RESUMO
BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.
Assuntos
Proteínas ADAM , Asma/sangue , Asma/genética , Subunidade alfa de Receptor de Interleucina-4 , Proteínas ADAM/sangue , Proteínas ADAM/genética , Adulto , Idoso , Asma/tratamento farmacológico , Seguimentos , Marcadores Genéticos , Humanos , Subunidade alfa de Receptor de Interleucina-4/sangue , Subunidade alfa de Receptor de Interleucina-4/genética , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.
Assuntos
Asma/genética , Asma/fisiopatologia , Variação Genética , Receptores de Glucocorticoides/genética , Administração por Inalação , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Idoso , Asma/tratamento farmacológico , Asma/imunologia , Moléculas de Adesão Celular/sangue , Eosinófilos/imunologia , Feminino , Volume Expiratório Forçado , Estudos de Associação Genética , Proteínas de Choque Térmico/genética , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Testes de Função Respiratória , Fatores de RiscoRESUMO
We investigated the non-genomic effects of glucocorticoids (GCs) on inhibition of plasma membrane lipid raft formation in activated human basophils. Human basophils obtained from house dust mite (HDM)-sensitive volunteers were pretreated with hydrocortisone (CORT) or dexamethasone (Dex) for 30 min and then primed with phorbol 12-myristate 13-acetate (PMA, 10 ng/ml) or HDM (10 µg/ml). The expression of CD63, a basophil activation marker, was assessed by flow cytometry. Membrane-bound GC receptors (mGCRs) were analysed by flow cytometry and confocal laser microscopy. Lipid rafts were assessed using a GM1 ganglioside probe and visualization by confocal laser microscopy. Pretreatment of basophils with CORT (10(-4) M and 10(-5) M) and Dex (10(-7) M) significantly inhibited CD63 expression 20 min after addition of PMA or HDM. The inhibitory effects of GCs were not altered by the nuclear GC receptor (GCR) antagonist RU486 (10(-5) M) or the protein synthesis inhibitor cycloheximide (10(-4) M) (P < 0·05). CORT coupled to bovine serum albumin (BSA-CORT) mimicked the rapid inhibitory effects of CORT, suggesting the involvement of mGCRs. mGCRs were detectable on the plasma membrane of resting basophils and formed nanoclusters following treatment with PMA or HDM. Pretreatment of cells with BSA-CORT inhibited the expression of mGCRs and nanoclustering of ganglioside GM1 in lipid rafts. The study provides evidence that non-genomic mechanisms are involved in the rapid inhibitory effect of GCs on the formation of lipid raft nanoclusters, through binding to mGCRs on the plasma membrane of activated basophils.
Assuntos
Basófilos/efeitos dos fármacos , Glucocorticoides/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Pyroglyphidae/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Basófilos/imunologia , Basófilos/metabolismo , Bovinos , Membrana Celular/imunologia , Membrana Celular/metabolismo , Células Cultivadas , Cicloeximida/farmacologia , Dexametasona/imunologia , Dexametasona/farmacologia , Citometria de Fluxo , Gangliosídeo G(M1)/metabolismo , Regulação da Expressão Gênica , Glucocorticoides/imunologia , Humanos , Hidrocortisona/imunologia , Hidrocortisona/farmacologia , Leucócitos Mononucleares/citologia , Microdomínios da Membrana/imunologia , Microdomínios da Membrana/metabolismo , Microscopia Confocal , Mifepristona/farmacologia , Pyroglyphidae/imunologia , Receptores de Glucocorticoides/análise , Receptores de Glucocorticoides/antagonistas & inibidores , Soroalbumina Bovina/metabolismo , Acetato de Tetradecanoilforbol/imunologia , Acetato de Tetradecanoilforbol/farmacologia , Tetraspanina 30/análise , Tetraspanina 30/antagonistas & inibidoresRESUMO
BACKGROUND: Although health-related quality of life (HRQL) has recently been considered to be an important outcome in clinical trials of idiopathic pulmonary fibrosis (IPF), its relationship with survival is unknown. OBJECTIVE: To determine the prognostic significance of HRQL scores in IPF assessed with the SGRQ. DESIGN: Eighty-seven consecutive patients with IPF, who had undergone evaluations and completed the St. George's Respiratory Questionnaire (SGRQ) at diagnosis were included in this study, as is the general practice. Cox proportional hazards analyses were performed to examine the relationship between HRQL scores and survival. RESULTS: The mean observation period was 44.2 +/- 29.6 mo, in the course of which 54 patients (62.0%) died. Univariate analysis revealed that the activity scores in the SGRQ(HR: 1.016, 95% CI: 1.004-1.029, P = 0.01) were significantly predictive of survival, although the symptoms, impacts, and total scores were not significantly related to mortality from all causes. However, multivariate analysis revealed that only the forced vital capacity percent predicted was a significant predictor of survival, and that the activity score in the SGRQwas not significantly related to mortality. CONCLUSIONS: There was no significant relationship between HRQL evaluated with the SGRQ and the subsequent mortality in IPF. The present negative result might suggest that HRQL is measuring an aspect other than one from physiological and functional impairment or disability.
