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Pesquisa : D12.776.543.750.695.024 [Categoria DeCS]
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  1 / 912 MEDLINE  
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[PMID]:29220376
[Au] Autor:Hornum L; Hansen AJ; Tornehave D; Fjording MS; Colmenero P; Wätjen IF; Søe Nielsen NH; Bliddal H; Bartels EM
[Ad] Endereço:Novo Nordisk A/S, Måløv, Denmark.
[Ti] Título:C5a and C5aR are elevated in joints of rheumatoid and psoriatic arthritis patients, and C5aR blockade attenuates leukocyte migration to synovial fluid.
[So] Source:PLoS One;12(12):e0189017, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Complement activation correlates to rheumatoid arthritis disease activity, and increased amounts of the complement split product C5a is observed in synovial fluids from rheumatoid arthritis patients. Blockade of C5a or its receptor (C5aR) is efficacious in several arthritis models. The aim of this study was to investigate the role of C5a and C5aR in human rheumatoid arthritis and psoriatic arthritis-both with respect to expression and function. Synovial fluid, blood and synovial samples were obtained from rheumatoid arthritis, psoriatic arthritis and osteoarthritis patients as a less inflammatory arthritis type, and blood from healthy subjects. Cells infiltrating synovial tissue were analysed by immunohistochemistry and flow cytometry. SF and blood were analysed for biomarkers by flow cytometry or ELISA. The effect of a blocking anti-human C5aR mAb on leukocyte migration was determined using a Boyden chamber. Appropriate statistical tests were applied for comparisons. C5aR+ cells were detected in most rheumatoid arthritis, in all psoriatic arthritis, but not in non-inflammatory control synovia. C5aR+ cells were primarily neutrophils and macrophages. C5aR+ macrophages were mainly found in lymphoid aggregates in close contact with T cells. C5a levels were increased in both rheumatoid arthritis and psoriatic arthritis synovial fluid compared to osteoarthritis, and in blood from rheumatoid arthritis compared to healthy subjects. Neutrophil and monocyte migration to rheumatoid arthritis synovial fluid was significantly inhibited by anti-C5aR. The data support that the C5a-C5aR axis may be driving the infiltration of inflammatory cells into the synovial fluid and synovium in both rheumatoid and psoriatic arthritis, and suggest that C5a or C5aR may be a promising treatment target in both diseases.
[Mh] Termos MeSH primário: Artrite Psoriásica/metabolismo
Artrite Reumatoide/metabolismo
Quimiotaxia de Leucócito
Complemento C5a/metabolismo
Leucócitos/patologia
Receptor da Anafilatoxina C5a/metabolismo
Líquido Sinovial/metabolismo
[Mh] Termos MeSH secundário: Ensaio de Imunoadsorção Enzimática
Citometria de Fluxo
Seres Humanos
Imuno-Histoquímica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptor, Anaphylatoxin C5a); 80295-54-1 (Complement C5a)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189017


  2 / 912 MEDLINE  
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[PMID]:29031586
[Au] Autor:Chen J; Li GQ; Zhang L; Tang M; Cao X; Xu GL; Wu YZ
[Ad] Endereço:Department of Immunology, Third Military Medical University, Chongqing 400038, PR China.
[Ti] Título:Complement C5a/C5aR pathway potentiates the pathogenesis of gastric cancer by down-regulating p21 expression.
[So] Source:Cancer Lett;412:30-36, 2018 Jan 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Although the complement C5a/C5aR pathway is suggested to play a critical role in tumor pathogenesis, the underlying mechanism has yet to be fully elucidated. In the present study, we found that in patients with gastric cancer in different clinical stages (from stageâ… to stage â…£), both C5aR and p-PI3K/AKT levels were significantly higher in tumoral tissues than in adjacent non-tumoral tissues. In contrast, p21/p-p21 levels were significantly lower in tumoral tissues than in adjacent non-tumoral tissues. In vitro recombinant C5a administration remarkably promoted p-PI3K/p-AKT expression, but inhibited p21/p-p21 expression. Blockage of C5a/C5aR signaling with a C5aR antagonist reversed the C5a-induced inhibitory effect on p21/p-p21 expression. C5a administration to cells pre-treated with a PI3K inhibitor also prevented this inhibitory effect, suggesting the involvement of the PI3K/AKT signaling pathway in C5a/C5aR-mediated suppression of p21/p-p21 expression. In vivo C5aR antagonist treatment caused significant reduction in tumor growth in mice, accompanied by a remarkable elevation in p21/p-p21 expression and reduction in p-PI3K/AKT activation. These results indicate that the C5a/C5aR pathway promotes gastric cancer pathogenesis by suppressing p21/p-p21 expression via activation of PI3K/AKT signaling.
