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1.
Physiol Rep ; 7(13): e14149, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31264386

RESUMO

A decreased lung diffusing capacity for carbon monoxide (DLCO ) in systemic sclerosis (SSc) is considered to reflect losses of alveolar membrane diffusive conductance for CO (DMCO ), due to interstitial lung disease, and/or pulmonary capillary blood volume (VC ), due to vasculopathy. However, standard DLCO does not allow separate DMCO from VC . Lung diffusing capacity for nitric oxide (DLNO ) is considered to be more sensitive to decrement of alveolar membrane diffusive conductance than DLCO . Standard DLCO and DLNO were compared in 96 SSc subjects with or without lung restriction. Data showed that DLNO was reduced in 22% of subjects with normal lung volumes and DLCO , whereas DLCO was normal in 30% of those with decreased DLNO . In 30 subjects with available computed tomography of the chest, both DLCO and DLNO were negatively correlated with the extent of pulmonary fibrosis. However, DLNO but not DLCO was always reduced in subjects with ≥ 5% fibrosis, and also decreased in some subjects with < 5% fibrosis. DMCO and VC partitioning and Doppler ultrasound-determined systolic pulmonary artery pressure could not explain individual differences in DLCO and DLNO . DLNO may be of clinical value in SSc because it is more sensitive to DMCO loss than standard DLCO , even in nonrestricted subjects without fibrosis, whereas DLCO partitioning into its subcomponents does not provide information on whether diffusion limitation is primarily due to vascular or interstitial lung disease in individual subjects. Moreover, decreased DLCO in the absence of lung restriction does not allow to suspect pulmonary arterial hypertension without fibrosis.


Assuntos
Capacidade de Difusão Pulmonar/métodos , Fibrose Pulmonar/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Adulto , Idoso , Monóxido de Carbono/administração & dosagem , Monóxido de Carbono/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/administração & dosagem , Óxido Nítrico/efeitos adversos , Capacidade de Difusão Pulmonar/normas , Sensibilidade e Especificidade
2.
Respir Res ; 18(1): 145, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754132

RESUMO

BACKGROUND: Muscarinic-receptor antagonists and ß-adrenoceptor agonists are used, alone or in combination, as first-line treatment for chronic obstructive pulmonary disease. Both drugs decrease airway smooth muscle tone by post-junctional mechanisms but they may have opposing effects on pre-junctional acetylcholine (ACh)-release. METHODS: We studied the effects of the muscarinic-receptor antagonist glycopyrronium (GLY), the ß-adrenoceptor agonist indacaterol (IND) and their combination on electrically-induced ACh-release and contractile response in isolated bovine trachealis. Data were analyzed by paired t-test and analysis of variance for repeated or independent measures with Newmann-Keuls post-hoc test when appropriate. RESULTS: GLY 10-8 M decreased contractile response by 19 ± 6% (p = 0.010) without altering ACh-release. GLY 10-7 M and 10-6 M almost abolished contractile responses even if the ACh-release was increased by 27 ± 19% (p < 0.001) and 20 ± 8% (p = 0.004), respectively. IND 10-7 M had no significant effects on contractile response and ACh-release, whereas IND 10-6 M reduced contractile response by 24 ± 12% (p = 0.002) without altering ACh-release. IND 10-5 M decreased contractile response by 51 ± 17% (p < 0.001) and ACh-release by 22 ± 11% (p = 0.004). Co-incubation with GLY 10-8 M and IND 10-7 M did not alter ACh-release but inhibited contractile response by 41 ± 8% (p < 0.001). The latter effect was greater than with GLY 10-8 M, or IND 10-7 M, or IND 10-6 M given separately (p < 0.001 for all). The increment of ACh-release caused by GLY was attenuated by IND 10-5 M, though this did not affect contractile response. CONCLUSIONS: At equimolar concentration, GLY alone attenuates airway smooth muscle contraction more than IND, despite an increased ACh-release. Combination of GLY with IND at submaximal concentrations has more than additive effect suggesting a synergistic post-junctional effect. Adding GLY to IND provides a greater inhibitory effect on airway smooth muscle contraction than increasing IND concentration.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncodilatadores/farmacologia , Fibras Colinérgicas/efeitos dos fármacos , Glicopirrolato/farmacologia , Indanos/farmacologia , Antagonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/inervação , Quinolonas/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Traqueia/inervação , Acetilcolina/metabolismo , Animais , Bovinos , Fibras Colinérgicas/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Estimulação Elétrica , Técnicas In Vitro
3.
J Appl Physiol (1985) ; 120(9): 1029-38, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-26893034