Assuntos
Nível de Saúde , Fibrose Pulmonar Idiopática/mortalidade , Qualidade de Vida , Idoso , Feminino , Seguimentos , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Fibrose Pulmonar Idiopática/psicologia , Japão/epidemiologia , Masculino , Prognóstico , Estudos Retrospectivos , Inquéritos e Questionários , Taxa de Sobrevida/tendências , Capacidade VitalRESUMO
Interleukin (IL)-18, which is produced by activated monocytes/macrophages and airway epithelial cells, is suggested to contribute to the pathophysiology of asthma by modulating airway inflammation. However, the involvement of IL-18 on modulating chronic airway inflammation and airway remodelling, which are characterized in a refractory asthma model exposed to long-term antigen, has not been investigated sufficiently. We examined the role of IL-18 in chronic airway inflammation and airway remodelling by long-term antigen exposure. IL-18-deficient and C57BL/6-wild-type mice were sensitized by ovalbumin (OVA) and were then exposed to aerosolized OVA twice a week for 12 weeks. We assessed airway inflammation by assessing the infiltration of cells into the airspace and lung tissues, and airway remodelling by airway mucus expression, peribronchial fibrosis and smooth muscle thickness. In IL-18-deficient mice, when exposed to OVA, the total cells and neutrophils of the bronchoalveolar lavage fluid (BALF) were diminished, as were the number of infiltrated cells in the lung tissues. IL-18-deficient mice exposed to OVA after 12 weeks showed significantly decreased levels of interferon (IFN)-gamma, IL-13 and transforming growth factor (TGF)-beta1 in the BALF. The airway hyperresponsiveness to acetyl-beta-methacholine chloride was inhibited in IL-18-deficient mice in comparison with wild-type mice. In addition, IL-18-deficient mice exposed to OVA had fewer significant features of airway remodelling. These findings suggest that IL-18 may enhance chronic airway inflammation and airway remodelling through the production of IFN-gamma, IL-13 and TGF-beta1 in the OVA-induced asthma mouse model.
Assuntos
Asma/imunologia , Interleucina-18/deficiência , Animais , Asma/patologia , Asma/fisiopatologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/biossíntese , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Interleucina-18/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso/patologia , Ovalbumina/imunologiaRESUMO
It is unclear whether inhaled lidocaine is effective against airway hyperreactivity and inflammation in asthma. The aim of this study was to investigate the effects of inhaled lidocaine on airway hyperreactivity and inflammation. Airway reactivity to inhaled histamine, cellular composition of bronchoalveolar lavage (BAL) fluid, plasma substance P (SP), and isolated lung tissue were evaluated in ovalbumin (OVA)-sensitized guinea pigs 7 days after OVA challenge. The effects of inhaled lidocaine on this model were also evaluated. Treatment with lidocaine was administered in two fashions: as single inhalation or inhalation bid for 7 consecutive days, for comparison with a saline-inhaled control group. Airway hyperreactivity to histamine, increase in number of total cells and increased proportion of eosinophils in BAL fluid, and marked eosinophil infiltration in airway walls were noted even 7 days after OVA challenge in the control group. Plasma SP level was also significantly increased. Although treatment with single lidocaine inhalation did not affect airway hyperreactivity, continued inhalation (bid for 7 days) attenuated airway hyperreactivity. Continued, but not single, inhalation of lidocaine also suppressed infiltration of eosinophils in BAL fluid and in airway walls. In addition, plasma SP levels were significantly reduced by continued but not by single inhalation. It appears possible that lidocaine when inhaled suppresses eosinophilic inflammation of the airway and SP-induced neurogenic inflammation, leading to alleviation of airway hyperreactivity.