[Mh] Termos MeSH primário: Complemento C5a/fisiologia
Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores
Receptor da Anafilatoxina C5a/fisiologia
Transdução de Sinais/fisiologia
Neoplasias Gástricas/etiologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Inibidor de Quinase Dependente de Ciclina p21/fisiologia
Regulação para Baixo
Feminino
Seres Humanos
Masculino
Camundongos
Fosfatidilinositol 3-Quinases/fisiologia
Proteínas Proto-Oncogênicas c-akt/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C5AR1 protein, human); 0 (CDKN1A protein, human); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (Receptor, Anaphylatoxin C5a); 80295-54-1 (Complement C5a); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


  3 / 912 MEDLINE  
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[PMID]:28931049
[Au] Autor:Wiese AV; Ender F; Quell KM; Antoniou K; Vollbrandt T; König P; Köhl J; Laumonnier Y
[Ad] Endereço:Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
[Ti] Título:The C5a/C5aR1 axis controls the development of experimental allergic asthma independent of LysM-expressing pulmonary immune cells.
[So] Source:PLoS One;12(9):e0184956, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:C5a regulates the development of maladaptive immune responses in allergic asthma mainly through the activation of C5a receptor 1 (C5aR1). Yet, the cell types and the mechanisms underlying this regulation are ill-defined. Recently, we described increased C5aR1 expression in lung tissue eosinophils but decreased expression in airway and pulmonary macrophages as well as in pulmonary CD11b+ conventional dendritic cells (cDCs) and monocyte-derived DCs (moDCs) during the allergic effector phase using a floxed green fluorescent protein (GFP)-C5aR1 knock-in mouse. Here, we determined the role of C5aR1 signaling in neutrophils, moDCs and macrophages for the pulmonary recruitment of such cells and the importance of C5aR1-mediated activation of LysM-expressing cells for the development of allergic asthma. We used LysM-C5aR1 KO mice with a specific deletion of C5aR1 in LysMCre-expressing cells and confirmed the specific deletion of C5aR1 in neutrophils, macrophages and moDCs in the airways and/or the lung tissue. We found that alveolar macrophage numbers were significantly increased in LysM-C5aR1 KO mice. Induction of ovalbumin (OVA)-driven experimental allergic asthma in GFP-C5aR1fl/fl and LysM-C5aR1 KO mice resulted in strong but similar airway resistance, mucus production and Th2/Th17 cytokine production. In contrast, the number of airway but not of pulmonary neutrophils was lower in LysM-C5aR1 KO as compared with GFP-C5aR1fl/fl mice. The recruitment of macrophages, cDCs, moDCs, T cells and type 2 innate lymphoid cells was not altered in LysM-C5aR1 KO mice. Our findings demonstrate that C5aR1 is critical for steady state control of alveolar macrophage numbers and the transition of neutrophils from the lung into the airways in OVA-driven allergic asthma. However, C5aR1 activation of LysM-expressing cells plays a surprisingly minor role in the recruitment and activation of such cells and the development of the allergic phenotype in OVA-driven experimental allergic asthma.
[Mh] Termos MeSH primário: Asma/patologia
Complemento C5a/metabolismo
Pulmão/imunologia
Muramidase/fisiologia
Receptor da Anafilatoxina C5a/fisiologia
Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Animais
Asma/induzido quimicamente
Asma/imunologia
Células Cultivadas
Células Dendríticas/imunologia
Células Dendríticas/metabolismo
Eosinófilos/imunologia
Eosinófilos/metabolismo
Pulmão/metabolismo
Pulmão/patologia
Macrófagos/imunologia
Macrófagos/metabolismo
Camundongos
Camundongos Knockout
Neutrófilos/imunologia
Neutrófilos/metabolismo
Ovalbumina/toxicidade
Linfócitos T/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C5ar1 protein, mouse); 0 (Receptor, Anaphylatoxin C5a); 80295-54-1 (Complement C5a); 9006-59-1 (Ovalbumin); EC 3.2.1.17 (Muramidase); EC 3.2.1.17 (lysozyme M, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184956


  4 / 912 MEDLINE  
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[PMID]:28864475
[Au] Autor:Karsten CM; Wiese AV; Mey F; Figge J; Woodruff TM; Reuter T; Scurtu O; Kordowski A; Almeida LN; Briukhovetska D; Quell KM; Sun J; Ender F; Schmudde I; Vollbrandt T; Laumonnier Y; Köhl J
[Ad] Endereço:Institute for Systemic Inflammation Research, University of Lübeck, Lübeck 23562, Germany; joerg.koehl@uksh.de christian.karsten@uksh.de.