RESUMO

Lung diffusing capacity for carbon monoxide (DLCO) is decreased in both usual interstitial pneumonia-idiopathic pulmonary fibrosis (UIP-IPF) and nonspecific interstitial pneumonia (NSIP), but is moderately related to computed tomography (CT)-determined fibrotic changes. This may be due to the relative insensitivity of DLCO to changes in alveolar membrane diffusive conductance (DMCO). The purpose of this study was to determine whether measurement of lung diffusing capacity for nitric oxide (DLNO) better reflects fibrotic changes than DLCO DLNO-DLCO were measured simultaneously in 30 patients with UIP-IPF and 30 with NSIP. Eighty-one matched healthy subjects served as a control group. The amount of pulmonary fibrosis was estimated by CT volumetric analysis of visually bounded areas showing reticular opacities and honeycombing. DMCO and pulmonary capillary volume (VC) were calculated. DLNO was below the lower limit of normal in all patients irrespective of extent and nature of disease, whereas DLCO was within the normal range in a nonnegligible number of patients. Both DLNO and DLCO were significantly correlated with visual assessment of fibrosis but DLNO more closely than DLCO DMCO was also below the lower limit of normal in all UIP-IPF and NSIP patients and significantly correlated with fibrosis extent in both diseases, whereas VC was weakly correlated with fibrosis in UIP-IPF and uncorrelated in NSIP, with normal values in half of patients. In conclusion, measurement of DLNO may provide a more sensitive evaluation of fibrotic changes than DLCO in either UIP-IPF or NSIP, because it better reflects DMCO.


Assuntos
Biomarcadores/metabolismo , Pneumonias Intersticiais Idiopáticas/metabolismo , Pneumonias Intersticiais Idiopáticas/fisiopatologia , Óxido Nítrico/metabolismo , Capacidade de Difusão Pulmonar/fisiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/fisiopatologia , Idoso , Monóxido de Carbono/metabolismo , Feminino , Humanos , Pulmão , Masculino , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
4.
J Appl Physiol (1985) ; 118(7): 796-802, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25414244

RESUMO

Current guidelines recommend severity of chronic obstructive pulmonary disease be graded by using forced expiratory volume in 1 s (FEV1). But this measurement is biased by thoracic gas compression depending on lung volume and airflow resistance. The aim of this study was to test the hypothesis that the effect of thoracic gas compression on FEV1 is greater in emphysema than chronic bronchitis because of larger lung volumes, and this influences severity classification and prognosis. FEV1 was simultaneously measured by spirometry and body plethysmography (FEV1-pl) in 47 subjects with dominant emphysema and 51 with dominant chronic bronchitis. Subjects with dominant emphysema had larger lung volumes, lower diffusion capacity, and lower FEV1 than those with dominant chronic bronchitis. However, FEV1-pl, patient-centered variables (dyspnea, quality of life, exercise tolerance, exacerbation frequency), arterial blood gases, and respiratory impedance were not significantly different between groups. Using FEV1-pl instead of FEV1 shifted severity distribution toward less severe classes in dominant emphysema more than chronic bronchitis. The body mass, obstruction, dyspnea, and exercise (BODE) index was significantly higher in dominant emphysema than chronic bronchitis, but this difference significantly decreased when FEV1-pl was substituted for FEV1. In conclusion, the FEV1 is biased by thoracic gas compression more in subjects with dominant emphysema than in those with chronic bronchitis. This variably and significantly affects the severity grading systems currently recommended.


