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1.
Animal Model Exp Med ; 7(3): 367-376, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38860566

RESUMO

BACKGROUND: Severe trauma is associated with systemic inflammation and organ dysfunction. Preclinical rodent trauma models are the mainstay of postinjury research but have been criticized for not fully replicating severe human trauma. The aim of this study was to create a rat model of multicompartmental injury which recreates profound traumatic injury. METHODS: Male Sprague-Dawley rats were subjected to unilateral lung contusion and hemorrhagic shock (LCHS), multicompartmental polytrauma (PT) (unilateral lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofracture), or naïve controls. Weight, plasma toll-like receptor 4 (TLR4), hemoglobin, spleen to body weight ratio, bone marrow (BM) erythroid progenitor (CFU-GEMM, BFU-E, and CFU-E) growth, plasma granulocyte colony-stimulating factor (G-CSF) and right lung histologic injury were assessed on day 7, with significance defined as p values <0.05 (*). RESULTS: Polytrauma resulted in markedly more profound inhibition of weight gain compared to LCHS (p = 0.0002) along with elevated plasma TLR4 (p < 0.0001), lower hemoglobin (p < 0.0001), and enlarged spleen to body weight ratios (p = 0.004). Both LCHS and PT demonstrated suppression of CFU-E and BFU-E growth compared to naïve (p < 0.03, p < 0.01). Plasma G-CSF was elevated in PT compared to both naïve and LCHS (p < 0.0001, p = 0.02). LCHS and PT demonstrated significant histologic right lung injury with poor alveolar wall integrity and interstitial edema. CONCLUSIONS: Multicompartmental injury as described here establishes a reproducible model of multicompartmental injury with worsened anemia, splenic tissue enlargement, weight loss, and increased inflammatory activity compared to a less severe model. This may serve as a more effective model to recreate profound traumatic injury to replicate the human inflammatory response postinjury.


Assuntos
Anemia , Modelos Animais de Doenças , Traumatismo Múltiplo , Ratos Sprague-Dawley , Choque Hemorrágico , Animais , Choque Hemorrágico/complicações , Masculino , Anemia/etiologia , Anemia/patologia , Traumatismo Múltiplo/complicações , Traumatismo Múltiplo/patologia , Ratos , Medula Óssea/patologia , Receptor 4 Toll-Like/metabolismo , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Fator Estimulador de Colônias de Granulócitos/sangue , Hemoglobinas
2.
Bull Exp Biol Med ; 176(5): 607-611, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38730105

RESUMO

The study presents the killer functions of circulating neutrophils: myeloperoxidase activity, the ability to generate ROS, phagocytic activity, receptor status, NETosis, as well as the level of cytokines IL-2, IL-4, IL-6, IL-17A, and IL-18, granulocyte CSF, monocyte chemotactic protein 1, and neutrophil elastase in the serum of patients with uterine myoma and endometrial cancer (FIGO stages I-III). The phagocytic ability of neutrophils in uterine myoma was influenced by serum levels of granulocyte CSF and IL-2 in 54% of the total variance. The degranulation ability of neutrophils in endometrial cancer was determined by circulating IL-18 in 50% of the total variance. In uterine myoma, 66% of the total variance in neutrophil myeloperoxidase activity was explained by a model dependent on blood levels of IL-17A, IL-6, and IL-4. The risk of endometrial cancer increases when elevated levels of monocyte chemotactic protein 1 in circulating neutrophils are associated with reduced ability to capture particles via extracellular traps (96% probability).


Assuntos
Quimiocina CCL2 , Neoplasias do Endométrio , Interleucina-17 , Interleucina-6 , Neutrófilos , Humanos , Feminino , Neutrófilos/metabolismo , Neutrófilos/imunologia , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/metabolismo , Interleucina-6/sangue , Quimiocina CCL2/sangue , Interleucina-17/sangue , Pessoa de Meia-Idade , Interleucina-4/sangue , Peroxidase/sangue , Peroxidase/metabolismo , Interleucina-18/sangue , Neoplasias Uterinas/sangue , Neoplasias Uterinas/imunologia , Neoplasias Uterinas/patologia , Fator Estimulador de Colônias de Granulócitos/sangue , Fator Estimulador de Colônias de Granulócitos/metabolismo , Fagocitose , Leiomioma/sangue , Leiomioma/imunologia , Leiomioma/patologia , Leiomioma/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Elastase de Leucócito/sangue , Elastase de Leucócito/metabolismo , Adulto , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/imunologia , Espécies Reativas de Oxigênio/metabolismo , Idoso , Interleucina-2
3.
Transfus Med Rev ; 38(2): 150824, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38569349

RESUMO

Limited data regarding elevation of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in mobilized donors with G-CSF is available. We extended these findings by examining serum NT-proBNP in a cohort study including 35 healthy donors and 69 patients who received G-CSF for CD34+ mobilization as well as 54 patients who did not receive G-CSF but who underwent collection of CD3+ cells for chimeric antigen receptor (CAR) T-cell manufacturing. No donor in the three cohorts experienced significant cardiac adverse events. NT-proBNP levels were measured before and after G-CSF administration and after finishing apheresis procedure. NT-proBNP increase was observed in mobilized healthy donors after G-CSF administration, but was not observed in mobilized or non-mobilized patients. Only in the cohort of healthy donors, pairwise comparisons using Wilcoxon signed ranks test showed a significant increase between the mean serum NT-proBNP level after G-CSF administration and the mean serum NT-proBNP level measured before G-CSF administration (231.09 ± 156.15 pg/mL vs. 58.88 ± 26.84 pg/mL; P < .01). No correlation was observed between NT-proBNP increase and G-CSF dose (rs = 0.09; n = 32; P = .6) and no other variables contributing to predict serum NT-proBNP increase were detected. In conclusion, we observed a statistically, although not clinically, significant increase of NT-proBNP in healthy donors who received G-CSF as CD34+ cell mobilization.


