RESUMO
PURPOSE: Lymphangioleiomyomatosis is a rare lung disease caused by proliferation of abnormal smooth muscle-like cells and typically occurs in premenopausal women. Sirolimus is now the first-line drug for the treatment of lymphangioleiomyomatosis. Sirolimus-induced stomatitis is the most frequent adverse event experienced during treatment. To identify risk factors, we investigated the association of stomatitis incidence with patient background data and treatment parameters, using data from the multicenter long-term sirolimus trial. METHODS: Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5 to 15 ng/mL. The incidence of stomatitis was correlated with baseline demographics, clinical characteristics, and changes in the longitudinal data. Risk factors at baseline were assessed by using univariate and multivariate analyses. RESULTS: The most frequent adverse event was stomatitis, with the cumulative rate reaching 88.9% by 9 months, higher than that reported in postrenal transplant patients. The repetition, the duration, and the severity of stomatitis events were variable among patients. We found that patients with low hemoglobin (Hb) (<14.5 g/dL) showed significantly higher incidence than those with high Hb (≥14.5 g/dL, P < .01). The cumulative rate for stomatitis incidence was significantly associated with a decrease in the mean corpuscular volume, while the Hb level was constant; thus, red blood cell count in patients increased during the study. CONCLUSIONS: Baseline Hb levels and a decrease in mean corpuscular volume during treatment were correlated with the incidence of stomatitis.
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Antibióticos Antineoplásicos/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Linfangioleiomiomatose/tratamento farmacológico , Sirolimo/efeitos adversos , Estomatite/epidemiologia , Adulto , Índices de Eritrócitos/efeitos dos fármacos , Feminino , Hemoglobinas/análise , Humanos , Incidência , Japão/epidemiologia , Neoplasias Pulmonares/sangue , Linfangioleiomiomatose/sangue , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Fatores de Risco , Estomatite/sangue , Estomatite/induzido quimicamenteRESUMO
Chronic obstructive pulmonary disease (COPD) is a disease common in elderly people, characterized by progressive destruction of lung parenchyma and chronic inflammation of the airways. The pathogenesis of COPD remains unclear, but recent studies suggest that oxidative stress-induced apoptosis in alveolar cells contributes to emphysematous lung destruction. The proteasome is a multicatalytic enzyme complex that plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by oxidative and other stresses. Proteasome activity decreases with aging in many organs including lungs, and an age-related decline in proteasomal function has been implicated in various age-related pathologies. However, the role of the proteasome system in the pathogenesis of COPD has not been investigated. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Importantly, apoptotic cells were found in the alveolar walls of the affected lungs. Impaired proteasomal activity also enhanced apoptosis in cigarette smoke extract (CSE)-exposed fibroblastic cells derived from mice and humans in vitro. Notably, aggresome formation and prominent nuclear translocation of apoptosis-inducing factor were observed in CSE-exposed fibroblastic cells isolated from Tg mice. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly.
Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/metabolismo , Fumaça/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Enfisema Pulmonar/patologia , NicotianaRESUMO
Exacerbations are among the major factors that may affect the natural history of chronic obstructive pulmonary disease (COPD). The aim was to investigate the clinical characteristics and determinants of COPD exacerbations in our 5-year observational cohort study which had a very low exacerbation frequency. A total of 279 patients with COPD participated in the Hokkaido COPD cohort study, and 268 subjects who had clinical data for multiple visits were analysed. Exacerbation was defined in multiple ways: the patient's subjective complaint, symptom definition, requiring prescription change, requiring antibiotic treatment, or requiring hospital admission. Exacerbation frequency (events per person per year) was 0.78 ± 1.16, 0.24 ± 0.47, 0.20 ± 0.43, 0.13 ± 0.28 and 0.06 ± 0.19 for subjective complaint and symptom, prescription, antibiotic and hospital admission definitions, respectively. Exacerbation events did not significantly affect the annual decline in forced expiratory volume in 1 s. A high St George's Respiratory Questionnaire total score, especially activity score, and a low body mass index were strongly associated with exacerbation-free survival, exacerbation frequency and development of recurrent exacerbations. Despite the low exacerbation frequency in our cohort, impaired health-related quality of life and weight loss were found to be independent risk factors for COPD exacerbations.
