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1.
Rev Mal Respir ; 40(5): 432-452, 2023 May.
Artigo em Francês | MEDLINE | ID: mdl-37080877

RESUMO

Patients with chronic cough experience major alteration in their quality of life. Given its numerous etiologies and treatments, this disease is a complex entity. To help clinicians involved in patient management of patients, guidelines have been issued by a group of French experts. They address definitions of chronic cough and initial management of patients with this pathology. We present herein the second-line tests that might be considered in patients whose coughing has persisted, notwithstanding initial management. The experts have also put forward a definition of unexplained or refractory chronic cough (URCC), the objective being to more precisely identify those patients whose cough persists despite optimal management. Lastly, these guidelines indicate the pharmacological and non-pharmacological interventions of use in URCC. Amitriptyline, pregabalin, gabapentin or morphine combined with speech and/or physical therapy are mainstays in treatment strategies. Other treatment options, such as P2X3 antagonists, are being developed and have generated high hopes among physicians and patients alike.


Assuntos
Tosse , Qualidade de Vida , Humanos , Adulto , Tosse/diagnóstico , Tosse/etiologia , Tosse/terapia , Doença Crônica , Gabapentina/uso terapêutico , Amitriptilina/uso terapêutico
2.
Front Pharmacol ; 13: 896167, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059986

RESUMO

Background: The Janus kinase (JAK) 1/2 inhibitor ruxolitinib has been approved in an indication of myelofibrosis and is a candidate for the treatment of a number of inflammatory or autoimmune diseases. We assessed the effects of ruxolitinib on lipopolysaccharide (LPS)- and poly (I:C)-induced cytokine production by human lung macrophages (LMs) and on the LMs' phagocytic activity. Methods: Human LMs were isolated from patients operated on for lung carcinoma. The LMs were cultured with ruxolitinib (0.5 × 10-7 M to 10-5 M) or budesonide (10-11 to 10-8 M) and then stimulated with LPS (10 ng·ml-1) or poly (I:C) (10 µg·ml-1) for 24 h. Cytokines released by the LMs into the supernatants were measured using ELISAs. The phagocytosis of labelled bioparticles was assessed using flow cytometry. Results: Ruxolitinib inhibited both the LPS- and poly (I:C)-stimulated production of tumor necrosis factor alpha, interleukin (IL)-6, IL-10, chemokines CCL2, and CXCL10 in a concentration-dependent manner. Ruxolitinib also inhibited the poly (I:C)- induced (but not the LPS-induced) production of IL-1ß. Budesonide inhibited cytokine production more strongly than ruxolitinib but failed to mitigate the production of CXCL10. The LMs' phagocytic activity was not impaired by the highest tested concentration (10-5 M) of ruxolitinib. Conclusion: Clinically relevant concentrations of ruxolitinib inhibited the LPS- and poly (I:C)-stimulated production of cytokines by human LMs but did not impair their phagocytic activity. Overall, ruxolitinib's anti-inflammatory activities are less intense than (but somewhat different from) those of budesonide-particularly with regard to the production of the corticosteroid-resistant chemokine CXCL-10. Our results indicate that treatment with a JAK inhibitor might be a valuable anti-inflammatory strategy in chronic obstructive pulmonary disease, Th1-high asthma, and both viral and non-viral acute respiratory distress syndromes (including coronavirus disease 2019).