Assuntos
Fator Estimulador de Colônias de Granulócitos , Mobilização de Células-Tronco Hematopoéticas , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Humanos , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Masculino , Fator Estimulador de Colônias de Granulócitos/sangue , Feminino , Mobilização de Células-Tronco Hematopoéticas/métodos , Pessoa de Meia-Idade , Adulto , Estudos de Coortes , Idoso , Doadores de Sangue , Antígenos CD34
4.
Ann Surg Oncol ; 31(6): 3707-3717, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38238536

RESUMO

BACKGROUND: Neutrophil extracellular traps (NETs) occur when neutrophil chromatin is decondensed and extruded into the extracellular space in a web-like structure. Originally described as an anti-microbial function, this process has been implicated in the pathogenesis of pancreatic disease. In addition, NETs are upregulated during physiologic wound-healing and coagulation. This study evaluated how the inflammatory response to pancreatic surgery influences NET formation. METHODS: For this study, 126 patients undergoing pancreatectomy gave consent before participation. Plasma was collected at several time points (preoperatively and through the postoperative outpatient visit). Plasma levels of NET markers, including cell-free DNA (cfDNA), citrullinated histone H3 (CitH3), interleukin (IL)-8, IL-6, and granulocyte colony-stimulating factor (G-CSF) were measured using enzyme-linked immunosorbent assay (ELISA). Patient clinical data were retrospectively collected from a prospectively maintained database. RESULTS: After pancreatic resection, NET markers (cfDNA and CitH3) were elevated, peaking on postoperative days 3 and 4. This increase in NETs was due to an inherent change in neutrophil biology. Postoperatively, NET-inducing cytokines (IL-8, IL-6, and G-CSF) were increased, peaking early in the postoperative course. The patients undergoing the robotic approach had a reduction in NETs during the postoperative period compared with those who underwent the open approach. The patients who experienced a pancreatic leak had an increase in NET markers during the postoperative period. CONCLUSIONS: Pancreatectomy induces cancer-promoting NET formation. The minimally invasive robotic approach may induce fewer NETs, although the current analysis was limited by selection bias. Pancreatic leak resulted in increased NETs. Further study into the potential for NET inhibition during the perioperative period is warranted.


Assuntos
Armadilhas Extracelulares , Pancreatectomia , Neoplasias Pancreáticas , Humanos , Armadilhas Extracelulares/metabolismo , Pancreatectomia/efeitos adversos , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Seguimentos , Neutrófilos/patologia , Neutrófilos/metabolismo , Estudos Retrospectivos , Prognóstico , Ácidos Nucleicos Livres/sangue , Estudos Prospectivos , Adulto , Histonas/metabolismo , Histonas/sangue , Fator Estimulador de Colônias de Granulócitos/sangue , Interleucina-6/sangue , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo
5.
BMC Infect Dis ; 22(1): 343, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35382755

RESUMO

BACKGROUND: Pneumonia is a common complication of influenza and closely related to mortality in influenza patients. The present study examines cytokines as predictors of the prognosis of influenza-associated pneumonia. METHODS: This study included 101 inpatients with influenza (64 pneumonia and 37 non-pneumonia patients). 48 cytokines were detected in the serum samples of the patients and the clinical characteristics were analyzed. The correlation between them was analyzed to identify predictive biomarkers for the prognosis of influenza-associated pneumonia. RESULTS: Seventeen patients had poor prognosis and developed pneumonia. Among patients with influenza-associated pneumonia, the levels of 8 cytokines were significantly higher in those who had a poor prognosis: interleukin-6 (IL-6), interferon-γ (IFN-γ), granulocyte colony-stimulating factor (G-CSF), monocyte colony-stimulating factor (M-CSF), monocyte chemoattractant protein-1 (MCP-1), monocyte chemoattractant protein-3, Interleukin-2 receptor subunit alpha and Hepatocyte growth factor. Correlation analysis showed that the IL-6, G-CSF, M-CSF, IFN-γ, and MCP-1 levels had positive correlations with the severity of pneumonia. IL-6 and G-CSF showed a strong and positive correlation with poor prognosis in influenza-associated pneumonia patients. The combined effect of the two cytokines resulted in the largest area (0.926) under the receiver-operating characteristic curve. CONCLUSION: The results indicate that the probability of poor prognosis in influenza patients with pneumonia is significantly increased. IL-6, G-CSF, M-CSF, IFN-γ, and MCP-1 levels had a positive correlation with the severity of pneumonia. Importantly, IL-6 and G-CSF were identified as significant predictors of the severity of influenza-associated pneumonia.


