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2.
Prostaglandins Other Lipid Mediat ; 121(Pt B): 145-54, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26159746

RESUMO

The aim of this study was to investigate the effects of resolvin D1 (RvD1), as well as the combined treatment of docosahexaenoic acid monoglyceride (MAG-DHA) and acetylsalicylic acid (ASA), on the resolution of inflammation markers and Ca(2+) sensitivity in IL-13-pretreated human bronchi (HB). Tension measurements performed with 300 nM RvD1 largely abolished (50%) the over-reactivity triggered by 10 ng/ml IL-13 pretreatment and reversed hyper Ca(2+) sensitivity. Addition of 300 nM 17(S)-HpDoHE, the metabolic intermediate between DHA and RvD1, displayed similar effects. In the presence of 100 µM ASA (a COX inhibitor), the inhibitory effect of 1 µM MAG-DHA on muscarinic tone was further amplified, but not in the presence of Ibuprofen. Western blot analysis revealed that the combined treatment of MAG-DHA and ASA upregulated GPR-32 expression and downregulated cytosolic TNFα detection, hence preventing IκBα degradation and p65-NFκB phosphorylation. The Ca(2+) sensitivity of HB was also quantified on ß-escin permeabilized preparations. The presence of ASA potentiated the inhibitory effects of MAG-DHA in reducing the Ca(2+) hypersensitivity triggered by IL-13 by decreasing the phosphorylation levels of the PKC-potentiated inhibitor protein-17 regulatory protein (CPI-17). In summary, MAG-DHA combined with ASA, as well as exogenously added RvD1, may represent valuable assets against critical AHR disorder.


Assuntos
Brônquios/efeitos dos fármacos , Bronquite/tratamento farmacológico , Broncodilatadores/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Ácidos Docosa-Hexaenoicos/metabolismo , Monoglicerídeos/farmacologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Brônquios/imunologia , Brônquios/metabolismo , Bronquite/imunologia , Bronquite/metabolismo , Broncodilatadores/agonistas , Sinergismo Farmacológico , Ácidos Graxos Ômega-3/antagonistas & inibidores , Ácidos Graxos Ômega-3/metabolismo , Humanos , Quinase I-kappa B/química , Quinase I-kappa B/metabolismo , Técnicas In Vitro , Interleucina-13/antagonistas & inibidores , Interleucina-13/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Monoglicerídeos/agonistas , Proteínas Musculares , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/metabolismo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
4.
Clin Exp Allergy ; 39(11): 1700-10, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19549024

RESUMO

BACKGROUND: Rhinoviruses (RVs) are responsible for the majority of acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations. RVs infect the lower airways and induce the production of pro-inflammatory and remodelling-associated mediators. Budesonide (BUD) and formoterol (FORM) synergize in controlling asthma and COPD exacerbations; however, their effects on virus-induced inflammation and remodelling are less known. OBJECTIVE: We investigated whether BUD and FORM synergize in suppressing RV-induced inflammation and remodelling in the airways. METHODS: In vitro models of RV infection of BEAS-2B and primary normal human bronchial epithelial (NHBE) cells were used. We assessed the effects of individual and combined drugs administered post-infection, at a clinically relevant concentration range (10(-6)-10(-10) m), on the production of CCL5, CXCL10, CXCL8, IL-6 and the remodelling-associated VEGF and bFGF, using ELISA and RT-PCR. RESULTS: BUD effectively suppressed RV-mediated induction of all mediators studied, in a concentration-dependent manner. FORM alone suppressed the production of CXCL8 and bFGF. The combination of BUD and FORM had concentration-dependent, additive or synergistic effects in the suppression of RV-induced CCL5, CXCL8 and CXCL10 in both cell types as well as VEGF in NHBE only. Combination treatment also resulted in an enhanced suppression of RV-induced IL-6, and CCL5 at the mRNA level as compared with BUD or FORM alone. CONCLUSION: BUD and FORM suppress RV-induced chemokines and growth factors in bronchial epithelial cells in a concentration-dependent, synergistic or additive manner. These data further support the combined use of BUD and FORM in asthma and COPD and intensification of this therapy during exacerbations.