[Ti] Título:Monitoring C5aR2 Expression Using a Floxed tdTomato-C5aR2 Knock-In Mouse.
[So] Source:J Immunol;199(9):3234-3248, 2017 Nov 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The biological significance of C5a receptor [(C5aR)2/C5L2], a seven-transmembrane receptor binding C5a and C5adesArg, remains ill-defined. Specific ligation of C5aR2 inhibits C5a-induced ERK1/2 activation, strengthening the view that C5aR2 regulates C5aR1-mediated effector functions. Although C5aR2 and C5aR1 are often coexpressed, a detailed picture of C5aR2 expression in murine cells and tissues is still lacking. To close this gap, we generated a floxed tandem dye (td)Tomato-C5aR2 knock-in mouse that we used to track C5aR2 expression in tissue-residing and circulating immune cells. We found the strongest C5aR2 expression in the brain, bone marrow, and airways. All myeloid-derived cells expressed C5aR2, although with different intensities. C5aR2 expression in blood and tissue neutrophils was strong and homogeneous. Specific ligation of C5aR2 in neutrophils from tdTomato-C5aR2 mice blocked C5a-driven ERK1/2 phosphorylation, demonstrating functionality of C5aR2 in the reporter mice. In contrast to neutrophils, we found tissue-specific differences in C5aR2 expression in eosinophils, macrophages, and dendritic cell subsets. Naive and activated T cells stained negative for C5aR2, whereas B cells from different tissues homogeneously expressed C5aR2. Also, NK cell subsets in blood and spleen strongly expressed C5aR2. Activation of C5aR2 in NK cells suppressed IL-12/IL-18-induced IFN-γ production. Intratracheal IL-33 challenge resulted in decreased C5aR2 expression in pulmonary eosinophils and monocyte-derived dendritic cells. In summary, we provide a detailed map of murine C5aR2 immune cell expression in different tissues under steady-state conditions and upon pulmonary inflammation. The C5aR2 knock-in mouse will help to reliably track and conditionally delete C5aR2 expression in experimental models of inflammation.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica/imunologia
Leucócitos/imunologia
Pneumonia/imunologia
Receptor da Anafilatoxina C5a/imunologia
[Mh] Termos MeSH secundário: Animais
Técnicas de Introdução de Genes
Genes Reporter/imunologia
Leucócitos/patologia
Camundongos
Camundongos Transgênicos
Especificidade de Órgãos/genética
Especificidade de Órgãos/imunologia
Pneumonia/genética
Pneumonia/patologia
Receptor da Anafilatoxina C5a/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C5ar2 protein, mouse); 0 (Receptor, Anaphylatoxin C5a)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700710


  5 / 912 MEDLINE  
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[PMID]:28733463
[Au] Autor:Zaal A; Nota B; Moore KS; Dieker M; van Ham SM; Ten Brinke A
[Ad] Endereço:Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
[Ti] Título:TLR4 and C5aR crosstalk in dendritic cells induces a core regulatory network of RSK2, PI3Kß, SGK1, and FOXO transcription factors.
[So] Source:J Leukoc Biol;102(4):1035-1054, 2017 Oct.