4.
Int J Biol Macromol ; 130: 429-436, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30797011

RESUMO

Fucoidans are sulfated polysaccharides from brown algae, known to have immunomodulatory activity. Their effects on the response of airway epithelial cells to Toll-like receptor 3 (TLR3) stimulation have not been characterized. Our objective was to evaluate the effects of a marine-sourced fucoidan solution (MFS) on the TLR3-induced expression and/or production of cytokines and prostaglandin by human primary bronchial epithelial cells as a model of the airway epithelium. The cells were incubated with MFS in the presence or absence of Poly(I:C) (a TLR3 agonist that mimics viral RNA). Cytokine expression and production were assessed using RT-qPCR and ELISA. The expression of cyclooxygenase-2 and the production of prostaglandin E2 were also measured. Relative to control, exposure to MFS was associated with lower Poly(I:C)-induced mRNA expression of various cytokines and chemokines, and lower COX-2 production. The MFS inhibited the production of some cytokines (IL-1α, IL-1ß, TNFα, and IL-6), chemokines (CCL5, CCL22, CXCL1, CXCL5 and CXCL8) and prostaglandin E2 but did not alter the production of IL-12/25, CCL2 and CCL20. At clinically relevant concentrations, the MFS inhibited the TLR3-mediated production of inflammatory mediators by human primary bronchial epithelial cells - suggesting that locally applied MFS might help to reduce airway inflammation in viral infections.


Assuntos
Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Polissacarídeos/farmacologia , Receptor 3 Toll-Like/metabolismo , Células Cultivadas , Dinoprostona/biossíntese , Humanos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo
5.
Anaesthesia ; 73(6): 719-729, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29411358

RESUMO

Tranexamic acid is used both pre-hospital and in-hospital as an antifibrinolytic drug to treat or prevent hyperfibrinolysis in trauma patients; dosing, however, remains empirical. We aimed to measure plasma levels of tranexamic acid in patients receiving pre-hospital anti-hyperfibrinolytic therapy and to build a population pharmacokinetic model to propose an optimised dosing regimen. Seventy-three trauma patients were enrolled and each received tranexamic acid 1 g intravenously pre-hospital. A blood sample was drawn after arrival in the emergency department, and we measured the plasma tranexamic acid concentration using liquid chromatography-mass spectrometry, and modelled the data using non-linear mixed effect modelling. Tranexamic acid was administered at a median (IQR [range]) time of 43 (30-55 [5-135]) min after trauma. Plasma tranexamic acid levels were determined on arrival at hospital, 57 (43-70 [20-148]) min after pre-hospital administration of the drug. The measured concentration was 28.7 (21.5-38.5 [8.7-89.0]) µg.ml-1 . Our subjects had sustained severe trauma; injury severity score 20 (16-29 [5-75]), including penetrating injury in 2.8% and isolated traumatic brain injury in 19.7%. The pharmacokinetics were ascribed a two-compartment open model with body-weight as the main covariate. As tranexamic acid concentrations may fall below therapeutic levels during initial hospital treatment, we propose additional dosing schemes to maintain a specific target blood concentration for as long as required. This is the first study to investigate plasma level and pharmacokinetics of tranexamic acid after pre-hospital administration in trauma patients. Our proposed dosing regimen could be used in subsequent clinical trials to better study efficacy and tolerance profiles with controlled blood concentrations.


Assuntos
Antifibrinolíticos/administração & dosagem , Antifibrinolíticos/farmacocinética , Ácido Tranexâmico/administração & dosagem , Ácido Tranexâmico/farmacocinética , Ferimentos e Lesões/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifibrinolíticos/efeitos adversos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Esquema de Medicação , Serviços Médicos de Emergência , Feminino , Humanos , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ácido Tranexâmico/efeitos adversos , Adulto Jovem
6.
Br J Anaesth ; 117(3): 332-40, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27543528

