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2.
Curr Opin Pharmacol ; 51: 29-33, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32480246

RESUMO

The worldwide socioeconomical burden associated with chronic respiratory diseases is substantial. Enzymes involved in the metabolism of nicotinamide adenine dinucleotide (NAD) are increasingly being implicated in chronic airway diseases. One such enzyme, CD38, utilizes NAD to produce several metabolites, including cyclic ADP ribose (cADPR), which is involved in calcium signaling in airway smooth muscle (ASM). Upregulation of CD38 in ASM caused by exposure to cytokines or allergens leads to enhanced calcium mobilization by agonists and the development of airway hyperresponsiveness (AHR) to contractile agonists. Glucocorticoids and microRNAs can suppress CD38 expression in ASM, whereas cADPR antagonists such as 8Br-cADPR can directly antagonize intracellular calcium mobilization. Bronchodilators act via CD38-independent mechanisms. CD38-dependent mechanisms could be developed for chronic airway diseases therapy.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , ADP-Ribose Cíclica/metabolismo , Pneumopatias Obstrutivas/metabolismo , Glicoproteínas de Membrana/metabolismo , Transdução de Sinais/fisiologia , ADP-Ribosil Ciclase 1/imunologia , Animais , Cálcio/imunologia , Cálcio/metabolismo , ADP-Ribose Cíclica/imunologia , Humanos , Pneumopatias Obstrutivas/imunologia , Glicoproteínas de Membrana/imunologia
3.
Curr Opin Pharmacol ; 51: 11-18, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32361678

RESUMO

Chronic pulmonary diseases, including chronic obstructive pulmonary disease (COPD) and asthma, are major causes of death and reduced quality of life. Characteristic of chronic pulmonary disease is excessive lung inflammation that occurs in response to exposure to inhaled irritants, chemicals, and allergens. Chronic inflammation leads to remodeling of the airways that includes excess mucus secretion, proliferation of smooth muscle cells, increased deposition of extracellular matrix proteins and fibrosis. Protein kinases have been implicated in mediating inflammatory signals and airway remodeling associated with reduced lung function in chronic pulmonary disease. This review will highlight the role of protein kinases in the lung during chronic inflammation and examine opportunities to use protein kinase inhibitors for the treatment of chronic pulmonary diseases.


Assuntos
Pneumopatias Obstrutivas/tratamento farmacológico , Pneumopatias Obstrutivas/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Remodelação das Vias Aéreas/efeitos dos fármacos , Remodelação das Vias Aéreas/fisiologia , Animais , Humanos , Pulmão/imunologia , Pneumopatias Obstrutivas/imunologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , Músculo Liso/imunologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/imunologia , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento
4.
Ter Arkh ; 89(8): 110-112, 2017.
Artigo em Russo | MEDLINE | ID: mdl-28914860

RESUMO

The paper considers current approaches to mucoregulatory therapy for various inflammatory diseases of the respiratory system. It gives the advantages and disadvantages of common drugs used in their treatment. Emphasis is laid on the use of inhaled hypertonic saline of NaCl in combination with hyaluronic acid (Hyaneb). Clinical examples of its use in chronic obstructive pulmonary disease, acute and chronic bronchitis, and severe asthma are considered.


Assuntos
Ácido Hialurônico/farmacologia , Inflamação , Pneumopatias Obstrutivas , Terapia Respiratória/métodos , Solução Salina Hipertônica/farmacologia , Adjuvantes Imunológicos/farmacologia , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Pneumopatias Obstrutivas/imunologia , Pneumopatias Obstrutivas/fisiopatologia , Pneumopatias Obstrutivas/terapia , Depuração Mucociliar/efeitos dos fármacos , Depuração Mucociliar/imunologia , Resultado do Tratamento
5.
J Immunol ; 199(3): 1170-1183, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28667160