Assuntos
Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Antibacterianos/uso terapêutico , Índice de Massa Corporal , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Volume Expiratório Forçado , Hospitalização , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Admissão do Paciente , Qualidade de Vida , Recidiva , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
RATIONALE: Although the rate of annual decline in FEV1 is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD), little is known about intersubject variability based on clinical phenotypes. OBJECTIVES: To examine the intersubject variability in a 5-year observational cohort study, particularly focusing on emphysema severity. METHODS: A total of 279 eligible patients with COPD (stages I-IV: 26, 45, 24, and 5%) participated. We conducted a detailed assessment of pulmonary function and computed tomography (CT) at baseline, and performed spirometry every 6 months before and after inhalation of bronchodilator. Smoking status, exacerbation, and pharmacotherapy were carefully monitored. Emphysema severity was evaluated by CT and annual measurements of carbon monoxide transfer coefficient. MEASUREMENTS AND MAIN RESULTS: Using mixed effects model analysis, the annual decline in post-bronchodilator FEV1 was -32±24 (SD) ml/yr (n=261). We classified the subjects of less than the 25th percentile as Rapid decliners, the 25th to 75th percentile as Slow decliners, and greater than the 75th percentile as Sustainers (-63±2, -31±1, and -2±1 [SE] ml/yr). Emphysema severity, but not %FEV1, showed significant differences among the three groups. Multiple logistic regression analysis demonstrated that the Rapid decliners were independently associated with emphysema severity assessed either by CT or carbon monoxide transfer coefficient. The Sustainers displayed less emphysema and higher levels of circulating eosinophils. CONCLUSIONS: Emphysema severity is independently associated with a rapid annual decline in FEV1 in COPD. Sustainers and Rapid decliners warrant specific attention in clinical practice.
Assuntos
Broncodilatadores/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fenômenos Fisiológicos Respiratórios/efeitos dos fármacos , Idoso , Estudos de Coortes , Feminino , Seguimentos , Volume Expiratório Forçado , Humanos , Pulmão/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Masculino , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/fisiopatologia , Testes de Função Respiratória , Índice de Gravidade de Doença , Espirometria/métodos , Tomografia Computadorizada por Raios X/métodosRESUMO
A 35-year-old woman experienced left back pain after a 2-h flight. She reported coughing and left back pain 1 day later when she presented to our hospital. Chest computed tomography showed pneumothorax of the left lung, bronchiectasis, thickening of the bronchial wall, nodules, and cavity lesions in both lungs. A pulmonary function test revealed obstructive ventilation disorder with normal lung diffusing capacity. She had a history of haematopoietic stem cell transplantation (HSCT) at 2 years and 3 months of age during the second disease remission of acute myeloid leukaemia. She was diagnosed with chronic graft-versus-host disease (cGVHD) presenting with bronchiolitis obliterans (BO) and pleuroparenchymal fibroelastosis (PPFE). To our knowledge, this is the first reported case of BO and PPFE diagnosed more than 30 years after HSCT.
RESUMO
Adverse events are potentially associated with an IgG response after BNT162b2 vaccination for severe acute respiratory syndrome coronavirus 2. In this study, we investigated the side effects of the BNT162b2 vaccine using a health questionnaire and examined its relationship with IgG antibody titers. Serum samples were collected from participants 3 months after the second vaccination, immediately before the third vaccination, and 1 and 3 months after the third vaccination. A total of 505 participants who received three doses of vaccine were eligible for inclusion in the analysis. The results showed that post-vaccination body temperature correlated with anti-spike-receptor-binding domain (anti-S-RBD) antibody titers measured 3 months after the second (r = 0.30, P < 0.001) and third (r = 0.14, P < 0.001) vaccinations. Multivariate linear regression analysis revealed that age and severe swelling were negatively associated, whereas female sex, body temperature, and heat sensation were positively associated with log-transformed anti-S-RBD antibody levels after the second vaccination. After the third vaccination, body temperature and fatigue were positively associated, and female sex was negatively associated, with the log-transformed anti-S-RBD antibody levels. These results suggest that post-vaccination fever may be a marker of a high antibody titer.
Assuntos
Vacina BNT162 , COVID-19 , Febre , Feminino , Humanos , Anticorpos Antivirais/sangue , Vacina BNT162/efeitos adversos , COVID-19/prevenção & controle , Imunoglobulina G/sangue , Japão , Vacinação/efeitos adversos , Febre/induzido quimicamenteRESUMO
CASE PRESENTATION: A 60-year-old woman, a care worker with no known comorbidities, presented to the pulmonary clinic for assessment of a left hilar tumor detected on chest radiography. She had a history of oophorocystectomy and was a 0.5-pack/day smoker. She was asymptomatic but desired a confirmative diagnosis.