Assuntos
Fator Estimulador de Colônias de Granulócitos , Influenza Humana , Interleucina-6 , Pneumonia Viral , Citocinas/sangue , Fator Estimulador de Colônias de Granulócitos/sangue , Humanos , Influenza Humana/complicações , Influenza Humana/imunologia , Interleucina-6/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Prognóstico
6.
PLoS One ; 17(2): e0264404, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35213631

RESUMO

BACKGROUND: Many studies have predicted major depressive disorder (MDD) as the leading cause of global health by 2030 due to its high prevalence, disability, and illness. However, the actual pathophysiological mechanism behind depression is unknown. Scientists consider alterations in cytokines might be tools for understanding the pathogenesis and treatment of MDD. Several past studies on several inflammatory cytokine expressions in MDD reveal that an inflammatory process is activated, although the precise causes of that changes in cytokine levels are unclear. Therefore, we aimed to investigate resistin and G-CSF in MDD patients and controls to explore their role in the pathogenesis and development of depression. METHODS: We included 220 participants in this study. Among them, 108 MDD patients and 112 age-sex matched healthy control (HCs). We used DSM-5 to evaluate study participants. Also, we applied the Ham-D rating scale to assess the severity of patients. Serum resistin and G-CSF levels were measured using ELISA kits (BosterBio, USA). RESULTS: The present study observed increased serum resistin levels in MDD patients compared to HCs (13.82 ± 1.24ng/mL and 6.35 ± 0.51ng/mL, p <0.001). However, we did not find such changes for serum G-CSF levels between the groups. Ham-D scores showed a significant correlation with serum resistin levels but not G-CSF levels in the patient group. Furthermore, ROC analysis showed a fairly predictive performance of serum resistin levels in major depression (AUC = 0.746). CONCLUSION: The present study findings suggest higher serum resistin levels are associated with the pathophysiology of MDD. This elevated serum resistin level may serve as an early risk assessment indicator for MDD. However, the role of serum G-CSF in the development of MDD is still unclear despite its neuroprotective and anti-inflammatory effects.


Assuntos
Transtorno Depressivo Maior/sangue , Fator Estimulador de Colônias de Granulócitos/sangue , Resistina/sangue , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
Sci Rep ; 12(1): 667, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35027593

RESUMO

Granulocyte colony stimulating factor (GCSF) can decrease mortality of patients undergo chemotherapy through increasing neutrophil counts. Many strategies have been developed to improve its blood circulating time. Albumin binding domain (ABD) was genetically fused to N-terminal end of GCSF encoding sequence and expressed as cytoplasmic inclusion bodies within Escherichia coli. Biological activity of ABD-GCSF protein was assessed by proliferation assay on NFS-60 cells. Physicochemical properties were analyzed through size exclusion chromatography, circular dichroism, intrinsic fluorescence spectroscopy and dynamic light scattering. Pharmacodynamics and pharmacokinetic properties were also investigated in a neutropenic rat model. CD and IFS spectra revealed that ABD fusion to GCSF did not significantly affect the secondary and tertiary structures of the molecule. DLS and SEC results indicated the absence of aggregation formation. EC50 value of the ABD-GCSF in proliferation of NFS-60 cells was 75.76 pg/ml after 72 h in comparison with control GCSF molecules (Filgrastim: 73.1 pg/ml and PEG-Filgrastim: 44.6 pg/ml). Animal studies of ABD-GCSF represented improved serum half-life (9.3 ± 0.7 h) and consequently reduced renal clearance (16.1 ± 1.4 ml/h.kg) in comparison with Filgrastim (1.7 ± 0.1 h). Enhanced neutrophils count following administration of ABD-GCSF was comparable with Filgrastim and weaker than PEG-Filgrastim treated rats. In vitro and in vivo results suggested the ABD fusion as a potential approach for improving GCSF properties.


Assuntos
Albuminas/farmacologia , Proliferação de Células/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/sangue , Fator Estimulador de Colônias de Granulócitos/farmacologia , Domínios Proteicos , Albuminas/química , Albuminas/farmacocinética , Animais , Linhagem Celular , Fenômenos Químicos , Modelos Animais de Doenças , Escherichia coli , Fator Estimulador de Colônias de Granulócitos/química , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Meia-Vida , Humanos , Corpos de Inclusão , Contagem de Leucócitos , Neutropenia/metabolismo , Neutrófilos/efeitos dos fármacos , Ligação Proteica , Ratos
8.
Clin Pharmacol Ther ; 111(1): 293-301, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34605552