RESUMO

Secondhand smoke (SHS) exposure has been linked to the worsening of ongoing lung diseases. However, whether SHS exposure affects the manifestation and natural history of imminent pediatric muco-obstructive airway diseases such as cystic fibrosis remains unclear. To address these questions, we exposed Scnn1b transgenic (Scnn1b-Tg+) mice to SHS from postnatal day (PND) 3-21 and lung phenotypes were examined at PND22. Although a majority of filtered air (FA)-exposed Scnn1b-Tg+ (FA-Tg+) mice successfully cleared spontaneous bacterial infections by PND22, the SHS-exposed Scnn1b-Tg+ (SHS-Tg+) mice failed to resolve these infections. This defect was associated with suppressed antibacterial defenses, i.e., phagocyte recruitment, IgA secretion, and Muc5b expression. Whereas the FA-Tg+ mice exhibited marked mucus obstruction and Th2 responses, SHS-Tg+ mice displayed a dramatic suppression of these responses. Mechanistically, downregulated expression of IL-33, a stimulator of type II innate lymphoid cells, in lung epithelial cells was associated with suppression of neutrophil recruitment, IgA secretions, Th2 responses, and delayed bacterial clearance in SHS-Tg+ mice. Cessation of SHS exposure for 21 d restored previously suppressed responses, including phagocyte recruitment, IgA secretion, and mucous cell metaplasia. However, in contrast with FA-Tg+ mice, the SHS-Tg+ mice had pronounced epithelial necrosis, alveolar space consolidation, and lymphoid hyperplasia; indicating lagged unfavorable effects of early postnatal SHS exposure in later life. Collectively, our data show that early postnatal SHS exposure reversibly suppresses IL-33 levels in airspaces which, in turn, results in reduced neutrophil recruitment and diminished Th2 response. Our data indicate that household smoking may predispose neonates with muco-obstructive lung disease to bacterial exacerbations.


Assuntos
Infecções Bacterianas/imunologia , Pneumopatias Obstrutivas/imunologia , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Animais Recém-Nascidos , Infecções Bacterianas/fisiopatologia , Carga Bacteriana , Movimento Celular , Fibrose Cística/imunologia , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Células Epiteliais/imunologia , Células Epiteliais/patologia , Canais Epiteliais de Sódio/deficiência , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/metabolismo , Feminino , Células Caliciformes/patologia , Humanos , Imunoglobulina A/imunologia , Interleucina-33/genética , Interleucina-33/imunologia , Interleucina-33/metabolismo , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Pneumopatias Obstrutivas/fisiopatologia , Camundongos , Camundongos Transgênicos , Mucina-5B , Muco/metabolismo , Neutrófilos/imunologia , Neutrófilos/patologia , Neutrófilos/fisiologia , Transdução de Sinais , Células Th2/imunologia , Células Th2/patologia
6.
J Agric Food Chem ; 65(4): 836-845, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28064485

RESUMO

Lung inflammation and oxidative stress are the major contributors to the development of obstructive pulmonary diseases. Macrophages are involved in pulmonary inflammation and alveolar damage in emphysema. Astragalin is an anti-inflammatory flavonoid present in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited inflammatory cell infiltration induced by 20 µM H2O2 and blocked airway thickening and alveolar emphysema induced by 20 µg of ovalbumin (OVA) in mice. OVA induced mouse pulmonary MCP-1, and H2O2 enhanced the expression of MCP-1/ICAM-1/αv integrin in bronchial airway epithelial BEAS-2B cells. Such induction was inhibited by supplying 10-20 mg/kg of astragalin to OVA-challenged mice and 1-20 µM astragalin to oxidant-stimulated cells. Oral administration of 20 mg/kg of astragalin reduced the induction of F4/80/CD68/CD11b in airways of mice challenged with OVA. Additionally, emphysema tissue damage was observed in OVA-exposed alveoli. Mast cell recruitment in the airway subepithelium was blocked by supplementing astragalin to OVA-challenged mice. Orally treating 20 mg/kg of astragalin reduced α-SMA induction in inflammation-occurring airways and appeared to reverse airway thickening and constriction induced by an OVA episode. These results revealed that astragalin may improve airway thickening and alveolar destruction with blockade of allergic inflammation in airways. Therefore, astragalin may be a therapeutic agent antagonizing asthma and obstructive pulmonary diseases.


