states. Even in patients with similar clinical appearances, the underlying signal transduction pathways are significantly different. To identify the heterogeneities of sepsis from multiple angles, we aimed to establish a combined risk model including the molecular risk score for rapid mortality prediction, pathway risk score for the identification of biological pathway variations, and immunity risk score for guidance with immune-modulation therapy. METHODS: We systematically searched and screened the mRNA expression profiles of patients with sepsis in the Gene Expression Omnibus public database. The screened datasets were divided into a training cohort and a validation cohort. In the training cohort, authentic prognostic predictor characteristics (differentially expressed mRNAs, pathway activity variations and immune cells) were screened for model construction through bioinformatics analysis and univariate Cox regression, and a P value less than 0.05 of univariate Cox regression on 28-day mortality was set as the cut-off value. The combined risk model was finally established by the decision tree algorithm. In the validation cohort, the model performance was assessed and validated by C statistics and the area under the receiver operating characteristic curve (AUC). Additionally, the current models were further compared in clinical value with traditional indicators, including procalcitonin (PCT) and interleukin-8 (IL-8). RESULTS: Datasets from two sepsis cohort studies with a total of 585 consecutive sepsis patients admitted to two intensive care units were downloaded as the training cohort (n = 479) and external validation cohort (n = 106). In the training cohort, 15 molecules, 20 pathways and 4 immune cells were eventually enrolled in model construction. These prognostic factors mainly reflected hypoxia, cellular injury, metabolic disorders and immune dysregulation in sepsis patients. In the validation cohort, the AUCs of the molecular model, pathway model, immune model, and combined model were 0.81, 0.82, 0.62 and 0.873, respectively. The AUCs of the traditional biomarkers (PCT and IL-8) were 0.565 and 0.585, respectively. The survival analysis indicated that patients in the high-risk group identified by models in the current study had a poor prognosis (P < 0.05). The above results indicated that the models in this study are all superior to the traditional biomarkers for the predicting the prognosis of sepsis patients. Furthermore, the current study provides some therapeutic recommendations for patients with high risk scores identified by the three submodels. CONCLUSIONS: In summary, the present study provides opportunities for bedside tests that could quantitatively and rapidly measure heterogeneous prognosis, underlying biological pathway variations and immune dysfunction in sepsis patients. Further therapeutic recommendations for patients with high risk scores could improve the therapeutic system for sepsis.


Assuntos
Escores de Disfunção Orgânica , Sepse/imunologia , Sepse/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Sepse/diagnóstico , Adulto Jovem
14.
Biochem Pharmacol ; 197: 114909, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35021044

RESUMO

Vascular endothelial cells are major participants in and regulators of immune responses and inflammation. Vascular endotheliitis is regarded as a host immune-inflammatory response of the endothelium forming the inner surface of blood vessels in association with a direct consequence of infectious pathogen invasion. Vascular endotheliitis and consequent endothelial dysfunction can be a principle determinant of microvascular failure, which would favor impaired perfusion, tissue hypoxia, and subsequent organ failure. Emerging evidence suggests the role of vascular endotheliitis in the pathogenesis of coronavirus disease 2019 (COVID-19) and its related complications. Thus, once initiated, vascular endotheliitis and resultant cytokine storm cause systemic hyperinflammation and a thrombotic phenomenon in COVID-19, leading to acute respiratory distress syndrome and widespread organ damage. Vascular endotheliitis also appears to be a contributory factor to vasculopathy and coagulopathy in sepsis that is defined as life-threatening organ dysfunction due to a dysregulated response of the host to infection. Therefore, protecting endothelial cells and reversing vascular endotheliitis may be a leading therapeutic goal for these diseases associated with vascular endotheliitis. In this review, we outline the etiological and pathogenic importance of vascular endotheliitis in infection-related inflammatory diseases, including COVID-19, and possible mechanisms leading to vascular endotheliitis. We also discuss pharmacological agents which may be now considered as potential endotheliitis-based treatment modalities for those diseases.


