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1.
J Allergy Clin Immunol ; 140(2): 395-406, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27931975

RESUMO

BACKGROUND: Severe asthma might be associated with overexpression of Th17 cytokines, which induce neutrophil recruitment via neutrophil-mobilizing cytokines in airways. OBJECTIVE: To study IL-17-related cytokines in nasal/bronchial biopsies from controls and mild asthmatics (MAs) to severe asthmatics (SAs) in relation to exacerbation rate. METHODS: Inflammatory cells and IL-17A+, IL-17F+, IL-21+, IL-22+, and IL-23+ cells were examined by immunohistochemistry in cryostat sections of bronchial/nasal biopsies obtained from 33 SAs (21 frequent exacerbators [FEs]), 31 MAs (3 FEs), and 14 controls. IL-17F protein was also measured by ELISA in bronchial/nasal lysates and by immunohistochemistry in bronchial tissue obtained from subjects who died because of fatal asthma. Immunofluorescence/confocal microscopy was used for IL-17F colocalization. RESULTS: Higher number (P < .05) of neutrophils, IL-17A+, IL-17F+, and IL-21+ cells in bronchial biopsies and higher numbers (P < .01) of IL-17F+ and IL-21+ cells in nasal biopsies were observed in SAs compared with MAs. Bronchial IL-17F+ cells correlated with bronchial neutrophils (r = 0.54), exacerbation rate (r = 0.41), and FEV1 (r = -0.46). Nasal IL-17F+ cells correlated with bronchial IL-17F (r = 0.35), exacerbation rate (r = 0.47), and FEV1 (r = -0.61). FEs showed increased number of bronchial neutrophils/eosinophils/CD4+/CD8+ cells and bronchial/nasal IL-17F+ cells. Receiver operating characteristic curve analysis evidenced predictive cutoff values of bronchial neutrophils and nasal/bronchial IL-17F for discriminating between asthmatics and controls, between MAs and SAs and between FEs and non-FEs. IL-17F protein increased in bronchial/nasal lysates of SAs and FEs and in bronchial tissue of fatal asthma. IL-17F colocalized in CD4+/CD8+ cells. CONCLUSIONS: IL-17-related cytokines expression was amplified in bronchial/nasal mucosa of neutrophilic asthma prone to exacerbation, suggesting a pathogenic role of IL-17F in FEs.


Assuntos
Asma/imunologia , Citocinas/imunologia , Mucosa Respiratória/imunologia , Adulto , Idoso , Brônquios/citologia , Brônquios/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infiltração de Neutrófilos , Neutrófilos/imunologia , Nariz/citologia , Nariz/imunologia , Mucosa Respiratória/citologia
2.
Eur Respir J ; 49(5)2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28536249

RESUMO

Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD.Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial mucosa of subjects with stable COPD of different severity (n=34), control smokers (n=12) and nonsmokers (n=12). The bronchial bacterial load of Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae was measured by quantitative real-time PCR.TLR4 and NOD1 expression was increased in the bronchial mucosa of patients with severe/very severe stable COPD compared with control subjects. TLR4 bronchial epithelial expression correlated positively with CD4+ and CD8+ cells and airflow obstruction. NOD1 expression correlated with CD8+ cells. The bronchial load of P. aeruginosa was directly correlated, but H. influenzae inversely correlated, with the degree of airflow obstruction. Bacterial load did not correlate with inflammatory cells.Bronchial epithelial overexpression of TLR4 and NOD1 in severe/very severe stable COPD, associated with increased bronchial inflammation and P. aeruginosa bacterial load, may play a role in the pathogenesis of COPD.


Assuntos
Bactérias/metabolismo , Inflamação/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptor 4 Toll-Like/metabolismo , Idoso , Antibacterianos/farmacologia , Carga Bacteriana , Brônquios/patologia , Feminino , Volume Expiratório Forçado , Haemophilus influenzae , Humanos , Masculino , Pessoa de Meia-Idade , Moraxella catarrhalis , Fosforilação , Domínios Proteicos , Pseudomonas aeruginosa , Reação em Cadeia da Polimerase em Tempo Real , Mucosa Respiratória/metabolismo , Transdução de Sinais , Fumar , Streptococcus pneumoniae , Capacidade Vital
3.
Respiration ; 89(4): 329-42, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25791156