Assuntos
Quempferóis/administração & dosagem , Pneumopatias Obstrutivas/tratamento farmacológico , Pneumopatias Obstrutivas/imunologia , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Modelos Animais de Doenças , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Pneumopatias Obstrutivas/induzido quimicamente , Pneumopatias Obstrutivas/genética , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/efeitos adversos
7.
J Immunol ; 196(1): 182-95, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26621857

RESUMO

Several lines of evidence indicate that chronic alcohol use disorder leads to increased susceptibility to several viral and bacterial infections, whereas moderate alcohol consumption decreases the incidence of colds and improves immune responses to some pathogens. In line with these observations, we recently showed that heavy ethanol intake (average blood ethanol concentrations > 80 mg/dl) suppressed, whereas moderate alcohol consumption (blood ethanol concentrations < 50 mg/dl) enhanced, T and B cell responses to modified vaccinia Ankara vaccination in a nonhuman primate model of voluntary ethanol consumption. To uncover the molecular basis for impaired immunity with heavy alcohol consumption and enhanced immune response with moderate alcohol consumption, we performed a transcriptome analysis using PBMCs isolated on day 7 post-modified vaccinia Ankara vaccination, the earliest time point at which we detected differences in T cell and Ab responses. Overall, chronic heavy alcohol consumption reduced the expression of immune genes involved in response to infection and wound healing and increased the expression of genes associated with the development of lung inflammatory disease and cancer. In contrast, chronic moderate alcohol consumption upregulated the expression of genes involved in immune response and reduced the expression of genes involved in cancer. To uncover mechanisms underlying the alterations in PBMC transcriptomes, we profiled the expression of microRNAs within the same samples. Chronic heavy ethanol consumption altered the levels of several microRNAs involved in cancer and immunity and known to regulate the expression of mRNAs differentially expressed in our data set.


Assuntos
Consumo de Bebidas Alcoólicas/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Humoral/genética , Linfócitos T/imunologia , Vaccinia virus/imunologia , Animais , Anticorpos Antivirais/sangue , Linfócitos B/imunologia , Doenças Cardiovasculares/imunologia , Modelos Animais de Doenças , Etanol/administração & dosagem , Etanol/sangue , Perfilação da Expressão Gênica , Pneumopatias Obstrutivas/imunologia , Macaca mulatta , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Neoplasias/genética , Neoplasias/imunologia , RNA Mensageiro/biossíntese , Vacina Antivariólica/imunologia , Vacinação , Cicatrização/genética , Cicatrização/imunologia
9.
Nanotoxicology ; 9(2): 210-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24814297

RESUMO

The wide use of nanotechnology is here to stay. However, the knowledge on the health effects of different engineered nanomaterials (ENMs) is lacking. In this study, irritation and inflammation potential of commercially available silica-coated TiO2 ENMs (10 × 40 nm, rutile) were studied. Single exposure (30 min) at mass concentrations 5, 10, 20 and 30 mg/m(3), and repeated exposure (altogether 16 h, 1 h/day, 4 days/week for 4 weeks) at mass concentration of 30 mg/m(3) to silica-coated TiO2 induced first phase of pulmonary irritation (P1), which was seen as rapid, shallow breathing. During repeated exposures, P1 effect was partly evolved into more intense pulmonary irritation. Also sensory irritation was observed at the beginning of both single and repeated exposure periods, and the effect intensified during repeated exposures. Airflow limitation started to develop during repeated exposures. Repeated exposure to silica-coated TiO2 ENMs induced also pulmonary inflammation: inflammatory cells infiltrated in peribronchial and perivascular areas of the lungs, neutrophils were found in BAL fluids, and the number of CD3 and CD4 positive T cells increased significantly. In line with these results, pulmonary mRNA expression of chemokines CXCL1, CXCL5 and CXCL9 was enhanced. Also expression of mRNA levels of proinflammatory cytokines TNF-α and IL-6 was elevated after repeated exposures. Taken together, these results indicated that silica-coated TiO2 ENMs induce pulmonary and sensory irritation after single and repeated exposure, and airflow limitation and pulmonary inflammation after repeated exposure.


Assuntos
Exposição Ambiental/efeitos adversos , Pneumopatias Obstrutivas/induzido quimicamente , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Dióxido de Silício/toxicidade , Titânio/toxicidade , Administração por Inalação , Animais , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/toxicidade , Relação Dose-Resposta a Droga , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pneumopatias Obstrutivas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dióxido de Silício/química , Titânio/química , Testes de Toxicidade
10.
Zhonghua Jie He He Hu Xi Za Zhi ; 36(5): 351-6, 2013 May.
Artigo em Chinês | MEDLINE | ID: mdl-24047809