Assuntos
Anestésicos Locais/farmacologia , Hiper-Reatividade Brônquica/prevenção & controle , Inflamação/prevenção & controle , Lidocaína/farmacologia , Ovalbumina/imunologia , Administração por Inalação , Anestésicos Locais/administração & dosagem , Anestésicos Locais/sangue , Animais , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Capsaicina , Contagem de Células , Tosse/induzido quimicamente , Tosse/prevenção & controle , Eosinófilos/efeitos dos fármacos , Eosinófilos/patologia , Cobaias , Histamina , Inflamação/induzido quimicamente , Inflamação/patologia , Lidocaína/administração & dosagem , Lidocaína/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Substância P/sangue , Substância P/metabolismoRESUMO
This study investigated the differences in apnoea-hypopnoea index (AHI) during rapid eye movement (REM) sleep (AHI-REM) and AHI during non-REM (NREM) sleep (AHI-NREM) in patients with obstructive sleep apnoea (OSA). Nocturnal polysomnography was performed in 102 Japanese OSA patients and their AHI along with a variety of other factors were retrospectively evaluated. Regardless of the severity of AHI, mean apnoea duration was longer and patients' lowest recorded oxygen saturation measured by pulse oximetry was lower during REM sleep than during NREM sleep. Approximately half of the patients (n = 50) had a higher AHI-NREM than AHI-REM. In subjects with AHI >or= 60 events/h, AHI-NREM was significantly higher than AHI-REM. On multivariate logistic regression, severe AHI >or= 30 events/h was the only predictor of a higher AHI-NREM than AHI-REM. This may indicate that important, but unknown, factors related to the mechanism responsible for the severity of OSA are operative during NREM sleep.
Assuntos
Apneia/fisiopatologia , Síndromes da Apneia do Sono/fisiopatologia , Apneia Obstrutiva do Sono/fisiopatologia , Sono REM/fisiologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Oximetria , Oxigênio/sangue , Polissonografia , Análise de RegressãoRESUMO
When five cytotoxicity methods compared the toxicity of eosinophil granule major basic protein (MBP) and melittin to K562 and HL-60 cells, strikingly discrepant results were noted. Trypan blue staining, propidium iodide/CellTrackerGreen staining and incorporation of 14C-leucine assays indicated MBP damages > 75% of cells by 1 h. In contrast, 51Cr and lactic dehydrogenase (LDH) release assays indicated MBP damages most cells only at 20 h. All methods indicated melittin damages nearly all cells by 1 h. Further studies showed that without cell transfer, dye staining methods indicated MBP produces < 10% cytotoxicity after 4 h. A modified 14C-leucine assay, employing sodium dodecyl sulfate solubilization and trichloroacetic acid precipitation, showed lower cytotoxicity, 48%, at 4 h. Modified 51Cr and LDH assays showed increased cytotoxicities at 4 h, 34% and 58%, respectively. Overall, MBP's ability to cause molecular and cellular adhesion systematically confounds standard cytotoxicity measurements. However, the modified 14C-leucine assay provides a valid measure of MBP's cytotoxicity and may be useful for analyses of 'sticky' cytotoxins.