Assuntos
Artefatos , Pletismografia Total/métodos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória/métodos , Índice de Gravidade de Doença , Algoritmos , Diagnóstico por Computador/métodos , Humanos , Pulmão/fisiopatologia , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/classificação , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Capacidade Pulmonar Total
5.
Respir Physiol Neurobiol ; 189(1): 162-6, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23911590

RESUMO

We investigated the signal transmission pathway by which activation of µ-opioid receptors attenuates acetylcholine (ACh) release in bovine trachealis. Electrical stimulation (ES)-induced [(3)H]-ACh release was determined in bovine tracheal smooth muscle strips pre-incubated with either the Gi-protein inhibitor pertussis toxin (PTX, 500 ng/ml and 1 µg/ml) or the Gz-protein specific inhibitor arachidonic acid (AA, 10(-6)M and 10(-5)M) and then treated with DAMGO (D-Ala(2),N-MePhe(4),Gly-ol(5)-enkephalin) 10(-5)M. Indomethacin 10(-5)M was used to block AA cascade. The inhibitory effect of DAMGO on ES-induced [(3)H]-ACh release was PTX-insensitive, but, by contrast, ablated by AA in a concentration-dependent manner. AA 10(-5)M alone reduced [(3)H]-ACh release, an effect that was prevented by iberiotoxin 10(-7)M, suggesting an involvement of Ca(2+)-activated K(+)-channels. Western blot analysis consistently showed immunoreactive bands against a specific antibody anti-Gz-α subunit at ∼40 kDa, consistent with the presence of Gz-protein. The present findings suggest that in isolated bovine trachealis, activation of µ-opioid receptors inhibits ACh-release through a signal transmission pathway involving Gz-protein rather than Gi-protein.


Assuntos
Acetilcolina/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Receptores Opioides mu/metabolismo , Transdução de Sinais/fisiologia , Traqueia/metabolismo , Analgésicos Opioides/farmacologia , Animais , Ácido Araquidônico/farmacologia , Western Blotting , Bovinos , Estimulação Elétrica , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Transdução de Sinais/efeitos dos fármacos , Traqueia/efeitos dos fármacos
6.
Respir Physiol Neurobiol ; 187(3): 244-9, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23584050

RESUMO

Lung ultrasonography (LUS) and computed tomography (CT) were compared for quantitative assessment of extravascular lung water (EVLW) in 10 isolated bovine lung lobes. LUS and CT were obtained at different inflation pressures before and after instillation with known amounts of hypotonic saline. A video-based quantitative LUS analysis was superior to both single-frame quantitative analysis and visual scoring in the assessment of EVLW. Video-based mean LUS intensity was strongly correlated with EVLW density (r(2)=0.87) but weakly correlated with mean CT attenuation (r(2)=0.49) and physical density (r(2)=0.49). Mean CT attenuation was weakly correlated with EVLW density (r(2)=0.62) but strongly correlated with physical density (r(2)=0.99). When the effect of physical density was removed by partial correlation analysis, EVLW density was significantly correlated with video-based LUS intensity (r(2)=0.75) but not mean CT attenuation (r(2)=0.007). In conclusion, these findings suggest that quantitative LUS by video gray-scale analysis can assess EVLW more reliably than LUS visual scoring or quantitative CT.


Assuntos
Água Extravascular Pulmonar/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Animais , Bovinos , Técnicas In Vitro , Pulmão/ultraestrutura , Microscopia Eletrônica de Varredura , Estatística como Assunto , Tomografia Computadorizada por Raios X , Ultrassonografia Doppler , Gravação em Vídeo
7.
Respir Physiol Neurobiol ; 185(2): 281-6, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23063739

RESUMO

The effects of the selective µ-opioid agonist DAMGO and the selective κ-opioid agonist U-50488H on tritiated acetylcholine release ([(3)H]-ACh) and contractile responses to electrical stimulation (ES) were simultaneously determined in isolated bovine trachealis. The inhibitory effect of DAMGO 10(-5)M on [(3)H]-ACh release was not significantly different from the effect of the non-selective muscarinic agonist pilocarpine 10(-5)M, whereas the effect of U-50488H 10(-5)M was significantly greater. The effects of both opioids were not significantly different when muscles were pre- or co-incubated with the unselective muscarinic antagonist atropine 10(-7)M. Both DAMGO and U-50488H attenuated ES-induced contraction and this effect was significantly correlated with the inhibition of [(3)H]ACh-release (r(2)=0.8552). These data suggest that (1) opioids are important modulators of airway smooth muscle tone, (2) their effect is not altered by the activity of muscarinic autoregulation, and (3) their inhibitory effect of airway smooth muscle contraction can be almost totally explained by inhibition of ACh release.