RESUMO

OBJECTIVE: To evaluate the diagnostic value of granulocyte-macrophage colony stimulating factor (GM-CSF) antibody in serum for pulmonary alveolar proteinosis (PAP). METHODS: Twelve PAP patients visiting Peking University People's Hospital or Fujian Provincial Hospital from January 1, 2002 to December 31, 2012, 25 patients with other pulmonary diseases (disease control), and 25 healthy volunteers (healthy control) were recruited in the study. The titer level of GM-CSF antibody in serum was determined with enzyme-linked immunosorbent assay (ELISA), and the clinical characteristics were collected in the PAP patients. RESULTS: The geometric mean titers of GM-CSF antibody in the PAP patients, the disease controls and the healthy controls were 1: 25 349, 1: 311 and 1: 256, respectively. The differences between the disease controls and the healthy controls were of no statistic significance (t = -1.14, P = 0.261) . With 3 times standard error (3s) above the mean value as the higher limit of X value(X = lgT, T standing for the reciprocal of the titer), the upper limit for T was 1698. With the T value ≥ 1698 as the diagnostic threshold for PAP, both the sensitivity and the specificity were 100%. The diagnostic value of GM-CSF antibody was similar to that of surgical lung biopsy and higher than that of transbronchial lung biopsy. CONCLUSION: The detection of serum GM-CSF is non-invasive, convenient and efficient for the diagnosis of PAP with high sensitivity and specificity.


Assuntos
Autoanticorpos/sangue , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Proteinose Alveolar Pulmonar/diagnóstico , Adulto , Biomarcadores/sangue , Biópsia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pulmão/patologia , Pneumopatias Obstrutivas/diagnóstico , Pneumopatias Obstrutivas/imunologia , Pneumopatias Obstrutivas/patologia , Masculino , Pessoa de Meia-Idade , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/patologia , Sensibilidade e Especificidade , Índice de Gravidade de Doença
11.
J Appl Physiol (1985) ; 113(10): 1594-603, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22961265

RESUMO

Resistive breathing (encountered in chronic obstructive pulmonary disease and asthma) results in cytokine upregulation and decreased nitric oxide (NO) levels in the strenuously contracting diaphragm. NO can regulate gene expression. We hypothesized that endogenously produced NO downregulates cytokine production triggered by strenuous diaphragmatic contraction. Wistar rats treated with vehicle, the nonselective NO synthase inhibitor NG-nitro-l-arginine-methylester (l-NAME), or the NO donor diethylenetriamine-NONOate (DETA) were subjected to inspiratory resistive breathing (IRB; 50% of maximal inspiratory pressure) for 6 h or sham operation. Additional groups of rats were subjected to IRB for 6 h with concurrent administration of l-NAME and inhibitors of NF-κB (BAY-11-7082), ERK1/2 (PD98059), or P38 (SB203580). Inhibition of NO production (with l-NAME) resulted in upregulation of IRB-induced diaphragmatic IL-6, IL-10, IL-2, TNF-α, and IL-1ß levels by 50%, 53%, 60%, 47%, and 45%, respectively. In contrast, the NO donor (DETA) attenuated the IRB-induced cytokine upregulation to levels characteristic of quietly breathing animals. l-NAME augmented IRB-induced activation of MAPKs (P38 and ERK1/2) and NF-κB, whereas DETA triggered the opposite effect. NF-κB and ERK1/2 inhibition in l-NAME-treated animals blunted the l-NAME-induced cytokine upregulation except IL-6, whereas P38 inhibition blunted all (including IL-6) cytokine upregulation. NO downregulates IRB-induced cytokine production in the strenuously contracting diaphragm through its action on MAPKs and NF-κB.


Assuntos
Citocinas/metabolismo , Diafragma/metabolismo , Inflamação/metabolismo , Inalação , Pneumopatias Obstrutivas/metabolismo , Contração Muscular , Óxido Nítrico/metabolismo , Animais , Diafragma/efeitos dos fármacos , Diafragma/imunologia , Inibidores Enzimáticos/farmacologia , Inflamação/imunologia , Inflamação/fisiopatologia , Pneumopatias Obstrutivas/imunologia , Pneumopatias Obstrutivas/fisiopatologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Oxirredução , Carbonilação Proteica , Ratos , Ratos Wistar , Transdução de Sinais , Fatores de Tempo , Trabalho Respiratório
12.
Eur J Clin Pharmacol ; 68(5): 479-503, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22105373

