RESUMO
BACKGROUND: We previously reported that in moderate-to-severe asthma there is a deficit of IL-10 secretion that could prevent the production of soluble HLA-G (sHLA-G), a non-classical human leucocyte antigen class I molecule with tissue-protective properties in inflammatory responses. OBJECTIVE: Our objective was to investigate the production of sHLA-G and the secretion of IL-10 by peripheral blood mononuclear cells (PBMCs) in asthma induced by isocyanates and to compare the results with those obtained in non-occupational allergic asthma. METHOD: sHLA-G and IL-10 were measured by ELISA in the culture supernatants of unstimulated or lipopolysaccharide (LPS)-stimulated PBMCs obtained from 20 subjects with isocyanate asthma, 16 asymptomatic subjects exposed to isocyanates, 18 subjects with non-occupational allergic asthma, and 26 healthy control subjects. RESULTS: Occupational exposure to isocyanates was associated with high baseline levels of secretion of IL-10 by PBMCs, whether or not the exposed subjects had asthmatic symptoms. However, spontaneous production of sHLA-G by PBMC was significantly higher in subjects with isocyanate asthma compared with asymptomatic-exposed controls. In contrast, PBMCs from subjects with non-occupational allergic asthma produced sHLA-G only after LPS stimulation. CONCLUSIONS: sHLA-G production and IL-10 secretion are influenced by workplace exposure to isocyanates and by development of asthma. The different behaviour of both sHLA-G and IL-10 in asthma induced by isocyanates compared with non-occupational allergic asthma suggests a heterogeneous biological role for HLA-G molecules and for IL-10, a key cytokine of immune and inflammatory responses.
Assuntos
Asma/imunologia , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Interleucina-10/imunologia , Isocianatos/efeitos adversos , Leucócitos Mononucleares/metabolismo , Doenças Profissionais/imunologia , Adulto , Células Cultivadas , Feminino , Antígenos HLA/biossíntese , Antígenos HLA-G , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Interleucina-10/biossíntese , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
Non-small cell lung cancer (NSCLC) shows a particular aggressive behaviour. Tumour associated macrophages (TAMs) play an important role in tumour growth and progression and CC ligand 2 (CCL2)/CCR2 axis is markedly involved in their recruitment in the tumour mass from the circulation. The aim of this study was to determine the plasma levels of CCL2 and the expression of CCR2 in the peripheral blood mononuclear cells (PBMCs) of 18 smokers with NSCLC, eight healthy smokers and nine non-smokers. Then, we investigated CCL2 levels in the supernatants of unstimulated and LPS-stimulated PBMC cultures of the same groups of patients. CCL2 levels in plasma and supernatants of PBMC cultures were determined by ELISA. CCR2 expression in PBMC cytospins was assessed by immunocytochemistry. CCL2 plasma levels and CCR2 expression by PBMCs were similar in patients with NSCLC, healthy smokers and non-smokers. In the supernatants of unstimulated PBMC cultures, CCL2 content was not different between the three groups of subjects. Supernatants of LPS-stimulated PBMCs of NSCLC patients showed a higher content of CCL2 as compared to supernatants of non-smokers (p<0.005). CCL2 content increased 28.5-fold vs baseline production in the group of NSCLC patients, 15-fold in healthy smokers and 13-fold in the group of non-smokers. In conclusion, after LPS stimulation, PBMCs of patients with NSCLC release higher levels of CCL2 as compared to those of non-smokers, supporting the hypothesis of a CCL2 involvement in NSCLC biology.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quimiocina CCL2/metabolismo , Neoplasias Pulmonares/metabolismo , Monócitos/metabolismo , Receptores CCR2/metabolismo , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Casos e Controles , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Fumar/efeitos adversosRESUMO
Chronic heart failure (CHF) is characterized by the inability of the heart to supply the body with sufficient amount of blood for metabolic and circulatory needs. The main risk factors for CHF development are: hypertension, type 2 diabetes, obesity, smoking, chronic kidney diseases. Many occupational exposures, such as extremes of heat or cold temperatures, prolonged exposure to noise, vibrations, pesticides, can contribute to etiology of this disease. The aim of our study was to evaluate if work can affect CHF severity. We analyzed retrospectively the first 76 smokers aged over 65 years who presented to the outpatient Clinic of Chronic Heart Failure. The patients were divided in 4 groups based on their previous job: white-collars, farmers, steelworkers and subjects performing different occupational activities (hairdressers, firemen, masons). Our results showed that farmers had a reduced left ventricular ejection fraction compared with white-collars (p = 0.0045) although NYHA class and the presence/absence of CHF risk factors were not different between the two groups. This data suggests that the farmer job could be associated with the severity of CHF.