[Is] ISSN:1938-3673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Crosstalk between complement component 5a receptors (C5aRs) and TLRs in dendritic cells (DCs) occurs upon pathogen invasion; however, studies on C5aR and TLR crosstalk mainly focused on the modulating effect of C5a on TLR-induced cytokine production. To elucidate the breadth of C5aR and TLR4 crosstalk, the effect of simultaneous treatment with C5a and LPS was investigated in human monocyte-derived DCs (moDCs) 2 h after stimulation using whole transcriptome sequencing analysis. Although the effect of C5a on hallmark genes defining TLR4-induced DC maturation was limited at this time point, RNA sequencing analysis revealed a great variety of novel C5a targets, of which many interfere with TLR4-mediated immune activation. Analysis of functional relationships among these genes uncovered induction of a central immune regulatory network upon C5aR and TLR4 crosstalk, involving the transcription factors forkhead box (FOX)O1 and FOXO3 and the signaling molecules serum- and glucocorticoid-inducible kinase (SGK1), ribosomal S6 kinase 2 (RSK2), and PI3Kß. C5aR and TLR crosstalk, furthermore, yielded down-regulation of mainly proinflammatory network branches, including IL-12B, IL-2Rα (IL-2RA), and jagged 1 (JAG1) and cooperative induction of predominantly anti-inflammatory network branches, including sphingosine kinase 1 (SPHK1), ß2 adrenergic receptor (ADRB2), gastric inhibitory polypeptide receptor (GIPR), and four-and-a-half Lin11, Isl-1, and Mec-3 domains protein 2 (FHL2). Together, these data point toward induction of generalized immune regulation of DC function. Motif enrichment analysis indicate a prominent role for basic leucine zipper (bZIP) and IFN regulatory factor 4 (IRF4) transcription factors upon C5aR and TLR4 crosstalk. Additionally, differences were observed in the modulating capacity of C5a on DCs in the absence or presence of a pathogen (TLR stimulus). Our findings shed new light on the depth and complexity of C5aR and TLR4 crosstalk and provide new foci of research for future studies.
[Mh] Termos MeSH primário: Células Dendríticas/imunologia
Proteína Forkhead Box O1/imunologia
Proteína Forkhead Box O3/imunologia
Proteínas Imediatamente Precoces/imunologia
Fosfatidilinositol 3-Quinases/imunologia
Proteínas Serina-Treonina Quinases/imunologia
Receptor da Anafilatoxina C5a/imunologia
Proteínas Quinases S6 Ribossômicas 90-kDa/imunologia
Transdução de Sinais/imunologia
Receptor 4 Toll-Like/imunologia
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C5AR1 protein, human); 0 (FOXO1 protein, human); 0 (FOXO3 protein, human); 0 (Forkhead Box Protein O1); 0 (Forkhead Box Protein O3); 0 (Immediate-Early Proteins); 0 (Receptor, Anaphylatoxin C5a); 0 (TLR4 protein, human); 0 (Toll-Like Receptor 4); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa); EC 2.7.11.1 (ribosomal protein S6 kinase, 90kDa, polypeptide 3); EC 2.7.11.1 (serum-glucocorticoid regulated kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170723
[St] Status:MEDLINE
[do] DOI:10.1189/jlb.2MA0217-058R


  6 / 912 MEDLINE  
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[PMID]:28671713
[Au] Autor:Denk S; Taylor RP; Wiegner R; Cook EM; Lindorfer MA; Pfeiffer K; Paschke S; Eiseler T; Weiss M; Barth E; Lambris JD; Kalbitz M; Martin T; Barth H; Messerer DAC; Gebhard F; Huber-Lang MS
[Ad] Endereço:Institute of Clinical and Experimental Trauma-Immunology, University Hospital Ulm, Ulm, Germany.
[Ti] Título:Complement C5a-Induced Changes in Neutrophil Morphology During Inflammation.
[So] Source:Scand J Immunol;86(3):143-155, 2017 Sep.
[Is] ISSN:1365-3083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The complement and neutrophil defence systems, as major components of innate immunity, are activated during inflammation and infection. For neutrophil migration to the inflamed region, we hypothesized that the complement activation product C5a induces significant changes in cellular morphology before chemotaxis. Exposure of human neutrophils to C5a dose- and time-dependently resulted in a rapid C5a receptor-1 (C5aR1)-dependent shape change, indicated by enhanced flow cytometric forward-scatter area values. Similar changes were observed after incubation with zymosan-activated serum and in blood neutrophils during murine sepsis, but not in mice lacking the C5aR1. In human neutrophils, Amnis high-resolution digital imaging revealed a C5a-induced decrease in circularity and increase in the cellular length/width ratio. Biomechanically, microfluidic optical stretching experiments indicated significantly increased neutrophil deformability early after C5a stimulation. The C5a-induced shape changes were inhibited by pharmacological blockade of either the Cl-/HCO3--exchanger or the Cl -channel. Furthermore, actin polymerization assays revealed that C5a exposure resulted in a significant polarization of the neutrophils. The functional polarization process triggered by ATP-P2X/Y-purinoceptor interaction was also involved in the C5a-induced shape changes, because pretreatment with suramin blocked not only the shape changes but also the subsequent C5a-dependent chemotactic activity. In conclusion, the data suggest that the anaphylatoxin C5a regulates basic neutrophil cell processes by increasing the membrane elasticity and cell size as a consequence of actin-cytoskeleton polymerization and reorganization, transforming the neutrophil into a migratory cell able to invade the inflammatory site and subsequently clear pathogens and molecular debris.