RESUMO

BACKGROUND: Macrolides have long been recognised to exert immunomodulary and anti-inflammatory actions. They are able to suppress the "cytokine storm" of inflammation and to confer an additional clinical benefit through their immunomodulatory properties. METHODS: A search of electronic journal articles was performed using combinations of the following keywords: macrolides, COPD, asthma, bronchitis, bronchiolitis obliterans, cystic fibrosis, immunomodulation, anti-inflammatory effect, diabetes, side effects and systemic diseases. RESULTS: Macrolide effects are time- and dose-dependent, and the mechanisms underlying these effects remain incompletely understood. Both in vitro and in vivo studies have provided ample evidence of their immunomodulary and anti-inflammatory actions. Importantly, this class of antibiotics is efficacious with respect to controlling exacerbations of underlying respiratory problems, such as cystic fibrosis, asthma, bronchiectasis, panbrochiolitis and cryptogenic organising pneumonia. Macrolides have also been reported to reduce airway hyper-responsiveness and improve pulmonary function. CONCLUSION: This review provides an overview on the properties of macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin), their efficacy in various respiratory diseases and their adverse effects.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose Cística/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Pneumopatias Obstrutivas/tratamento farmacológico , Macrolídeos/uso terapêutico , Animais , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Fibrose Cística/imunologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Pneumopatias Obstrutivas/imunologia , Macrolídeos/administração & dosagem , Macrolídeos/efeitos adversos , Macrolídeos/farmacologia
13.
Biol Blood Marrow Transplant ; 18(7): 1044-54, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22155140

RESUMO

Subacute lung disease, manifested as either obstructive (OLD) or restrictive (RLD) lung dysfunction, is a common complication following allogeneic stem cell transplantation. In each case, therapeutic options are limited, morbidity remains high, and long-term survival is poor. Between 2001 and 2008, 34 patients with noninfectious, obstructive (25) or RLD restrictive lung dysfunction (nine) received etanercept (Enbrel®, Amgen Inc.) 0.4 mg/kg/dose, subcutaneously, twice weekly, for 4 (group A) or 12 weeks (group B). Corticosteroids (if present at study entry) were kept constant for the initial 4 weeks of therapy and then tapered as tolerated. Thirty-one of 34 (91%) subjects were evaluable for response, and 10 (32%) met primary response criteria. There was no difference in response based on the duration of treatment (29% group A versus 35% group B; P = .99), the presence of RLD or OLD (33% versus 32%; P = .73), or the severity of pulmonary disease at study onset. Estimated 5-year overall survival rates following therapy were 61% (95% confidence interval, 46%-80%) for all subjects and 90% (95% confidence level, 73%-100%) for the 10 who met the primary response criteria. Five-year survival estimates for subjects treated with RLD was 44%, compared with 67% for those treated for OLD (P = .19). Etanercept was well tolerated, with no bacteremia or viremia observed. Pathogens were noted on posttherapy bronchoalveolar lavage in two cases. These data support the development of expanded clinical trials to study etanercept as a therapeutic agent for subacute lung injury after allogeneic stem cell transplantation.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoglobulina G/uso terapêutico , Pneumopatias Obstrutivas/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Doença Aguda , Adolescente , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Adulto , Idoso , Criança , Citocinas/sangue , Citocinas/imunologia , Esquema de Medicação , Etanercepte , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Estudos Longitudinais , Pneumopatias Obstrutivas/etiologia , Pneumopatias Obstrutivas/imunologia , Pneumopatias Obstrutivas/mortalidade , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/administração & dosagem , Testes de Função Respiratória , Índice de Gravidade de Doença , Taxa de Sobrevida , Transplante Homólogo , Resultado do Tratamento
14.
Pol J Vet Sci ; 14(3): 343-51, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21957726