RESUMO

A long-acting granulocyte colony-stimulating factor, tripegfilgrastim, was approved in Korea for the prevention of chemotherapy-induced neutropenia in adult patients. In this study, we evaluated the pharmacokinetics, pharmacodynamics, and safety of tripegfilgrastim in pediatric patients. A phase I, open-label, single ascending-dose study was performed in pediatric patients with solid tumors or lymphoma (ClinicalTrials.gov, NCT02963389). The patients were stratified according to age groups (aged 6 to 12 or 12 to 19 years) and received a single subcutaneous dose of tripegfilgrastim 60 µg/kg or 100 µg/kg. Tripegfilgrastim was administered 24 hours after the end of the chemotherapy, and serial blood sampling and safety monitoring were conducted. Twenty-seven patients with solid tumors were enrolled in this study. Tripegfilgrastim was detectable in plasma for an extended period (terminal half-life > 40 hours), and plasma concentrations increased slightly less than dose proportionally. The mean duration of grade 4 neutropenia was reduced as the average tripegfilgrastim concentration during the initial neutrophil recovery process increased. No substantial differences in the pharmacokinetic and pharmacodynamic responses were observed between the two age groups. When stratified by body weight, weighing more than 45 kg has a higher risk of a prolonged neutropenia period when receiving the lower dose (60 µg/kg) of tripegfilgrastim. Tripegfilgrastim was generally safe and well-tolerated in the pediatric patients. These results justify further clinical investigations of tripegfilgrastim at 100 µg/kg dose in pediatric patients.


Assuntos
Filgrastim/análogos & derivados , Filgrastim/farmacocinética , Fármacos Hematológicos/farmacocinética , Neutropenia/tratamento farmacológico , Adolescente , Criança , Feminino , Filgrastim/administração & dosagem , Filgrastim/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/sangue , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Fármacos Hematológicos/administração & dosagem , Fármacos Hematológicos/efeitos adversos , Fármacos Hematológicos/sangue , Humanos , Injeções Subcutâneas , Masculino , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Neutrófilos/efeitos dos fármacos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , República da Coreia
9.
PLoS One ; 16(12): e0260623, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34855834

RESUMO

PURPOSE: Cytokines are major mediators of COVID-19 pathogenesis and several of them are already being regarded as predictive markers for the clinical course and outcome of COVID-19 cases. A major pitfall of many COVID-19 cytokine studies is the lack of a benchmark sampling timing. Since cytokines and their relative change during an infectious disease course is quite dynamic, we evaluated the predictive value of serially measured cytokines for COVID-19 cases. METHODS: In this single-center, prospective study, a broad spectrum of cytokines were determined by multiplex ELISA assay in samples collected at admission and at the third day of hospitalization. Appropriateness of cytokine levels in predicting mortality were assessed by receiver-operating characteristic (ROC) analyses for both sampling times in paralel to conventional biomarkers. RESULTS: At both sampling points, higher levels of IL-6, IL-7, IL-10, IL-15, IL-27 IP-10, MCP-1, and GCSF were found to be more predictive for mortality (p<0.05). Some of these cytokines, such as IL-6, IL-10, IL-7 and GCSF, had higher sensitivity and specificity in predicting mortality. AUC values of IL-6, IL-10, IL-7 and GCSF were 0.85 (0.65 to 0.92), 0.88 (0.73 to 0.96), 0.80 (0.63 to 0.91) and 0.86 (0.70 to 0.95), respectively at hospital admission. Compared to hospital admission, on the 3rd day of hospitalization serum levels of IL-6 and, IL-10 decreased significantly in the survivor group, unlike the non-survivor group (IL-6, p = 0.015, and IL-10, p = 0.016). CONCLUSION: Our study results suggest that single-sample-based cytokine analyzes can be misleading and that cytokine levels measured serially at different sampling times provide a more precise and accurate estimate for the outcome of COVID-19 patients.


Assuntos
COVID-19/sangue , Citocinas/sangue , Idoso , Idoso de 80 Anos ou mais , COVID-19/mortalidade , Quimiocina CCL2/sangue , Quimiocina CXCL10/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Fator Estimulador de Colônias de Granulócitos/sangue , Humanos , Interleucina-10/sangue , Interleucina-15/sangue , Interleucina-27/sangue , Interleucina-6/sangue , Interleucina-7/sangue , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Resultado do Tratamento
10.
Sci Rep ; 11(1): 23303, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34857759

RESUMO

Differentiation of Crohn's disease (CD) from intestinal tuberculosis (ITB) is a big challenge to gastroenterologists because of their indistinguishable features and insensitive diagnostic tools. A non-invasive biomarker is urgently required to distinguish ITB/CD patients particularly in India, a TB endemic region, where CD frequency is increasing rapidly due to urbanization. Among the three differentially expressed miRNAs obtained from small RNA transcriptomic profiling of ileocaecal/terminal ileal tissue of ITB/CD patients (n = 3), only two down-regulated miRNAs, miR-31-5p, and miR-215-5p showed comparable data in qRT-PCR. Out of which, only miR-215-5p was detectable in the patient's plasma, but there was no significant difference in expression between ITB/CD. On the other hand, miR-375-3p, the pulmonary TB specific marker was found in higher amount in the plasma of ITB patients than CD while reverse expression was observed in the ileocaecal/terminal ileal tissues of the same patients. Next, using Bioplex pro-human cytokine 48-plex screening panel, only three chemokines, Eotaxin-1/CCL11, SDF-1α/CXCL12, and G-CSF have noted significantly different levels in the serum of ITB/CD patients. ROC analysis has revealed that compared to a single molecule, a combination of miR-375-3p + Eotaxin-1/CCL11 + SDF-1α /CXCL12 + G-CSF showed a better AUC of 0.83, 95% CI (0.69-0.96) with 100% specificity and positive predictive value while sensitivity, negative predictive value, and accuracy were 56%, 69%, and 78% respectively in distinguishing ITB from CD. This study suggests that a combination of plasma markers shows better potential in differentiating ITB from CD than a single marker and this panel of markers may be used for clinical management of ITB/CD patients.