[Mh] Termos MeSH primário: Citoesqueleto de Actina/imunologia
Forma Celular/imunologia
Complemento C5a/metabolismo
Inflamação/imunologia
Neutrófilos/imunologia
[Mh] Termos MeSH secundário: Actinas/metabolismo
Trifosfato de Adenosina/metabolismo
Células Cultivadas
Quimiotaxia
Antiportadores de Cloreto-Bicarbonato/metabolismo
Complemento C5a/imunologia
Seres Humanos
Ativação de Neutrófilo
Neutrófilos/patologia
Receptor da Anafilatoxina C5a/metabolismo
Receptores Purinérgicos P2X/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (C5AR1 protein, human); 0 (Chloride-Bicarbonate Antiporters); 0 (Receptor, Anaphylatoxin C5a); 0 (Receptors, Purinergic P2X); 80295-54-1 (Complement C5a); 8L70Q75FXE (Adenosine Triphosphate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1111/sji.12580


  7 / 912 MEDLINE  
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[PMID]:28630122
[Au] Autor:Konar M; Granoff DM
[Ad] Endereço:Center for Immunobiology and Vaccine Development, UCSF Benioff Children's Hospital Oakland, Oakland, CA.
[Ti] Título:Eculizumab treatment and impaired opsonophagocytic killing of meningococci by whole blood from immunized adults.
[So] Source:Blood;130(7):891-899, 2017 Aug 17.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eculizumab, a humanized anti-complement C5 monoclonal antibody (mAb) for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome, blocks the terminal complement pathway required for serum bactericidal activity (SBA). Because treated patients are at >1000-fold increased risk of meningococcal disease, vaccination is recommended; whether vaccination can protect by opsonophagocytic activity in the absence of SBA is not known. Meningococci were added to anticoagulated blood from 12 healthy adults vaccinated with meningococcal serogroup B and serogroup A, C, W, Y vaccines. Bacterial survival was measured after 3-hour incubation in the presence of eculizumab or control complement factor D inhibitor ACH-4471, which blocks the complement alternative pathway (AP) and is in phase 2 development for treatment of PNH. In the absence of inhibitors, colony formation units (CFUs) per milliliter in blood from all 12 immunized subjects decreased from ∼4000 at time 0 to sterile cultures at 3 hours. In the presence of eculizumab, there was a >22-fold increase in geometric mean CFUs per milliliter (90 596 and 114 683 CFU/mL for serogroup B and C strains, respectively; < .0001 compared with time 0). In the presence of ACH-4471, there was a >12-fold decrease (23 and 331 CFU/mL, respectively; < .0001). The lack of meningococci killing by blood containing eculizumab resulted from inhibition of release of C5a, a C5 split product needed for upregulation of phagocytosis. The results provide an explanation for the large number of cases of meningococcal disease in immunized patients being treated with eculizumab and suggest that vaccination may provide better protection against meningococcal disease in patients treated with an AP-specific inhibitor.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/farmacologia
Imunização
Viabilidade Microbiana/efeitos dos fármacos
Neisseria meningitidis/efeitos dos fármacos
Proteínas Opsonizantes/metabolismo
Fagocitose/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adulto
Idoso
Via Alternativa do Complemento/efeitos dos fármacos
Proteínas do Sistema Complemento/imunologia
Feminino
Seres Humanos
Masculino
Meia-Idade
Receptor da Anafilatoxina C5a/antagonistas & inibidores
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (C5AR1 protein, human); 0 (Opsonin Proteins); 0 (Receptor, Anaphylatoxin C5a); 9007-36-7 (Complement System Proteins); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-05-781450


  8 / 912 MEDLINE  
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[PMID]:28614388
[Au] Autor:Bergdolt S; Kovtun A; Hägele Y; Liedert A; Schinke T; Amling M; Huber-Lang M; Ignatius A
[Ad] Endereço:Institute of Orthopedic Research and Biomechanics, University of Ulm, Ulm, Germany.