Assuntos
COVID-19/patologia , Células Endoteliais/patologia , Endotélio Vascular/patologia , Doenças Vasculares/patologia , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/imunologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Sepse/tratamento farmacológico , Sepse/etiologia , Sepse/imunologia , Sepse/patologia , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia , Doenças Vasculares/imunologia
15.
Clin Immunol ; 235: 108915, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34995813

RESUMO

Cytokines interact closely with each other and play a crucial role in the progression of sepsis. We focused on the associations of a cytokine network with IL-35 in sepsis. First, the retrospective study included 42 patients with sepsis and 23 healthy controls. Blood samples were collected from patients on days 1, 2, 4. Levels of IL-35, IL-1ß, IL-4, IL-6, IL-10, IL-17A, TNF-α and IFN-γ were measured. They all increased to various extend on days 1, 2, 4, and strongly associated with markers of disease severity. Network analysis revealed a network formed by IL-35, with IL-6, IL-10, IL-17A, TNF-α and IFN-γ throughout the acute phase of sepsis(days 1, 2 and4). Then, the CLP-induced septic rats were used. The recombinant human IL-35(rIL-35) upregulated the levels of IL-10, but downregulated IL-4, IL-6, IL-17A, TNF-α and IFN-γ, while it had no significant effect on IL-1ß, and upregulated the percentages of CD4+CD25+Tregs, and iTR35, but downregulated Teff cells in the peripheral blood. The rIL-35 reduced inflammation damage and improved prognosis of the septic rats. IL-35 forms a network with other cytokines and plays a major role in the immunopathogenesis of sepsis.


Assuntos
Citocinas/metabolismo , Inflamação/metabolismo , Interleucinas/metabolismo , Interleucinas/farmacologia , Sepse/imunologia , Linfócitos T/fisiologia , Idoso , Animais , Citocinas/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Estudos Retrospectivos , Organismos Livres de Patógenos Específicos
16.
Pediatr Res ; 91(2): 359-367, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34711945

RESUMO

Sepsis, a dysregulated host response to infection, has been difficult to accurately define in children. Despite a higher incidence, especially in neonates, a non-specific clinical presentation alongside a lack of verified biomarkers has prevented a common understanding of this condition. Platelets, traditionally regarded as mediators of haemostasis and thrombosis, are increasingly associated with functions in the immune system with involvement across the spectrum of innate and adaptive immunity. The large number of circulating platelets (approx. 150,000 cells per microlitre) mean they outnumber traditional immune cells and are often the first to encounter a pathogen at a site of injury. There are also well-described physiological differences between platelets in children and adults. The purpose of this review is to place into context the platelet and its role in immunology and examine the evidence where available for its role as an immune cell in childhood sepsis. It will examine how the platelet interacts with both humoral and cellular components of the immune system and finally discuss the role the platelet proteome, releasate and extracellular vesicles may play in childhood sepsis. This review also examines how platelet transfusions may interfere with the complex relationships between immune cells in infection. IMPACT: Platelets are increasingly being recognised as important "first responders" to immune threats. Differences in adult and paediatric platelets may contribute to differing immune response to infections. Adult platelet transfusions may affect infant immune responses to inflammatory/infectious stimuli.


Assuntos
Plaquetas/metabolismo , Mediadores da Inflamação/metabolismo , Sepse/sangue , Plaquetas/imunologia , Proteínas Sanguíneas/metabolismo , Criança , Humanos , Imunidade Celular , Imunidade Humoral , Imunidade Inata , Recém-Nascido , Proteoma , Sepse/imunologia , Transdução de Sinais
17.
Int Immunopharmacol ; 102: 108385, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34862128