Assuntos
(trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Acetilcolina/metabolismo , Analgésicos Opioides/farmacologia , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Traqueia/efeitos dos fármacos , Analgésicos não Narcóticos/farmacologia , Animais , Atropina/farmacologia , Bovinos , Interações Medicamentosas , Estimulação Elétrica , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Técnicas In Vitro , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Pilocarpina/farmacologia , Trítio/metabolismo
8.
Respir Physiol Neurobiol ; 180(1): 45-51, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22024550

RESUMO

UNLABELLED: We searched for pre-junctional inhibitory muscarinic receptors in isolated bovine trachealis strips and bronchial rings. Electric stimulation (ES)-induced tritiated acetylcholine ([(3)H]-ACh)-release and isometric contractions were determined in muscles incubated with the non-selective muscarinic agonist pilocarpine, the non-selective muscarinic antagonist atropine, the selective M(2)-receptor antagonists methoctramine and gallamine, or the selective M(4)-receptor antagonist PD102807. Electric field stimulation (EFS)-induced isometric contractile responses were assessed in trachealis strips and bronchial rings treated with 10(-9)-10(-5)M methoctramine, gallamine or PD102807. Pilocarpine (10(-6) and 10(-5)M) and atropine (10(-7)M) significantly decreased and increased ES-evoked [(3)H]-ACh-release, respectively. The enhancing effect of atropine on [(3)H]-ACh-release prevailed over the inhibitory effect of pilocarpine. M(2)- and M(4)-receptor antagonists did not increase EFS-induced contraction or ES-induced [(3)H]-ACh-release. However, 10(-7)M methoctramine, gallamine or PD102807 significantly attenuated the inhibitory effects of pilocarpine 10(-5)M on ES-induced [(3)H]-ACh-release. CONCLUSIONS: Muscarinic autoregulation is present in bovine airways but is not fully accounted for by M(2)- and M(4)-receptor subtypes.


Assuntos
Autorreceptores/biossíntese , Brônquios/metabolismo , Receptores Muscarínicos/biossíntese , Traqueia/metabolismo , Animais , Autorreceptores/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Bovinos , Estimulação Elétrica , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Traqueia/efeitos dos fármacos
9.
J Aerosol Med Pulm Drug Deliv ; 24(5): 235-43, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21689019

RESUMO

BACKGROUND: We compared the efficacy and safety of formoterol given by a pressurized metered-dose inhaler (pMDI) (Atimos®, Chiesi Farmaceutici, Italy), using a chlorine-free hydrofluoroalkane (HFA-134a) propellant developed to provide stable and uniform dose delivery (Modulite™, Chiesi Farmaceutici, Italy), with formoterol by dry powder inhaler (DPI) (Foradil® Aerolizer®, Novartis Pharmaceuticals) and placebo, in reducing airflow obstruction and lung hyperinflation, in moderate-to-severe, partially reversible chronic obstructive pulmonary disease (COPD). METHODS: Forty-eight patients were randomized to a 1-week, double-blind, double-dummy, three-period crossover study with 12 µg b.i.d. of formoterol given by pMDI or DPI, or placebo. Spirometry, specific airway conductance, and lung volumes were measured at the beginning and at the end of each treatment period from predose to 4 h postdose. A 6-min walking test was carried out 4 h after the first and the last dose, with dyspnea assessed by Borg scale. Safety was assessed through adverse events monitoring electrocardiography and vital signs. RESULTS: The two formulations of formoterol were significantly superior to placebo but not different from each other in increasing 1-sec forced expiratory volume, specific airway conductance, inspiratory capacity, and inspiratory-to-total lung capacity ratio. The two active treatments were also equivalent and superior to placebo in reducing dyspnea at rest and on exertion. No differences in terms of safety between the two active forms and placebo were detected. CONCLUSIONS: Formoterol given with chlorine-free pMDI was equivalent to DPI in reducing airway obstruction and lung hyperinflation in COPD patients. Both formoterol formulations confirmed the good safety profile similar to placebo.