Assuntos
Proteínas Sanguíneas/farmacologia , Testes Imunológicos de Citotoxicidade/métodos , Eosinófilos/imunologia , Ribonucleases , Adesão Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas Granulares de Eosinófilos , Citometria de Fluxo , Células HL-60 , Humanos , Células K562 , L-Lactato Desidrogenase/metabolismo , Leucina/metabolismo , Meliteno/farmacologiaRESUMO
A remarkable "steroid sparing" effect of Saiboku-to was noted within 6 to 12 months of treatment in steroid-dependent asthmatic patients. Saiboku-to spared the downregulation of glucocorticoid receptor of human lymphocytes, plasma ACTH, and cortisol levels. It also spared downregulation of beta 2 receptor by beta 2 agonists and suppressed mACh receptor at the same time. Saiboku-to increased tyrosine aminotransferase (TAT) production, which was inhibited by actinomycin-D, thus having steroid-like activity. In mite-allergic asthma, Saiboku-to inhibited the induction of expression of IgE-Fc epsilon R/CD23 in the lymphocytes by mite allergen. It also inhibited IgE production by mite allergens. In experimental asthma in guinea pigs the use of Saiboku-to resulted in a decrease in the number of eosinophils in the bronchoalveolar lavage fluid during late asthmatic response. These findings suggest that Saiboku-to may be effective in inhibiting both the expression of IgE-Fc epsilon R2 and the induction of expression of IgE-Fc epsilon R1. Saiboku-to also has a steroid-like action and polyhedral anti-asthmatic activities.
Assuntos
Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Imunossupressores/farmacologia , Medicina Kampo , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de IgE/efeitos dos fármacos , Animais , Asma/imunologia , Medicamentos de Ervas Chinesas/uso terapêutico , Cobaias , Humanos , Imunoglobulina E/biossíntese , Ativação Linfocitária/efeitos dos fármacos , Receptores Adrenérgicos beta/análise , Receptores de Glucocorticoides/análise , Receptores de IgE/análiseRESUMO
Syn- And anti-[3.3](3,9)carbazolophanes, which are suitable model compounds for sandwich and partial-overlap excimers, respectively, have been synthesized and characterized; the structures of both singlet and triplet carbazole excimer have been described.
RESUMO
In bronchial asthma, eosinophils and neutrophils are activated, so that the production of active oxygen species increases, causing airway epithelial injury. Suplatast tosilate (IPD Capsules) is a novel immunomodulating antiallergic drug that acts against bronchial asthma through a new mechanism. To evaluate the effects of suplatast tosilate on mononuclear cell-mediated IL-8 production, and neutrophil-mediated active oxygen species production at sites of inflammation, we collected peripheral blood from healthy subjects and separated the neutrophils as well as mononuclear cells. Suplatast tosilate was added at a concentration of 1 x 10(-6), 1 x 10(-7) or 1 x 10(-8) M, and cells were incubated for 10 min at 37 degrees C. Then, the neutrophils were stimulated with fMLP, and luminol-dependent chemiluminescence (LDCL) was measured, while IL-8 production was determined with an ELISA kit. Suplatast tosilate (1 x 10(-6) M) inhibited neutrophil-mediated active oxygen species production by 12.4% in terms of the peak, and by 16% in terms of the integral value. Moreover, it significantly inhibited mononuclear cell-mediated IL-8 production at concentrations of 1 x 10(-6), 1 x 10(-7) and 1 x 10(-8) M, in a concentration-dependent manner. This study indicated that suplatast tosilate may inhibit neutrophil infiltration by suppressing monocyte-mediated IL-8 production, and it may also inhibit the activation of neutrophils at sites of inflammation. These results suggest the possibility that suplatast tosilate may not only be of benefit for asthma, but may also prevent or control pulmonary fibrosis or emphysema, for which no effective treatment is presently available.