Assuntos
Neoplasias do Mediastino , Feminino , Humanos , Pulmão , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/cirurgia , Mediastino , Pessoa de Meia-Idade , RadiografiaRESUMO
A 65-year-old woman presented to a local hospital with a 4-day history of cough, fever, and dyspnea. She had started using a composter and had been exposed to the vapor for 18 days before her first visit. She was diagnosed with acute eosinophilic pneumonia (AEP) based on her symptoms, the presence of bilateral pulmonary opacities on computed tomography, and alveolar eosinophilia confirmed by bronchoalveolar lavage. Inhalation of the composter vapor was thought to be the cause of AEP. Aspergillus fumigatus was cultured from the composter soil and the bronchoalveolar lavage fluid. She fully recovered without systemic corticosteroid administration by avoiding the composter.
Assuntos
Eosinofilia Pulmonar , Humanos , Feminino , Idoso , Eosinofilia Pulmonar/induzido quimicamente , Eosinofilia Pulmonar/diagnóstico por imagem , Doença Aguda , Líquido da Lavagem Broncoalveolar , Lavagem Broncoalveolar , Administração por Inalação , GasesRESUMO
IgG4-related lung disease (IgG4-RLD) can present with various types of radiological findings such as nodule, ground-glass opacity, alveolar interstitial, and bronchovascular involvement. IgG4-RLD generally manifests as mild clinical symptoms, despite evidence from the image findings. Herein we report an asymptomatic patient with IgG4-RLD mimicking multiple pleural disseminated lung cancer.
RESUMO
BACKGROUND: Previous studies have shown that polymorphisms in the ß2-adrenergic receptor gene (ADRB2) may influence bronchodilator response (BDR) to both ß2-agonists and anticholinergics, possibly by intracellular cross-talk, but in opposite ways, in the Japanese population. We hypothesized that the preferential response to either class of bronchodilators might be determined by ADRB2 polymorphisms in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE: To examine the association of ADRB2 polymorphisms and preferential BDR to ß2-agonists and anticholinergics in patients with COPD. DESIGN AND PARTICIPANTS: The participants had been enrolled in the Hokkaido COPD cohort study. BDR to either class of bronchodilators (salbutamol or oxytropium, 0.4 mg) was measured every 6 months for 2 years. Considering the variation of BDR within and between days, mean values of postbronchodilator increases in forced expiratory volume in 1 s (ΔFEV1) for the two agents measured at two different visits were initially used for the primary analysis (N=189). To confirm the results of the primary analysis, ΔFEV1 measured at a single visit was also used for secondary analyses. RESULTS: Although a significant correlation between BDRs to salbutamol and to oxytropium was observed (P<0.001, r=0.36), there were individuals who responded preferentially to one of the two agents. When the participants were classified into two groups based on the bronchodilator causing the better response (salbutamol-dominant group and oxytropium-dominant group), Arg allele was significantly more common in the oxytropium-dominant group than in the salbutamol-dominant group (0.001
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Povo Asiático/genética , Broncodilatadores/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptores Adrenérgicos beta 2/genética , Idoso , Albuterol/uso terapêutico , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Doença Pulmonar Obstrutiva Crônica/genética , Derivados da Escopolamina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Catalase is preferentially expressed in bronchiolar and alveolar epithelial cells, and acts as an endogenous antioxidant enzyme in normal lungs. We thus postulated epithelial damage would be associated with a functional deficiency of catalase during the development of lung fibrosis. METHODS: The present study evaluates the expression of catalase mRNA and protein in human interstitial pneumonias and in mouse bleomycin-induced lung injury. We examined the degree of bleomycin-induced inflammation and fibrosis in the mice with lowered catalase activity. RESULTS: In humans, catalase was decreased at the levels of activity, protein content and mRNA expression in fibrotic lungs (n = 12) compared to control lungs (n = 10). Immunohistochemistry revealed a decrease in catalase in bronchiolar epithelium and abnormal re-epithelialization in fibrotic areas. In C57BL/6J mice, catalase activity was suppressed along with downregulation of catalase mRNA in whole lung homogenates after bleomycin administration. In acatalasemic mice, neutrophilic inflammation was prolonged until 14 days, and there was a higher degree of lung fibrosis in association with a higher level of transforming growth factor-ß expression and total collagen content following bleomycin treatment compared to wild-type mice. CONCLUSIONS: Taken together, these findings demonstrate diminished catalase expression and activity in human pulmonary fibrosis and suggest the protective role of catalase against bleomycin-induced inflammation and subsequent fibrosis.
