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1.
Medicine (Baltimore) ; 99(33): e21550, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872002

RESUMO

To study the relationship between neutrophil to lymphocyte ratio (NLR) and exercise tolerance of patients with chronic obstructive pulmonary disease (COPD).235 patients with COPD were selected as the study subjects. Complete blood count, C reactive protein (CRP), pulmonary function tests, the 6-minute walk distance (6MWD), Modified Medical Respiratory Council, the COPD assessment test, and clinical COPD questionnaire were tested. Heart rate, oxygen saturation, and Borg scale were tested before or after 6MWD test.By the median of NLR, the subjects were divided into 2 groups, NLR ≥4.5 group and NLR <4.5 group. The white blood cell count (WBC), CRP and deoxygenation saturation in the NLR ≥4.5 group were higher than those in the NLR <4.5 group, while the age, body mass index (BMI), 6MWD, and heart rate variation were lower than those in the NLR <4.5 group. CRP, WBC, and deoxygenation saturation had positive effects on NLR, BMI, 6MWT, and heart rate variation had negative effects on NLR. The Pearson correlation analysis showed NLR was positively correlated with WBC, CRP, BMI index, 6MWT, and deoxygenation saturation, while it was negatively correlated with BMI and heart rate variation.NLR might associate with exercise tolerance and cardiorespiratory reserve of COPD patients, and could be used as an indicator of muscle function in COPD patients.


Assuntos
Tolerância ao Exercício , Linfócitos/metabolismo , Neutrófilos/metabolismo , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Feminino , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Inquéritos e Questionários , Teste de Caminhada
2.
Mol Cell ; 80(1): 87-101.e5, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931746

RESUMO

Studies in three mouse models of breast cancer identified profound discrepancies between cell-autonomous and systemic Akt1- or Akt2-inducible deletion on breast cancer tumorigenesis and metastasis. Although systemic Akt1 deletion inhibits metastasis, cell-autonomous Akt1 deletion does not. Single-cell mRNA sequencing revealed that systemic Akt1 deletion maintains the pro-metastatic cluster within primary tumors but ablates pro-metastatic neutrophils. Systemic Akt1 deletion inhibits metastasis by impairing survival and mobilization of tumor-associated neutrophils. Importantly, either systemic or neutrophil-specific Akt1 deletion is sufficient to inhibit metastasis of Akt-proficient tumors. Thus, Akt1-specific inhibition could be therapeutic for breast cancer metastasis regardless of primary tumor origin. Systemic Akt2 deletion does not inhibit and exacerbates mammary tumorigenesis and metastasis, but cell-autonomous Akt2 deletion prevents breast cancer tumorigenesis by ErbB2. Elevated circulating insulin level induced by Akt2 systemic deletion hyperactivates tumor Akt, exacerbating ErbB2-mediated tumorigenesis, curbed by pharmacological reduction of the elevated insulin.


Assuntos
Neoplasias Mamárias Animais/enzimologia , Neoplasias Mamárias Animais/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Carcinogênese/patologia , Feminino , Deleção de Genes , Humanos , Insulina/metabolismo , Isoenzimas/metabolismo , Metástase Neoplásica , Neutrófilos/metabolismo , Receptor ErbB-2/metabolismo
3.
Nat Commun ; 11(1): 4078, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843630

RESUMO

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage.


Assuntos
Substitutos Sanguíneos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Encéfalo/metabolismo , Animais , Encéfalo/patologia , Infarto Encefálico/tratamento farmacológico , Isquemia Encefálica/patologia , Morte Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia
4.
PLoS Pathog ; 16(8): e1008230, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797076

