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1.
Chin Med J (Engl) ; 133(5): 542-551, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32053571

RESUMO

BACKGROUND: The eosinophilic chronic obstructive pulmonary disease (COPD) is known to be more sensitive to corticosteroid. The sputum microbiome has been shown to affect COPD prognosis, but its role in acute exacerbations of eosinophilic COPD is unclear. This study aimed to investigate the dynamic changes of the airway microbiome in patients with acute exacerbations of eosinophilic COPD. METHODS: Fifty-seven patients with acute exacerbations of COPD from the First Affiliated Hospital of Guangxi Medical University between June 2017 and June 2018 were divided into two groups. Patients with eosinophils ≥300 cells/µL in the peripheral venous blood were assigned to the eosinophilic group (Eos) and the rest to the non-eosinophilic group (Noneos). All patients received similar treatment including inhaled budesonide according to the guidelines. The induced sputum microbiome was analyzed on the 1st and 7th day of treatment using the 16S ribosomal RNA (rRNA) method. The levels of interleukin (IL)-6 and IL-8 were measured in the plasma and the sensitivity to corticosteroids was determined in isolated peripheral blood mononuclear cells. Quantitative data were compared between the two groups using the independent samples t test or Mann-Whitney U test. Categorical data were evaluated using Chi-squared test or Fisher's exact test. RESULTS: Twenty-six patients were classified into Eos group and 31 patients were classified into Noneos group. Prior to treatment, the alpha diversity (Shannon index) (2.65 ±â€Š0.63 vs. 2.56 ±â€Š0.54, t = 0.328, P = 0.747) and the structure of the sputum microbiome were similar in the Eos group and the Noneos group. After 7 days of treatment, alpha diversity increased in both groups, while the microbiome richness (Ace index) was significantly lower in the Eos group (561.87 ±â€Š109.13 vs. 767.88 ±â€Š148.48, t = -3.535, P = 0.002). At the same time, IL-6 (12.09 ±â€Š2.85 pg/mL vs. 15.54 ±â€Š2.45 pg/mL, t = -4.913, P < 0.001) and IL-8 (63.64 ±â€Š21.69 pg/mL vs. 78.97 ±â€Š17.13 pg/mL, t = -2.981, P = 0.004) decreased more significantly in the Eos group, and the percentages of inhibition of IL-8 at dexamethasone concentrations 10 to 10 mol/L were significantly higher in the Eos group than those in the Noneos group (all P < 0.05). CONCLUSIONS: The induced sputum microbiome richness decreased more significantly following treatment in the Eos patients compared to the Noneos patients. The lower plasma inflammatory factor levels and the higher percentage of inhibition of IL-8 might be due to higher corticosteroid sensitivity in Eos patients.

2.
Free Radic Biol Med ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31770582

RESUMO

Corticosteroid insensitivity is a feature of airway inflammation in chronic obstructive pulmonary disease (COPD). Erythromycin exhibits anti-inflammatory activity in COPD, but the concrete mechanism is still unclear. This study aimed to investigate the effects of erythromycin on corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) and U937 cells (a human monocytic cell line). PBMCs were collected from non-smokers, healthy smoker volunteers, and COPD subjects. U937 cells were incubated with or without erythromycin and stimulated with TNF-α in the presence or absence of cigarette smoke extract (CSE). The dexamethasone (Dex) concentration required to achieve 50% inhibition of TNF-α-induced interleukin (IL)-8 production was determined and the mitogen-activated protein kinase (MAPK)/Activator protein-1 (AP-1) pathway was also evaluated. Erythromycin improved corticosteroid sensitivity in PBMCs obtained from COPD patients and CSE-treated U937 cells. This improvement in corticosteroid sensitivity was associated with reduced c-Jun expression, which resulted from the inhibition of P38 Mitogen-activated protein kinase (P38MAPK), extracellular signal-regulated protein kinase (ERK)1/2, and c-Jun N-terminal kinase (JNK) phosphorylation. Erythromycin had no effects on the phosphorylated and total protein expression levels of P38MAPK and ERK; however, it induced inhibition of the phosphorylated and total protein expression levels of JNK. This study provides evidence that erythromycin restores corticosteroid sensitivity in PBMCs and U937 cells. JNK inhibition by erythromycin restores corticosteroid sensitivity via the inhibition of c-Jun expression. Thus, JNK/c-Jun is a potential novel therapeutic target for COPD.