Assuntos
Adjuvantes Imunológicos/farmacologia , Antialérgicos/farmacologia , Sulfonatos de Arila/farmacologia , Interleucina-8/biossíntese , Monócitos/metabolismo , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfônio/farmacologia , Humanos , Técnicas In Vitro , Monócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacosRESUMO
Stress is one of the important factors influencing bronchial asthma, but many questions still remain unanswered. To clarify this point we examined airway hypersensitivity before and after electric shock stress and the role of substance P in an animal model of asthma. We determined airway hypersensitivity to histamine and the substance P levels in serum, bronchoalveolar lavage fluid, and bronchial tissue before and after electric shock stress in biphasic asthma-responsive guinea pigs which had been sensitized using ovalbumin. The cell components in bronchoalveolar lavage fluid were also examined. Airway hypersensitivity to histamine (4.9-156 micrograms/ml) was significantly increased (p < 0.01) by electric shock stress. The substance P level was also significantly increased in plasma and bronchoalveolar lavage fluid, but it was significantly decreased in bronchial tissue. The number of eosinophils in bronchoalveolar lavage fluid increased significantly after electric shock stress. These findings demonstrated that airway hypersensitivity to histamine was increased by stress and suggested that substance P, as well as eosinophils, contribute to the pathogenesis of hypersensitivity.
Assuntos
Asma/metabolismo , Hiper-Reatividade Brônquica/metabolismo , Estresse Fisiológico/metabolismo , Substância P/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Eletrochoque , CobaiasRESUMO
The effect of a new anti-asthmatic drug, TYB-2285 (3,5-bis(acetoxyacetylamino)-4-chlorobenzonitrile), was investigated in ovalbumin-sensitized guinea-pigs. When guinea-pigs were pretreated with TYB-2285 (300 mg kg-1, p.o., single dose or consecutively for 7 days), the immediate asthmatic response was inhibited as demonstrated by diminished cyanosis, but not the bronchoconstriction. TYB-2285, given singly or consecutively, inhibited the appearance of late asthmatic response and the infiltration of inflammatory cells, such as eosinophils, into the airway. Additionally, airway hyper-responsiveness was also reversed by the single administration of TYB-2285. Luminol-dependent chemiluminescence of airway-infiltrated cells stimulated with A23187 was inhibited by TYB-2285 in a dose-dependent manner. The present study suggests that TYB-2285 inhibits late asthmatic response and airway hyperresponsiveness by inhibiting the accumulation of eosinophils and other inflammatory cells into the airway, and also by inhibiting the production of oxygen radicals from airway-infiltrated cells.
Assuntos
Asma/tratamento farmacológico , Nitrilas/uso terapêutico , Hipersensibilidade Respiratória/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/citologia , Calcimicina/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Histamina/farmacologia , Medições Luminescentes , Luminol , Masculino , Ovalbumina/imunologia , Testes de Função RespiratóriaRESUMO
The effects of cytokines (interleukin-2, tumor necrosis factor-alpha and interferon-gamma) on the ability of peripheral blood monocytes and alveolar macrophages to produce oxygen radicals were examined by the chemiluminescence assay in patients with lung cancer. Oxygen radical production by peripheral blood monocytes before stimulation with cytokines was lower in the lung cancer group than in healthy controls, suggesting reduced immune function in lung cancer patients. However, the activity in the lung cancer group was elevated to the control level when the monocytes were stimulated by any of the three aforementioned cytokines. Oxygen radical production by alveolar macrophages did not differ significantly between nonstimulated monocytes from lung cancer patients and those from healthy controls. In the lung cancer group, stimulation of the macrophages with any of the three cytokines elevated their ability to produce oxygen radicals to the same extent as in the control group. The results suggest that stimulation of macrophages by interleukin-2, tumor necrosis factor-alpha or interferon-gamma can exert an antitumor action in patients with lung cancer.