RESUMO

BACKGROUND: A disintegrin and metalloproteinase 17 (ADAM17) is a proteolytic cleaving protein with a crucial function in the inflammatory responses, especially sepsis. But the clear role of ADAM17 in sepsis and the underlying mechanism remained unknown. In this study, we aim to determine the clinical association of ADAM17 -172A > G (rs12692386) promoter polymorphism with sepsis and to further explore the effect and mechanism of the early growth response 1 (EGR1)/ADAM17 pathway in inflammatory process during sepsis. METHODS: A total of 477 sepsis patients and 750 controls were enrolled in this study to determine the association of ADAM17 -172A > G polymorphism with sepsis. The transcription factor binding to the promoter region of ADAM17 gene was predicted by bioinformatics analysis and verified by Chromatin Immunoprecipitation (ChIP) and luciferase assays. Quantitative real-time PCR and Western blot were performed to detect EGR1 and ADAM17 expression. Cytokine production was detected by enzyme-linked immunosorbent assay. The effect of EGR1/ADAM17 pathway on sepsis-induced inflammatory responses was evaluated in EGR1-silenced cells and endotoxemia mouse model. RESULTS: The frequencies of non-survivors among the sepsis patients with the -172AG/GG genotypes and G allele were distinctly higher than those among patients with the AA genotype (53.9% vs. 39.7%, OR = 1.779, 95% CI = 1.119-2.829, P = 0.0142) and A allele (30.9% vs. 22.2%, OR = 1.570, 95% CI = 1.095-2.251, P = 0.0136). The Kaplan-Meier survival analysis indicated that the 28-day survival in septic patients with -172AG/GG genotypes of this functional ADAM17 promoter polymorphism was much worse than in the AA genotype carriers (log-rank = 5.358, P = 0.021). The results of in vitro lipopolysaccharide-stimulated and luciferase assays indicated that the -172 A-to-G variation could functionally upregulate promoter activity and transcription of ADAM17 gene via enhancing the binding affinity of its promoter region with the EGR1. The ChIP assay identified the direct interaction. Further studies demonstrated that inhibition of EGR1 significantly decreased ADAM17 expression and the pro-inflammatory cytokine secretion in vitro, and improved the survival and inflammatory response of sepsis mouse model. CONCLUSIONS: These results provided evidence that the ADAM17 -172A > G polymorphism functionally promoted ADAM17 expression and enhanced sepsis-induced inflammatory responses via the EGR1/ADAM17 pathway, which ultimately conferred susceptibility to sepsis mortality and poor prognosis.


Assuntos
Proteína ADAM17/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Sepse/genética , Sepse/mortalidade , Proteína ADAM17/imunologia , Adulto , Idoso , Animais , Citocinas/sangue , Citocinas/imunologia , Proteína 1 de Resposta de Crescimento Precoce/imunologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Regiões Promotoras Genéticas , Células RAW 264.7 , Sepse/imunologia
18.
Am J Respir Crit Care Med ; 205(1): 46-59, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34731593

RESUMO

Rationale: Sepsis is the leading cause of death in adult ICUs. At present, sepsis diagnosis relies on nonspecific clinical features. It could transform clinical care to have immune-cell biomarkers that could predict sepsis diagnosis and guide treatment. For decades, neutrophil phenotypes have been studied in sepsis, but a diagnostic cell subset has yet to be identified. Objectives: To identify an early, specific immune signature of sepsis severity that does not overlap with other inflammatory biomarkers and that distinguishes patients with sepsis from those with noninfectious inflammatory syndrome. Methods: Mass cytometry combined with computational high-dimensional data analysis was used to measure 42 markers on whole-blood immune cells from patients with sepsis and control subjects and to automatically and comprehensively characterize circulating immune cells, which enables identification of novel, disease-specific cellular signatures. Measurements and Main Results: Unsupervised analysis of high-dimensional mass cytometry data characterized previously unappreciated heterogeneity within the CD64+ immature neutrophils and revealed two new subsets distinguished by CD123 and PD-L1 (programmed death ligand 1) expression. These immature neutrophils exhibited diminished activation and phagocytosis functions. The proportion of CD123-expressing neutrophils correlated with clinical severity. Conclusions: This study showed that these two new neutrophil subsets were specific to sepsis and detectable through routine flow cytometry by using seven markers. The demonstration here that a simple blood test distinguishes sepsis from other inflammatory conditions represents a key biological milestone that can be immediately translated into improvements in patient care.