Assuntos
Quimiocina CCL11/sangue , Quimiocina CXCL12/sangue , Doença de Crohn/diagnóstico , Fator Estimulador de Colônias de Granulócitos/sangue , MicroRNAs/sangue , Tuberculose Gastrointestinal/diagnóstico , Adulto , Biomarcadores/sangue , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Thorac Cancer ; 12(20): 2680-2690, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34498383

RESUMO

INTRODUCTION: Immune cells and molecules are considered as clinical biomarkers and potential targets for immunotherapy. Analyses of the composition of peripheral blood cells hold promise for providing a basis for diagnosing and prognosis lung cancer. In this study, we assessed correlations between immune cell subset profiles in peripheral blood and disease prognosis in patients with lung cancer. METHODS: One hundred and thirteen patients with lung cancer and 99 age-matched healthy people were enrolled in this study. The percentage and cell count of monocytes, neutrophils, T cells, B cells, natural killer (NK), and NKT cells in peripheral blood were analyzed by flow cytometry or peripheral blood analyzer. Serum cytokines and colony-stimulating factors were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: A reduction in antitumor NK cells (p < 0.0001) and an increase in the protumor MDSCs (p < 0.0001) were observed in the lung cancer patients compared with the controls. Monocyte counts were significantly higher in lung cancer patients with histories of smoking (p < 0.05) or drinking (p < 0.01) than in patients with no relevant history or healthy controls. The number of neutrophils and the neutrophil-to-lymphocyte ratio (NLR) were particularly higher in patients with liver metastasis (p < 0.01) compared with no metastasis patients or healthy controls. Levels of the monocyte-derived cytokine interleukin-6 (p < 0.05), granulocyte colony-stimulating factor (G-CSF) (p < 0.0001), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (p < 0.0001) were higher in patients than in controls. G-CSF levels decreased during the remission phase (p < 0.05), and positively correlated with carbohydrate antigen 19-9 (p < 0.05) and gene mutation (p < 0.05). CONCLUSION: Monocyte and neutrophil counts were higher in peripheral blood in lung cancer patients than in controls, especially when patients had histories of smoking, drinking, and liver metastasis. Serum levels of G-CSF and GM-CSF were higher in lung cancer patients, and G-CSF levels positively correlated with disease severity.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Fator Estimulador de Colônias de Granulócitos/sangue , Neoplasias Pulmonares/sangue , Monócitos/metabolismo , Neutrófilos/metabolismo , Carcinoma de Pequenas Células do Pulmão/sangue , Idoso , Feminino , Humanos , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/metabolismo , Linfócitos T/metabolismo
12.
Eur J Haematol ; 107(5): 583-591, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34342052

RESUMO

OBJECTIVES: The aim of this study was to clarify the mechanisms of the transient increase in neutrophils after running standard marathon races by measurement of cytokines involved in the production and survival of neutrophils, and cortisol. METHODS: Fourteen male runners who participated in the Hokkaido Marathon, which is the sole marathon race held in summer in Japan, and finished the standard marathon were analyzed sequentially from the start until a maximum of 8 days after the finish. RESULTS: Neutrophilia was observed in all runners just after they reached the goal (mean neutrophils: 13 226/µL). IL-6, G-CSF, and cortisol, but not GM-CSF, increased at the same time. Time-course studies with complete blood counts, biochemical markers, cytokines, and cortisol showed transient increases in neutrophils, monocytes, myoglobin, high-sensitivity C-reactive protein (hsCRP), G-CSF, IL-6, and cortisol. The increase in hsCRP was delayed 6 hours from the first increase in neutrophils. Correlations were observed between the neutrophil count and G-CSF, IL-6, and cortisol (G-CSF; r = .667, IL-6; r = .667, cortisol; r = .623). CONCLUSION: These results suggest that G-CSF is directly involved, and IL-6 is involved via cortisol in the transient neutrophilia that occurs after marathon races.


Assuntos
Fator Estimulador de Colônias de Granulócitos/sangue , Hidrocortisona/sangue , Interleucina-6/sangue , Corrida de Maratona , Neutrófilos/metabolismo , Adulto , Humanos , Masculino , Adulto Jovem
13.
J Clin Invest ; 131(14)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34263738