[Ti] Título:Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing.
[So] Source:PLoS One;12(6):e0179512, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The anaphylatoxin receptor C5aR1 plays an important role not only in innate immune responses, but also in bone metabolism and fracture healing, being highly expressed on immune and bone cells, including osteoblasts and osteoclasts. C5aR1 induces osteoblast migration, cytokine generation and osteoclastogenesis, however, the exact role of C5aR1-mediated signaling in osteoblasts is not entirely known. Therefore, we hypothesized that osteoblasts are essential target cells for C5a and that fracture healing should be disturbed in mice with an osteoblast-specific C5aR1 overexpression (Col1a1-C5aR1). Osteoblast activity in vitro, bone phenotype and fracture healing after isolated osteotomy and after combined osteotomy with additional thoracic trauma were analyzed. The systemic and local inflammatory reactions were analyzed by determining C5a and IL-6 concentrations in blood, bronchoalveolar lavage fluid and fracture callus and the recruitment of immune cells. In vitro, osteoblast proliferation and differentiation were similar to wildtype cells, and phosphorylation of p38 and expression of IL-6 and RANKL were increased in osteoblasts derived from Col1a1-C5aR1 mice. Bone phenotype and the inflammatory reaction were unaffected in Col1a1-C5aR1 mice. Fracture healing was significantly impaired as demonstrated by significantly reduced bone content, bone mineral density and flexural rigidity, possibly due to significantly increased osteoclast numbers. C5aR1 signaling in osteoblasts might possibly affect RANKL/OPG balance, leading to increased bone resorption. Additional trauma significantly impaired fracture healing, particularly in Col1a1-C5aR1 mice. In conclusion, the data indicate that C5aR1 signaling in osteoblasts plays a detrimental role in bone regeneration after fracture.
[Mh] Termos MeSH primário: Consolidação da Fratura/genética
Regulação da Expressão Gênica
Osteoblastos/metabolismo
Receptor da Anafilatoxina C5a/genética
[Mh] Termos MeSH secundário: Animais
Western Blotting
Líquido da Lavagem Broncoalveolar/química
Células Cultivadas
Colágeno Tipo I/genética
Colágeno Tipo I/metabolismo
Complemento C5a/metabolismo
Fêmur/diagnóstico por imagem
Fêmur/metabolismo
Fêmur/cirurgia
Interleucina-6/genética
Interleucina-6/metabolismo
Camundongos
Osteoblastos/citologia
Osteogênese/genética
Osteoprotegerina/genética
Osteoprotegerina/metabolismo
Fosforilação
Ligante RANK/genética
Ligante RANK/metabolismo
Receptor da Anafilatoxina C5a/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Transdução de Sinais/genética
Regulação para Cima
Microtomografia por Raio-X/métodos
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C5ar1 protein, mouse); 0 (Collagen Type I); 0 (Interleukin-6); 0 (Osteoprotegerin); 0 (RANK Ligand); 0 (Receptor, Anaphylatoxin C5a); 0 (TNFSF11 protein, human); 0 (collagen type I, alpha 1 chain); 80295-54-1 (Complement C5a); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179512


  9 / 912 MEDLINE  
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[PMID]:28576324
[Au] Autor:Hawksworth OA; Li XX; Coulthard LG; Wolvetang EJ; Woodruff TM
[Ad] Endereço:School of Biomedical Sciences, University of Queensland, St. Lucia, Australia; Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St. Lucia, Australia.
[Ti] Título:New concepts on the therapeutic control of complement anaphylatoxin receptors.