Assuntos
Obstrução das Vias Respiratórias/tratamento farmacológico , Broncodilatadores/administração & dosagem , Etanolaminas/administração & dosagem , Capacidade Inspiratória/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/complicações , Aerossóis , Idoso , Estudos Cross-Over , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Fumarato de Formoterol , Humanos , Capacidade Inspiratória/fisiologia , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Pós , Doença Pulmonar Obstrutiva Crônica/fisiopatologia
10.
Chest ; 138(5): 1133-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20495110

RESUMO

BACKGROUND: Low-density gas mixtures and oxygen (O2) supplementation are known to improve physical performance and ventilatory adaptation during incremental maximal exercise in COPD. We investigated whether their combined use during intense physical training is also effective in ameliorating exercise tolerance in patients affected by moderate to severe COPD. METHODS: Thirty patients (FEV1 < 60% of predicted) underwent a 2-month rehabilitation program. Leg-cycle training was conducted thrice weekly at 80% of the initial peak work rate for at least 20 min breathing room air, a 60% helium and 40% O2 mixture, or supplemental O2 (40%) inhaled from a Douglas bag. The study was randomized with a double-blind design. Before and at the end of the training period the subjects were tested for spirometry, arterial gas tension, diffusing lung capacity for CO, and incremental and constant work rate exercise test on a cycle ergometer. RESULTS: Physical training resulted in a significant improvement in peak oxygen consumption and power output (P < .01 for both) and in exercise endurance time (P < .05) independently of the kind of inhaled gas during the rehabilitation program (P ≥ .42). No changes were observed in lung function tests or gas exchange. CONCLUSIONS: We concluded that the use of a low-density gas mixture or O2 supplementation does not contribute to improved exercise performance in patients with moderate to severe COPD without a significantly decreased diffusion lung capacity for CO who are able to tolerate intense physical training.


Assuntos
Terapia por Exercício/métodos , Tolerância ao Exercício/efeitos dos fármacos , Hélio/administração & dosagem , Oxigenoterapia/métodos , Oxigênio/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/reabilitação , Idoso , Método Duplo-Cego , Teste de Esforço , Feminino , Seguimentos , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Resultado do Tratamento
11.
Pharmaceuticals (Basel) ; 3(4): 1016-1044, 2010 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-27713285

RESUMO

Inhaled ß2-adrenoceptor (ß2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the ß2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of ß2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and ß-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled ß2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.

12.
Ther Adv Respir Dis ; 3(4): 163-74, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19661157

RESUMO

Airway hyper-responsiveness (AHR) is a cardinal feature of asthma. Its absence has been considered useful in excluding asthma, whereas it may be present in other diseases such as atopic rhinitis and chronic obstructive pulmonary disease. AHR is often considered an epiphenomenon of airway inflammation. Actually, the response of airways to constrictor stimuli is modulated by a complex array of factors, some facilitating and others opposing airway narrowing. Thus, it has been suggested that AHR, and perhaps asthma, might be present even without or before the development of airway inflammation. We begin this review by highlighting some terminological and methodological issues concerning the measurement of AHR. Then we describe the neurohumoral mechanisms controlling airway tone. Finally, the pivotal role of airway smooth muscle and internal and external modulation of airway caliber in vivo are discussed in detail.


Assuntos
Asma/fisiopatologia , Hiper-Reatividade Brônquica/fisiopatologia , Broncoconstritores , Animais , Asma/diagnóstico , Brônquios/fisiopatologia , Hiper-Reatividade Brônquica/diagnóstico , Broncoconstritores/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Músculo Liso/metabolismo , Testes de Função Respiratória/métodos
13.
J Appl Physiol (1985) ; 107(2): 494-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19541736

RESUMO

In asthmatic patients, either bronchodilatation or bronchoconstriction may develop during exercise. In 18 patients with mild-to-moderate asthma, we conducted two studies with the aims to 1) quantify the bronchodilator effect of hyperpnea induced by incremental-load maximum exercise compared with effects of inhaled albuterol (study 1, n=10) and 2) determine the time course of changes in airway caliber during prolonged constant-load exercise (study 2, n=8). In both studies, it was also investigated whether the bronchodilator effects of exercise hyperpnea and albuterol are additive. Changes in airway caliber were measured by changes in partial forced expiratory flow. In study 1, incremental-load exercise was associated with a bronchodilatation that was approximately 60% of the maximal bronchodilatation obtainable with 1,500 microg of albuterol. In study 2, constant-load exercise was associated with an initial moderate bronchodilatation and a late airway renarrowing. In both studies, premedication with inhaled albuterol (400 microg) promoted sustained bronchodilatation during exercise, which was additive to that caused by exercise hyperpnea. In conclusion, in mild-to-moderate asthmatic individuals, hyperpnea at peak exercise was associated with a potent yet not complete bronchodilatation. During constant-load exercise, a transient bronchodilatation was followed by airway renarrowing, suggesting prevalence of constrictor over dilator effects of hyperpnea. Finally, the bronchodilator effect of hyperpnea was additive to that of albuterol.