3.
Int J Chron Obstruct Pulmon Dis ; 14: 2145-2162, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571851

RESUMO

Purpose: To explore the potential mechanism underpinning the development of chronic obstructive pulmonary disease (COPD) and to investigate the role of the Roundabout signaling pathway in COPD. Methods: Three microarray datasets (GSE1650, GSE38974 and GSE76925) including 139 cases of severe COPD and 52 cases of normal smokers without carcinoma, were integrated to screen differentially expressed genes (DEGs) using bioinformatics methods. Gene ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the DEGs were performed by a DAVID online tool. Finally, a cigarette smoke (CS)- induced emphysema mice model was established, the lung mRNA expression levels of genes associated with Slit guidance ligand 2 (SLIT2) -Roundabout (ROBO) signaling pathway were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR), and the protein level of SLIT2 was examined by immunohistochemistry staining. Results: A total of 315 DEGs were identified in three databases. GO and KEGG pathway analyses suggested that the inflammatory response, extracellular matrix disassembly, immune response, the apoptotic signaling pathway, ubiquitination and the Roundabout signaling pathway all together were involved in the development of COPD. The genes SLIT2 and ROBO2 were decreased in patients with COPD and these decreases were significantly negatively correlated with the disease stages of COPD. Consistently, the mRNA expression levels of SLIT2, ROBO1 and ROBO2, and the protein level of SLIT2 were revealed to be lower in the lungs of CS-induced emphysema mice compared with the air-exposed control mice. In addition, the SLIT2 protein level was negatively associated with alveolar mean linear intercept. Conclusion: Integrated bioinformatics analysis may provide novel insights into the complicated pathogenesis of COPD, and to the best of our knowledge, this study is the first to provide evidence to suggest that the Roundabout signaling pathway may be involved in the pathogenesis of COPD.

4.
Cell Death Dis ; 10(9): 678, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515489

RESUMO

Neutrophil extracellular traps (NETs) may play a critical role in smoking-related chronic airway inflammation. However, the mechanism by which NETs induced by cigarette smoke initiate the adaptive immunity in chronic obstructive pulmonary disease (COPD) is not fully understood. In this study, we explored the effects of NETs induced by cigarette smoke on the myeloid dendritic cells (mDCs) and Th1 and Th17 cells. Additionally, we observed the inhibitory effect of erythromycin on NETs induced by cigarette smoke. We found that elevated NET levels in the sputum of COPD patients were correlated with the circulating Th1 response, mDC activation and airflow limitation. NETs induced by cigarette smoke extract (CSE) could activate monocyte-derived mDCs and promote Th1 and Th17 differentiation in vitro. Erythromycin effectively inhibited NET formation induced by CSE. In vivo, erythromycin decreased NETs in the airway and ameliorated emphysema with Th1 and Th17 cell down-regulation and CD40+ and CD86+ mDCs suppression in mice chronically exposed to cigarette smoke. These findings provide direct evidence that NETs promote the differentiation of Th1 and Th17 and play a role in the adaptive immunity of smoking-related chronic lung inflammation. Erythromycin is a potential therapeutic strategy for NETs inhibition in COPD.

5.
Biomed Pharmacother ; 118: 109380, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545224

RESUMO

BACKGROUND: Corticosteroid is one of the main treatments for interstitial lung disease (ILD). Cryptogenic-organizing pneumonia (COP) is sensitive to corticosteroid therapy, whereas idiopathic pulmonary fibrosis (IPF) is not. Glucocorticoid receptor-α (GR-α) and histone deacetylase 2 (HDAC2) play critical roles in the sensitivity to corticosteroid therapy; however, it is unclear whether HDAC2 and/or GR-α are expressed in the lung tissues of patients with COP and/or IPF. Possible aberrant expressions of HDAC2 and GR-α in IPF and COP were investigated in the current study. METHODS: Lung tissue samples were obtained from patients with COP (n = 9), IPF (n = 8), pulmonary abscesses (n = 7), or pulmonary inflammatory pseudotumors (n = 6) before corticosteroid treatment, as well as from control subjects (n = 10). The expression of GR-α, HDAC2, PI3K-δ, and NF-κBp65 in the samples was assessed by immunohistochemistry. RESULTS: GR-α expression was the same in lung tissues from COP patients and control subjects, but was significantly lower in lung tissue from IPF. In addition, HDAC2 was significantly higher in lung tissues of COP patients compared to both IPF and control subjects. Furthermore, the transcription factor NF-κBp65 was significantly lower in lung tissues from both COP and control compared to IPF subjects, whereas there was no difference in NF-κBp65 when comparing tissues from COP patients to controls. HDAC2 and GR-α were negatively correlated with NF-κBp65 in COP lung tissue. CONCLUSION: HDAC2 and GR-α expression in lung tissues are potential biomarkers for predicting corticosteroid sensitivity when initially treating COP and IPF, as well as other forms of ILD.