RESUMO

BACKGROUNDNecrotizing soft-tissue infections (NSTIs) are rapidly progressing infections frequently complicated by septic shock and associated with high mortality. Early diagnosis is critical for patient outcome, but challenging due to vague initial symptoms. Here, we identified predictive biomarkers for NSTI clinical phenotypes and outcomes using a prospective multicenter NSTI patient cohort.METHODSLuminex multiplex assays were used to assess 36 soluble factors in plasma from NSTI patients with positive microbiological cultures (n = 251 and n = 60 in the discovery and validation cohorts, respectively). Control groups for comparative analyses included surgical controls (n = 20), non-NSTI controls (i.e., suspected NSTI with no necrosis detected upon exploratory surgery, n = 20), and sepsis patients (n = 24).RESULTSThrombomodulin was identified as a unique biomarker for detection of NSTI (AUC, 0.95). A distinct profile discriminating mono- (type II) versus polymicrobial (type I) NSTI types was identified based on differential expression of IL-2, IL-10, IL-22, CXCL10, Fas-ligand, and MMP9 (AUC >0.7). While each NSTI type displayed a distinct array of biomarkers predicting septic shock, granulocyte CSF (G-CSF), S100A8, and IL-6 were shared by both types (AUC >0.78). Finally, differential connectivity analysis revealed distinctive networks associated with specific clinical phenotypes.CONCLUSIONSThis study identifies predictive biomarkers for NSTI clinical phenotypes of potential value for diagnostic, prognostic, and therapeutic approaches in NSTIs.TRIAL REGISTRATIONClinicalTrials.gov NCT01790698.FUNDINGCenter for Innovative Medicine (CIMED); Region Stockholm; Swedish Research Council; European Union; Vinnova; Innovation Fund Denmark; Research Council of Norway; Netherlands Organisation for Health Research and Development; DLR Federal Ministry of Education and Research; and Swedish Children's Cancer Foundation.


Assuntos
Infecções dos Tecidos Moles , Adulto , Idoso , Biomarcadores/sangue , Citocinas/sangue , Intervalo Livre de Doença , Proteína Ligante Fas/sangue , Feminino , Fator Estimulador de Colônias de Granulócitos/sangue , Humanos , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Necrose , Estudos Prospectivos , Infecções dos Tecidos Moles/sangue , Infecções dos Tecidos Moles/mortalidade , Taxa de Sobrevida , Trombomodulina/sangue
14.
Med Oncol ; 38(6): 70, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34003398

RESUMO

Mechanisms for late-onset neutropenia (LON) after rituximab treatment are poorly defined both for non-Hodgkin lymphoma (NHL) and for autoimmune disorders. We performed a case-control analysis of a prospective cohort of 169 evaluable consecutive rituximab-treated NHL patients to assess cytokines involved in neutro- and lymphopoiesis (G-CSF, SDF1, BAFF, APRIL) and inflammation (CRP) as possible LON mechanisms. Fifteen patients (9%) developed LON (peripheral blood /PB/ absolute neutrophil counts /ANC/ < 0.5 G/L, all with marked depletion of CD20+ B-lymphocytes in bone marrows); they were compared with 20 matched NHL controls without LON. At start of LON, significantly higher PB G-CSF and BAFF levels (P = 0.0004 and 0.006, respectively), as well as CRP rises were noted compared to controls; these G-CSF and BAFF and most CRP values returned to levels of the controls in post-LON samples. G-CSF (but not BAFF) changes correlated to CRP rises (but not to ANC levels). BAFF levels correlated significantly to absolute monocyte counts and PB large granular lymphocyte counts (but not to ANC, C-CSF or CRP values). No changes of SDF1 or APRIL levels were noted. Neither LON cases nor controls displayed anti-neutrophil autoantibodies. Collectively, LON in NHL patients was timewise related to transient bursts of blood G-CSF and BAFF concentrations, suggesting that these neutro- and lymphopoiesis growth factors play a role in emergence of rituximab-induced LON, and that inflammation may be a trigger for G-CSF production during LON.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Fator Ativador de Células B/sangue , Fator Estimulador de Colônias de Granulócitos/sangue , Linfoma não Hodgkin/tratamento farmacológico , Neutropenia/induzido quimicamente , Rituximab/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Casos e Controles , Quimiocina CXCL12/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Estudos Prospectivos , Receptores Imunológicos/sangue , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue
15.
Kyobu Geka ; 74(5): 347-351, 2021 May.
Artigo em Japonês | MEDLINE | ID: mdl-33980793

RESUMO

A 38-year-old man was admitted to our hospital because of right chest pain and high fever. Chest X-ray and computed tomography scan revealed right pleural effusion and pleural thickness. Diagnosis of malignant mesothelioma was established by pleural biopsy. Serum level of granulocyte colony stimulating factor (G-CSF) was high. We performed extrapleural pneumonectomy which improved high fever and inflammation, however the patient died three months after surgery.


Assuntos
Fator Estimulador de Colônias de Granulócitos/sangue , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Adulto , Humanos , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma/cirurgia , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/cirurgia
16.
Int J Hematol ; 113(3): 348-361, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33398631

RESUMO

Histidine decarboxylase (HDC), a histamine synthase, is expressed in various hematopoietic cells and is induced by hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF). We previously showed that nitrogen-containing bisphosphonate (NBP)-treatment induces extramedullary hematopoiesis via G-CSF stimulation. However, the function of HDC in NBP-induced medullary and extramedullary hematopoiesis remains unclear. Here, we investigated changes in hematopoiesis in wild-type and HDC-deficient (HDC-KO) mice. NBP treatment did not induce anemia in wild-type or HDC-KO mice, but did produce a gradual increase in serum G-CSF levels in wild-type mice. NBP treatment also enhanced Hdc mRNA expression and erythropoiesis in the spleen and reduced erythropoiesis in bone marrow and the number of vascular adhesion molecule 1 (VCAM-1)-positive macrophages in wild-type mice, as well as increased the levels of hematopoietic progenitor cells and proliferating cells in the spleen and enhanced expression of bone morphogenetic protein 4 (Bmp4), CXC chemokine ligand 12 (Cxcl12), and hypoxia inducible factor 1 (Hif1) in the spleen. However, such changes were not observed in HDC-KO mice. These results suggest that histamine may affect hematopoietic microenvironments of the bone marrow and spleen by changing hematopoiesis-related factors in NBP-induced extramedullary hematopoiesis.


