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1.
Front Immunol ; 12: 626235, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33584733

RESUMO

Objectives: The coordinated immune response of the host is the key of the successful combat of the body against SARS-CoV-2 infection and is decisive for the development and progression of COVID-19. In this study, we aimed to investigate whether the immunological phenotype of patients are associated with duration of illness in patients with severe COVID-19. Method: In this single-center study, 69 patients with severe or critical COVID-19 were recruited retrospectively. Immunological parameters including counts of white blood cells, neutrophils, lymphocytes, the neutrophil-to-lymphocyte ratio, and levels of circulating cytokines and cytokine receptors were screened for their association with disease severity, survival and duration of illness of COVID-19. Results: Our data confirmed previous results that neutrophil-to-lymphocyte ratio and circulating levels of IL-6 represent prominent biomarker for the prediction of disease severity and survival of COVID-19. However, this study shows for the first time that duration of illness in patients with severe COVID-19 is positively associated with serum levels of IL-8 (P=0.004) and soluble IL-2Rα (P=0.025). Conclusion: The significant association of duration of illness with circulating levels of IL-8 and soluble IL-2Rα in patients with severe COVID-19 implicates that neutrophils and T cells are involved in the evolution of COVID-19.


Assuntos
/sangue , Interleucina-8/sangue , Receptores de Interleucina-2/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Interleucina-8/imunologia , Contagem de Leucócitos , Contagem de Linfócitos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Receptores de Interleucina-2/imunologia , Estudos Retrospectivos , Índice de Gravidade de Doença
2.
Science ; 371(6529): 595-602, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33542131

RESUMO

Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Transplante de Microbiota Fecal , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/terapia , Linfócitos T CD8-Positivos/imunologia , Microbioma Gastrointestinal , Humanos , Interleucina-8/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Células Mieloides/imunologia , Microambiente Tumoral/imunologia
3.
Eur Rev Med Pharmacol Sci ; 24(23): 12536-12544, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336774

RESUMO

OBJECTIVE: We aimed to study the dynamics of cytokines and lymphocyte subsets and their correlation with the prognosis of patients with severe COVID-19. PATIENTS AND METHODS: The lymphocyte subsets and cytokines of 31 patients with severe COVID-19 (7 deaths and 24 survivals) were longitudinally analyzed. RESULTS: The mean age of enrolled patients was 64 years, 24 (77.4%) patients were men, and 23 (74.2%) patients had comorbidities. Compared with survival group, the death group showed significant and sustained increases in the levels of IL-6, IL-8, and IL-10 from baseline to 28 days after admission (all p<0.05). No significant differences were observed in the levels of TNF-α, IL-1b, IL-2, IL-4, IL-5, IL-12P70, IL-17, IFN-α, and IFN-γ between the death group and survival group during the follow-up (all p>0.05). The absolute counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD45+ T cells were lower in both survival group and death group patients from hospital admission to 3 days after admission, and gradually recovered in 4 to 35 days in the survival group, but continually stayed at low levels in the death group during the follow-up. CONCLUSIONS: The kinetic changes of cytokines and lymphocyte subsets are related with the prognosis of patients with severe COVID-19.


Assuntos
/imunologia , Citocinas/imunologia , Subpopulações de Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , /mortalidade , Feminino , Humanos , Interferon-alfa/imunologia , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-17/imunologia , Interleucina-1beta/imunologia , Interleucina-2/imunologia , Interleucina-4/imunologia , Interleucina-5/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Antígenos Comuns de Leucócito/imunologia , Estudos Longitudinais , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/imunologia
4.
BMC Pulm Med ; 20(1): 301, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33198751