Assuntos
Catalase/metabolismo , Pulmão/enzimologia , Fibrose Pulmonar/enzimologia , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Distribuição TecidualRESUMO
Purpose: Causes of death may be unique and different in Japanese patients with COPD because they are generally older, thinner, experience fewer exacerbations, and live longer than those in other countries. We investigated the detailed mortality profile in the Hokkaido COPD cohort study, which completed a 10-year follow-up with a very low dropout rate. Patients and Methods: We prospectively examined the 10-year natural history in 279 Japanese patients with COPD (GOLD 1, 26%; GOLD 2, 45%; GOLD 3, 24%; and GOLD 4, 5%). The majority of patients were male, and the average age at baseline was 69 years old. About 95% of all patients had accurate mortality data. The risk factors for mortality were also analyzed. Results: During the 10 years, 112 patients (40%) died. Their median survival time was 6.1 years (interquartile range: 4.7-7.9 years), and age at death was 79 ± 6 years old (mean ± SD). Respiratory diseases, including pneumonia, were the leading causes of death in 45 (40%), followed by lung cancer in 24 (21%), other cancers in 18 (16%), and cardiovascular diseases in 12 (11%). In particular, lung cancer-related death was equally distributed across all COPD stages, with a higher proportion of lung cancer in the relatively younger generation (<64 years old). Older age at baseline, lower BMI, and severer emphysema were significant risk factors for all-cause mortality. Conclusion: The unique mortality profile observed in this study should be considered when designing strategies for the management of patients with COPD in any geographic region.
Assuntos
Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Enfisema Pulmonar/diagnóstico , Fatores de RiscoRESUMO
Long-term decline in lung function is generally considered to be progressive in individuals with established chronic obstructive pulmonary disease (COPD), despite the presence of intersubject variation. We hypothesized that the annualized rate of decline in forced expiratory volume in 1 second (FEV1) would not be constant among different time periods in the natural history of established COPD. We compared the annual change rates in FEV1 during the first 5 years and the last 5 years, estimated separately using a linear mixed-effects model in 10-year survivors (n = 110). The subjects were classified into three FEV1 decline groups, based on the 25th and 75th percentile values in each time period. The rates of FEV1 changes, calculated from the first 5 years and the last 5 years, did not correlate with each other among 10-year survivors; the subjects of each FEV1 decline group during the first 5 years did not consistently remain in the same FEV1 decline group during the last 5 years. Smoking status and exacerbation frequency were not associated with decline in FEV1. In conclusion, the disease activity, which is often expressed as annualized change in FEV1, might be changeable either way over years in patients with established COPD.
Assuntos
Volume Expiratório Forçado/fisiologia , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Testes de Função Respiratória/métodos , Fumar/efeitos adversos , SobreviventesRESUMO
Pulmonary macrophages are one of the sources of various antioxidant and detoxification enzymes for which NF-E2-related factor 2 (Nrf2) is a key transcriptional factor. Although Nrf2 deficiency reportedly induces severe emphysema in mice exposed to cigarette smoke (CS), no reports have studied Nrf2 regulation in chronic obstructive pulmonary disease (COPD). In this study, Nrf2 activation in response to CS was evaluated in human alveolar macrophages, and age-related differences in CS-induced Nrf2 regulation in mouse alveolar macrophages were determined. Furthermore, Nrf2 mRNA levels in human macrophages harvested by bronchoalveolar lavage or laser capture microdissection were measured. CS induced nuclear Nrf2 accumulation and up-regulation of Nrf2 target genes without substantial changes in Nrf2 mRNA levels in human alveolar macrophages. In humans, the Nrf2 mRNA level in lavaged macrophages of young subjects (n = 14) was independent of smoking status; however, the Nrf2 mRNA level was down-regulated in the lavaged macrophages of older current smokers (n = 14) compared with older nonsmokers (n = 9) (P < 0.001). Among older subjects, the macrophage Nrf2 mRNA level was inversely correlated with oxidized glutathione and carbonylated albumin levels in bronchoalveolar lavage fluid. In mice, aging suppressed the CS-induced up-regulation of Nrf2 target genes, as well as Nrf2, in alveolar macrophages. Furthermore, the Nrf2 mRNA level was decreased in laser capture microdissection-retrieved macrophages obtained from subjects with COPD (n = 10) compared with control subjects (n = 10) (P = 0.001). In conclusion, CS induces Nrf2 activation in macrophages, and Nrf2 expression is decreased in the macrophages of older current smokers and patients with COPD.