RESUMO

During an 18 day test, we measured the cytokine mRNA expression (Interleukin-1beta [IL-1beta], Interleukin-8 [IL-8], Interferon-gamma [IFN-gamma], Tumor Necrosis Factor-alpha [TNF-alpha]) of cells from bronchoalveolar lavage fluid [BALF] in five horses previously diagnosed with RAO, before and during challenge exposure, and after the desensitization phase which involved dexamethasone treatment and environmental modification. Simultaneously, the same cytokine mRNA expression of cells from BALF in four asymptomatic RAO-affected horses maintained outdoors was analyzed. An evident respiratory distress was observed in the challenge group within 3 days, with a significant overexpression of IL-8 and TNF-alpha mRNA on the ninth day. The pharmacological and environmental desensitization provided a down regulation of all the cytokines. No statistical modification characterized the cytokine kinetics of the asymptomatic horses maintained outdoors. A comparison for each time point of the cytokines between the exposed and unexposed horses showed no significant differences. The study suggested that a standardized exposure protocol and sampling time in experimental studies of RAO is mandatory for a correct comparison of the results obtained by different Authors. However, the absence of significant changes between the exposed and unexposed horses could depend on the lack of the sample uniformity since the evolution of the disease represents a continuum from a healthy to a pathological condition.


Assuntos
Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Doenças dos Cavalos/imunologia , Pneumopatias Obstrutivas/veterinária , RNA Mensageiro/metabolismo , Animais , Citocinas/química , Citocinas/genética , Feminino , Doenças dos Cavalos/patologia , Cavalos , Pneumopatias Obstrutivas/imunologia , Pneumopatias Obstrutivas/patologia , Masculino , RNA Mensageiro/genética , Recidiva , Fatores de Tempo
15.
Allergy ; 65(9): 1134-40, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20219060

RESUMO

BACKGROUND: Allergic sensitisation increases the risk for asthma development. In this prospective birth cohort (Environment and Childhood Asthma) study, we hypothesized that combining quantitative measures of IgE antibodies (Sigma-IgE) and Severity score of obstructive airways disease (OAD) at 2 years of age (Severity score) is superior to predict current asthma (CA) at 10 years than either measure alone. Secondarily, we assessed if gender modified the prediction of CA. METHODS: A follow-up study at 10 years of age was performed in 371 2-year-old children with recurrent (n = 219) or no (n = 152) bronchial obstruction with available serum analysed for Sigma-IgE to common food and inhalant allergens through a panel test, Phadiatop Infant) (Phadia, Uppsala, Sweden). Clinical variables included allergic sensitisation and exercise testing to characterise children with CA vs not CA at 10 years and the Severity score (0-12, 0 indicating no OAD) was used to assess risk modification. RESULTS: Severity score alone explained 24% (Nagelkerke R(2) = 0.24) of the variation in CA, whereas Sigma-IgE explained only 6% (R(2) = 0.06). Combining the two increased the explanatory capacity to R(2) = 0.30. Gender interacted significantly with Sigma-IgE; whereas Severity score predicted CA in both genders, the predictive capacity of Sigma-IgE for CA at 10 years was significant in boys only. CONCLUSION: Combining Sigma-IgE to inhalant allergens and Severity score at 2 years was superior to predict asthma at 10 years than either alone. Severity score predicted CA in both genders, whereas Sigma-IgE significantly predicted CA in boys only.


Assuntos
Asma/diagnóstico , Imunoglobulina E/sangue , Pneumopatias Obstrutivas/fisiopatologia , Índice de Gravidade de Doença , Alérgenos/imunologia , Asma/imunologia , Asma/fisiopatologia , Criança , Estudos de Coortes , Teste de Esforço , Feminino , Seguimentos , Humanos , Hipersensibilidade/imunologia , Pneumopatias Obstrutivas/imunologia , Masculino , Valor Preditivo dos Testes
16.
Antioxid Redox Signal ; 13(10): 1535-48, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20214495

RESUMO

Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are a significant and increasing global health problem. These diseases are characterized by airway inflammation, which develops in response to various stimuli. In asthma, inflammation is driven by exposure to a variety of triggers, including allergens and viruses, which activate components of both the innate and acquired immune responses. In COPD, exposure to cigarette smoke is the primary stimulus of airway inflammation. Activation of airway inflammatory cells leads to the release of excessive quantities of reactive oxygen species (ROS), resulting in oxidative stress. Antioxidants provide protection against the damaging effects of oxidative stress and thus may be useful in the management of inflammatory airways disease. Resveratrol, a polyphenol that demonstrates both antioxidative and anti-inflammatory functions, has been shown to improve outcomes in a variety of diseases, in particular, in cancer. We review the evidence for a protective role of resveratrol in respiratory disease. Mechanisms of resveratrol action that may be relevant to respiratory disease are described. We conclude that resveratrol has potential as a therapeutic agent in respiratory disease, which should be further investigated.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Pneumopatias Obstrutivas/tratamento farmacológico , Estilbenos/uso terapêutico , Animais , Humanos , Inflamação/tratamento farmacológico , Pneumopatias Obstrutivas/imunologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Resveratrol
17.
J Vet Intern Med ; 24(2): 407-13, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20102498