RESUMO

Neutrophil extracellular traps (NETs) evolved as a unique effector mechanism contributing to resistance against infection that can also promote tissue damage in inflammatory conditions. Malaria infection can trigger NET release, but the mechanisms and consequences of NET formation in this context remain poorly characterized. Here we show that patients suffering from severe malaria had increased amounts of circulating DNA and increased neutrophil elastase (NE) levels in plasma. We used cultured erythrocytes and isolated human neutrophils to show that Plasmodium-infected red blood cells release macrophage migration inhibitory factor (MIF), which in turn caused NET formation by neutrophils in a mechanism dependent on the C-X-C chemokine receptor type 4 (CXCR4). NET production was dependent on histone citrullination by peptidyl arginine deiminase-4 (PAD4) and independent of reactive oxygen species (ROS), myeloperoxidase (MPO) or NE. In vitro, NETs functioned to restrain parasite dissemination in a mechanism dependent on MPO and NE activities. Finally, C57/B6 mice infected with P. berghei ANKA, a well-established model of cerebral malaria, presented high amounts of circulating DNA, while treatment with DNAse increased parasitemia and accelerated mortality, indicating a role for NETs in resistance against Plasmodium infection.


Assuntos
Eritrócitos/imunologia , Armadilhas Extracelulares/imunologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Malária/imunologia , Neutrófilos/imunologia , Plasmodium/imunologia , Receptores CXCR4/metabolismo , Animais , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/parasitologia , Humanos , Malária/metabolismo , Malária/parasitologia , Malária/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Neutrófilos/parasitologia , Parasitemia/imunologia , Parasitemia/metabolismo , Parasitemia/parasitologia , Parasitemia/patologia
5.
PLoS Pathog ; 16(8): e1008781, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32810179

RESUMO

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that has a heterogeneous population composed of a pool of strains with distinct characteristics, including variable levels of virulence. In previous work, transcriptome analyses of parasite genes after infection of human foreskin fibroblasts (HFF) with virulent (CL Brener) and non-virulent (CL-14) clones derived from the CL strain, revealed a reduced expression of genes encoding parasite surface proteins in CL-14 compared to CL Brener during the final steps of the intracellular differentiation from amastigotes to trypomastigotes. Here we analyzed changes in the expression of host genes during in vitro infection of HFF cells with the CL Brener and CL-14 strains by analyzing total RNA extracted from cells at 60 and 96 hours post-infection (hpi) with each strain, as well as from uninfected cells. Similar transcriptome profiles were observed at 60 hpi with both strains compared to uninfected samples. However, at 96 hpi, significant differences in the number and expression levels of several genes, particularly those involved with immune response and cytoskeleton organization, were observed. Further analyses confirmed the difference in the chemokine/cytokine signaling involved with the recruitment and activation of immune cells such as neutrophils upon T. cruzi infection. These findings suggest that infection with the virulent CL Brener strain induces a more robust inflammatory response when compared with the non-virulent CL-14 strain. Importantly, the RNA-Seq data also exposed an unexplored role of fibroblasts as sentinel cells that may act by recruiting neutrophils to the initial site of infection. This role for fibroblasts in the regulation of the inflammatory response during infection by T. cruzi was corroborated by measurements of levels of different chemokines/cytokines during in vitro infection and in plasma from Chagas disease patients as well as by neutrophil activation and migration assays.


Assuntos
Doença de Chagas/metabolismo , Fibroblastos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Ativação de Neutrófilo , Neutrófilos , Trypanosoma cruzi/metabolismo , Doença de Chagas/genética , Doença de Chagas/patologia , Fibroblastos/metabolismo , Fibroblastos/parasitologia , Fibroblastos/patologia , Humanos , Neutrófilos/metabolismo , Neutrófilos/parasitologia , Neutrófilos/patologia , Trypanosoma cruzi/genética , Trypanosoma cruzi/patogenicidade , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
6.
PLoS One ; 15(8): e0237034, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745117