Assuntos
Histona Desacetilase 2/metabolismo , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/metabolismo , Receptores de Glucocorticoides/metabolismo , Esteroides/uso terapêutico , Pneumonia em Organização Criptogênica/complicações , Pneumonia em Organização Criptogênica/patologia , Pneumonia em Organização Criptogênica/fisiopatologia , Feminino , Humanos , Pulmão/patologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Transcrição RelA/metabolismo
6.
Pathobiology ; 86(5-6): 237-247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242482

RESUMO

BACKGROUND: Macrolides have anti-inflammatory and antioxidative stress function, but their pharmacological regulation remains unclear. Sirtuin 1 (SIRT1) is redox-sensitive protein belongs to class III histone/protein deacetylases, SIRT1 regulates the acetylation/expression of nuclear factor κB (NF-κB) and is involved in the airway inflammation of chronic obstructive pulmonary disease. OBJECTIVES: The present study was designed to examine the effects of erythromycin (EM) on the SIRT1-NF-κB axis and NF-κB-dependent proinflammatory cytokines. METHODS: Human macrophages were preincubated with EM and then treated with cigarette smoke extract (CSE). The mice were treated by injecting drugs to gastric with EM before cigarette smoke exposure. Reactive oxygen species (ROS) released by treated human macrophages were detected using flow cytometry. The expression of SIRT1 and NF-κB was analyzed by western blotting. SIRT1 and the RelA/p65 subunits of NF-κB interaction were detected by coimmunoprecipitation. We found that EM suppressed CSE-induced ROS released in human macrophages, which coincided with increases in SIRT1 protein expression in the macrophages and lungs of mice, resulting in suppressed -NF-κB acetylation and expression correlated with a reduction of inflammatory mediators. CONCLUSION: These findings suggest that EM increased SIRT1, leading to acetylation/expression of NF-κB, and thereby decreasing cigarette smoke-driven NF-κB-dependent proinflammatory cytokine.

7.
Clin Immunol ; 195: 107-118, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29127016

RESUMO

Plasmacytoid dendritic cells (pDCs) are key cells bridging the innate with adaptive immunity. However, the phenotypic characteristics of circulating pDCs and its role in smoking related-Chronic Obstructive Pulmonary Disease (COPD) remain largely unknown. The aim of this study was analyzed the phenotype of circulating pDCs and the expression of IFN-γ producing CD8+T cells and IL-17-producing CD8+T cells in patients with COPD by using multi-colour flow cytometry. The cytokine profiles in peripheral blood from all subjects were measured by ELISA. The influence of cigarette smoke on pDCs was evaluated in an experimental mouse model of emphysema. Circulating pDCs in patients with COPD and in mice exposed to cigarette smoke expressed high levels of co-stimulatory molecules CD40 or CD86 accompanied by exaggerated IFN-γ producing CD8+T cells and IL-17-producing CD8+T cells. In vitro, cigarette smoke directly promoted pDCs maturation and release of IFN-α, IL-6 and IL-12, subsequently inducing differentiation of IFN-γ producing CD8+T cells and IL-17-producing CD8+T cells from mouse naïve CD8+T cells. These data suggested that circulating pDCs display an enhanced activation phenotype in patients with COPD and in experimental smoking mouse model of emphysema, which might contribute to exaggerated IFN-γ producing CD8+T and IL-17-producing CD8+T cell-mediated immune responses.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Enfisema Pulmonar/imunologia , Idoso , Animais , Circulação Sanguínea , Diferenciação Celular , Células Cultivadas , Fumar Cigarros/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Enfisema Pulmonar/induzido quimicamente
8.
Thorax ; 72(12): 1084-1093, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28720648