RESUMO

BACKGROUND: Automated titration of propofol and remifentanil guided by the bispectral index (BIS) has been used for numerous surgical procedures. Orthotopic liver transplantation (OLT) uniquely combines major changes in circulating volume, an anhepatic phase, and ischaemia-reperfusion syndrome. We assessed the behaviour of this automated controller during OLT. METHODS: Adult patients undergoing OLT were included in this pilot study. Consumption of propofol and remifentanil was calculated for each surgery period (dissection, anhepatic, and liver reperfusion phases). Arterial blood samples were collected at several time points to allow comparison of actual with calculated propofol and remifentanil concentrations. Data are presented as median [25th and 75th percentiles] or percentage (95% confidence interval). RESULTS: Thirteen patients were studied. System performance, defined as the percentage of time with BIS in the range 40-60, was 88% (86-94) of the total duration of anaesthesia. Propofol requirement was decreased during the anhepatic phase compared with the dissection phase (2.9 [1.9-5.0] mg kg(-1) h(-1) and 4.6 [3.5-8.1] mg kg(-1) h(-1); P<0.03) while remifentanil consumption was unchanged (0.11 [0.09-0.19] µg kg- (1) min(-1)). Bland-Altman analysis showed a weak concordance for propofol (bias of 0.7 µg ml(-1) and limits of agreement of -2.2 to +3.7 µg ml(-1)) and remifentanil (bias of 1.3 ng ml(-1) and limits of agreement -4.3 to +6.8 ng ml(-1)). No adverse events were reported during anaesthesia. CONCLUSIONS: This pilot study indicates that automated titration of propofol and remifentanil guided by the BIS is feasible during OLT.


Assuntos
Anestesia/métodos , Transplante de Fígado/métodos , Adulto , Idoso , Monitores de Consciência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Piperidinas/administração & dosagem , Propofol/administração & dosagem , Remifentanil
7.
Clin Exp Allergy ; 46(11): 1456-1464, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27562177

RESUMO

BACKGROUND: The impact of grass pollen-induced allergic rhinitis (AR) on classroom/work productivity and activities can be assessed with a specific instrument: the Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions: Allergy Specific (WPAI-AS). This study evaluated the relationships between the WPAI-AS and other outcome measures in AR. METHODS: Adolescents (aged 12-17) and adults (aged 18-65) consulting specialists for AR were enrolled in a four-week, multicentre, observational study. The management of AR was left to the physicians' discretion. Participants regularly rated the WPAI-AS, their symptoms (using the Rhinoconjunctivitis Total Symptom Score (RTSS) and a 0- to 100-mm visual analogue scale (VAS)) and quality of life (according to the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)). RESULTS: A total of 247 adolescents and 292 adults showed similar baseline impairments in classroom/work productivity and activities other than work. In both age groups, the WPAI-AS scores were moderately correlated with the RQLQ score and, to a lesser extent, with the VAS score and the RTSS. A multiple regression analysis indicated that the RQLQ score was a weak but statistically significant predictor of both impaired work/classroom productivity and daily activities. A 50-mm VAS cut-off categorized patients in whom AR had the greatest impact on productivity. CONCLUSIONS: Grass pollen-induced AR impairs work/classroom and daily activity to a similar extent in adults and adolescents. The weak-to-moderate correlations with AR symptom scores and quality-of-life scores suggest that a specific tool (such as the WPAI-AS) should be used to assess AR's impact on word/classroom productivity and daily activities.


Assuntos
Atividades Cotidianas , Eficiência , Inabilitação Profissional , Rinite Alérgica/epidemiologia , Instituições Acadêmicas , Local de Trabalho , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Vigilância da População , Qualidade de Vida , Rinite Alérgica/diagnóstico , Inquéritos e Questionários , Adulto Jovem
8.
Br J Pharmacol ; 172(17): 4319-30, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26040494