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19. METHODS: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels. RESULTS: ICU patients showed a marked increase in neutrophils (1.24 × 105 ml- 1, 0.85-2.07), lower lymphocyte (0.97 × 105 ml- 1, 0.024-0.34) and macrophages fractions (0.43 × 105 ml- 1, 0.34-1.62) compared to IMW patients (0.095 × 105 ml- 1, 0.05-0.73; 0.47 × 105 ml- 1, 0.28-1.01 and 2.14 × 105 ml- 1, 1.17-3.01, respectively) (p < 0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p < 0.01, IL8 p < 0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p < 0.1) or antivirals (p < 0.05). CONCLUSIONS: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/imunologia , Inflamação/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Leucócitos/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Pneumonia Viral/imunologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Corticosteroides/uso terapêutico , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Combinação de Medicamentos , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Unidades de Terapia Intensiva , Interleucina-10/imunologia , Itália , Leucócitos Mononucleares/virologia , Lopinavir/uso terapêutico , Pulmão/citologia , Pulmão/virologia , Linfócitos/imunologia , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/terapia , Prognóstico , Estudos Prospectivos , Respiração Artificial/métodos , Ritonavir/uso terapêutico , Glicoproteína da Espícula de Coronavírus/metabolismo , Taxa de Sobrevida , Vírion/metabolismo , Vírion/ultraestrutura
5.
Signal Transduct Target Ther ; 5(1): 235, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037188

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.


Assuntos
Apoptose/imunologia , Betacoronavirus/patogenicidade , Caspase 8/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Necroptose/imunologia , Pneumonia Viral/imunologia , Fibrose Pulmonar/imunologia , Animais , Caspase 8/genética , Linhagem Celular Tumoral , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-7/genética , Interleucina-7/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Fibrose Pulmonar/virologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
6.
Virology ; 548: 93-100, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32838950

RESUMO

Human cytomegalovirus (HCMV) infects the chorioamnion, but whether these infections cause fetal membrane dysfunction remains poorly understood. We sought to assess whether guinea pig cytomegalovirus (GPCMV) infects amnion-derived cells in vitro, compare the inflammatory response of amnion cells to GPCMV and HCMV, and determine if GPCMV infects the amnion in vivo. We found that GPCMV replicates in primary guinea pig amnion derived cells and HPV16 E6/E7-transduced amniotic epithelial cells (AEC[E6/E7]s). HCMV and GPCMV infection of amnion cells increased the transcription of the chemokines CCL5/Ccl5, CXCL8/Cxcl8, and CXCL10/Cxcl10. Myd88-knockdown decreased Ccl5 and Cxc8 transcription in GPCMV-infected AEC[E6/E7]s. GPCMV was detected in the guinea pig amnion after primary maternal infection, revealing that guinea pigs are an appropriate model to study fetal membrane physiology after cytomegalovirus infection. As inflammation is known to cause fetal membrane weakening, the amnion's response to cytomegalovirus infection may cause preterm birth and other adverse pregnancy outcomes.


Assuntos
Âmnio/imunologia , Quimiocinas/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Complicações na Gravidez/imunologia , Âmnio/virologia , Animais , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Quimiocinas/genética , Citomegalovirus/genética , Citomegalovirus/imunologia , Infecções por Citomegalovirus/genética , Feminino , Cobaias , Humanos , Interleucina-8/genética , Interleucina-8/imunologia , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/virologia
7.
Nat Med ; 26(10): 1636-1643, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32839624

RESUMO

Several studies have revealed that the hyper-inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of disease severity and death. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1ß in hospitalized patients with coronavirus disease 2019 (COVID-19) upon admission to the Mount Sinai Health System in New York. Patients (n = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected. We found that high serum IL-6, IL-8 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival (P < 0.0001, P = 0.0205 and P = 0.0140, respectively). Notably, when adjusting for disease severity, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. These findings were validated in a second cohort of patients (n = 231). We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of patients with COVID-19 to stratify prospective clinical trials, guide resource allocation and inform therapeutic options.


Assuntos
Infecções por Coronavirus/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Pneumonia Viral/imunologia , Fator de Necrose Tumoral alfa/imunologia , Idoso , Betacoronavirus , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Citocinas/imunologia , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Índice de Gravidade de Doença , Taxa de Sobrevida
8.
Proc Natl Acad Sci U S A ; 117(28): 16475-16480, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601180