Assuntos
Alendronato/antagonistas & inibidores , Medula Óssea/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Hematopoese Extramedular/efeitos dos fármacos , Histidina Descarboxilase/deficiência , Baço/efeitos dos fármacos , Alendronato/farmacologia , Alendronato/toxicidade , Anemia/induzido quimicamente , Animais , Medula Óssea/metabolismo , Proteína Morfogenética Óssea 4/biossíntese , Proteína Morfogenética Óssea 4/genética , Quimiocina CXCL12/biossíntese , Quimiocina CXCL12/genética , Indução Enzimática/efeitos dos fármacos , Células Eritroides/patologia , Citometria de Fluxo , Fator Estimulador de Colônias de Granulócitos/sangue , Histamina/biossíntese , Histidina Descarboxilase/biossíntese , Histidina Descarboxilase/genética , Histidina Descarboxilase/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Baço/metabolismo
17.
Ann N Y Acad Sci ; 1489(1): 78-90, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33188643

RESUMO

This study investigates follicular fluid (FF) from patients with poor and normal ovarian response undergoing natural assisted reproductive technology cycles. We report about (1) cell-free DNA (cfDNA), which reflects apoptosis; (2) corticotropin-releasing hormone (CRH); (3) interleukin (IL)-15, which reflects inflammation; (4) granulocyte colony-stimulating factor (G-CSF); (5) vascular endothelial growth factor (VEGF); and (6) insulin-like growth factor I (IGF-I), which reflects follicular growth. Forty-four poor responders and 44 normal responders-according to the Bologna criteria-were recruited. FF samples were prepared for cfDNA quantification employing Q-PCR and for CRH, IL-15, G-CSF, VEGF, and IGF-I quantification employing ELISA. Statistically nonsignificant different levels of FF cfDNA, CRH, IL-15, VEGF, and IGF-I were observed. Interestingly, statistically significant higher G-CSF levels were observed in normal responders (302.48 ± 474.36 versus 200.10 ± 426.79 pg/mL, P = 0.003). Lower cfDNA integrity was observed in cycles resulting in clinical pregnancy for both groups (normal: 0.07 ± 0.04 versus 0.25 ± 0.17 ng/µL, P < 0.001; poor: 0.10 ± 0.06 versus 0.26 ± 0.12 ng/µL, P < 0.001). The results predominantly showcase similarities between normal and poor responders pertaining to inflammatory, apoptotic, and growth factors. This may be attributed to the employment of natural cycles in order to exclude controlled ovarian stimulation as a factor-indicating its detrimental effect. As G-CSF levels presented significantly higher in normal responders, its vital role in understanding a compromised ovarian response is highlighted.


Assuntos
Apoptose/genética , Biomarcadores/sangue , Fator Estimulador de Colônias de Granulócitos/sangue , Inflamação/genética , Adulto , Ácidos Nucleicos Livres/sangue , Hormônio Liberador da Corticotropina/sangue , Feminino , Fertilização in vitro/métodos , Líquido Folicular/metabolismo , Humanos , Inflamação/sangue , Inflamação/metabolismo , Inflamação/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-15/sangue , Projetos Piloto , Gravidez , Fator A de Crescimento do Endotélio Vascular/sangue
18.
J Immunol ; 205(10): 2786-2794, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32998984

RESUMO

BP180 (also termed type XVII collagen) is a hemidesmosomal protein and plays a critical role in cell-cell matrix adhesion in the skin; however, its other biological functions are largely unclear. In this study, we generated a BP180 functional-deficient mouse strain by deleting its extracellular domain of humanized NC16A (termed ΔNC16A mice). We found that BP180 is expressed by bone marrow mesenchymal stem cells (BM-MSC), and its functional deficiency leads to myeloid hyperplasia. Altered granulopoiesis in ΔNC16A mice is through bone marrow stromal cells evidenced by bone marrow transplantation. Furthermore, the level of G-CSF in bone marrow and circulation were significantly increased in ΔNC16A mice as compared with wild-type mice. The increased G-CSF was accompanied by an increased activation of the NF-κB signaling pathway in bone marrow and BM-MSC of ΔNC16A mice. Blockade of G-CSF restored normal granulopoiesis in ΔNC16A mice. Inhibition of NF-κB signaling pathway significantly reduces the release of G-CSF from ΔNC16A BM-MSC in vitro and the level of serum G-CSF in ΔNC16A mice. To our knowledge, these findings provide the first direct evidence that BP180 plays an important role in granulopoiesis through regulating NF-κB signaling pathway in BM-MSC.