RESUMO

Production of IFN-γ is a key innate immune mechanism that limits replication of intracellular bacteria such as Francisella tularensis (Ft) until adaptive immune responses develop. Previously, we demonstrated that the host cell types responsible for IFN-γ production in response to murine Francisella infection include not only natural killer (NK) and T cells, but also a variety of myeloid cells. However, production of IFN-γ by mouse dendritic cells (DC) is controversial. Here, we directly demonstrated substantial production of IFN-γ by DC, as well as hybrid NK-DC, from LVS-infected wild type C57BL/6 or Rag1 knockout mice. We demonstrated that the numbers of conventional DC producing IFN-γ increased progressively over the course of 8 days of LVS infection. In contrast, the numbers of conventional NK cells producing IFN-γ, which represented about 40% of non-B/T IFN-γ-producing cells, peaked at day 4 after LVS infection and declined thereafter. This pattern was similar to that of hybrid NK-DC. To further confirm IFN-γ production by infected cells, DC and neutrophils were sorted from naïve and LVS-infected mice and analyzed for gene expression. Quantification of LVS by PCR revealed the presence of Ft DNA not only in macrophages, but also in highly purified, IFN-γ producing DC and neutrophils. Finally, production of IFN-γ by infected DC was confirmed by immunohistochemistry and confocal microscopy. Notably, IFN-γ production patterns similar to those in wild type mice were observed in cells derived from LVS-infected TLR2, TLR4, and TLR2xTLR9 knockout (KO) mice, but not from MyD88 KO mice. Taken together, these studies demonstrate the pivotal roles of DC and MyD88 in IFN-γ production and in initiating innate immune responses to this intracellular bacterium.


Assuntos
Interferon gama/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Receptores Toll-Like/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Francisella tularensis/imunologia , Imunidade Inata/imunologia , Células Matadoras Naturais/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Neutrófilos/metabolismo , Baço/metabolismo , Linfócitos T/imunologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/imunologia , Tularemia/microbiologia
7.
EBioMedicine ; 58: 102925, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32745993

RESUMO

BACKGROUND: Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. METHODS: Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. PATIENT FINDINGS: Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. INTERPRETATION: These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. FUNDING: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung.


Assuntos
Infecções por Coronavirus/patologia , Armadilhas Extracelulares/metabolismo , Microvasos/patologia , Neutrófilos/metabolismo , Pneumonia Viral/patologia , Trombose/metabolismo , Células Cultivadas , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Microvasos/metabolismo , Neutrófilos/patologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Trombose/etiologia , Trombose/patologia
8.
Circulation ; 142(12): 1176-1189, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32755393

RESUMO

BACKGROUND: Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19. METHODS: A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction-confirmed COVID-19 and n=24 non-COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well. RESULTS: We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non-COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability. CONCLUSIONS: Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.


Assuntos
Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Insuficiência Respiratória/etiologia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , Plaquetas/citologia , Plaquetas/metabolismo , Plaquetas/patologia , Estudos de Casos e Controles , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/metabolismo , Humanos , Rim/patologia , Pulmão/patologia , Neutrófilos/citologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Pandemias , Fenótipo , Ativação Plaquetária , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Insuficiência Respiratória/diagnóstico , Índice de Gravidade de Doença , Trombose/complicações , Trombose/diagnóstico
9.
PLoS One ; 15(8): e0237746, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810144

RESUMO

In recent years, several studies suggested that the ability of hyperbaric oxygen therapy (HBOT) to promote healing in patients with diabetic ulcers and chronic wounds is due to the reduction of inflammatory cytokines and to a significant decrease in neutrophils recruitment to the damaged area. α4 and ß2 integrins are receptors mediating the neutrophil adhesion to the endothelium and the comprehension of the effects of hyperbaric oxygenation on their expression and functions in neutrophils could be of great importance for the design of novel therapeutic protocols focused on anti-inflammatory agents. In this study, the α4 and ß2 integrins' expression and functions have been evaluated in human primary neutrophils obtained from patients with chronic non-healing wounds and undergoing a prolonged HBOT (150 kPa per 90 minutes). The effect of a peptidomimetic α4ß1 integrin antagonist has been also analyzed under these conditions. A statistically significant decrease (68%) in ß2 integrin expression on neutrophils was observed during the treatment with HBO and maintained one month after the last treatment, while α4 integrin levels remained unchanged. However, cell adhesion function of both neutrophilic integrins α4ß1 and ß2 was significantly reduced 70 and 67%, respectively), but α4ß1 integrin was still sensitive to antagonist inhibition in the presence of fibronectin, suggesting that a combined therapy between HBOT and integrin antagonists could have greater antinflammatory efficacy.