RESUMO

Autism spectrum disorder (ASD) is characterized by impaired social interactions and communication. The pathogenesis of ASD is not known, but it involves activation of microglia. We had shown that the peptide neurotensin (NT) is increased in the serum of children with ASD and stimulates cultured adult human microglia to secrete the proinflammatory molecules IL-1ß and CXCL8. This process is inhibited by the cytokine IL-37. Another cytokine, IL-38, has been reported to have antiinflammatory actions. In this report, we show that pretreatment of cultured adult human microglia with recombinant IL-38 (aa3-152, 1-100 ng/mL) inhibits (P < 0.0001) NT-stimulated (10 nM) secretion of IL-1ß (at 1 ng/mL) and CXCL8 (at 100 ng/mL). In fact, IL-38 (aa3-152, 1 ng/mL) is more potent than IL-37 (100 ng/mL). Here, we report that pretreatment with IL-38 (100 ng/mL) of embryonic microglia (HMC3), in which secretion of IL-1ß was undetectable, inhibits secretion of CXCL8 (P = 0.004). Gene expression of IL-38 and its receptor IL-36R are decreased (P = 0.001 and P = 0.04, respectively) in amygdala from patients with ASD (n = 8) compared to non-ASD controls (n = 8), obtained from the University of Maryland NeuroBioBank. IL-38 is increased (P = 0.03) in the serum of children with ASD. These findings indicate an important role for IL-38 in the inhibition of activation of human microglia, thus supporting its development as a treatment approach for ASD.


Assuntos
Tonsila do Cerebelo/imunologia , Transtorno do Espectro Autista/imunologia , Interleucinas/imunologia , Microglia/imunologia , Adolescente , Transtorno do Espectro Autista/sangue , Células Cultivadas , Criança , Pré-Escolar , Humanos , Interleucina-16/sangue , Interleucina-16/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-8/imunologia , Interleucinas/sangue , Masculino , Neurotensina/sangue , Neurotensina/imunologia
9.
JCI Insight ; 5(17)2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32706339

RESUMO

BACKGROUNDElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare with those observed in critically ill patients with acute respiratory distress syndrome (ARDS) or sepsis due to other causes.METHODSWe used a Luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTSFifteen hospitalized COVID-19 patients, 9 of whom were critically ill, were compared with critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONLevels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDINGFunding was received from NHLBI K23 HL125663 (AJR); The Bill and Melinda Gates Foundation OPP1113682 (AJR and CAB); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687 NIH/NIAID U19AI057229-16; Stanford Maternal Child Health Research Institute; and Chan Zuckerberg Biohub (CAB).


Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Pneumonia Viral/imunologia , Sepse/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Síndrome da Liberação de Citocina/sangue , Citocinas/sangue , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-18/sangue , Interleucina-18/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Sepse/sangue , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
10.
JCI Insight ; 5(13)2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32544099

RESUMO

BACKGROUNDFatal cases of COVID-19 are increasing globally. We retrospectively investigated the potential of immunologic parameters as early predictors of COVID-19.METHODSA total of 1018 patients with confirmed COVID-19 were enrolled in our 2-center retrospective study. Clinical feature, laboratory test, immunological test, radiological findings, and outcomes data were collected. Univariate and multivariable logistic regression analyses were performed to evaluate factors associated with in-hospital mortality. Receiver operator characteristic (ROC) curves and survival curves were plotted to evaluate their clinical utility.RESULTSThe counts of all T lymphocyte subsets were markedly lower in nonsurvivors than in survivors, especially CD8+ T cells. Among all tested cytokines, IL-6 was elevated most significantly, with an upward trend of more than 10-fold. Using multivariate logistic regression analysis, IL-6 levels of more than 20 pg/mL and CD8+ T cell counts of less than 165 cells/µL were found to be associated with in-hospital mortality after adjusting for confounding factors. Groups with IL-6 levels of more than 20 pg/mL and CD8+ T cell counts of less than 165 cells/µL had a higher percentage of older and male patients as well as a higher proportion of patients with comorbidities, ventilation, intensive care unit admission, shock, and death. Furthermore, the receiver operating curve of the model combining IL-6 (>20 pg/mL) and CD8+ T cell counts (<165 cells/µL) displayed a more favorable discrimination than that of the CURB-65 score. The Hosmer-Lemeshow test showed a good fit of the model, with no statistical significance.CONCLUSIONIL-6 (>20 pg/mL) and CD8+ T cell counts (<165 cells/µL) are 2 reliable prognostic indicators that accurately stratify patients into risk categories and predict COVID-19 mortality.FundingThis work was supported by funding from the National Natural Science Foundation of China (no. 81772477 and 81201848).