RESUMO

BACKGROUND: Neutrophil extracellular traps (NETs) represent a distinct strategy by which neutrophils trap, confine and eliminate invading microorganisms. Emerging evidence suggests that NETs exert a deleterious effect to the host in the absence of microbial stimuli. However, the role of NETs in smoking-related lung diseases remains to be elucidated. OBJECTIVES: To evaluate the formation of NETs in the context of chronic inflammation induced by cigarette smoking and explore its potential role in an experimental mouse model of emphysema. METHODS: The formation and degradation of NETs in cigarette smoke exposed mice was assessed with a fluorescence microscope. The potential influences of NETs on plasmacytoiddendritic cells were also investigated. RESULTS: NETs were more prone to formation by polymorphonuclearneutrophils but defective in degradation in cigarette smoke exposed mice. Cigarette smoke extract (CSE) served as an important facilitator that triggered neutrophils to undergo NETosis in vitro. Furthermore, CSE-induced NETs were capable of driving plasmacytoiddendritic cell maturation and activation, thereby initiating a T-cell-mediated immune response. CONCLUSIONS: NETs may represent a critical connection between innate and adaptive immune responses under conditions of chronic inflammation induced by cigarette smoke exposure.


Assuntos
Células Dendríticas/imunologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Enfisema Pulmonar/imunologia , Poluição por Fumaça de Tabaco/efeitos adversos , Imunidade Adaptativa , Animais , Linfócitos T CD4-Positivos/imunologia , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Técnicas de Cocultura , Imunidade Inata , Inflamação/imunologia , Masculino , Camundongos Endogâmicos BALB C , Enfisema Pulmonar/etiologia , Células Th1/imunologia , Células Th17/imunologia
9.
Am J Physiol Lung Cell Mol Physiol ; 311(3): L581-9, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27448664

RESUMO

Dendritic cells and CD8(+) T cells participate in the pathology of chronic obstructive pulmonary disease, including emphysema, but little is known of the involvement of the CD40/CD40L pathway. We investigated the role of the CD40/CD40L pathway in Tc1 cell differentiation induced by dendritic cells in a mouse model of emphysema, and in vitro. C57BL/6J wild-type and CD40(-/-) mice were exposed to cigarette smoke (CS) or not (control), for 24 wk. In vitro experiments involved wild-type and CD40(-/-) dendritic cells treated with CS extract (CSE) or not. Compared with the control groups, the CS mice (both wild type and CD40(-/-)) had a greater percentage of lung dendritic cells and higher levels of major histocompatability complex (MHC) class I molecules and costimulatory molecules CD40 and CD80. Relative to the CS CD40(-/-) mice, the CS wild type showed greater signs of lung damage and Tc1 cell differentiation. In vitro, the CSE-treated wild-type cells evidenced more cytokine release (IL-12/p70) and Tc1 cell differentiation than did the CSE-treated CD40(-/-) cells. Exposure to cigarette smoke increases the percentage of lung dendritic cells and promotes Tc1 cell differentiation via the CD40/CD40L pathway. Blocking the CD40/CD40L pathway may suppress development of emphysema in mice exposed to cigarette smoke.


Assuntos
Antígenos CD40/fisiologia , Ligante de CD40/fisiologia , Células Dendríticas/fisiologia , Enfisema Pulmonar/imunologia , Fumaça/efeitos adversos , Animais , Linfócitos T CD8-Positivos , Diferenciação Celular , Células Cultivadas , Citocinas/biossíntese , Citocinas/genética , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Contagem de Linfócitos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Transdução de Sinais , Fumar/efeitos adversos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Tabaco/efeitos adversos
10.
Clin Exp Rheumatol ; 34 Suppl 100(5): 14-22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26750756

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is characterised by fibrosis of the skin and internal organs, such as the lungs. Enhanced Th17 responses are associated with skin fibrosis in patients with SSc, however, whether they are associated with lung fibrosis has not been clarified. This study aimed to investigate the potential association of Th17 responses with the skin and pulmonary fibrosis as well as the potential mechanisms in a mouse bleomycin (BLM) model of SSc. METHODS: BALB/c mice were injected subcutaneously with phosphate buffered saline (PBS) (control) or BLM for 28 days and the skin and pulmonary inflammation and fibrosis were characterized by histology. The percentages of circulating, skin and pulmonary infiltrating Th17 cells and the contents of collagen in mice were analysed. The levels of RORγt, IL-17A, IL-6 and TGF-ß1 mRNA transcripts in the skin and lungs were determined by quantitative RTPCR and the levels of serum IL-17A, IL-6 and TGF-ß1 were determined by ELISA. Furthermore, the effect of rIL-17A on the proliferation of pulmonary fibroblasts and their cytokine expression was analysed. The potential association of Th17 responses with the severity of skin and lung fibrosis was analysed. RESULTS: In comparison with the control mice, significantly increased skin and pulmonary inflammation and fibrosis and higher levels of hydroxyproline were detected in the BLM mice. Significantly higher frequency of circulating, skin and lung infiltrating Th17 cells and higher levels of serum, skin and lung IL-17A, TGF-ß1, IL-6 and RORγt were detected in the BLM mice. The concentrations of serum IL-17A were correlated positively with the percentages of Th17 cells and the contents of skin hydroxyproline in the BLM mice. The levels of IL-17A expression were positively correlated with the skin and lung inflammatory scores as well as the skin fibrosis in the BLM mice. In addition, IL-17A significantly enhanced pulmonary fibroblast proliferation and their type I collagen, TGF-ß and IL-6 expression in vitro, which were attenuated by treatment with anti-IL-17A. CONCLUSIONS: Our results indicate that Th17 cells participate in the pathogenesis of skin and lung fibrosis by enhancing fibroblast proliferation and cytokine production in a mouse BLM model of SSc.