Assuntos
Oxigenação Hiperbárica , Integrina alfa4beta1/antagonistas & inibidores , Neutrófilos/imunologia , Peptidomiméticos/uso terapêutico , Úlcera Cutânea/terapia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD18/análise , Antígenos CD18/metabolismo , Adesão Celular/imunologia , Doença Crônica/terapia , Terapia Combinada/métodos , Feminino , Seguimentos , Humanos , Integrina alfa4beta1/análise , Integrina alfa4beta1/metabolismo , Masculino , Pessoa de Meia-Idade , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Peptidomiméticos/farmacologia , Cultura Primária de Células , Úlcera Cutânea/sangue , Úlcera Cutânea/imunologia , Úlcera Cutânea/patologia , Resultado do Tratamento , Cicatrização/efeitos dos fármacos , Cicatrização/imunologia
10.
Am J Hum Genet ; 107(3): 527-538, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758447

RESUMO

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.


Assuntos
Inflamação/genética , Interleucinas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Adulto , Animais , Citocinas/genética , Armadilhas Extracelulares/genética , Feminino , Humanos , Inflamação/patologia , Interleucina-1/genética , Interleucinas/metabolismo , Masculino , Camundongos , Mutação/genética , Neutrófilos/metabolismo , Psoríase/patologia , Doenças Raras/enzimologia , Doenças Raras/genética , Doenças Raras/patologia , Pele/enzimologia , Pele/patologia , Dermatopatias/patologia
11.
Ann Surg ; 272(2): 277-283, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32675540

RESUMO

: Since their discovery, neutrophil extracellular traps (NETs) have been implicated in a broad array of functions, both beneficial and detrimental to the host. Indeed, NETs have roles in infection, sepsis, wound healing, thrombotic disease, and cancer propagation, all of which are directly implicated in the care of surgical patients. Here we provide an updated review on the role of NETs in the perioperative period with specific emphasis on perioperative infections, wound healing, vascular complications, cancer propagation, as well as discussing ongoing, and future therapeutic targets. Surgeons will benefit from understanding the latest discoveries in neutrophil biology and how these novel functions affect the care of surgical patients. Furthermore, novel anti-NET therapies are being developed which may have profound effects on the care of surgical patients.


Assuntos
Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Procedimentos Cirúrgicos Operatórios/métodos , Infecção da Ferida Cirúrgica/metabolismo , Cicatrização/fisiologia , Animais , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Camundongos , Assistência Perioperatória/métodos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/metabolismo , Medição de Risco , Sensibilidade e Especificidade , Infecção da Ferida Cirúrgica/diagnóstico
12.
Medicine (Baltimore) ; 99(27): e20888, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629679

RESUMO

This study aims to identify prognostic value of neutrophil-to-lymphocyte ratio (NLR) in early miscarriages. A total of 260 pregnant women with vaginal spotting were recruited from the Department of Obstetrics and Gynecology of the Kyung Hee Medical Center from January 1, 2011, and December 31, 2018. Venous samples were obtained from the women for measurements of platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and NLR. All the patients were in < 14 gestational weeks of their pregnancy. Eighty-four patients were excluded because of incomplete data, loss of follow-up, and serious medical diseases. We enrolled 176 women for analysis and divided them into two groups. Group 1 included 104 women with threatened abortion; and group 2, 72 women with missed abortion. A significant difference in NLR was found between the groups (p = 0.001; P < .01). The multivariate analysis also revealed that NLR was the only prognostic factor of early miscarriage (odd ratio [OR], 0.732; 95% confidence interval [CI], 0.612-0.881, P = .001). The area under the Receiver-operating characteristic of NLR for distinguishing between the missed and threatened abortion groups was 0.792, and the best cutoff value was 5.72 (P < .05).