Assuntos
Insuficiência Cardíaca/etiologia , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Idoso , Doença Crônica , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Cigarette smoking and occupational exposure to respiratory irritants are the major riskfactors for chronic obstructive pulmonary disease (COPD), which is characterized by small-airway obstruction and destruction of pulmonary parenchyma: emphysema. We studied two groups of subjects: one exposed and the other one not-exposed to respiratory irritants, to investigate the relationship, if any, between occupational exposure and COPD. Subjects underwent high-resolution computed tomography-density mask of the chest to quantify pulmonary emphysema, pulmonary function tests, sputum induction and analysis for cell counts and measurements of metalloproteinase (MMP)-9 and its tissue inhibitor TIMP-1. Subjects with occupational exposure to respiratory irritants had higher residual volume and functional residual capacity, higher total inflammatory cells and neutrophils in induced sputum. By contrast, sputum levels of MMP-9, TIMP-1 and MMP-91TIMP-1 ratio did not differ between the 2 groups. We conclude that sputum induction and analysis could be a useful and non-invasive tool to study and follow subjects with occupational exposure to respiratory irritants.
Assuntos
Irritantes/efeitos adversos , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/etiologia , Idoso , Contagem de Células , Feminino , Humanos , Masculino , Metaloproteases/análise , Neutrófilos , Doenças Profissionais/diagnóstico , Doenças Profissionais/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/fisiopatologia , Radiografia Torácica , Testes de Função Respiratória , Fatores de Risco , Fumar/efeitos adversos , Escarro/citologia , Escarro/enzimologia , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-1/análise , Tomografia Computadorizada por Raios XRESUMO
1. We have investigated the ability of prostacyclin (PGI2) to contract guinea-pig isolated bronchi and the possible involvement of capsaicin-sensitive primary afferents in the response to PGI2. 2. PGI2 (0.1-100 microM) produced concentration-dependent contractions of the guinea-pig isolated bronchi. In vitro capsaicin desensitization (10 microM for 30 min followed by washing) significantly reduced the PGI2-induced contraction at all concentrations tested. A capsaicin-resistant component of contraction (40-60% of the overall response) was also evident. 3. Ruthenium red (3 microM), an inorganic dye which acts as a selective functional antagonist of capsaicin, significantly decreased PGI2-induced contractions, without affecting the response to substance P, neurokinin A or acetylcholine. 4. MEN 10, 207, (Tyr5, D-Trp6,8,9, Arg10)-neurokinin A (4-10) (3 microM), a selective antagonist of NK2-tachykinin receptors, significantly decreased PGI2-induced contractions and neurokinin A-induced contractions, without affecting the response to acetylcholine. 5. The effect of ruthenium red and MEN 10,207 on the one hand, and that of ruthenium red and capsaicin on the other was non additive. 6. These results indicate that PGI2-induced contraction of the guinea-pig isolated bronchi involves two distinct mechanisms, one of which involves transmitter (tachykinins) release from peripheral endings of capsaicin-sensitive primary afferents. In as much as PGI2-activation of primary afferents is sensitive to ruthenium red, we suggest that PGI2 shares a common mechanism of tachykinin release with that activated by capsaicin.