Assuntos
Albuterol/administração & dosagem , Asma/tratamento farmacológico , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/administração & dosagem , Exercício Físico , Ventilação Pulmonar , Adaptação Fisiológica , Administração por Inalação , Adulto , Asma/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado , Capacidade Residual Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo , Capacidade Pulmonar Total , Resultado do Tratamento , Capacidade Vital , Adulto Jovem
14.
Respirology ; 13(5): 716-21, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18713093

RESUMO

BACKGROUND AND OBJECTIVE: Several studies describe damage from passive smoking in humans. However, it is not clearly understood how different chemical and physical components relate to mechanisms of damage. This investigation was focused on the particulate phase of environmental cigarette smoke. The size of particles is very important in the inhalation process and subsequent deposition of particles in the airways. METHODS: The granulometry of suspended dust and bacterial particles was studied in a 120-m(3) no-smoking room during and after the smoking of one cigarette in ten separate experiments. Granulometry was assessed by a six-channel particle counter. Suspended microbial load was evaluated by a surface air system. The sedimented bacterial load was evaluated by the air microbial index technique, which expresses the total number of microorganisms settling on a Petri plate under gravity. RESULTS: The number of large particles increased during the first minute of smoking, and then decreased to basal levels. The number of medium-sized particles increased during the first 10 min of cigarette smoking, and then decreased to basal levels. The number of small particles increased over the whole experimental period. Bacterial and mycotic load decreased during and up to 60 min after cigarette smoking. Gram-positive cocci did not decrease, while chromogenous bacteria and mycetes decreased at 30 min. There was an increase in the numbers of sedimented bacteria and mycetes at 60 min, a decrease at 120 min and stabilization at 180 min. CONCLUSIONS: Smoking of tobacco accelerates the sedimentation of larger agglomerates of mean-sized smoke particles and bacteria, which may be re-suspended by the movement of people in the room and consequently inhaled.


Assuntos
Poluentes Atmosféricos/análise , Bacillus/isolamento & purificação , Poeira/análise , Pseudomonas/isolamento & purificação , Streptococcus/isolamento & purificação , Poluição por Fumaça de Tabaco/análise , Poluentes Atmosféricos/efeitos adversos , Humanos , Tamanho da Partícula , Infecções Respiratórias/etiologia , Infecções Respiratórias/microbiologia , Fatores de Tempo , Poluição por Fumaça de Tabaco/efeitos adversos
15.
Ther Adv Respir Dis ; 2(3): 129-39, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19124365

RESUMO

Bronchial asthma as such exists because airway smooth muscle (ASM) contracts excessively in response to various stimuli. After several decades during which research was mainly focused on airway inflammation, increasing attention is now being paid to a possible abnormal behaviour of ASM. Thus, ASM is regarded as a major target for anti-asthma treatments. This review first describes the mechanisms of ASM contraction and airway hyperresponsiveness, through cellular, animal and human models. The developments of new drugs targeting extra and/or intracellular pathway of ASM contraction are discussed.


Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Contração Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Animais , Asma/imunologia , Drogas em Investigação , Humanos , Contração Muscular/fisiologia , Relaxamento Muscular/efeitos dos fármacos , Relaxamento Muscular/fisiologia , Músculo Liso/metabolismo
16.
J Allergy Clin Immunol ; 121(2): 403-7, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17980415