Assuntos
Aborto Espontâneo/sangue , Linfócitos/metabolismo , Neutrófilos/metabolismo , Adulto , Plaquetas/metabolismo , Feminino , Humanos , Monócitos/metabolismo , Gravidez , Prognóstico , Estudos Retrospectivos
14.
BMC Infect Dis ; 20(1): 534, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698769

RESUMO

BACKGROUND: To analyze the clinical characteristics of Mycoplasma pneumoniae pneumonia with hypoxia in children, and identify the associated risk factors of hypoxia in MPP. METHODS: A retrospective case-control study was performed on 345 children with Mycoplasma pneumoniae pneumonia (MPP) admitted to our hospital wards from January 2017 to June 2019. They were divided into three groups, namely MPP with hypoxia, refractory Mycoplasma pneumoniae pneumonia (RMPP), and general Mycoplasma pneumoniae pneumonia (GMPP). The clinical features, laboratory findings, imaging, and management were collected and compared in the three groups. RESULTS: The MPP with hypoxia patients (n = 69) had longer disease duration, a higher extra-pulmonary complications rate, and more severe radiological abnormalities (P < 0.05). They also needed more complicated treatments (P < 0.05). Meanwhile, the levels of white blood cell count (WBC), C-reactive protein (CRP), lactic dehydrogenase (LDH), interleukin (IL)-6, ferritin, D-dimer, fibrinogen (FG), alanine aminotransferase (ALT) and the percentage of neutrophils in the MPP with hypoxia group were significantly higher than those in the RMPP group and the GMPP group (P < 0.05). In ROC curve analysis, the percentage of neutrophils, WBC, CRP, LDH, IL-6, ferritin, D-dimer, and ALT were contributed to identify the MPP with hypoxia patients. Multivariate logistic regression analysis revealed that ferritin> 174.15 ng/mL, IL-6 > 25.475 pg/ml, and pleural effusion were significantly associated with the incidence of hypoxia in MPP (P < 0.01). CONCLUSION: MPP with hypoxia patients presented more serious clinical manifestations. Ferritin> 174.15 ng/mL, IL-6 > 25.475 pg/ml and pleural effusion were related risk factors for hypoxia in MPP.


Assuntos
Hipóxia/sangue , Hipóxia/complicações , Mycoplasma pneumoniae , Pneumonia por Mycoplasma/sangue , Pneumonia por Mycoplasma/complicações , Proteína C-Reativa/análise , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Ferritinas/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Interleucina-6/sangue , Contagem de Leucócitos , Masculino , Neutrófilos/metabolismo , Derrame Pleural , Pneumonia por Mycoplasma/microbiologia , Curva ROC , Estudos Retrospectivos , Fatores de Risco
16.
Arterioscler Thromb Vasc Biol ; 40(9): 2279-2292, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32611241

RESUMO

OBJECTIVE: Recruitment of neutrophils and formation of neutrophil extracellular traps (NETs) contribute to lethality in acute mesenteric infarction. To study the impact of the gut microbiota in acute mesenteric infarction, we used gnotobiotic mouse models to investigate whether gut commensals prime the reactivity of neutrophils towards formation of neutrophil extracellular traps (NETosis). Approach and Results: We applied a mesenteric ischemia-reperfusion (I/R) injury model to germ-free (GF) and colonized C57BL/6J mice. By intravital imaging, we quantified leukocyte adherence and NET formation in I/R-injured mesenteric venules. Colonization with gut microbiota or monocolonization with Escherichia coli augmented the adhesion of leukocytes, which was dependent on the TLR4 (Toll-like receptor-4)/TRIF (TIR-domain-containing adapter-inducing interferon-ß) pathway. Although neutrophil accumulation was decreased in I/R-injured venules of GF mice, NETosis following I/R injury was significantly enhanced compared with conventionally raised mice or mice colonized with the minimal microbial consortium altered Schaedler flora. Also ex vivo, neutrophils from GF and antibiotic-treated mice showed increased LPS (lipopolysaccharide)-induced NETosis. Enhanced TLR4 signaling in GF neutrophils was due to elevated TLR4 expression and augmented IRF3 (interferon regulatory factor-3) phosphorylation. Likewise, neutrophils from antibiotic-treated conventionally raised mice had increased NET formation before and after ischemia. Increased NETosis in I/R injury was abolished in conventionally raised mice deficient in the TLR adaptor TRIF. In support of the desensitizing influence of enteric LPS, treatment of GF mice with LPS via drinking water diminished LPS-induced NETosis in vitro and in the mesenteric I/R injury model. CONCLUSIONS: Collectively, our results identified that the gut microbiota suppresses NETing neutrophil hyperreactivity in mesenteric I/R injury, while ensuring immunovigilance by enhancing neutrophil recruitment.