Assuntos
Linfócitos T CD8-Positivos , Infecções por Coronavirus/imunologia , Mortalidade Hospitalar , Interleucina-6/imunologia , Pneumonia Viral/imunologia , Idoso , Área Sob a Curva , Betacoronavirus , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Feminino , Humanos , Interleucina-10/imunologia , Interleucina-8/imunologia , Modelos Logísticos , Contagem de Linfócitos , Linfopenia/sangue , Linfopenia/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Prognóstico , Curva ROC , Receptores de Interleucina-2/imunologia , Estudos Retrospectivos , Fator de Necrose Tumoral alfa/imunologia
11.
Am J Respir Crit Care Med ; 202(6): 812-821, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32584597

RESUMO

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.


Assuntos
Reação de Fase Aguda/imunologia , Proteínas de Transporte/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Citocinas/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ácido Láctico/metabolismo , Proteínas de Membrana/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Hormônios Tireóideos/metabolismo , alfa 1-Antitripsina/imunologia , Reação de Fase Aguda/metabolismo , Adulto , Idoso , Betacoronavirus , Western Blotting , Estudos de Casos e Controles , Infecções Comunitárias Adquiridas/imunologia , Infecções Comunitárias Adquiridas/metabolismo , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Estado Terminal , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Feminino , Hospitalização , Humanos , Unidades de Terapia Intensiva , Interleucina-10/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pandemias , Fosforilação , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Índice de Gravidade de Doença , alfa 1-Antitripsina/metabolismo
12.
Ann Allergy Asthma Immunol ; 125(5): 503-504, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32585180

Assuntos
Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Síndrome da Liberação de Citocina/prevenção & controle , Dexametasona/uso terapêutico , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Administração por Inalação , Asma/imunologia , Asma/patologia , Asma/virologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Endorribonucleases/antagonistas & inibidores , Endorribonucleases/genética , Endorribonucleases/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/antagonistas & inibidores , Interleucina-8/genética , Interleucina-8/imunologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/genética , Receptores Virais/imunologia , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia
13.
Clin Exp Immunol ; 201(1): 76-84, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32365221

RESUMO

Effective laboratory markers for the estimation of disease severity and predicting the clinical progression of coronavirus disease-2019 (COVID-19) is urgently needed. Laboratory tests, including blood routine, cytokine profiles and infection markers, were collected from 389 confirmed COVID-19 patients. The included patients were classified into mild (n = 168), severe (n = 169) and critical groups (n = 52). The leukocytes, neutrophils, infection biomarkers [such as C-reactive protein (CRP), procalcitonin (PCT) and ferritin] and the concentrations of cytokines [interleukin (IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α] were significantly increased, while lymphocytes were significantly decreased with increased severity of illness. The amount of IL-2R was positively correlated with the other cytokines and negatively correlated with lymphocyte number. The ratio of IL-2R to lymphocytes was found to be remarkably increased in severe and critical patients. IL-2R/lymphocytes were superior compared with other markers for the identification of COVID-19 with critical illness, not only from mild but also from severe illness. Moreover, the cytokine profiles and IL-2R/lymphocytes were significantly decreased in recovered patients, but further increased in disease-deteriorated patients, which might be correlated with the outcome of COVID-19. Lymphopenia and increased levels of cytokines were closely associated with disease severity. The IL-2R/lymphocyte was a prominent biomarker for early identification of severe COVID-19 and predicting the clinical progression of the disease.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Subunidade alfa de Receptor de Interleucina-2/sangue , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Linfócitos T/virologia , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Biomarcadores/sangue , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , China/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Progressão da Doença , Feminino , Ferritinas/sangue , Ferritinas/imunologia , Humanos , Interleucina-10/sangue , Interleucina-10/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pró-Calcitonina/sangue , Pró-Calcitonina/imunologia , Prognóstico , Índice de Gravidade de Doença , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
14.
PLoS One ; 15(5): e0233644, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469940

RESUMO

Cytotoxic and pro-inflammatory histones are present in neutrophil extracellular traps (NETs) and are elevated in blood in several inflammatory conditions, sepsis being a major example. Compounds which can attenuate activities of histones are therefore of interest, with heparin being one such material that has previously been shown to bind to histones. Heparin, a successful anticoagulant for nearly a century, has been shown experimentally to bind to histones and exhibit a protective effect in inflammatory conditions. In the present study carried out in whole blood, heparin and selectively desulfated heparin reduced histone induced inflammatory markers such as interleukin 6 (IL 6), interleukin 8 (IL 8) and tissue factor and C3a, a complement component. The selectively desulfated heparins, with reduced anticoagulant activities, retained a high degree of effectiveness as an anti-histone agent, whereas fully desulfated heparin was found to be ineffective. The results from this study indicate that the presence of sulfate and other specific structural features are required for heparin to attenuate the inflammatory action of histones in whole blood.