RESUMO

BACKGROUND AND PURPOSE: 15-Lipoxygenase (15-LOX) activity is associated with inflammation and immune regulation. The objectives of the present study were to investigate the expression of 15-LOX-1 and 15-LOX-2 and evaluate the enzymes' roles in the polarization of human lung macrophages (LMs) in response to LPS and Th2 cytokines (IL-4/-13). EXPERIMENTAL APPROACH: LMs were isolated from patients undergoing surgery for carcinoma. The cells were cultured with a 15-LOX inhibitor (PD146176 or ML351), a COX inhibitor (indomethacin), a 5-LOX inhibitor (MK886) or vehicle and then stimulated with LPS (10 ng · mL(-1)), IL-4 (10 ng · mL(-1)) or IL-13 (50 ng · mL(-1)) for 24 h. Levels of ALOX15 (15-LOX-1) and ALOX15B (15-LOX-2) transcripts were determined by real-time quantitative PCR. Immunoassays were used to measure levels of LPS-induced cytokines (TNF-α, CCL2, CCL3, CCL4, CXCL1, CXCL8 and CXCL10) and Th2 cytokine-induced chemokines (CCL13, CCL18 and CCL22) in the culture supernatant. KEY RESULTS: Stimulation of LMs with LPS was associated with increased expression of ALOX15B, whereas stimulation with IL-4/IL-13 induced the expression of ALOX15. PD146176 and ML351 (10 µM) reduced the release of the chemokines induced by LPS and Th2 cytokines. The effects of these 15-LOX inhibitors were maintained in the presence of indomethacin and MK886. Furthermore, indomethacin revealed the inhibitory effect of PD146176 on TNF-α release. CONCLUSIONS AND IMPLICATIONS: Inhibition of the 15-LOX pathways is involved in the down-regulation of the in vitro production of chemokines in LMs. Our results suggest that the 15-LOX pathways have a role in the pathogenesis of inflammatory lung disorders and may thus constitute a potential drug target.


Assuntos
Araquidonato 15-Lipoxigenase/fisiologia , Quimiocinas/biossíntese , Inibidores de Lipoxigenase/farmacologia , Macrófagos Alveolares/metabolismo , Idoso , Células Cultivadas , Feminino , Humanos , Macrófagos Alveolares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade
9.
Rev Mal Respir ; 31(8): 700-13, 2014 Oct.
Artigo em Francês | MEDLINE | ID: mdl-25391505

RESUMO

The combination of an inhaled corticosteroid and a long acting beta-2 agonist is indicated for the regular treatment of persistent moderate-to-severe asthmatics whose asthma is not controlled by inhaled corticosteroids and the occasional use of a short acting beta-2 agonist. The aim of this review is to give an overview of the rationale of combining formoterol and fluticasone and to analyze the clinical data concerning a new fixed combination of fluticasone and formoterol in a pressurised metered-dose inhaler with a dose counter (Flutiform(®)) that was approved for the treatment of asthma in France in 2013. The clinical studies provide evidence that combined fluticasone/formoterol is more efficacious than fluticasone or formoterol given alone, and provides similar improvements in lung function to fluticasone (Flixotide(®)) and formoterol (Foradil(®)) administered concurrently. The combination of fluticasone/formoterol gave a more rapid bronchodilatation than the combination fluticasone/salmeterol. As a whole, the combination of fluticasone/formoterol had similar efficacy and tolerability profiles to the combinations of either budesonide/formoterol or fluticasone/salmeterol.


Assuntos
Androstadienos/administração & dosagem , Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Etanolaminas/administração & dosagem , Inaladores Dosimetrados , Administração por Inalação , Albuterol/administração & dosagem , Albuterol/análogos & derivados , Combinação de Medicamentos , Fluticasona , Combinação Fluticasona-Salmeterol , Fumarato de Formoterol , Humanos
10.
Rev Pneumol Clin ; 70(3): 148-55, 2014 Jun.
Artigo em Francês | MEDLINE | ID: mdl-24646786

RESUMO

The receptors responsible for taste perception distinguish the four basic tastes : salty, sweet, bitter and umami. Among them, the bitter taste receptors (TAS2R) are G protein coupled receptors, including 25 subtypes identified in humans to date. Although the existence of endogenous agonists remains uncertain, the TAS2R receptors have the ability to recognize natural or synthetic molecules, as various molecules produced by bacteria, or caffeine, chloroquine, or erythromycin. The expression of these receptors, initially thought to be confined to the oral cavity, has recently been described in extra-oral tissues such as the gastrointestinal tract and the lungs. The effects in the lung tissue are essentially at three levels : TAS2R receptors expressed on the cilia of epithelial cells increase the cilia vibration frequency; the stimulation of TAS2R receptors expressed in bronchial smooth muscle cells leads to bronchial relaxation; while TAS2R receptors expressed on immune cells in the lung tissue, including macrophages, are involved in the modulation of the production of pro-inflammatory cytokines. In conclusion, in view of these complementary mechanisms, TAS2R receptors may become a pharmacological target of interest for the treatment of obstructive lung diseases.