Assuntos
Armadilhas Extracelulares/metabolismo , Microbioma Gastrointestinal , Isquemia Mesentérica/metabolismo , Mesentério/irrigação sanguínea , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Traumatismo por Reperfusão/metabolismo , Vênulas/metabolismo , Animais , Bacillus subtilis/patogenicidade , Adesão Celular , Células Cultivadas , Modelos Animais de Doenças , Escherichia coli/patogenicidade , Armadilhas Extracelulares/microbiologia , Feminino , Vida Livre de Germes , Interações Hospedeiro-Patógeno , Migração e Rolagem de Leucócitos , Leucócitos/metabolismo , Leucócitos/microbiologia , Masculino , Isquemia Mesentérica/microbiologia , Isquemia Mesentérica/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão/microbiologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Vênulas/microbiologia , Vênulas/patologia
17.
Arterioscler Thromb Vasc Biol ; 40(9): 2265-2278, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673525

RESUMO

OBJECTIVE: Macrophages are immune cells, capable to remodel the extracellular matrix, which can harbor extracellular DNA incorporated into neutrophil extracellular traps (NETs). To study the breakdown of NETs we studied the capability of macrophage subsets to degrade these structures in vitro and in vivo in a murine thrombosis model. Furthermore, we analyzed human abdominal aortic aneurysm samples in support of our in vitro and in vivo results. Approach and Results: Macrophages were seeded onto blood clots or isolated NETs and polarized. All macrophages were capable to degrade NETs. For initial breakdown, macrophages relied on extracellular deoxyribonucleases. Proinflammatory polarization enhanced NET degradation. The boost in degradation was because of increased macropinocytosis, as inhibition by imipramine diminished their NET breakdown. Inhibition of macropinocytosis in a murine thrombosis model led to increased NET burden and reduced thrombus resolution in vivo. When analyzing abdominal aortic aneurysm samples, macrophage density furthermore corresponded negatively with the amount of local NETs in the intraluminal thrombi as well as in the vessel wall, as increased macrophage density was associated with a reduction in NET burden. CONCLUSIONS: We provide evidence that macrophages degrade NETs by extracellular predigestion and subsequent uptake. Furthermore, we show that proinflammatory macrophages increase NET degradation through enhanced macropinocytosis, priming them for NET engulfment. Based on our findings, that inhibition of macropinocytosis in mice corresponded to increased NET amounts in thrombi and that local macrophage density in human abdominal aortic aneurysm is negatively associated with surrounding NETs, we hypothesize, that macrophages are able to degrade NETs in vivo.


Assuntos
Endodesoxirribonucleases/metabolismo , Armadilhas Extracelulares/metabolismo , Ativação de Macrófagos , Macrófagos/enzimologia , Neutrófilos/metabolismo , Pinocitose , Animais , Aneurisma da Aorta Abdominal/metabolismo , Células Cultivadas , Desoxirribonuclease I/metabolismo , Desoxirribonucleases/metabolismo , Modelos Animais de Doenças , Exodesoxirribonucleases/metabolismo , Feminino , Humanos , Imipramina/farmacologia , Interferon gama/farmacologia , Interleucina-13/farmacologia , Interleucina-4/farmacologia , Cinética , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Fagocitose , Fenótipo , Fosfoproteínas/metabolismo , Pinocitose/efeitos dos fármacos , Veia Cava Inferior/metabolismo , Trombose Venosa/metabolismo
18.
Mol Immunol ; 125: 51-62, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32645550