Assuntos
Anti-Inflamatórios/farmacologia , Anticoagulantes/farmacologia , Heparina/farmacologia , Histonas/imunologia , Inflamação/tratamento farmacológico , Anti-Inflamatórios/química , Anticoagulantes/química , Complemento C3a/análise , Complemento C3a/imunologia , Heparina/análogos & derivados , Histonas/sangue , Humanos , Inflamação/sangue , Inflamação/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia
15.
J Leukoc Biol ; 107(6): 1057-1067, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32362028

RESUMO

γδ T cells contribute to the immune response against many cancers, notably through their powerful effector functions that lead to the elimination of tumor cells and the recruitment of other immune cells. However, their presence in the tumor microenvironment has been associated with poor prognosis in breast, colon, and pancreatic cancer, suggesting that γδ T cells may also display pro-tumor activities. Here, we identified in blood from healthy donors a subpopulation of Vδ1T cells that represents around 20% of the whole Vδ1 population, expresses CD73, and displays immunosuppressive phenotype and functions (i.e., production of immunosuppressive molecules, such as IL-10, adenosine, and the chemotactic factor IL-8, and inhibition of αß T cell proliferation). We then found that in human breast tumors, γδ T cells were present particularly in late stage breast cancer samples, and that ∼20% of tumor-infiltrating γδ T cells expressed CD73. Taken together, these results suggest that regulatory γδ T cells are present in the breast cancer microenvironment and may display immunosuppressive functions through the production of immunosuppressive molecules, such as IL-10, IL-8, and adenosine, thus promoting tumor growth.


Assuntos
5'-Nucleotidase/imunologia , Neoplasias da Mama/imunologia , Linhagem da Célula/imunologia , Regulação Neoplásica da Expressão Gênica , Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T Reguladores/imunologia , 5'-Nucleotidase/genética , Adenosina/imunologia , Adenosina/metabolismo , Adolescente , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Diferenciação Celular , Linhagem da Célula/genética , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Transdução de Sinais , Linfócitos T Reguladores/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
16.
Nature ; 583(7816): 437-440, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32434211

RESUMO

In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, China)1; it soon spread across the world. In this ongoing pandemic, public health concerns and the urgent need for effective therapeutic measures require a deep understanding of the epidemiology, transmissibility and pathogenesis of COVID-19. Here we analysed clinical, molecular and immunological data from 326 patients with confirmed SARS-CoV-2 infection in Shanghai. The genomic sequences of SARS-CoV-2, assembled from 112 high-quality samples together with sequences in the Global Initiative on Sharing All Influenza Data (GISAID) dataset, showed a stable evolution and suggested that there were two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially reduced CD4+ and CD8+ T cell counts upon hospital admission, was predictive of disease progression. High levels of interleukin (IL)-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age and lymphocytopenia (and its associated cytokine storm), whereas viral genetic variation did not significantly affect outcomes.


Assuntos
Betacoronavirus/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno/imunologia , Linfopenia/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , /virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Animais , Infecções Assintomáticas/epidemiologia , Betacoronavirus/classificação , Betacoronavirus/isolamento & purificação , China/epidemiologia , Estudos de Coortes , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Estado Terminal/epidemiologia , Progressão da Doença , Evolução Molecular , Feminino , Variação Genética , Genoma Viral/genética , Hospitalização/estatística & dados numéricos , Humanos , Mediadores da Inflamação/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia , Contagem de Linfócitos , Linfopenia/complicações , Masculino , Pessoa de Meia-Idade , Pandemias , Filogenia , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Linfócitos T/citologia , Linfócitos T/imunologia , Fatores de Tempo , Resultado do Tratamento , Virulência/genética , Eliminação de Partículas Virais , Adulto Jovem , Zoonoses/transmissão , Zoonoses/virologia
17.
Transplant Proc ; 52(4): 1127-1131, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32307138