Assuntos
Bleomicina , Dermatite/imunologia , Mediadores da Inflamação/imunologia , Interleucina-17/imunologia , Pulmão/imunologia , Pneumonia/imunologia , Fibrose Pulmonar/imunologia , Escleroderma Sistêmico/imunologia , Pele/imunologia , Células Th17/imunologia , Animais , Proliferação de Células , Células Cultivadas , Colágeno/metabolismo , Dermatite/etiologia , Dermatite/metabolismo , Dermatite/patologia , Modelos Animais de Doenças , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Mediadores da Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-17/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos BALB C , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Índice de Gravidade de Doença , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
11.
Int J Rheum Dis ; 19(4): 392-404, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25545680

RESUMO

AIM: Systemic sclerosis (SSc) is characterized by immune abnormalities, progressive fibrosis of the skin and internal organs, and microvascular injury and damage. Interleukin-21 receptor (IL-21R) is expressed in the epidermis from patients with SSc. However, information describing the role of IL-21 in SSc is limited. METHODS: We established a mouse model of bleomycin (BLM)-induced fibrosis. The frequency of CD4(+) IL-21(+) T, CD4(+) IL-21R(+) T and IL-21(+) Th17 cells in peripheral blood, skin and lungs of BLM-induced mice were detected by flow cytometry; IL-21 levels in the peripheral blood were evaluated by enzyme-linked immunosorbent assay (ELISA). CD4(+) T cells were isolated from the spleen of BLM-induced and control mice and cultured in vitro alone or in the presence of mrIL-21 or mrIL-21 plus transforming growth factor (TGF)-ß1. The frequency of Th17 cells was detected by flow cytometry; levels of IL-17 were evaluated by ELISA, and the expression of IL-17A and retinoic-acid-receptor-related orphan receptors gamma t (RORγt) messenger RNA were analyzed by real-time polymerase chain reaction. RESULTS: Compared to control mice, the frequency of CD4(+) IL-21(+) T, CD4(+) 21R(+) T and IL-21(+) Th17 cells and the levels of IL-21 were significantly increased in BLM-induced mice. The frequency of CD4(+) IL-21(+) T, CD4(+) 21R(+) T and IL-21(+) Th17 cells and the levels of IL-21 were correlated with dermal and pulmonary inflammation and fibrosis. In vitro analyses indicate that IL-21 promoted the differentiation of Th17 cells from CD4(+) cells isolated from the spleen of BLM-induced mice. CONCLUSION: IL-21 may play an important role in the pathogenesis of SSc as a Th17 effector cytokine, and IL-21 may induce the differentiation of Th17 cells in the BLM-induced SSc mouse model.


Assuntos
Bleomicina , Linfócitos T CD4-Positivos/metabolismo , Erupção por Droga/metabolismo , Subunidade alfa de Receptor de Interleucina-21/metabolismo , Interleucinas/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Fibrose Pulmonar/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/metabolismo , Células Th17/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Erupção por Droga/etiologia , Erupção por Droga/imunologia , Erupção por Droga/patologia , Feminino , Fibrose , Hidroxiprolina/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Subunidade alfa de Receptor de Interleucina-21/sangue , Subunidade alfa de Receptor de Interleucina-21/imunologia , Interleucinas/sangue , Interleucinas/imunologia , Pulmão/imunologia , Pulmão/patologia , Camundongos Endogâmicos BALB C , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fenótipo , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Pele/imunologia , Pele/patologia , Baço/imunologia , Baço/metabolismo , Células Th17/imunologia , Regulação para Cima
12.
Am J Physiol Lung Cell Mol Physiol ; 309(2): L139-46, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25957293