Assuntos
Envelhecimento/metabolismo , Regulação para Baixo/genética , Macrófagos Alveolares/metabolismo , Fator 2 Relacionado a NF-E2/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumar/metabolismo , Adulto , Idoso , Animais , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar , Feminino , Humanos , Imuno-Histoquímica , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Dual oxidase (Duox) 1 and Duox2 are important sources of hydrogen peroxide production and play a role in host defense in airways. Little is known about their regulation in association with smoking or chronic obstructive pulmonary disease (COPD). We investigated the epithelial expression of Duox1 and Duox2 in the airways of smokers, and the relationship between this expression and COPD at early stage. First, using bronchoscopy, we harvested tracheal and bronchial epithelium from individuals who have never smoked and current smokers. Duox1 expression in brushed tracheal and bronchial epithelium was significantly downregulated, whereas Duox2 was upregulated, in current smokers as compared to individuals who have never smoked. Second, laser capture microdissection and microscope-assisted manual dissection were performed in surgically resected lung tissues to collect bronchiolar epithelium and alveolar septa. Subjects with mild/moderate COPD, who were all former smokers, exhibited downregulation of bronchiolar Duox1 and Duox2 when compared to individuals who have never smoked, whereas a difference between former smokers, with and without COPD, was observed only for Duox1. Alveolar Duox1 and Duox2 expression was low and did not differ among the groups. These results imply that the airway expression of Duox1 and Duox2 is diversely associated with smoking and COPD.
Assuntos
Expressão Gênica/genética , NADPH Oxidases/genética , Doença Pulmonar Obstrutiva Crônica/genética , Mucosa Respiratória/metabolismo , Fumar , Idoso , Broncoscopia , Oxidases Duais , Epitélio/metabolismo , Epitélio/patologia , Humanos , Interferon gama/genética , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Mucosa Respiratória/patologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Vascular endothelial growth factor (VEGF) signaling is crucial for lung structure maintenance. Although VEGF deficiency plays a role in the pathogenesis of emphysema in animals, little is known about VEGF expression levels and functions, as well as VEGF receptors, in airway epithelial cells, which are in direct contact with the environment. In this study, C57BL/6J mice were exposed to cigarette smoke (CS) for short (approximately 10 days) and long (4-24 wk) time periods, and bronchiolar expressions of VEGF and its receptors VEGFR-1 and VEGFR-2 were examined. The relationships between the expressions of VEGF, VEGFR-1, and VEGFR-2 and smoking histories and/or chronic obstructive pulmonary disease (COPD) were examined in humans. The mRNA levels were quantified in bronchiolar epithelium harvested by laser capture microdissection in both mouse and human lung tissues or in human bronchial epithelium harvested by bronchoscopic brushing. The VEGF protein level was assessed by immunohistochemistry or enzyme-linked immunosorbent assay. Repeated CS exposure downregulated bronchiolar expressions of VEGF and both VEGF receptors at various time points prior to the development of emphysema. In humans, bronchiolar VEGF was significantly decreased in smokers with COPD compared to lifelong nonsmokers, as well as to smokers without COPD; however, there was no difference in bronchiolar VEGF levels between lifelong nonsmokers and smokers without COPD. On the other hand, bronchiolar VEGFR-2 was downregulated in smokers with and without COPD compared to lifelong nonsmokers. These findings suggest the association of downregulation of bronchiolar VEGF and its receptors with cigarette smoking and COPD.