RESUMO

BACKGROUND: The role of mitogen-activated protein kinases (MAPK) in regulating the inflammatory response in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthmatic patients is unclear. OBJECTIVES: To investigate the expression of activated MAPK in lungs of COPD patients and in bronchial biopsies of asthmatic patients and to study MAPK expression in bronchial epithelial cells in response to oxidative and inflammatory stimuli. METHODS: Immunohistochemical expression of phospho (p)-p38 MAPK, p-JNK1 and p-ERK1/2 was measured in bronchial mucosa in patients with mild/moderate (n = 17), severe/very severe (n = 16) stable COPD, control smokers (n = 16), control non-smokers (n = 9), in mild asthma (n = 9) and in peripheral airways from COPD patients (n = 15) and control smokers (n = 15). Interleukin (IL)-8 and MAPK mRNA was measured in stimulated 16HBE cells. RESULTS: No significant differences in p-p38 MAPK, p-JNK or p-ERK1/2 expression were seen in bronchial biopsies and peripheral airways between COPD and control subjects. Asthmatics showed increased submucosal p-p38 MAPK expression compared to COPD patients (p < 0.003) and control non-smokers (p < 0.05). Hydrogen peroxide (H2O2), cytomix (tumour necrosis factor-α + IL-1ß + interferon-γ) and lipopolysaccharide (LPS) upregulated IL-8 mRNA at 1 or 2 h. p38 MAPKα mRNA was significantly increased after H2O2 and LPS treatment. JNK1 and ERK1 mRNA were unchanged after H2O2, cytomix or LPS treatments. CONCLUSION: p-p38 MAPK expression is similar in stable COPD and control subjects but increased in the bronchi of mild asthmatics compared to stable COPD patients. p38 MAPK mRNA is increased after bronchial epithelial challenges in vitro. These data together suggest a potential role for this MAPK in Th2 inflammation and possibly during COPD exacerbations.


Assuntos
Asma/enzimologia , Brônquios/enzimologia , Doença Pulmonar Obstrutiva Crônica/enzimologia , Mucosa Respiratória/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Idoso , Western Blotting , Brônquios/imunologia , Estudos de Casos e Controles , Linhagem Celular , Feminino , Humanos , Imuno-Histoquímica , Interleucina-8/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mucosa Respiratória/imunologia , Fator de Transcrição RelA/metabolismo
4.
Biomarkers ; 19(3): 214-21, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24617547

RESUMO

BACKGROUND: Fibrosis suppressors/activators in chronic heart failure (CHF) is a topic of investigation. AIM: To quantify serum levels of fibrosis regulators in CHF. METHODS: ELISA tests were used to quantify fibrosis regulators, procollagen type-(PIP)I, (PIP)III, collagen-I, III, BMP1,2,3,7, SDF1α, CXCR4, fibulin 1,2,3, BMPER, CRIM1 and BAMBI in 66 CHF (NYHA class I, n = 9; II, n = 34; III n = 23), and in 14 controls. RESULTS: In CHF, TGFßR2, PIPIII, SDF1α and CRIM1 were increased. PIPIII correlated with CRIM1. CONCLUSIONS: The BMPs inhibitor CRIM1 is increased and correlates with higher levels of serum PIPIII showing an imbalance in favor of pro-fibrotic mechanisms in CHF.


Assuntos
Insuficiência Cardíaca/metabolismo , Proteínas de Membrana/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas , Doença Crônica , Eletrocardiografia , Insuficiência Cardíaca/fisiopatologia , Humanos , Índice de Gravidade de Doença
5.
Biomarkers ; 18(5): 418-24, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23805979

RESUMO

The pathophysiology of chronic heart failure (CHF) involves multiple hystologic and molecular alterations. To determine the effects of physical training on circulating endothelial progenitor cells (EPCs), angiogenesis (angiogenin, angiopoietin-1 and -2, VEGF, Tie-2, SDF-1α) and inflammation (IL-6, CRP), we compared data obtained from 11 CHF pts before and after 3 months aerobic exercise training, to those from 10 non trained CHF pts (CHF-C group, age 64 + 2 years, NYHA 2). At the end of the study, EPCs count and AP-2 serum levels significantly increased in the CHF-TR group. These preliminary data suggest a significant effect of even a short program of physical training on angiogenic activation and endothelial dysfunction.