Assuntos
Pulmão/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Paladar/fisiologia , Animais , Cílios/fisiologia , Células Epiteliais/fisiologia , Humanos , Pulmão/química , Pulmão/citologia , Relaxamento Muscular/fisiologia , Miócitos de Músculo Liso/fisiologia , Receptores de Superfície Celular/fisiologia , Receptores Acoplados a Proteínas G/agonistas
11.
Br J Pharmacol ; 171(11): 2767-77, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24467410

RESUMO

BACKGROUND AND PURPOSE: Marijuana smoking is widespread in many countries, and the use of smoked synthetic cannabinoids is increasing. Smoking a marijuana joint leads to bronchodilation in both healthy subjects and asthmatics. The effects of Δ(9) -tetrahydrocannabinol and synthetic cannabinoids on human bronchus reactivity have not previously been investigated. Here, we sought to assess the effects of natural and synthetic cannabinoids on cholinergic bronchial contraction. EXPERIMENTAL APPROACH: Human bronchi isolated from 88 patients were suspended in an organ bath and contracted by electrical field stimulation (EFS) in the presence of the phytocannabinoid Δ(9) -tetrahydrocannabinol, the endogenous 2-arachidonoylglycerol, the synthetic dual CB1 and CB2 receptor agonists WIN55,212-2 and CP55,940, the synthetic, CB2 -receptor-selective agonist JWH-133 or the selective GPR55 agonist O-1602. The receptors involved in the response were characterized by using selective CB1 and CB2 receptor antagonists (SR141716 and SR144528 respectively). KEY RESULTS: Δ(9) -tetrahydrocannabinol, WIN55,212-2 and CP55,940 induced concentration-dependent inhibition of cholinergic contractions, with maximum inhibitions of 39, 76 and 77% respectively. JWH-133 only had an effect at high concentrations. 2-Arachidonoylglycerol and O-1602 were devoid of any effect. Only CB1 receptors were involved in the response because the effects of cannabinoids were antagonized by SR141716, but not by SR144528. The cannabinoids did not alter basal tone or contractions induced by exogenous Ach. CONCLUSIONS AND IMPLICATIONS: Activation of prejunctional CB1 receptors mediates the inhibition of EFS-evoked cholinergic contraction in human bronchus. This mechanism may explain the acute bronchodilation produced by marijuana smoking.


Assuntos
Brônquios/efeitos dos fármacos , Canabinoides/farmacologia , Receptor CB1 de Canabinoide/fisiologia , Idoso , Idoso de 80 Anos ou mais , Brônquios/fisiologia , Estimulação Elétrica , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Contração Muscular/efeitos dos fármacos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/fisiologia , Receptores de Canabinoides , Receptores Acoplados a Proteínas G/genética
12.
Br J Anaesth ; 111(6): 916-24, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23880099