Assuntos
Brônquios/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Fumaça/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Animais , Brônquios/metabolismo , Brônquios/patologia , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Exposição por Inalação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , RNA Mensageiro/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Pulmonary Mycobacterium avium complex (MAC) infection is increasing in prevalence worldwide even in immunocompetent individuals. Despite its variable clinical course, the clinical and immunological factors associated with radiographical severity and progression are not largely unknown. We aimed to study the association between the inflammatory cell and cytokine profiles at the local infected site, and the radiological severity and/or progression of pulmonary MAC infection. In this retrospective cohort study, 22 healthy subjects and 37 consecutive patients who were diagnosed as having pulmonary MAC infection by positive cultures of bronchoalveolar lavage (BAL) fluids were enrolled. The 37 patients were divided into 2 groups based on the predominant BAL inflammatory cell type: the lymphocyte-dominant (LD) group and neutrophil-dominant (ND) groups. The high-resolution computed tomography score in both the lavaged segment and whole lung and cytokines profiles were compared between the 2 groups. The clinical course after the BAL procedure was also compared between the 2 groups. Both the segment and whole lung scores in the ND group were significantly higher than the LD group (P < 0.001). Levels of IL-8 in the BAL fluids were significantly higher in the ND group compared to the LD group (P = 0.01). In contrast, levels of IL-22 were significantly lower in the ND group compared to the LD group (P < 0.001). The prevalence of patients who showed deterioration of the disease was significantly higher in the ND group (83.3%) than the LD group (12.5%) (P < 0.01). Neutrophil-predominant inflammatory response at the infected site is associated with the radiographical severity and progression of pulmonary MAC infection.
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Líquido da Lavagem Broncoalveolar/imunologia , Infecção por Mycobacterium avium-intracellulare/imunologia , Neutrófilos/imunologia , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Estudos de Casos e Controles , Quimiocinas/metabolismo , Citocinas/metabolismo , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecção por Mycobacterium avium-intracellulare/diagnóstico por imagem , Infecção por Mycobacterium avium-intracellulare/patologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
RATIONALE: Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. OBJECTIVES: To explore novel severe asthma phenotypes by cluster analysis when including smoking patients with asthma. METHODS: We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. RESULTS: Five clinical clusters, including two characterized by low forced expiratory volume in 1 second/forced vital capacity, were identified. When characteristics of smoking subjects in these two clusters were compared, there were marked differences between the two groups: one had high levels of circulating eosinophils, high immunoglobulin E levels, and a high sinus score, and the other was characterized by low levels of the same parameters. Sputum analysis revealed intriguing differences of cytokine/chemokine pattern in these two groups. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 3 years later. CONCLUSIONS: This study reveals two distinct phenotypes with potentially different biological pathways contributing to fixed airflow limitation in cigarette smokers with severe asthma.
Assuntos
Asma/diagnóstico , Fenótipo , Fumantes , Fumar/efeitos adversos , Adulto , Idoso , Análise por Conglomerados , Eosinófilos/citologia , Feminino , Humanos , Imunoglobulina E/sangue , Japão , Contagem de Leucócitos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Índice de Gravidade de Doença , Escarro/química , Adulto JovemRESUMO
BACKGROUND: COPD is characterized by a persistent airflow limitation that is not fully reversible; thus, the reversibility of airflow limitations in response to a bronchodilator is an important component of COPD. Several studies have established that two common nonsynonymous polymorphisms in the beta2-adrenergic receptor gene (ADRB2), Arg16Gly and Gln27Glu, have important effects in modulating responses to beta2-agonists; however, the effects of these polymorphisms on responses to beta2-agonists in patients with COPD is unknown. OBJECTIVE: To examine whether different genotypes at these two polymorphisms are related to differential responses to inhaled beta2-agonists in patients with COPD. DESIGN AND PARTICIPANTS: A total of 246 patients with COPD who were participants in a longitudinal study of COPD (ie, the Hokkaido COPD cohort study) were studied. We compared short-term bronchodilator responses (BDRs) to salbutamol according to ADRB2 genotypes at codons 16 and 27. RESULTS: The presence of the Arg16 allele was associated with lower BDRs to beta2-agonist inhalation. The mean (+/-SD) log (postbronchodilator FEV1-prebronchodilator FEV1) values of Gly16 homozygotes (n=65), Arg16Gly16 heterozygotes (n=106), and Arg16 homozygotes (n=75) were 2.19+/-0.43, 2.09+/-0.42, and 2.01+/-0.42, respectively (p<0.05). The genetic effects of the Arg16Gly polymorphism were independent of the severity of airflow limitation, age, and smoking status. The most common Arg16-Gln27 haplotype was also significantly associated with decreased BDRs to salbutamol (p<0.01). CONCLUSION: The genetic effects of ADRB2 gene polymorphisms may explain some of the variability in response to therapeutic doses of a short-acting beta2-agonists in patients with COPD.