Assuntos
Terapia por Exercício , Insuficiência Cardíaca/terapia , Neovascularização Fisiológica , Idoso , Proteínas Angiogênicas/sangue , Biomarcadores/sangue , Artéria Braquial/fisiopatologia , Doença Crônica , Células Endoteliais/metabolismo , Exercício Físico , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Células-Tronco/metabolismo , Volume Sistólico , Resultado do Tratamento , Vasodilatação
6.
Int J Chron Obstruct Pulmon Dis ; 14: 1879-1893, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686800

RESUMO

Background: Airway inflammation may drive the progression of chronic obstructive pulmonary disease (COPD) associated with alpha-1 antitrypsin deficiency (AATD), but the relationship between airway microbiota and inflammation has not been investigated. Methods: We studied 21 non-treated AATD (AATD-noT) patients, 20 AATD-COPD patients under augmentation therapy (AATD-AT), 20 cigarette smoke-associated COPD patients, 20 control healthy smokers (CS) and 21 non-smokers (CON) with normal lung function. We quantified sputum inflammatory cells and inflammatory markers (IL-27, CCL3, CCL5, CXCL8, LTB4, MPO) by ELISA, total bacterial load (16S) and pathogenic bacteria by qRT-PCR. Results: AATD-AT patients were younger but had similar spirometric and DLCO values compared to cigarette smoke-associated COPD, despite a lower burden of smoking history. Compared to cigarette smoke-associated COPD, AATD-noT and AATD-AT patients had lower sputum neutrophil levels (p=0.0446, p=0.0135), total bacterial load (16S) (p=0.0081, p=0.0223), M. catarrhalis (p=0.0115, p=0.0127) and S. pneumoniae (p=0.0013, p=0.0001). Sputum IL-27 was significantly elevated in CS and cigarette smoke-associated COPD. AATD-AT, but not AATD-noT patients, had IL-27 sputum levels (pg/ml) significantly lower than COPD (p=0.0297) and these positively correlated with FEV1% predicted values (r=0.578, p=0.0307). Conclusions: Compared to cigarette smoke-associated COPD, AATD-AT (COPD) patients have a distinct airway inflammatory and microbiological profile. The decreased sputum bacterial load and IL-27 levels in AATD-AT patients suggests that augmentation therapy play a role in these changes.


Assuntos
Bactérias/isolamento & purificação , Mediadores da Inflamação/análise , Pulmão/imunologia , Pulmão/microbiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Fumar/efeitos adversos , Deficiência de alfa 1-Antitripsina/complicações , Idoso , Bactérias/genética , Bactérias/patogenicidade , Carga Bacteriana , Estudos de Casos e Controles , Feminino , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Fatores de Risco , Escarro/imunologia , Escarro/microbiologia , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/imunologia , Deficiência de alfa 1-Antitripsina/microbiologia
7.
Int J Immunopathol Pharmacol ; 30(4): 333-340, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28976240

RESUMO

HSP60 has been implicated in chronic inflammatory disease pathogenesis, including chronic obstructive pulmonary disease (COPD), but the mechanisms by which this chaperonin would act are poorly understood. A number of studies suggest a role for extracellular HSP60, since it can be secreted from cells and bind Toll-like receptors; however, the effects of this stimulation have never been extensively studied. We investigated the effects (pro- or anti-inflammatory) of HSP60 in human bronchial epithelial cells (16-HBE) alone and in comparison with oxidative, inflammatory, or bacterial challenges. 16-HBE cells were cultured for 1-4 h in the absence or presence of HSP60, H2O2, lipopolysaccharide (LPS), or cytomix. The cell response was evaluated by measuring the expression of IL-8 and IL-10, respectively, pro- and anti-inflammatory cytokines involved in COPD pathogenesis, as well as of pertinent TLR-4 pathway mediators. Stimulation with HSP60 up-regulated IL-8 at mRNA and protein levels and down-regulated IL-10 mRNA and protein. Likewise, CREB1 mRNA was up-regulated. H2O2 and LPS up-regulated IL-8. Experiments with an inhibitor for p38 showed that this mitogen-activated protein kinase could be involved in the HSP60-mediated pro-inflammatory effects. HSP60 showed pro-inflammatory properties in bronchial epithelial cells mediated by activation of TLR-4-related molecules. The results should prompt further studies on more complex ex-vivo or in-vivo models with the aim to elucidate further the role of those molecules in the pathogenesis of COPD.


Assuntos
Chaperonina 60/genética , Células Epiteliais/metabolismo , Proteínas Mitocondriais/genética , Brônquios/citologia , Linhagem Celular , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética
8.
Breathe (Sheff) ; 12(4): 341-348, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28210320

RESUMO

General Practitioners need support to recognise rare lung disorders and advise patients on the best available care http://ow.ly/kDgy304rX94.

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