Assuntos
Antígeno B7-H1/sangue , Subunidade alfa de Receptor de Interleucina-3/sangue , Neutrófilos/metabolismo , Sepse/diagnóstico , Biomarcadores/sangue , Estudos de Casos e Controles , Regras de Decisão Clínica , Diagnóstico Diferencial , Citometria de Fluxo , Humanos , Modelos Lineares , Estudos Longitudinais , Receptores de IgG/sangue , Sensibilidade e Especificidade , Sepse/sangue , Sepse/imunologia , Índice de Gravidade de Doença
19.
Biomed Pharmacother ; 146: 112490, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34891115

RESUMO

Sepsis remains one of the main causes of death in intensive care unit (ICU) worldwide, despite all technological and scientific advances. Microvesicles (MV) have become promising biomarkers for quick and accurate monitoring of several illnesses. The aim of this pilot study was to characterize and evaluate the performance of MV as biomarker of clinical outcome in septic and trauma patients. For this purpose, 39 subjects, both genders, aging from 18 to 85 years were included in three groups referred as Sepsis, Trauma and Healthy Control. Kinetic analysis of MV was carried out at four consecutive time points: admission (baseline)/T1, 24 h/T2, 72 h/T3 and outcome/T4 of discharge or death. At admission, an overall increase in total MV (Annexin V+) was observed in Sepsis.MV CD14+ (monocytes) was a putative biomarker to identify trauma patients, while MV CD3+ (T-cells) and CD41+ (platelets) were qualified to discriminated Trauma from Sepsis. Sepsis (Death) presented an increase in MV Annexin V+, CD45+, CD16+, CD14+, and CD41+ in comparison to Sepsis (Discharge). Moreover, Trauma (Death) presented an increase of MV CD3+ and CD235+ as compared to Trauma (Discharge). Analysing the ROC curve of specific MV evaluated according to performance, an accuracy of 100% was found to segregate the outcome in sepsis, and 95% in trauma. Our findings suggest that MV might be useful as a potential role in discriminating outcome in patients with sepsis/septic shock and trauma with high accuracy. However, further studies with a larger number of participants will be necessary to validate our findings.


Assuntos
Biomarcadores , Micropartículas Derivadas de Células , Sepse/sangue , Ferimentos e Lesões/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Estudos Retrospectivos , Sepse/imunologia , Ferimentos e Lesões/imunologia , Adulto Jovem
20.
Shock ; 57(2): 205-211, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34812186

RESUMO

BACKGROUND: Innate immune dysregulation may contribute to age-related differences in outcomes among critically ill adults. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is an important innate immune marker with prognostic value in sepsis, but age-related differences have not been studied. METHODS: This was a prospective cohort from a large tertiary care hospital enrolling adults from both medical and trauma-surgical intensive care units (ICUs). Plasma sTREM-1 was measured in participants within 24 h of ICU admission. We analyzed associations between age (≤50 and >50 years) and sTREM-1 using linear regression. We then examined associations between sTREM-1 and both 28-day mortality and persistent organ dysfunction (defined as need for dialysis, vasopressors, or invasive mechanical ventilation) 7 days following admission using relative risk regression. RESULTS: Of 231 critically ill adults, older patients (n = 122) had higher prevalence of chronic disease and sepsis on enrollment than younger patients, but acute illness severity was similar. Age over 50 was associated with 27% higher sTREM-1 concentrations (95% CI 6%-53%), adjusted for sex and Charlson comorbidity index (CCI). Two-fold higher sTREM-1 was associated with 2.42-fold higher risk for mortality (95% CI 1.57, 3.73) and 1.86-fold higher risk for persistent organ dysfunction (95% CI 1.45, 2.39), adjusted for sex, CCI, and age. CONCLUSIONS: sTREM-1 was elevated among critically ill older adults, and strongly associated with both death and persistent organ dysfunction. Immune responses associated with sTREM-1 may contribute to age-related differences in ICU outcomes, warranting further study as a potential therapeutic target in older adults.


Assuntos
Sepse/sangue , Sepse/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptor Gatilho 1 Expresso em Células Mieloides/fisiologia
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