RESUMO

BACKGROUND: Equine recurrent airway obstruction (RAO) shares many characteristics with human asthma. In humans, an inverse relationship between susceptibility to asthma and resistance to parasites is suspected. HYPOTHESIS/OBJECTIVES: Members of a high-incidence RAO half-sibling family (F) shed fewer strongylid eggs compared with RAO-unaffected pasture mates (PM) and that RAO-affected horses shed fewer eggs than RAO-unaffected half-siblings. ANIMALS: Seventy-three F and 73 unrelated, age matched PM. METHODS: Cases and controls kept under the same management and deworming regime were examined. Each individual was classified as RAO affected or RAO unaffected and fecal samples were collected before and 1-3 weeks and 3 months after deworming. Samples were analyzed by combined sedimentation-flotation and modified McMaster methods and classified into 3 categories of 0 eggs per gram of feces (EpG), 1-100 EpG, and > 100 EpG, respectively. RESULTS: PM compared with RAO-affected F had a 16.7 (95% confidence interval [CI]: 2.0-136.3) times higher risk for shedding > 100 EpG compared with 0 EpG and a 5.3 (95% CI: 1.0-27.4) times higher risk for shedding > 100 EpG compared with 0 EpG. There was no significant effect when RAO-unaffected F were compared with their PM. RAO-unaffected compared with RAO-affected offspring had a 5.8 (95% CI: 0.0-1.0) times higher risk for shedding 1-100 EpG. Age, sex, breed, and sharing pastures with other species had no significant confounding effects. CONCLUSION AND CLINICAL IMPORTANCE: RAO is associated with resistance against strongylid parasites in a high-prevalence family.


Assuntos
Doenças dos Cavalos/imunologia , Pneumopatias Obstrutivas/veterinária , Infecções por Strongylida/veterinária , Animais , Anti-Helmínticos/uso terapêutico , Fezes/parasitologia , Feminino , Predisposição Genética para Doença , Doenças dos Cavalos/tratamento farmacológico , Doenças dos Cavalos/genética , Cavalos , Modelos Logísticos , Pneumopatias Obstrutivas/genética , Pneumopatias Obstrutivas/imunologia , Masculino , Contagem de Ovos de Parasitas/veterinária , Prevalência , Estrongilídios/isolamento & purificação , Infecções por Strongylida/tratamento farmacológico , Infecções por Strongylida/genética , Infecções por Strongylida/imunologia
18.
Inflamm Allergy Drug Targets ; 8(2): 87-95, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19530990

RESUMO

Spleen Tyrosine Kinase (Syk) is widely expressed in the immune system and functions in the transmission of inflammatory signals via ITAM-bearing cell surface receptors. The broad expression pattern and importance of Syk in regulating innate immunity and the inflammatory response have led to significant interest from the pharmaceutical industry to developing anti-Syk therapeutics for the treatment of inflammatory disorders such as allergic rhinitis and rheumatoid arthritis. While the function and regulation of Syk has been well-described in leukocytes, where its primary role is an early transducer of signaling following immunoreceptor engagement, Syk has recently been described in non-immune cells, such as the airway epithelium, that also play an important role in mediating the inflammatory response. This manuscript will focus on the expression and function of Syk in the context of inflammatory lung diseases, and review recent data that have demonstrated novel roles for Syk in airway epithelial cells, particularly its role in mediating the human rhinovirus (HRV) induced inflammatory response and viral cell entry. In addition, data describing the efficacy of novel Syk inhibitors in the management of inflammatory diseases in animal models and early clinical trials are also reviewed.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Pneumopatias Obstrutivas/imunologia , Infecções por Picornaviridae/imunologia , Proteínas Tirosina Quinases/metabolismo , Mucosa Respiratória/metabolismo , Rhinovirus/fisiologia , Transdução de Sinais/imunologia , Aminopiridinas , Animais , Anti-Inflamatórios/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Pneumopatias Obstrutivas/complicações , Pneumopatias Obstrutivas/terapia , Pneumopatias Obstrutivas/virologia , Morfolinas , Oxazinas/uso terapêutico , Infecções por Picornaviridae/complicações , Infecções por Picornaviridae/terapia , Infecções por Picornaviridae/virologia , Pneumonia Viral/etiologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/imunologia , Piridinas/uso terapêutico , Pirimidinas , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Mucosa Respiratória/virologia , Rhinovirus/patogenicidade , Transdução de Sinais/efeitos dos fármacos , Quinase Syk , Virulência/imunologia , Internalização do Vírus
19.
Pharmacol Ther ; 123(1): 105-16, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19426761