Assuntos
Capsaicina/farmacologia , Epoprostenol/farmacologia , Músculo Liso/inervação , Neurônios Aferentes/efeitos dos fármacos , Taquicininas/metabolismo , Animais , Brônquios/efeitos dos fármacos , Brônquios/inervação , Cobaias , Técnicas In Vitro , Indicadores e Reagentes , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Neurocinina A/análogos & derivados , Neurocinina A/farmacologia , Neurônios Aferentes/metabolismo , Neurotransmissores/farmacologia , Fragmentos de Peptídeos/farmacologia , Rutênio Vermelho/farmacologiaRESUMO
1. Toluene diisocyanate produced concentration-dependent contractions of the rat isolated urinary bladder. 2. The contractions were tetrodotoxin-resistant and were abolished by previous exposure of the strips to capsaicin. 3. Indomethacin (5 microM) and ruthenium red (30 microM) inhibited toluene diisocyanate-induced contractions. Responses expressed as a percentage of the response obtained with substance P, 30 nM, were respectively 141.6 +/- 24.8% and 20.1 +/- 5.1% in control and indomethacin-treated strips (P less than 0.005); 123.0 +/- 30.2% and 14.0 +/- 6.5% in control and ruthenium red-treated strips (0.01 less than P less than 0.05). 4. These results suggest that toluene diisocyanate-induced contractions of the rat isolated bladder are the result of the release of cyclo-oxygenase products which may act by activating the capsaicin receptor.
Assuntos
Músculo Liso/efeitos dos fármacos , Tolueno 2,4-Di-Isocianato/farmacologia , Animais , Atropina/farmacologia , Capsaicina/farmacologia , Técnicas In Vitro , Indometacina/farmacologia , Masculino , Metilprednisolona/farmacologia , Contração Muscular/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Rutênio Vermelho/farmacologia , Tetrodotoxina/farmacologia , Bexiga Urinária/efeitos dos fármacosRESUMO
1. The effect of bilateral adrenalectomy on the sensitivity of blood vessels in rat airways to mediators that increase vascular permeability was examined. 2. An increase in vascular permeability was induced by intravenous platelet activating factor (PAF, 50, 100, 500, 1000 ng kg-1) and measured by quantifying the extravasation of Evans blue dye. 3. PAF consistently increased the amount of Evans blue extravasation in the larynx, trachea, main bronchi and intrapulmonary airways in sham-operated rats. 4. The magnitude of this extravasation was significantly greater in the larynx (P less than 0.05), trachea (P less than 0.05) and main bronchi (P less than 0.05) of the adrenalectomized rats than it was in these tissues of the sham-operated rats. 5. When adrenalectomized rats were given subcutaneous dexamethasone (0.2 mg kg-1 4 h before PAF) the amount of plasma extravasation produced by PAF was decreased to the level of the sham-operated rats. 6. We conclude that adrenalectomy potentiates the increase in airway vascular permeability induced by PAF in rats and that this effect may be due to the depletion of endogenous corticosteroids.
Assuntos
Adrenalectomia , Permeabilidade Capilar/efeitos dos fármacos , Fator de Ativação de Plaquetas/farmacologia , Sistema Respiratório/irrigação sanguínea , Animais , Corticosterona/sangue , Dexametasona/farmacologia , Exsudatos e Transudatos/metabolismo , Técnicas In Vitro , Masculino , Ratos , Ratos Endogâmicos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacosRESUMO
We investigated whether leukotriene B4 (LTB4) is released from the lungs of sensitized subjects during asthmatic reactions induced by toluene diisocyanate (TDI). We examined three groups of TDI-sensitized subjects, one after no exposure to TDI, the second 8 h after an exposure to TDI that caused an early asthmatic reaction, and the third 8 h after an exposure to TDI that caused a late asthmatic reaction. We analyzed bronchoalveolar lavage (BAL) fluid by reverse-phase high-performance liquid chromatography and by specific radioimmunoassay. The mean concentration of LTB4 was higher [0.31 +/- 0.09 (SE) ng/ml, range 0.15-0.51] in BAL fluid of sensitized subjects who developed a late asthmatic reaction than in BAL fluid of subjects who developed an early asthmatic reaction (0.05 +/- 0.04 ng/ml, range 0-0.224), and no LTB4 was detectable in the control subjects. We also performed BAL 8 h after TDI exposure on four TDI-sensitized late-dual reactors who were on steroid treatment. In this group of subjects no LTB4 was detectable. These results suggest that LTB4 may be involved in late asthmatic reactions induced by TDI.