RESUMO

BACKGROUND: Airway hyperresponsiveness in asthma is believed to be caused in part by the inability of deep inspirations to modulate airway narrowing. OBJECTIVE: We investigated whether deep inspirations taken before or after methacholine inhalation attenuate bronchoconstriction in subjects with rhinitis. The results were compared with a group of healthy subjects. METHODS: Ten subjects with rhinitis without asthma and 10 healthy subjects were studied on 3 different occasions at random. Bronchial challenges were performed with a single dose of methacholine known to decrease the FEV(1) by 17% to 40%. Challenges were performed with avoidance of deep inspirations, or with 5 deep inspirations preceding or following the inhalation of methacholine. Lung function measurements were specific airway conductance, forced expiratory flow at 30% to 40% of vital capacity on a maneuver started from end-tidal inspiration (partial flow), and residual volume (partial residual volume). RESULTS: In healthy subjects, deep inspirations taken after methacholine caused less changes in specific airway conductance, partial flow, and partial residual volume (P < .005 for all) than deep inspirations taken before methacholine or avoidance. In subjects with rhinitis, methacholine produced similar functional changes independently of the presence or absence of any deep inspirations. Compared with normal subjects, the attenuating effects of deep inspirations after methacholine on partial flow and partial residual volume were blunted in the subjects with rhinitis (P = .02 and P = .05, respectively). CONCLUSION: The ability to dilate methacholine-constricted airways by deep inspirations is impaired in subjects with rhinitis, possibly because of an abnormal behavior of airway smooth muscle.


Assuntos
Brônquios/fisiopatologia , Broncoconstritores/administração & dosagem , Inalação , Cloreto de Metacolina/administração & dosagem , Rinite/fisiopatologia , Administração por Inalação , Adulto , Testes de Provocação Brônquica , Feminino , Humanos , Masculino , Ventilação Pulmonar , Volume Residual
17.
Allergy Asthma Proc ; 28(4): 449-53, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17883913

RESUMO

Previously, evidence has been provided that sensitization is frequent in asthmatic children and polysensitization represents the natural history of allergy. The aim of this study was to investigate whether polysensitization may occur primarily in infants with wheezing. Thus, 98 infants (<1 year of age) were studied at the onset of wheezing symptoms. All children underwent three visits (each including skin-prick test): at baseline and after 2 and 5 years. At onset of wheezing, approximately 20% of infants were sensitized, whereas at 6 years the percentage was >60%. The most important finding was that there was no polysensitized infant at baseline, whereas most of the sensitized children were polysensitized at 6 years. Moreover, the number of sensitizations increased with age. House-dust mites were the most important cause of allergic symptoms. Wheezing may disappear mainly in nonallergic children. In conclusion, this study provided the first evidence that respiratory allergy always starts with monosensitization and confirms previous studies concerning the natural history of allergy characterized by the progression toward polysensitization.


Assuntos
Hipersensibilidade Imediata/etiologia , Sons Respiratórios/etiologia , Fatores Etários , Alérgenos/efeitos adversos , Progressão da Doença , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos Prospectivos
18.
Respir Res ; 7: 103, 2006 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-16875498

RESUMO

BACKGROUND: The response to beta2-adrenoceptor agonists is reduced in asthmatic airways. This desensitization may be in part due to inflammatory mediators and may involve cysteinyl-leukotrienes (cysteinyl-LTs). Cysteinyl-LTs are pivotal inflammatory mediators that play important roles in the pathophysiology of asthma, allergic rhinitis, and other inflammatory conditions. We tested the hypothesis that leukotriene D4 (LTD4) and allergen challenge cause beta2-adrenoceptor desensitization through the activation of protein kinase C (PKC). METHODS: The isoproterenol-induced cAMP accumulation was evaluated in human airway smooth muscle cell cultures challenged with exogenous LTD4 or the PKC activator phorbol-12-myristate-13-acetate with or without pretreatments with the PKC inhibitor GF109203X or the CysLT1R antagonist montelukast. The relaxant response to salbutamol was studied in passively sensitized human bronchial rings challenged with allergen in physiological salt solution (PSS) alone, or in the presence of either montelukast or GF109203X. RESULTS: In cell cultures, both LTD4 and phorbol-12-myristate-13-acetate caused significant reductions of maximal isoproterenol-induced cAMP accumulation, which were fully prevented by montelukast and GF109203X, respectively. More importantly, GF109203X also prevented the attenuating effect of LTD4 on isoproterenol-induced cAMP accumulation. In bronchial rings, both montelukast and GF109203X prevented the rightward displacement of the concentration-response curves to salbutamol induced by allergen challenge. CONCLUSION: LTD4 induces beta2-adrenoceptor desensitization in human airway smooth muscle cells, which is mediated through the activation of PKC. Allergen exposure of sensitized human bronchi may also cause a beta2-adrenoceptor desensitization through the involvement of the CysLT1R-PKC pathway.