RESUMO

The main complication associated with renal graft loss is immune rejection. The gold standard for the diagnosis of renal graft rejection is percutaneous renal biopsy, which is expensive and can lead to complications. Inflammation is one of the main pathogenic pathways in allograft rejection, and urine samples seem to be efficient windows to explore the allograft condition with a high cost-benefit ratio. This study aimed to evaluate the messenger ribonucleic acid (mRNA) profile expression pattern for interleukin (IL) 2, IL-4, IL-6, IL-8, and IL-10; tumor necrosis factor alfa; gamma interferon; and transforming growth factor ß1 in the urine renal cells of patients with a diagnosis of humoral rejection and patients with a diagnosis of normal biopsy. METHODS: An observational, cross-sectional analytical study was performed. All kidney transplants were performed at the Organ Transplant Department between 2018 and 2019. Also, a healthy control with a normal blood test and no apparent infection was included. mRNA from urine samples and biopsies was isolated, and the expression of interleukins was analyzed in PCR real time. Data were analyzed by Shapiro-Wilk and Kruskal-Wallis tests. RESULTS: The proinflammatory IL expression pattern in urine samples of kidney rejection group showed overexpression for IL-8 (P = .0001). No differences were observed in the rest of the interleukins analyzed. When we compared the results in the rejected versus not rejected transplanted patients with a group of apparently healthy subjects, the difference remains consistent. Thus, mRNA of IL-8 could function as a diagnostic tool in cases of chronic damage secondary to fibrosis.


Assuntos
Biomarcadores/urina , Rejeição de Enxerto/urina , Interleucina-8/urina , Transplante de Rim/efeitos adversos , Adulto , Estudos Transversais , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Humanos , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Transplante Homólogo
18.
Am J Respir Crit Care Med ; 202(3): 383-392, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32293914

RESUMO

Rationale: Mesenchymal stromal cell (MSC) therapy is a promising intervention for acute respiratory distress syndrome (ARDS), although trials to date have not investigated its use alongside extracorporeal membrane oxygenation (ECMO). Recent preclinical studies have suggested that combining these interventions may attenuate the efficacy of ECMO.Objectives: To determine the safety and efficacy of MSC therapy in a model of ARDS and ECMO.Methods: ARDS was induced in 14 sheep, after which they were established on venovenous ECMO. Subsequently, they received either endobronchial induced pluripotent stem cell-derived human MSCs (hMSCs) (n = 7) or cell-free carrier vehicle (vehicle control; n = 7). During ECMO, a low Vt ventilation strategy was employed in addition to protocolized hemodynamic support. Animals were monitored and supported for 24 hours. Lung tissue, bronchoalveolar fluid, and plasma were analyzed, in addition to continuous respiratory and hemodynamic monitoring.Measurements and Main Results: The administration of hMSCs did not improve oxygenation (PaO2/FiO2 mean difference = -146 mm Hg; P = 0.076) or pulmonary function. However, histological evidence of lung injury (lung injury score mean difference = -0.07; P = 0.04) and BAL IL-8 were reduced. In addition, hMSC-treated animals had a significantly lower cumulative requirement for vasopressor. Despite endobronchial administration, animals treated with hMSCs had a significant elevation in transmembrane oxygenator pressure gradients. This was accompanied by more pulmonary artery thromboses and adherent hMSCs found on explanted oxygenator fibers.Conclusions: Endobronchial hMSC therapy in an ovine model of ARDS and ECMO can impair membrane oxygenator function and does not improve oxygenation. These data do not recommend the safe use of hMSCs during venovenous ECMO.


Assuntos
Lesão Pulmonar Aguda/patologia , Oxigenação por Membrana Extracorpórea , Pulmão/patologia , Transplante de Células-Tronco Mesenquimais , /terapia , Lesão Pulmonar Aguda/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Adesão Celular , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas , Interleucina-8/imunologia , Pulmão/imunologia , Oxigenadores de Membrana , Artéria Pulmonar , Distribuição Aleatória , Respiração Artificial , /patologia , Ovinos , Carneiro Doméstico , Trombose/patologia , Vasoconstritores/uso terapêutico
19.
Transpl Infect Dis ; 22(4): e13286, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32279418