Assuntos
Autoantígenos/metabolismo , Medula Óssea/patologia , Leucopoese/imunologia , Células-Tronco Mesenquimais/metabolismo , Neutrófilos/fisiologia , Colágenos não Fibrilares/metabolismo , Animais , Autoantígenos/genética , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos/sangue , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Hiperplasia/genética , Hiperplasia/imunologia , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Colágenos não Fibrilares/genética , Domínios Proteicos/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Colágeno Tipo XVII
19.
Nutr Res ; 80: 89-105, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32738564

RESUMO

Unlike polyphenols, which are widely available in the diet, polyacetylenes are available only from the Apiaceae family vegetables, including carrot, parsnip, fennel, celery, and many herbs (parsley, lovage, etc). The aim of this study was to investigate the hypothesis that polyacetylene falcarinol (FA) reduces intestinal inflammation and examine its similarity of effect to isothiocyanate R-sulforaphane during the late phase of acute inflammation. To this end, 3-month-old male CB57BL/6 mice were fed twice daily for 1 week with 5 mg/kg of FA, sulforaphane, or vehicle before receiving an intraperitoneal injection of 5 mg/kg endotoxin (lipopolysaccharide [LPS]) to induce modest acute inflammation. The expression of intestinal and hepatic heme oxygenase-1 at the mRNA and protein levels, circulating cytokines, as well as intestinal and mesenteric n-6 and n-3 fatty acid lipid mediators was compared 24 hours after LPS administration to examine its effects on the late phase of inflammation. Intestinal nuclear factor (erythroid-derived 2)-like 2 target enzyme heme oxygenase-1 was upregulated 8.42-fold at the mRNA level and 10.7-fold at the protein level by FA-supplemented diet. However, the FA-supplemented diet produced a unique type-2 plasma cytokine skew after LPS treatment. Plasma cytokines interleukin (IL)-4, IL-13, IL-9, and IL-10 were upregulated, reflecting the cytokine profile of reduced type 1 inflammation. A detailed lipidomic analysis of n-6 and n-3 fatty acid pro- and anti-inflammatory pathways in the mesentery and intestinal mucosa showed that FA diet was more similar to the control groups than to other LPS treated groups. In this study, we demonstrated that FA-supplemented diet produced a unique immunomodulatory effect not observed with sulforaphane in late phases of inflammation. These results support the hypothesis that FA may have role as a dietary immunosuppressant in patients with inflammatory gastrointestinal as well as other inflammatory disorders that may be alleviated by increasing consumption of carrot or other FA-containing food sources.


Assuntos
Citocinas/sangue , Suplementos Nutricionais , Di-Inos/administração & dosagem , Álcoois Graxos/administração & dosagem , Heme Oxigenase-1/genética , Inflamação/metabolismo , Intestinos/enzimologia , Proteínas de Membrana/genética , Animais , Ácidos Graxos Insaturados/metabolismo , Fator Estimulador de Colônias de Granulócitos/sangue , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Heme Oxigenase-1/metabolismo , Fatores Imunológicos/administração & dosagem , Inflamação/genética , Isotiocianatos/administração & dosagem , Jejuno/metabolismo , Lipopolissacarídeos , Fígado/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Mesentério/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Fitoquímicos/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Baço/metabolismo , Sulfóxidos/administração & dosagem , Regulação para Cima
20.
Immunobiology ; 225(4): 151979, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32747024

RESUMO

Streptococcus suis serotype 2 is an important porcine bacterial pathogen and emerging zoonotic agent. Infections induce an exacerbated inflammation that can result in sudden death (septic shock) and meningitis. Though neutrophilic leukocytosis characterizes S. suis infection, the mediators involved are poorly understood. Among them, granulocyte-colony stimulating factor (G-CSF), a pro-inflammatory cytokine, triggers proliferation of neutrophil progenitors and neutrophil mobilization. However, the systemic production of G-CSF induced during S. suis infection, the cell types involved, and the underlying mechanisms remain unknown. In a S. suis serotype 2 mouse model of systemic infection, plasma levels of G-CSF rapidly increased after infection. S. suis activation of DCs and macrophages resulted in high (> 1000 pg/mL) and comparable production levels of G-CSF, as measured by ELISA. By using mutant strains deficient in capsular polysaccharide (CPS) or lipoprotein maturation in combination with purified lipoteichoic acid (LTA) from the latter mutant strain, it was showed that G-CSF production is mainly mediated by S. suis lipoproteins. The Toll-like receptor (TLR) pathway via myeloid differentiation primary response 88 (MyD88) is required for G-CSF production by DCs and macrophages following S. suis activation, with a partial involvement of TLR2. On the other hand, TLR2-independant G-CSF production induced by S. suis requires internalization and bacterial DNA might play a role in this pathway. Finally, these signals activated nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways leading to G-CSF production. In conclusion, this study demonstrated for the first time that S. suis induces G-CSF production in vivo and DCs and macrophages are key cellular sources of this cytokine mediator, mainly via the binding of lipoproteins to TLR2. The CPS significantly reduced this activation, confirming the powerful role of this component in S. suis virulence. As such, this study contributes to better understand how DCs and macrophages produce G-CSF in response to S. suis, and potentially to other streptococci.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fator Estimulador de Colônias de Granulócitos/biossíntese , Macrófagos/imunologia , Macrófagos/metabolismo , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Streptococcus suis/imunologia , Animais , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos/sangue , Interações Hospedeiro-Patógeno , Camundongos , Transdução de Sinais , Streptococcus suis/classificação
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