Assuntos
Asma/metabolismo , Cianatos/efeitos adversos , Leucotrieno B4/metabolismo , Tolueno 2,4-Di-Isocianato/efeitos adversos , Adulto , Asma/induzido quimicamente , Asma/patologia , Líquido da Lavagem Broncoalveolar/análise , Líquido da Lavagem Broncoalveolar/citologia , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Contagem de Leucócitos , Masculino , Neutrófilos/patologiaRESUMO
Contractility of tracheal smooth muscle strips and spiral strips of fourth to fifth generation bronchi was studied in organ baths. The relationship among contractility, airway smooth muscle myosin, and smooth muscle thickness was also examined. The trachea was divided into three segments, each consisting of 12-14 rings. Smooth muscle strips from each of the three regions (top, middle, and bottom of the trachea) and from fourth to fifth generation bronchi were studied. Acetylcholine (ACh) sensitivity (-log EC50) was 8.1, 7.1, 7.9, and 6.1 for the top, middle, and bottom of the trachea and the bronchi, respectively. At P = 0.01, the EC50 ACh value of the top of the trachea differed from the EC50 value of the bronchi. Maximal tension (Tmax) generated in bronchi (3.2 g) was lower (P less than 0.01) than in the top (10.4 g), middle (7.1 g), and bottom of the trachea (5.1 g). Differences between trachea and bronchi disappeared when Tmax was corrected for smooth muscle myosin content. Thickness of smooth muscle in bronchi was less (P less than 0.01) than in the three regions of trachea. Tmax was significantly correlated with airway smooth muscle thickness (r = 0.56; P less than 0.05). These results suggest that in mongrel dogs sensitivity to ACh shows a gradient from the top of the trachea to the bronchi and that Tmax is greater in the trachea than in the bronchi and is significantly correlated with thickness of smooth muscle.
Assuntos
Acetilcolina/farmacologia , Brônquios/fisiologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Miosinas/fisiologia , Traqueia/fisiologia , Animais , Brônquios/anatomia & histologia , Cães , Músculo Liso/anatomia & histologia , Traqueia/anatomia & histologiaRESUMO
We have investigated the ability of ruthenium red, an inorganic dye with Ca2+ entry-blocking properties and a selective antagonist of capsaicin, and of indomethacin, a cyclooxygenase inhibitor, to inhibit bronchial smooth muscle responses evoked by toluene diisocyanate in guinea pigs. Previous exposure of isolated guinea pig bronchi to ruthenium red significantly decreased the response produced by toluene diisocyanate. Further, the response to toluene diisocyanate was significantly decreased by pretreatment with indomethacin. These findings provide evidence that toluene diisocyanate-induced contractions of guinea pig bronchi are produced indirectly by generation of a prostanoid that activates capsaicin-sensitive afferents via a ruthenium red-sensitive mechanism.
Assuntos
Indometacina/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Rutênio Vermelho/farmacologia , Tolueno 2,4-Di-Isocianato/farmacologia , Animais , Brônquios , Cobaias , Masculino , Músculo Liso/efeitos dos fármacos , Tolueno 2,4-Di-Isocianato/antagonistas & inibidoresRESUMO
We have investigated the ability of the products of the reaction between toluene diisocyanate (TDI) and water to contract bronchial smooth muscle. The experiments were performed in isolated guinea pig bronchi. TDI, both 2,4- and 2,6-toluenediamine (TDA) and mixtures of 2,4- and 2,6-TDA (ratio 80:20 and 20:80) caused concentration-dependent contraction in the isolated bronchi. The mixture of disubstituted urea and biuret also contracted the bronchi, but not in a concentration-dependent fashion. Our results provide evidence that all products of the reaction between toluene diisocyanate and water have the ability to contract isolated bronchial smooth muscle in guinea pigs. Whatever the role of toluenediamine in the adverse respiratory effects induced by exposure to isocyanates, our findings reveal the necessity of in vivo studies on the metabolism of inhaled toluene diisocyanate in humans to improve our understanding of the mechanism of action of isocyanates.