RESUMO

BACKGROUND: Interest in antifibrinolytic tranexamic acid (TA) has grown since the widespread removal of aprotinin, but its dosing during cardiac surgery is still debated. The objectives of this study were to investigate the population pharmacokinetics (PK) of TA given with either low- or high-dose continuous infusion schemes in adult cardiac surgery patients during cardiopulmonary bypass (CPB). METHODS: Patients were randomized to receive either low-dose (10 mg kg(-1) followed by an infusion of 1 mg kg(-1) h(-1) throughout the operation, and 1 mg kg(-1) into the CPB) or high-dose (30 mg kg(-1), then 16 mg kg(-1) h(-1), and 2 mg kg(-1) into the CPB) TA. Serum TA concentrations were measured in 61 patients and the data were modelled using Monolix. RESULTS: TA concentrations were 28-55 µg ml(-1) in the low-dose group and 114-209 µg ml(-1) in the high-dose group throughout surgery. TA PK was best described by a two-compartment open model. The main covariate effect was bodyweight, whereas the CPB did not influence the PK. Assuming a bodyweight of 70 kg, the population estimates were 4.8 litre h(-1) for clearance, 6.6 litre for the volume of the central compartment, 32.2 litre h(-1) for the diffusional clearance, and the peripheral volume of distribution was 10.8 litre. CONCLUSIONS: The PK of TA was satisfactorily described by an open two-compartmental model, which was used to propose a dosing scheme suitable for obtaining and maintaining the desired plasma concentration in a stable and narrow range in cardiac surgery patients.


Assuntos
Antifibrinolíticos/sangue , Procedimentos Cirúrgicos Cardíacos/métodos , Ponte Cardiopulmonar , Ácido Tranexâmico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifibrinolíticos/administração & dosagem , Peso Corporal/fisiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Cuidados Intraoperatórios/métodos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ácido Tranexâmico/administração & dosagem
13.
Rev Mal Respir ; 29(2): 232-44, 2012 Feb.
Artigo em Francês | MEDLINE | ID: mdl-22405116

RESUMO

Asthma exacerbations are responsible for many emergency medical interventions and account for a significant proportion of the health costs of the disease. Increased airway inflammation is a key feature of exacerbations in asthma and therefore inhaled corticosteroids (ICS) are considered as first-line therapy for long-term asthma control. ICS have been demonstrated to reduce the risk of asthma exacerbations, as well as improving lung function. Oral leukotriene receptor antagonists also reduce the incidence of asthma exacerbations but are less effective than ICS. In patients with inadequately controlled persistent asthma despite low-dose ICS, the addition of a long-acting inhaled beta-agonist (LABA) should be considered. LABA should not be given alone and should always be associated with ICS in asthma. The anti-immunoglobulin E antibody, omalizumab, reduces severe exacerbations and emergency visits in patients with severe allergic asthma. In clinical trials measurement of the inflammatory response in induced sputum could provide information concerning appropriate drug therapy. Asthma-associated comorbidities should be investigated and treated, particularly in severe asthma. Despite a high prevalence of both gastro-oesophageal reflux and allergic rhinitis among patients with asthma, treatment with proton-pump inhibitors or nasal corticosteroids does not reduce the rate of asthma exacerbations.


Assuntos
Asma/tratamento farmacológico , Asma/prevenção & controle , Corticosteroides/uso terapêutico , Agonistas Adrenérgicos beta/uso terapêutico , Antagonistas Adrenérgicos beta/efeitos adversos , Antiasmáticos/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Humanos , Imunoglobulina E/imunologia , Vacinas contra Influenza/efeitos adversos , Antagonistas de Leucotrienos/uso terapêutico , Nebulizadores e Vaporizadores , Inibidores de Fosfodiesterase/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Abandono do Hábito de Fumar
14.
Br J Pharmacol ; 165(6): 1877-1890, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21913898