RESUMO

Chronic lung diseases such as asthma, chronic obstructive pulmonary disease and interstitial lung disease are characterized by inflammation and tissue remodeling processes that compromise pulmonary function. Adenosine is produced in the inflamed and damaged lung where it plays numerous roles in the regulation of inflammation and tissue remodeling. Extracellular adenosine serves as an autocrine and paracrine signaling molecule by engaging cell surface adenosine receptors. Preclinical and cellular studies suggest that adenosine plays an anti-inflammatory role in processes associated with acute lung disease, where activation of the A(2A)R and A(2B)R has promising implications for the treatment of these disorders. In contrast, there is growing evidence that adenosine signaling through the A(1)R, A(2B)R and A(3)R may serve pro-inflammatory and tissue remodeling functions in chronic lung diseases. This review discusses the current progress of research efforts and clinical trials aimed at understanding the complexities of these signaling pathway as they pertain to the development of treatment strategies for chronic lung diseases.


Assuntos
Adenosina/metabolismo , Doenças Pulmonares Intersticiais/metabolismo , Pneumopatias Obstrutivas/metabolismo , Transdução de Sinais , Doença Aguda , Adenosina Desaminase/genética , Adenosina Desaminase/fisiologia , Animais , Doença Crônica , Modelos Animais de Doenças , Humanos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Pneumopatias Obstrutivas/tratamento farmacológico , Pneumopatias Obstrutivas/imunologia , Pneumopatias Obstrutivas/patologia , Agonistas do Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Receptores Purinérgicos P1/metabolismo
20.
Curr Opin Allergy Clin Immunol ; 9(2): 93-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19326503

RESUMO

PURPOSE OF REVIEW: Induced sputum noninvasively provides information on cellular and soluble material from airways. It has been successfully applied for assessing airway inflammation in asthma and chronic obstructive pulmonary disease, producing reliable results comparable to biopsy and bronchoalveolar lavage. Induced sputum research in the field of occupational medicine has mainly focused upon occupational asthma, and less to other types of occupational diseases. RECENT FINDINGS: Particulate size distribution in induced sputum samples points to accumulation over time, leading to the consideration that this measurement may serve as a time-dependent marker for biological monitoring. Qualitative analysis of chemical composition of induced sputum particles is well correlated to the chemical elements spectrum in bronchoalveolar lavage lung cells and in biopsy thin sections. T cell subsets in induced sputum can be used as a marker of granulomatosis in chronic beryllium disease. Cytokines retrieved from induced sputum samples in exposed workers show a differential pattern compared to nonexposed workers. SUMMARY: Induced sputum is a well tolerated, noninvasive technique that is opening a new window in the field of occupational diseases of the lung and can be integrated into the well established criteria for diagnosing and monitoring these diseases, especially when invasive techniques are clinically contraindicated or impractical.


Assuntos
Beriliose/diagnóstico , Pneumopatias Obstrutivas/diagnóstico , Doenças Profissionais/diagnóstico , Escarro/química , Subpopulações de Linfócitos T/metabolismo , Animais , Beriliose/imunologia , Beriliose/fisiopatologia , Biomarcadores/análise , Biópsia , Lavagem Broncoalveolar , Doença Crônica , Citocinas/análise , Técnicas de Diagnóstico do Sistema Respiratório , Granuloma do Sistema Respiratório/diagnóstico , Granuloma do Sistema Respiratório/imunologia , Humanos , Pneumopatias Obstrutivas/imunologia , Pneumopatias Obstrutivas/fisiopatologia , Doenças Profissionais/imunologia , Doenças Profissionais/fisiopatologia , Material Particulado/análise , Escarro/imunologia , Escarro/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia
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