Assuntos
Brônquios/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Tolueno 2,4-Di-Isocianato/farmacologia , Água/farmacologia , Animais , Interações Medicamentosas , Cobaias , Masculino , Músculo Liso/efeitos dos fármacos , Fenilenodiaminas/farmacologiaRESUMO
Isocyanates are an important cause of occupational asthma. The mechanism of isocyanate-induced asthma is still unknown. To determine whether toluene diisocyanate stimulates the 'efferent' function of peripheral endings of capsaicin-sensitive sensory nerves, we investigated the effect of toluene diisocyanate in the rat isolated urinary bladder, a preparation in which the action of capsaicin has been well characterized. Toluene diisocyanate (0.03-3 mM) produced a concentration-dependent contraction of the bladder strips. Its maximal effect was about 50% of the response to capsaicin (1 microM). Previous exposure of the strips to capsaicin followed by washing out produced complete unresponsiveness, both to the first exposure to toluene diisocyanate and to a second exposure of capsaicin. Further, the response to both toluene diisocyanate and capsaicin was completely prevented by extrinsic bladder denervation, achieved by bilateral removal of pelvic ganglia (72 h before). Repeated exposure of the rat bladder to toluene diisocyanate reduced the capsaicin-evoked release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI), taken as biochemical marker of activation of these sensory nerves. These experiments provide the first evidence that toluene diisocyanate activates directly or indirectly the efferent function of capsaicin-sensitive primary sensory nerves.
Assuntos
Capsaicina/farmacologia , Cianatos/farmacologia , Neurônios Eferentes/efeitos dos fármacos , Tolueno 2,4-Di-Isocianato/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Estimulação Elétrica , Gânglios Autônomos/efeitos dos fármacos , Técnicas In Vitro , Masculino , Denervação Muscular , Ratos , Ratos Endogâmicos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/inervaçãoRESUMO
This study was designed to evaluate whether metabolites of arachidonic acid play a role in the contractile response to toluene diisocyanate in isolated guinea pig airways. In control experiments we collected the supernatant from an organ bath over a time period of 2 h, after the addition of toluene diisocyanate (100 and 300 microM), and after the addition of toluene diisocyanate (300 microM) in the presence of indomethacin (5 microM). We measured prostaglandin E2, 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, thromboxane B2, leukotriene B4, leukotriene C4/D4/E4/F4 by radioimmunoassays. Levels of prostaglandin F2 alpha and 6-keto-prostaglandin F1 alpha increased significantly after addition of toluene diisocyanate in the absence of indomethacin. These results suggest that prostaglandins are involved in toluene diisocyanate-induced contractions in guinea-pig airways.
Assuntos
Ácidos Araquidônicos/metabolismo , Brônquios/efeitos dos fármacos , Tolueno 2,4-Di-Isocianato/farmacologia , Animais , Brônquios/metabolismo , Cobaias , Técnicas In Vitro , Indometacina/farmacologia , Masculino , Prostaglandinas/metabolismoRESUMO
We have investigated the ability of compound 48/80 and of histamine H1 and H2 receptor antagonists to inhibit toluene diisocyanate-induced contractions in isolated guinea-pig bronchi. Compound 48/80 (100 micrograms/ml) significantly inhibited toluene diisocyanate-induced contractions. By contrast, the two histamine H1 and H2 receptor antagonists, chlorpheniramine (10 microM) and cimetidine, (10 microM) did not affect toluene diisocyanate-induced contractions, but significantly inhibited contractions induced by exogenously applied histamine (100 microM) and by 48/80. We investigated which mechanisms 48/80 used to inhibit toluene diisocyanate-induced contractions, paying particular attention to the possible involvement of capsaicin-sensitive primary afferents. In vitro capsaicin desensitization (10 microM for 30 min followed by washing) significantly reduced compound 48/80-induced contractions. A capsaicin-resistant component of contraction was also evident. Ruthenium red (3 microM), an inorganic dye which acts as a selective functional antagonist of capsaicin, did not affect 48/80-induced contraction. MEN 10,207 (Tyr5,D-Trp6,8,9,Arg10)-neurokinin A (4-10) (3 microM) a selective antagonist of NK2-tachykinin receptors significantly reduced 48/80-induced contractions. These results show that compound 48/80 inhibits toluene diisocyanate-induced contractions in isolated guinea-pig bronchi. It is likely that two mechanisms are involved in the inhibition: (1) the release of mediators other than histamine by mast cells, (2) an effect of 48/80 on sensory nerves.