Assuntos
Brônquios/metabolismo , Broncodilatadores/farmacologia , Budesonida/farmacologia , Células Epiteliais/metabolismo , Etanolaminas/farmacologia , Mediadores da Inflamação/metabolismo , Infecções por Picornaviridae/tratamento farmacológico , Mucosa Respiratória/metabolismo , Rhinovirus , Asma/tratamento farmacológico , Asma/metabolismo , Brônquios/virologia , Broncodilatadores/agonistas , Broncodilatadores/uso terapêutico , Budesonida/agonistas , Budesonida/uso terapêutico , Quimiocina CXCL10/biossíntese , Quimiocinas/biossíntese , Sinergismo Farmacológico , Células Epiteliais/virologia , Etanolaminas/agonistas , Etanolaminas/uso terapêutico , Fator 2 de Crescimento de Fibroblastos/biossíntese , Fumarato de Formoterol , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/biossíntese , Infecções por Picornaviridae/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/virologia , Fator A de Crescimento do Endotélio Vascular/biossíntese
5.
Respiration ; 68(5): 452-9, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11694805

RESUMO

BACKGROUND: It has been suggested that the effect of a beta2-agonist is additive with that of a cysteinyl leukotriene 1 receptor antagonist. OBJECTIVES: The present study was designed to answer the question of whether combined administration of inhaled salmeterol and oral zafirlukast at the standard doses would result in greater bronchodilation in patients with chronic airway obstruction than the use of either drug alone. METHODS: The study was performed using a double-blind, double-dummy, crossover, randomised design, and was conducted on 4 non-consecutive days. Sixteen patients with moderate to severe chronic obstructive pulmonary disease (COPD) and 10 non-smoker asthmatic patients received 40 mg of oral zafirlukast, 50 microg of inhaled salmeterol, 50 microg of inhaled salmeterol plus 40 mg of oral zafirlukast of placebo. Lung function was assessed before drug administration and 30, 60, 120, 180 and 240 min thereafter. At the end of the 4-hour period, each patient received 400 microg of inhaled salbutamol and spirometric testing was performed 30 min later. RESULTS: In both asthmatic and COPD patients, the overall effect of salmeterol and zafirlukast on the forced expiratory volume in 1 s (FEV1) was considered extremely significant (p < 0.0001), with a maximum bronchodilation above baseline after 180 min (20.7 and 11.0%, respectively) in asthmatics and after 2 h (21.7 and 11.2%, respectively) in COPD subjects. Zafirlukast did not produce any further significant acute bronchodilation in addition to that achieved with salmeterol alone in either asthmatic or COPD patients. Nevertheless, 7 out of 16 COPD patients and 7 out of 10 asthmatic patients had a further improvement after the combination of salmeterol and zafirlukast. The mean difference in pre- and post-salbutamol FEV1 values in both asthmatic and COPD patients after zafirlukast was significant (p < 0.05), but that after salmeterol and the combination of the two drugs was not significant (p > 0.05). The difference between placebo and zafirlukast was not significant following inhaled salbutamol given 4 h after each treatment. CONCLUSIONS: Both salmeterol and zafirlukast induced a significant increase in FEV1, although salmeterol elicited a greater improvement in both asthmatic and COPD patients. Apparently, zafirlukast at the clinically recommended dose did not produce any further significant acute bronchodilation in addition to that achieved with salmeterol alone, either in asthma or COPD. In any case, evaluation of the effect of the combination over a 12-hour period is mandatory.


Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Albuterol/análogos & derivados , Albuterol/agonistas , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/agonistas , Broncodilatadores/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Compostos de Tosil/antagonistas & inibidores , Compostos de Tosil/uso terapêutico , Adulto , Idoso , Brônquios/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Indóis , Masculino , Pessoa de Meia-Idade , Fenilcarbamatos , Xinafoato de Salmeterol , Sulfonamidas
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