RESUMO

Corticosteroid insensitivity, which is induced by cigarette smoke extract (CSE), is a significant barrier when treating chronic obstructive pulmonary disease (COPD). Erythromycin (EM) has been shown to have an anti-inflammatory role in some chronic airway inflammatory diseases, particularly diffuse panbronchiolitis and cystic fibrosis. Here, we explored whether the combination therapy of EM and dexamethasone (Dex) reverses corticosteroid insensitivity and investigated the molecular mechanism by which this occurs. We demonstrated that the combination of EM and Dex restored corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from COPD patients and U937 cells after CSE exposure. Moreover, pretreatment with 10, 50, or 100 µg/ml EM reversed the HDAC2 protein reduction induced by CSE exposure in a dose-dependent manner. U937 cells exposed to CSE show a reduction in histone deacetylase (HDAC) activity, which was potently reversed by EM or combination treatment. Although 10 and 17.5% CSE increased phosphorylated Akt (PAkt) expression in a concentration-dependent manner, preapplication of EM and the combination treatment in particular blocked this PAkt increase. Total Akt levels were unaffected by CSE or EM treatments. Furthermore, the combination treatment enhanced glucocorticoid receptor (GR)α expression. Our results demonstrate that the combination therapy of EM and Dex can restore corticosteroid sensitivity through inhibition of the PI3K-δ/Akt pathway and enhancing GRα expression.


Assuntos
Corticosteroides/farmacologia , Dexametasona/farmacologia , Eritromicina/farmacologia , Leucócitos Mononucleares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Glucocorticoides/metabolismo , Fumar/efeitos adversos , Anti-Inflamatórios/farmacologia , Western Blotting , Estudos de Casos e Controles , Quimioterapia Combinada , Fármacos Gastrointestinais/farmacologia , Histona Desacetilase 2/metabolismo , Humanos , Interleucina-8/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Células U937
13.
Cell Biol Int ; 39(4): 388-99, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25492803

RESUMO

Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs. Th17 cells and interleukin-17 (also called IL-17A) have been found to be increased in peripheral blood and skin in patients with SSc. IL-21 is a potent inducer of Th17 differentiation that is produced by activated T cells, and whose relationship with Th17 cells in SSc is unclear. Here, using a bleomycin (BLM)-induced mouse model of skin fibrosis, we detected the frequency of CD4+/IL-17+ (Th17) cells, CD4+/IL-21+ T cells and IL-21+ Th17 cells in peripheral blood, skin and lungs, as well as the serum content of IL-17A and IL-21. In addition, we assessed the differentiation of CD4+ T cells cultured from these mice into Th17 cells in response to treatment with IL-21. Compared with the control mice, Th17 cell counts and IL-17A levels were significantly increased and correlated with inflammatory and fibrotic indices in the skin and lungs of the BLM-induced fibrosis mice. Moreover, serum levels of CD4+/IL-21+ T cells, IL-21+ Th17 cells, and IL-21 were significantly increased in these mice, and correlated positively with serum levels of Th17 cells. In vitro experiments showed that IL-21 treated CD4+ T cells derived from BLM-induced mice differentiated into Th17 cells. Our results indicate that Th17 cells and IL-17A contributes to inflammatory and fibrotic processes in the skin and lungs in a BLM-induced mouse model of SSc. Moreover, the expansion of the Th17 cell population may be subsequent to IL-21 promotion of the differentiation of CD4+ T cells in these mice.


Assuntos
Bleomicina/toxicidade , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular/efeitos dos fármacos , Interleucinas/farmacologia , Células Th17/citologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Feminino , Fibrose , Hidroxiprolina/análise , Interleucina-17/sangue , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucinas/sangue , Interleucinas/genética , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Pele/metabolismo , Pele/patologia , Células Th17/imunologia , Regulação para Cima/efeitos dos fármacos
15.
J Immunol Res ; 2014: 730380, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24872958