[So] Source:Mol Immunol;89:36-43, 2017 Sep.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The complement system is a pivotal driver of innate immunity, coordinating the host response to protect against pathogens. At the heart of the complement response lie the active fragments, C3a and C5a, acting through their specific receptors, C3aR, C5aR1, and C5aR2, to direct the cellular response to inflammation. Their potent function however, places them at risk of damaging the host, with aberrant C3a and C5a signaling activity linked to a wide range of disorders of inflammatory, autoimmune, and neurodegenerative etiologies. As such, the therapeutic control of these receptors represents an attractive drug target, though, the realization of this clinical potential remains limited. With the success of eculizumab, and the progression of a number of novel C5a-C5aR1 targeted drugs to phase II and III clinical trials, there is great promise for complement therapeutics in future clinical practice. In contrast, the toolbox of drugs available to modulate C3aR and C5aR2 signaling remains limited, however, the emergence of new selective ligands and molecular tools, and an increased understanding of the function of these receptors in disease, has highlighted their unique potential for clinical applications. This review provides an update on the growing arsenal of drugs now available to target C5, and C5a and C3a receptor signaling, and discusses their utility in both clinical and pre-clinical development.
[Mh] Termos MeSH primário: Ativação do Complemento/imunologia
Complemento C3a/imunologia
Complemento C5a/imunologia
Receptor da Anafilatoxina C5a/imunologia
Receptores de Quimiocinas/imunologia
Receptores de Complemento/imunologia
[Mh] Termos MeSH secundário: Anticorpos Monoclonais Humanizados/uso terapêutico
Ativação do Complemento/efeitos dos fármacos
Inativadores do Complemento/uso terapêutico
Seres Humanos
Inflamação/tratamento farmacológico
Inflamação/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (C5AR1 protein, human); 0 (Complement Inactivating Agents); 0 (GPR77 protein, human); 0 (Receptor, Anaphylatoxin C5a); 0 (Receptors, Chemokine); 0 (Receptors, Complement); 0 (complement C3a receptor); 80295-42-7 (Complement C3a); 80295-54-1 (Complement C5a); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170604
[St] Status:MEDLINE


  10 / 912 MEDLINE  
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[PMID]:28572445
[Au] Autor:Fattahi F; Kalbitz M; Malan EA; Abe E; Jajou L; Huber-Lang MS; Bosmann M; Russell MW; Zetoune FS; Ward PA
[Ad] Endereço:Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
[Ti] Título:Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction.
[So] Source:FASEB J;31(9):4129-4139, 2017 Sep.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Polymicrobial sepsis in mice causes myocardial dysfunction after generation of the complement anaphylatoxin, complement component 5a (C5a). C5a interacts with its receptors on cardiomyocytes (CMs), resulting in redox imbalance and cardiac dysfunction that can be functionally measured and quantitated using Doppler echocardiography. In this report we have evaluated activation of MAPKs and Akt in CMs exposed to C5a and after cecal ligation and puncture (CLP) In both cases, C5a caused activation (phosphorylation) of MAPKs and Akt in CMs, which required availability of both C5a receptors. Using immunofluorescence technology, activation of MAPKs and Akt occurred in left ventricular (LV) CMs, requiring both C5a receptors, C5aR1 and -2. Use of a water-soluble p38 inhibitor curtailed activation of MAPKs and Akt in LV CMs as well as the appearance of cytokines and histones in plasma from CLP mice. When mouse macrophages were exposed to LPS, activation of MAPKs and Akt also occurred. The copresence of the p38 inhibitor blocked these activation responses. Finally, the presence of the p38 inhibitor in CLP mice reduced the development of cardiac dysfunction. These data suggest that polymicrobial sepsis causes cardiac dysfunction that appears to be linked to activation of MAPKs and Akt in heart.-Fattahi, F., Kalbitz, M., Malan, E. A., Abe, E., Jajou, L., Huber-Lang, M. S., Bosmann, M., Russell, M. W., Zetoune, F. S., Ward, P. A. Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction.
[Mh] Termos MeSH primário: Complemento C5a/metabolismo
Regulação da Expressão Gênica/fisiologia
Cardiopatias/etiologia
Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Sepse/metabolismo
[Mh] Termos MeSH secundário: Animais
Complemento C5a/genética
Cardiopatias/metabolismo
Interleucinas
Masculino
Quinases de Proteína Quinase Ativadas por Mitógeno/genética
Proteínas Proto-Oncogênicas c-akt/genética
Ratos
Ratos Sprague-Dawley
Receptor da Anafilatoxina C5a/genética
Receptor da Anafilatoxina C5a/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C5ar1 protein, mouse); 0 (C5ar2 protein, mouse); 0 (Interleukins); 0 (Receptor, Anaphylatoxin C5a); 80295-54-1 (Complement C5a); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201700140R



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