RESUMO

Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of TBK1 and interferon pathway and the expression of SOCS3 is closely correlated with symptoms of influenza patients. However, whether deletion of Socs3 in the lung epithelial cells would affect influenza lung replication and inflammation in vivo is unknown. To test this, we approached the influenza infected Socs3f/f and SpcCre.Socs3f/f mice. We first found that knockdown of Socs3 in lung epithelial cells reduced influenza replication. However, in the in vivo study, there was a reduction of SOCS3 in the influenza-infected neutrophils coincided with an increase of SOCS3 in the CD45-CD326+ lung epithelial cells in PR8-infected SpcCre.Socs3f/f mice. SOCS3-deficient neutrophils expressed higher levels of IL-17 that enhanced chemokine expression in the lung epithelial cells. Lung SOCS3-dificient epithelial cells increased expression of GM-CSF and PGE2 which promoted SpcCre.Socs3f/f neutrophils to yield SOCS3. SpcCre.Socs3f/f lung epithelial cells internalized SOCS3 released from GM-CSF + PGE2-stimulated SpcCre.Socs3f/f neutrophils, which could boost influenza replication in the lung epithelial cells. Thus, in the in vivo study, deletion of SOCS3 from lung epithelium could be nullified by the uptake from SOCS3 from infiltrated neutrophils. In addition, deletion of Socs3 from myeloid cells reduced lung influenza infection, but increased lung inflammation. Taken together, deletion of SOCS3 could suppress influenza replication, but intracellular SOCS3 communication between neutrophils and lung epithelial cells confounds this effect.


Assuntos
Células Epiteliais Alveolares/imunologia , Neutrófilos/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções Respiratórias/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/imunologia , Células Epiteliais Alveolares/metabolismo , Animais , Vírus da Influenza A , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Infecções Respiratórias/metabolismo , Infecções Respiratórias/virologia , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
19.
Nat Commun ; 11(1): 3547, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669546

RESUMO

Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81-/- mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection.


Assuntos
Células da Medula Óssea/imunologia , Ácido Láctico/metabolismo , Neutrófilos/imunologia , Receptores Acoplados a Proteínas-G/metabolismo , Infecções por Salmonella/imunologia , Animais , Medula Óssea/irrigação sanguínea , Células da Medula Óssea/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Feminino , Humanos , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Knockout , Neutrófilos/metabolismo , Receptores Acoplados a Proteínas-G/genética , Infecções por Salmonella/microbiologia , Salmonella typhimurium/imunologia , Transdução de Sinais/imunologia
20.
Cells ; 9(6)2020 06 02.
Artigo em Inglês | MEDLINE | ID: covidwho-459483

RESUMO

The COVID-19 pandemic is progressing worldwide with an alarming death toll. There is an urgent need for novel therapeutic strategies to combat potentially fatal complications. Distinctive clinical features of severe COVID-19 include acute respiratory distress syndrome, neutrophilia, and cytokine storm, along with severe inflammatory response syndrome or sepsis. Here, we propose the putative role of enhanced neutrophil infiltration and the release of neutrophil extracellular traps, complement activation and vascular thrombosis during necroinflammation in COVID-19. Furthermore, we discuss how neutrophilic inflammation contributes to the higher mortality of COVID-19 in patients with underlying co-morbidities such as diabetes and cardiovascular diseases. This perspective highlights neutrophils as a putative target for the immunopathologic complications of severely ill COVID-19 patients. Development of the novel therapeutic strategies targeting neutrophils may help reduce the overall disease fatality rate of COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Animais , Betacoronavirus/fisiologia , Doenças Cardiovasculares/complicações , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Complicações do Diabetes/virologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Necrose/imunologia , Necrose/patologia , Neutrófilos/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico
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