RESUMO

Pathogenic mechanisms underlying the development of lung cancer are very complex and not yet entirely clarified. T lymphocytes and their immune-regulatory cytokines play a pivotal role in controlling tumor growth and metastasis. Following activation by unique cytokines, CD4+ T helper cells differentiate into Th1, Th2, Th17, and regulatory T cells (Tregs). Traditionally, research in lung cancer immunity has focused almost exclusively on Th1/Th2 cell balance. Recently, Th17 cells and Tregs represent an intriguing issue to be addressed in lung cancer pathogenesis. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against tumor cells. Th17 cells directly or via other proinflammatory cytokines modulate antitumor immune responses. Notably, there is a close relation between Tregs and Th17 cells. However, the possible interaction between these subsets in lung cancer remains to be elucidated. In this setting, targeting Treg/Th17 balance for therapeutic purposes may represent a useful tool for lung cancer treatment in the future. The purpose of this review is to discuss recent findings of the role of these novel populations in lung cancer immunity and to highlight the pleiotropic effects of these subsets on the development and regulation of lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Hepáticas/imunologia , Pulmão/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Citocinas/biossíntese , Citocinas/imunologia , Humanos , Tolerância Imunológica , Neoplasias Hepáticas/patologia , Pulmão/patologia , Linfócitos T Reguladores/patologia , Células Th1/imunologia , Células Th1/patologia , Equilíbrio Th1-Th2 , Células Th17/patologia , Células Th2/imunologia , Células Th2/patologia
16.
Int J Infect Dis ; 23: 1-3, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24657269

RESUMO

Penicillium marneffei is a thermally dimorphic pathogenic fungus that causes systemic infection similar to disseminated cryptococcosis. P. marneffei is endemic in Southeast Asia, usually infecting HIV-infected individuals; infection of HIV-negative individuals is extremely rare. Here, we describe a disseminated P. marneffei infection within an osteolytic lesion in an HIV-negative patient. A 40-year-old Chinese woman presented with intermittent fever, generalized lymphadenopathy, and a skin rash. Following a sternum biopsy, the patient was diagnosed with P. marneffei infection. An emission computed tomography bone scan revealed the presence of increased radioactivity in the left clavicle and sternum, indicative of an osteolytic lesion. In addition to reporting this very rare case, we also present a brief review of the literature, highlighting the differences in clinical manifestations between HIV-positive and HIV-negative patients infected with P. marneffei as it applies to our case.


Assuntos
Micoses/diagnóstico , Osteólise/microbiologia , Penicillium/isolamento & purificação , Adulto , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Ásia Sudeste , Grupo com Ancestrais do Continente Asiático , Feminino , Infecções por HIV , Humanos , Micoses/tratamento farmacológico , Osteólise/diagnóstico , Osteólise/tratamento farmacológico , Tomografia Computadorizada de Emissão
17.
Clin Dev Immunol ; 2013: 350727, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24489575

RESUMO

Th17 and Tc17 cells may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD), a disease caused predominantly by cigarette smoking. Smoking cessation is the only intervention in the management of COPD. However, even after cessation, the airway inflammation may be present. In the current study, mice were exposed to room air or cigarette smoke for 24 weeks or 24 weeks followed by 12 weeks of cessation. Morphological changes were evaluated by mean linear intercepts (Lm) and destructive index (DI). The frequencies of CD8(+)IL-17(+)(Tc17) and CD4(+)IL-17(+)(Th17) cells, the mRNA levels of ROR gamma and IL-17, and the levels of IL-8, TNF-alpha, and IFN-gamma in lungs or bronchoalveolar lavage fluid of mice were assayed. Here we demonstrated that alveolar enlargement and destruction induced by cigarette smoke exposure were irreversible and that cigarette smokeenhanced these T-cell subsets, and related cytokines were not significantly reduced after smoking cessation. In addition, the frequencies of Th17 and Tc17 cells in lungs of smoke-exposed mice and cessation mice were positively correlated with emphysematous lesions. More important, the frequencies of Tc17 cells were much higher than Th17 cells, and there was a significantly positive correlation between Th17 and Tc17. These results suggested that Th17/Tc17 infiltration in lungs may play a critical role in sustaining lung inflammation in emphysema. Blocking the abnormally increased numbers of Tc17 and Th17 cells may be a reasonable therapeutic strategy for emphysema.


Assuntos
Enfisema Pulmonar/etiologia , Abandono do Hábito de Fumar , Fumar , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-8/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Chin Med J (Engl) ; 125(17): 3183-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22932205

RESUMO

Pulmonary sparganosis mansoni is rare in humans and bronchial sparganosis mansoni has not been reported. We reported a patient with a soft-tissue mass in the right hilum area on a chest computed tomography (CT) scan that was suspected of being lung cancer. Bronchoscopy identified sparganum larvae. Bronchial sparganosis mansoni accompanied by abnormal hyperplasia was diagnosed by histopathology. We introduced our experience and reviewed the clinical characteristics of three pulmonary sparganosis mansoni cases and three pleural cavity sparganosis mansoni cases that have been reported.