Assuntos
Citocinas/fisiologia , Radicais Livres/metabolismo , Neoplasias Pulmonares/metabolismo , Macrófagos Alveolares/metabolismo , Monócitos/metabolismo , Oxigênio , Adulto , Idoso , Feminino , Humanos , Interferon gama/fisiologia , Interleucina-2/fisiologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
Eosinophils play an important role in the development of bronchial asthma, and the association between ICAM-1 and activation and migration of local eosinophils is attracting attention. Using an asthmatic model of dual phase bronchial response, the effects of anti-ICAM-1 antibody on the airway resistance, cell composition in the bronchoalveolar lavage fluid (BALF) and ultrastructure of bronchial ciliated epithelium were examined under the provoked response by inhalation of the antigen. By administration of anti-ICAM-1 antibody, the late asthmatic response (LAR) was suppressed. In the examination of bronchoalveolar lavage fluid, a significant decrease in eosinophils was found in LAR. In examining transmission and scanning electron microscopies, no difference was found in the immediate asthmatic response, but marked suppression of deciduation of bronchial ciliated epithelium was observed in LAR. These results indicated that anti-ICAM-1 antibody suppressed bronchial asthmatic attack, mainly in LAR, by controlling differentiation and migration of eosinophils.
Assuntos
Resistência das Vias Respiratórias/efeitos dos fármacos , Asma/imunologia , Líquido da Lavagem Broncoalveolar/química , Molécula 1 de Adesão Intercelular/fisiologia , Administração por Inalação , Animais , Anticorpos/imunologia , Brônquios/imunologia , Movimento Celular/efeitos dos fármacos , Cílios/efeitos dos fármacos , Cílios/patologia , Eosinófilos/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Epitélio/ultraestrutura , Cobaias , Molécula 1 de Adesão Intercelular/imunologia , Masculino , Microscopia Eletrônica , Microscopia Eletrônica de Varredura , Fatores de TempoRESUMO
In recent years, bronchial asthma has come to be regarded pathologically as a chronic inflammatory disease of the respiratory tract. Inhalational steroids and antiinflammatory drugs are recognized as being effective against bronchial asthma. In this study, the effects of Saiboku-to, a Chinese herbal (Kampo) formulation, were investigated on asthmatic guinea pigs sensitized to ovalbumin (OA). Following 7-day administration of Saiboku-to (500 micrograms/kg), the late asthmatic response (LAR) to an antigen challenge was found to be inhibited. The number of eosinophils in fluid obtained by bronchoalveolar lavage (BAL) 4 h after antigen challenge was decreased while the infiltration of eosinophils and T-lymphocytes into the lung parenchyma was inhibited. These findings suggest that Saiboku-to has the potential to become a useful drug in the treatment of bronchial asthma.
Assuntos
Asma/fisiopatologia , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Animais , Antígenos/administração & dosagem , Asma/tratamento farmacológico , Asma/imunologia , Asma/patologia , Broncoconstrição/imunologia , Modelos Animais de Doenças , Cobaias , Masculino , Medicina Tradicional Chinesa , Ovalbumina/administração & dosagemRESUMO
In recent years, bronchial asthma has come to be regarded as a chronic inflammatory disease of the respiratory tract, with mast cells, lymphocytes and eosinophils playing important roles in its pathogenesis. Proteins contained in eosinophil granules, especially major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPO), can cause tissue injury. When stimulated, eosinophils release mediators such as leukotriene C4 (LTC4) and platelet activating factors (PAF). Thus, they are recognized as effector cells that are actively involved in the development of allergic inflammation. In this study, eosinophils from healthy volunteers were used to investigate the effects of Saiboku-to on eosinophils whose survival had been prolonged through stimulation with eosinophil-activating cytokines such as interleukin (IL)-3, IL-5 and granulocyte macrophage colony stimulating factors (GM-CSF). As a result, the cytokine-enhanced survival of eosinophils was significantly shortened by the addition of Saiboku-to. These findings suggest that Saiboku-to has the potential to inhibit allergic responses by directly affecting eosinophils which are related to allergic inflammation.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Eosinófilos/efeitos dos fármacos , Imunossupressores/farmacologia , Medicina Kampo , Sobrevivência Celular/efeitos dos fármacos , Citocinas/biossíntese , Citocinas/farmacologia , Fator Estimulador de Colônias de Granulócitos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Técnicas In Vitro , Interleucina-3/antagonistas & inibidores , Interleucina-3/farmacologia , Interleucina-5/antagonistas & inibidores , Interleucina-5/farmacologia , Fatores de TempoRESUMO
The influence of a once-a-day sustained-release theophylline (Uniphyl) on lymphocytes and eosinophils in the peripheral blood and sputum of patients with bronchial asthma was investigated. The peripheral blood lymphocytes included CD4, CD8, CD25 and HLA-DR. The sputum lymphocytes and eosinophils included CD4, CD8, CD25 and HLA-DR, and EG2, respectively. The results revealed that theophylline administration did not affect the numbers of activated CD4 and CD8 T lymphocytes in peripheral blood. No significant change in the lymphocyte count was observed in sputum, but the eosinophil count in the sputum decreased significantly after theophylline administration. EG2-positive eosinophils also decreased in number. CD4+HLA-DR+ and CD4+CD25+ T lymphocytes were significantly decreased, whereas CD8+ T lymphocytes in the sputum were not significantly reduced in number. Respiratory function test showed that forced expiratory volume in 1 s was significantly increased after theophylline administration. The results suggest that a new once-a-day sustained-release theophylline formulation would be useful in the treatment of chronic respiratory tract inflammation.