RESUMO

During the novel coronavirus pandemic, organ transplant recipients represent a frail susceptible category due to long-term immunosuppressive therapy. For this reason, clinical manifestations may differ from general population and different treatment approaches may be needed. We present the case of a 36-year-old kidney-transplanted woman affected by Senior-Loken syndrome diagnosed with COVID-19 pneumonia after a contact with her positive mother. Initial symptoms were fatigue, dry cough, and coryza; she never had fever nor oxygen supplementation. Hydroxychloroquine and lopinavir/ritonavir were started, and the antiviral drug was replaced with darunavir/cobicistat after 2 days for diarrhea. Immunosuppressant levels were closely monitored, and we observed very high tacrolimus trough levels despite initial dose reduction. The patient was left with steroid therapy alone. The peculiarity of clinical presentation and the management difficulties represent the flagship of our case report. We stress the need for guidelines in transplant recipients with COVID-19 infection with particular regard to the management of therapy.


Assuntos
Antivirais/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Imunossupressores/efeitos adversos , Transplante de Rim , Lopinavir/efeitos adversos , Pneumonia Viral/tratamento farmacológico , Ritonavir/efeitos adversos , Tacrolimo/efeitos adversos , Adulto , Antivirais/uso terapêutico , Betacoronavirus , Proteína C-Reativa/imunologia , Ciliopatias/complicações , Cobicistat/uso terapêutico , Resfriado Comum/etiologia , Resfriado Comum/fisiopatologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Tosse/etiologia , Tosse/fisiopatologia , Darunavir/uso terapêutico , Desprescrições , Combinação de Medicamentos , Interações Medicamentosas , Inibidores Enzimáticos/uso terapêutico , Fadiga/etiologia , Fadiga/fisiopatologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Hospedeiro Imunocomprometido/imunologia , Interleucina-10/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Doenças Renais Císticas/complicações , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Amaurose Congênita de Leber/complicações , Metilprednisolona/uso terapêutico , Atrofias Ópticas Hereditárias/complicações , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Índice de Gravidade de Doença
20.
J Leukoc Biol ; 107(6): 1167-1173, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32272490

RESUMO

CXCL8 is the principal human neutrophil-attracting chemokine and a major mediator of inflammation. The chemokine exerts its neutrophil-chemotactic and neutrophil-activating activities via interaction with glycosaminoglycans (GAGs) and activation of the G protein-coupled receptors (GPCRs) CXCR1 and CXCR2. Natural CXCL8 displays an exceptional degree of amino (NH2 )-terminal heterogeneity. Most CXCL8 forms result from proteolytic processing of authentic CXCL8(1-77). Here, we compared the potencies to activate and recruit neutrophils of the 3 most abundant natural CXCL8 forms: full-length 77 amino acid CXCL8 and the 2 major natural truncated forms lacking 5 or 8 NH2 -terminal amino acids. NH2 -terminal truncation hardly affected the capacity of CXCL8 to induce shedding of CD62L or to up-regulate the expression of the adhesion molecules CD11a, CD11b, or CD15 on human neutrophils. In addition, the potency of CXCL8 to induce neutrophil degranulation and its effect on phagocytosis remained unaltered upon removal of 5 or 8 NH2 -terminal residues. However, NH2 -terminal truncation strongly potentiated CXCL8-induced actin polymerization. CXCL8(6-77) and CXCL8(9-77) showed a comparable capacity to induce Ca2+ signaling in human neutrophils and to direct in vitro neutrophil migration. Strikingly, the ability of CXCL8(9-77) to recruit neutrophils into the peritoneal cavity of mice was significantly enhanced compared to CXCL8(6-77). These results suggest that NH2 -terminal truncation influences specific biological activities of CXCL8 and indicate that CXCL8(9-77) may be the most potent neutrophil-attracting CXCL8 form in vivo.


Assuntos
Actinas/genética , Sequência de Bases , Interleucina-8/genética , Neutrófilos/metabolismo , Processamento de Proteína Pós-Traducional/imunologia , Deleção de Sequência , Actinas/imunologia , Animais , Antígeno CD11a/genética , Antígeno CD11a/imunologia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Quimiotaxia de Leucócito , Feminino , Regulação da Expressão Gênica , Glicosaminoglicanos , Humanos , Interleucina-8/imunologia , Interleucina-8/farmacologia , Antígenos CD15/genética , Antígenos CD15/imunologia , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/imunologia , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Polimerização , Cultura Primária de Células , Receptores de Interleucina-8A/genética , Receptores de Interleucina-8A/imunologia , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia
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