Assuntos
Asma/metabolismo , Cisteína/metabolismo , Leucotrienos/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Albuterol/administração & dosagem , Albuterol/farmacologia , Alérgenos/imunologia , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/fisiologia , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacologia , Células Cultivadas , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Isoproterenol/farmacologia , Leucotrieno D4/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Proteína Quinase C/metabolismo , Receptores Adrenérgicos beta 2/efeitos dos fármacos
19.
Cell Biochem Biophys ; 44(1): 129-38, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16456241

RESUMO

A reduced response to beta-adrenoceptor agonists has been reported in airways of asthmatic subjects. Mechanisms for beta-adrenoceptor dysfunction are (1) inactivation or downregulation of beta-adrenoceptors by specific agonists (homologous desensitization) or by inflammatory mediations (heterologous desensitization), (2) inactivation or downregulation of second messengers of beta-adrenoceptor pathway. Studies from our laboratory have shown that allergen challenge of passively sensitized human bronchi causes a beta-adrenoceptor dysfunction as a result of reduced activity of the receptor-coupled Gs protein. The dysfunction was prevented by leukotriene-receptor antagonists or a cell membrane stabilizer, but not by an antihistimine or indomethacin, suggesting a central role of leukotrienes released from resident inflammatory cells in its genesis. Furthermore, the beta-adrenoceptor response and Gs protein function after allergen exposure were restored by short-term (3 h) incubation with beclomethasone dipropionate, suggesting an effect independent of gene transcription. Restoration of the intracellular beta-adrenoceptor effector pathway may contribute to the efficacy of corticosteroids in the acute treatment of asthma.


Assuntos
Asma/fisiopatologia , Receptores Adrenérgicos beta/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Alérgenos/farmacologia , Beclometasona/farmacologia , Humanos , Técnicas In Vitro , Antagonistas de Leucotrienos/farmacologia , Modelos Biológicos , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia
20.
Ann Allergy Asthma Immunol ; 94(2): 273-8, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15765745

RESUMO

BACKGROUND: In our previous in vitro model, allergen incubation of passively sensitized human airways reduced the response to salbutamol. However, whether cytokines play a role in this model is still unknown. OBJECTIVE: To investigate interleukin 1beta and tumor necrosis factor a expression in allergen-challenged human airways. METHODS: Nonasthmatic airways (n = 13) were passively sensitized by overnight atopic serum incubation and then challenged with allergen for 1 hour (n = 9). After repeated washouts, airways were immersed in physiologic salt solution for 6 hours and finally in formaldehyde for immunohistochemical studies. The effect of co-incubation in anti-interleukin 1beta and anti-tumor necrosis factor a specific neutralizing antibodies on salbutamol response was also studied (n = 4). RESULTS: No differences were found among control, sensitized, and challenged rings in the number of inflammatory cells. The percentage of basement membrane covered by epithelium was similar in the different conditions. There was a higher percentage of degranulating to total mast cells in allergen-challenged rings than in sensitized rings (P < .001). A significant correlation was observed between allergen-induced contraction and mast cell degranulation (r = 0.88; P < .001). The sensitization procedure was validated by paired allergen-induced contractions. No expression of the 2 cytokines was detectable up to 6 hours after allergen challenge, and specific neutralizing antibodies did not attenuate the impaired response to salbutamol in allergen-challenged rings. CONCLUSION: These data suggest that in our in vitro model of allergic inflammation, beta2 pathway dysfunction can occur without cytokine involvement, thus supporting previous results that suggest a role for leukotrienes.


Assuntos
Alérgenos/imunologia , Brônquios/imunologia , Interleucina-1/biossíntese , Modelos Imunológicos , Fator de Necrose Tumoral alfa/biossíntese , Agonistas Adrenérgicos beta/farmacologia , Idoso , Albuterol/farmacologia , Antígenos de Dermatophagoides/imunologia , Western Blotting , Brônquios/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imunização , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/efeitos dos fármacos
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