Assuntos
Broncoconstrição/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Tolueno 2,4-Di-Isocianato/antagonistas & inibidores , p-Metoxi-N-metilfenetilamina/farmacologia , Animais , Capsaicina/farmacologia , Degranulação Celular/efeitos dos fármacos , Glicopeptídeos/farmacologia , Cobaias , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Técnicas In Vitro , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/ultraestrutura , Contração Muscular/efeitos dos fármacos , Neprilisina/antagonistas & inibidores , Neurocinina A/análogos & derivados , Neurocinina A/farmacologia , Fragmentos de Peptídeos/farmacologia , Rutênio Vermelho/farmacologia , Tolueno 2,4-Di-Isocianato/farmacologiaRESUMO
Toluene diisocyanate (TDI)-induced asthma is a frequent occupational airway disease. To determine whether a calibrated dosage of oral slow-release theophylline inhibits asthmatic reactions and the associated increase of airway responsiveness to methacholine induced by TDI, we examined six asthmatic subjects who developed a late or a dual asthmatic reaction after TDI inhalation challenge. We administered oral slow-release theophylline or placebo to each subject for 7 days according to a double-blind, randomized, cross-over study design. When the subjects received a placebo, TDI caused a late or a dual asthmatic reaction. When the subjects received theophylline. TDI caused significantly reduced late asthmatic reactions. Mean serum theophylline concentrations were within the therapeutic range. Theophylline neither modified the baseline airway responsiveness to methacholine, nor the increase of airway responsiveness to methacholine induced by TDI. These results suggest that slow-release theophylline may improve TDI-induced late asthmatic reactions, but it does not change the baseline airway responsiveness to methacholine and the increase of airway responsiveness to methacholine induced by TDI.
Assuntos
Asma/tratamento farmacológico , Teofilina/uso terapêutico , Tolueno 2,4-Di-Isocianato/antagonistas & inibidores , Administração por Inalação , Administração Oral , Análise de Variância , Asma/induzido quimicamente , Testes de Provocação Brônquica , Método Duplo-Cego , Humanos , Placebos , Teofilina/administração & dosagem , Teofilina/sangueRESUMO
Toluene diisocyanate contracts guinea-pig bronchial smooth muscle through a mechanism involving capsaicin-sensitive sensory nerves. In the present study, we investigated the effects of toluene diisocyanate, capsaicin and tachykinins on isolated human bronchi. In 44 rings, toluene diisocyanate (0.3 mM) produced a relaxation which averaged 16.9 +/- 1.1%, in ten rings it produced a shortening that was 15.1 +/- 3.3% and in ten preparations it gave no response. A second administration of toluene diisocyanate (0.3 mM) always produced a relaxation (n = 13, 18.1 +/- 3.9%). Capsaicin (0.03 mM) produced shortening in 15 (35 +/- 6.6%) and relaxation in 11 preparations (41 +/- 6.8%), whereas a second administration caused shortening in nine (25.1 +/- 6.1%) and relaxation in 16 rings (36.4 +/- 4.9%). When toluene diisocyanate was given after two consecutive capsaicin administrations, we observed shortening in two rings (10.0 +/- 3.6%), relaxation in ten rings (15.9 +/- 3.6%), and no response in four preparations. To test the role of NK1 and NK2 receptors in these conflicting responses, we performed concentration-response curves to different tachykinins. Substance P, neurokinin A and neurokinin A-(4-10), a specific NK2 receptor agonist, gave a concentration-dependent shortening, with neurokinin A being the most effective and neurokinin A-(4-10) the least. The specific NK1 receptor agonist, [Sar9, Met(O2)11]substance P, produced both shortening and relaxation. We conclude that toluene diisocyanate and capsaicin may produce both shortening and relaxation in isolated human bronchi through NK1 receptors.