Assuntos
Brônquios/patologia , Broncopatias/patologia , Broncoscopia , Esquistossomose mansoni/patologia , Esparganose/patologia , Idoso , Humanos , Hiperplasia , Masculino
19.
Zhonghua Yi Xue Za Zhi ; 92(16): 1129-32, 2012 Apr 24.
Artigo em Chinês | MEDLINE | ID: mdl-22781775

RESUMO

OBJECTIVE: To evaluate the expression of interleukin (IL)-21 in a cigarette smoke-induced mice model of emphysema and explore its effects on the differentiation of CD4(+)T cell. METHODS: Twenty male Balb/c mice were randomly divided into two groups: control group and smoke-exposed group. Morphological changes were evaluated by mean linear intercepts and alveolar destructive index. The proportion of CD4(+)IL-21R(+)T cells in lungs of mice was determined by flow cytometry. And the levels of IL-21 in lungs of mice were analyzed by enzyme-linked immunosorbent assay (ELISA). Fresh lung mononuclear cells were isolated from the smoke-exposed group and divided further into two sub-groups: blank sub-group and co-culture sub-group. Two sub-groups were cultured in medium with or without IL-21 for 24 h and 48 h. The proportions of Th1 and Th17 cells in cell culture medium were determined by flow cytometry. RESULTS: Mean linear intercepts and alveolar destructive index in the smoke-exposed group ((48.6 ± 4.8) µm and 44.9 ± 2.8) were significantly higher than the control group ((32.4 ± 4.0) µm and 28.1 ± 2.1, both P < 0.05). In lungs, the percentage of CD4(+)IL-21R(+)T cells in the smoke-exposed group (4.1% ± 1.5%) significantly increased than that in the control group (1.4% ± 0.4%) (P < 0.05). The levels of IL-21 in lung of the smoke-exposed group ((851 ± 28) ng/L) were higher than those in the control group ((415 ± 39) ng/L, P < 0.05). In lungs, the levels of IL-21 had positive correlations with mean linear intercepts and alveolar destructive index (r = 0.892 and 0.955, both P < 0.05). The percentages of Th1 and Th17 cells in cell culture medium of the co-culture sub-group for 24 h and 48 h significantly increased versus those in the blank group (all P < 0.05). CONCLUSION: IL-21 may participate in the occurrence and development of emphysema through the induced differentiation of CD4(+)T cells and the promotion of Th1 and Th17-cell responses in lungs.


Assuntos
Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Interleucinas/metabolismo , Enfisema Pulmonar/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fumaça/efeitos adversos , Tabaco/efeitos adversos
20.
Mediators Inflamm ; 2012: 410232, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22701274

RESUMO

Heavy smoking can induce airway inflammation and emphysema. Macrolides can modulate inflammation and effector T-cell response in the lungs. However, there is no information on whether erythromycin can modulate regulatory T-cell (Treg) response. This study is aimed at examining the impact of erythromycin on Treg response in the lungs in a rat model of smoking-induced emphysema. Male Wistar rats were exposed to normal air or cigarette smoking daily for 12 weeks and treated by gavage with 100 mg/kg of erythromycin or saline daily beginning at the forth week for nine weeks. The lung inflammation and the numbers of inflammatory infiltrates in bronchoalveolar lavage fluid (BALF) were characterized. The frequency, the number of Tregs, and the levels of Foxp3 expression in the lungs and IL-8, IL-35, and TNF-α in BALF were determined by flow cytometry, RT-PCR and ELISA, respectively. Treatment with erythromycin reduced smoking-induced inflammatory infiltrates, the levels of IL-8 and TNF-α in the BALF and lung damages but increased the numbers of CD4+Foxp3+ Tregs and the levels of Foxp3 transcription in the lungs, accompanied by increased levels of IL-35 in the BALF of rats. Our novel data indicated that erythromycin enhanced Treg responses, associated with the inhibition of smoking-induced inflammation in the lungs of rats.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Eritromicina/uso terapêutico , Fatores de Transcrição Forkhead/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Fumar/efeitos adversos , Animais , Ensaio de Imunoadsorção Enzimática , Interleucina-8/metabolismo , Pneumonia/imunologia , Pneumonia/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/metabolismo
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