Assuntos
Eosinófilos/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Escarro/citologia , Teofilina/farmacologia , Asma/tratamento farmacológico , Eosinófilos/imunologia , Humanos , Imunofenotipagem , Linfócitos/imunologia , Teofilina/uso terapêuticoRESUMO
The effect of a new thromboxane A2 receptor antagonist, AA-2414, (+/-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid, on dual bronchoconstriction and airway hyper-reactivity in actively sensitized guinea-pigs was investigated. Immediate and late bronchial responses were seen 1-10 min and 4-7 h, respectively, after inhalation of antigen. In guinea-pigs pretreated with AA-2414, 5 mg/kg orally, the immediate bronchial response was inhibited. An administration of AA-2414 inhibited the late bronchial response. The numbers of eosinophils, neutrophils and macrophages, but not of lymphocytes, in bronchoalveolar lavage fluid were increased at 4 h after antigen inhalation. AA-2414 did not affect the numbers of total cells, eosinophils, neutrophils or macrophages. Sensitized guinea-pigs showed a significant airway hyperreactivity to inhaled histamine, which was not influenced by an administration of AA-2414. Luminol-dependent chemiluminescence of airway-infiltrated cells from sensitized guinea-pigs stimulated with A23187 was slightly inhibited by AA-2414. These results show that AA-2414 inhibits the late asthmatic response and the production of oxygen radicals from airway-infiltrated cells.
Assuntos
Benzoquinonas/farmacologia , Brônquios/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Tromboxano A2/antagonistas & inibidores , Animais , Líquido da Lavagem Broncoalveolar/citologia , Cobaias , Histamina/administração & dosagem , Contagem de Leucócitos , Medições Luminescentes , Ovalbumina/administração & dosagem , Espécies Reativas de OxigênioRESUMO
We evaluated eight cases of pulmonary mycosis in immuno compromised hosts. The underlying diseases were lung cancer with chemotherapy in one case, post bone marrow transplantation (post BMT) in two cases, acquired immunodeficiency syndrome (AIDS) in one case and bronchial asthma with massive steroid therapy in four cases. The causative fungi were Candida sp. in three cases, Aspergillus sp. in four cases, Tricosporon sp. in one case. Prognosis was guarded despite antifungal treatment. Five cases deteriorated and died of fungal infection. In five cases, who died of deterioration, 31.6 days was required from appearance of abnormal infiltration in the chest X-ray to determination of the causative fungi (including two cases who were diagnosed by autopsy) on the average. In three successfully treated cases, the average duration from the appearance of abnormal infiltration in the chest X-ray for the determination of the causative fungi was 8.3 days. On the contrary, the average duration between the appearance of abnormal infiltration in the chest X-ray and the initiation of antifungal treatment was 2.6 days who died of deterioration and 8.3 days who survived. We conclude that early identification of causative fungi and not quick institution of antifungal treatment was mandatory in the treatment of opportunistic fungal pneumonia.