RESUMO

BACKGROUND AND PURPOSE: Lung macrophages are critically involved in respiratory diseases. This study assessed the effects of the PDE4 inhibitor roflumilast and its active metabolite, roflumilast N-oxide on the release of a range of chemokines (CCL2, 3, 4, CXCL1, 8, 10) and of TNF-α, from human lung macrophages, stimulated with bacterial lipopolysaccharide LPS. EXPERIMENTAL APPROACH: Lung macrophages isolated from resected human lungs were incubated with roflumilast, roflumilast N-oxide, PGE(2), the COX inhibitor indomethacin, the COX-2 inhibitor NS-398 or vehicle and stimulated with LPS (24 h). Chemokines, TNF-α, PGE(2) and 6-keto PGF(1α) were measured in culture supernatants by immunoassay. COX-2 mRNA expression was assessed with RT-qPCR. PDE activities were determined in macrophage homogenates. KEY RESULTS: Expression of PDE4 in lung macrophages was increased after incubation with LPS. Roflumilast and roflumilast N-oxide concentration-dependently reduced the LPS-stimulated release of CCL2, CCL3, CCL4, CXCL10 and TNF-α from human lung macrophages, whereas that of CXCL1 or CXCL8 was not altered. This reduction by the PDE4 inhibitors was further accentuated by exogenous PGE(2) (10 nM) but abolished in the presence of indomethacin or NS-398. Conversely, addition of PGE(2) (10 nM), in the presence of indomethacin restored inhibition by roflumilast. LPS also increased PGE(2) and 6-keto PGF(1α) release from lung macrophages which was associated with an up-regulation of COX-2 mRNA. CONCLUSIONS AND IMPLICATIONS: Roflumilast and roflumilast N-oxide reduced LPS-induced release of CCL2, 3, 4, CXCL10 and TNF-α in human lung macrophages.


Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Quimiocinas/antagonistas & inibidores , Inibidores da Fosfodiesterase 4/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Células Cultivadas , Quimiocinas/metabolismo , Ciclopropanos/farmacologia , Dinoprostona/metabolismo , Epoprostenol/metabolismo , Feminino , Humanos , Lipopolissacarídeos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Pessoa de Meia-Idade , Diester Fosfórico Hidrolases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Br J Pharmacol ; 159(6): 1304-11, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20136829

RESUMO

BACKGROUND AND PURPOSE: Adenosine is a major endogenous regulator of macrophage function, and activates four specific adenosine receptors (A(1), A(2A), A(2B) and A(3)). Here, we have assessed in human lung macrophages the modulation of the expression of adenosine receptor mRNA by lipopolysaccharide (LPS), and the relative contributions of the different adenosine receptors to LPS-induced production of tumour necrosis factor (TNF)-alpha and chemokines. EXPERIMENTAL APPROACH: Lung macrophages isolated from resected lungs were stimulated with LPS and treated with adenosine receptor agonists or/and antagonists. Adenosine receptor expression was assessed with qRT-PCR. Cytokines were measured in lung macrophage supernatants with elisa. KEY RESULTS: LPS increased (about 400-fold) mRNA for A(2A) adenosine receptors, decreased mRNA for A(1) and A(2B), but had no effect on A(3) adenosine receptor mRNA. The adenosine receptor agonist NECA inhibited TNF-alpha production concentration dependently, whereas the A(1) receptor agonist, CCPA, and the A(3) receptor agonist, AB-MECA, inhibited TNF-alpha production only at concentrations affecting A(2A) receptors. NECA also inhibited the production of CCL chemokines (CCL2, CCL3, CCL4, CCL5) and CXCL chemokines (CXCL9 and CXCL10), but not that of CXCL1, CXCL8 and CXCL5. Reversal of NECA-induced inhibition of TNF-alpha and chemokine production by the selective A(2A) adenosine receptor antagonist ZM 241385, but not the A(2B) receptor antagonist, MRS 1754, or the A(3) receptor antagonist, MRS 1220, indicated involvement of A(2A) receptors. CONCLUSIONS AND IMPLICATIONS: LPS up-regulated A(2A) adenosine receptor gene transcription, and this receptor subtype mediated inhibition of the LPS-induced production of TNF-alpha and of a subset of chemokines in human lung macrophages.


Assuntos
Quimiocinas/biossíntese , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Receptores Purinérgicos P1/fisiologia , Fator de Necrose Tumoral alfa/biossíntese , Acetamidas/farmacologia , Células Cultivadas , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Pulmão/citologia , Macrófagos Alveolares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Subunidades Proteicas , Agonistas do Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Purinas/farmacologia , Quinazolinas/farmacologia , Receptores Purinérgicos P1/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Triazinas/farmacologia , Triazóis/farmacologia
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