Assuntos
Brônquios/efeitos dos fármacos , Capsaicina/farmacologia , Músculo Liso/efeitos dos fármacos , Tolueno 2,4-Di-Isocianato/farmacologia , Acetilcolina/farmacologia , Idoso , Feminino , Humanos , Técnicas In Vitro , Isoproterenol/farmacologia , Contração Isotônica/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1 , Fisalemina/análogos & derivados , Fisalemina/farmacologia , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-2/efeitos dos fármacos , Substância P/análogos & derivados , Substância P/farmacologiaRESUMO
We investigated whether acute exposure to nitrogen dioxide (NO2) causes major inflammatory responses (inflammatory cell recruitment, oedema and smooth muscle hyperresponsiveness) in guinea pig airways. Anaesthetised guinea pigs were exposed to 18 ppm NO2 or air for 4 h through a tracheal cannula. Bronchoalveolar lavage was performed and airway microvascular permeability and in vitro bronchial smooth muscle responsiveness were measured. Exposure to NO2 induced a significant increase in eosinophils and neutrophils in bronchoalveolar lavage fluid, microvascular leakage in the trachea and main bronchi (but not in peripheral airways), and a significant in vitro hyperresponsiveness to acetylcholine, electrical field stimulation, and neurokinin A, but not to histamine. Thus, this study shows that in vivo exposure to high concentrations of NO2 induces major inflammatory responses in guinea pig airways that mimic acute bronchitis induced by exposure to irritant gases in man.
Assuntos
Bronquite/induzido quimicamente , Broncoconstrição/efeitos dos fármacos , Hipersensibilidade a Drogas/etiologia , Dióxido de Nitrogênio/toxicidade , Traqueíte/induzido quimicamente , Acetilcolina/farmacologia , Anestesia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Cobaias , Histamina/farmacologia , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Neurocinina A/farmacologiaRESUMO
The effect of a week treatment with inhaled salbutamol plus placebo (S+P) vs. salbutamol combined with beclomethasone dipropionate (S+BDP) on early and late asthmatic responses to inhaled allergen was studied in ten atopic patients in a randomized, double-blind, cross-over study. All patients had previously shown a dual type response to the specific bronchial provocative test (sBPT). Each patient performed two periods of treatment for a week, with a 15 day interval between them: (a) salbutamol 0.3 mg, tid + placebo; (b) salbutamol 0.3 mg+BDP 0.2 mg, tid; at the end of each treatment period, sBPT was performed and the last treatments were given 1.5-2 h before and 3-4 h after allergen challenge. S + BDP completely prevented both early and late responses to allergen, while S + P reduced but did not completely inhibit early and late responses. The difference between the two treatments was significant for early and late asthmatic responses. Non-specific bronchial hyperresponsiveness to methacholine was performed before each treatment period, after 6 days of treatment before sBPT and the day after sBPT at the end of the treatment period; there was only a mild increase in PD15FEV1 methacholine after 6 days of treatment with S + BDP in comparison with S + P treatment. These results suggest that salbutamol plus beclomethasone may be used effectively in the prophylaxis of early and late asthmatic reactions induced by allergen in sensitized subjects.
Assuntos
Albuterol/uso terapêutico , Asma/prevenção & controle , Beclometasona/uso terapêutico , Adolescente , Adulto , Asma/fisiopatologia , Testes de Provocação Brônquica , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
The present study was designed to evaluate whether pre-incubation with serum, obtained from both control and toluene diisocyanate (TDI)-immunized guinea-pigs, modified the contractile response to TDI in isolated guinea-pig bronchial rings. Guinea-pigs were anaesthetized and the main bronchi dissected in two rings. Bronchial rings were incubated with normal or immune serum (100 microl ml(-1) for 2 h) and dose-response curves to TDI (0.03-1000 microM) were studied isometrically. Before serum incubation, in eight bronchial rings, epithelium was removed by rubbing the luminal surface gently with a gauze. In control rings, TDI produced a concentration-dependent contraction, whereas in rings pre-incubated with either normal or TDI-immune serum, it produced a concentration-dependent relaxation. Relaxation was 101.4 (SEM 17.4)% and 94.9 (SEM 21)% of the relaxation induced by isoproterenol (1 mM) respectively with normal and TDI-immune serum. Similarly to the pre-incubation with serum, pre-incubation with albumin produced a concentration-dependent relaxation to TDI. Serum-induced relaxant response to TDI was not affected by capsaicin desensitization, it was only partially inhibited by an NK1-tachykinin antagonist, whereas it was blocked by indomethacin. In bronchial rings without epithelium, pre-incubated with serum, TDI caused contraction at highest doses, while it still induced relaxation at the lowest doses. This study shows that one or more components of the serum modify the contractile response to TDI in isolated guinea-pig bronchi. In bronchial rings without epithelium serum was able to inhibit the contration induced by low doses of TDI.