RESUMEN
BACKGROUND: Some patients with idiopathic interstitial pneumonia (IIP) show autoimmune features. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept in these patients. However, retrospective studies reported conflicting results of its prognosis. Therefore, this study was conducted to prospectively evaluate the clinical significance of autoimmune features in patients with IIP. METHODS: This nationwide multicentre study prospectively enrolled consecutive patients with IIP. At the diagnosis, we systematically evaluated 63 features suggestive of connective tissue diseases using a checklist including symptoms/signs and autoantibodies, which contained most items of the IPAF criteria and followed up with the patients. Clinical phenotypes were included in a cluster analysis. RESULTS: In 376 patients with IIP enrolled, 70 patients (18.6%) met the IPAF criteria. The proportion of patients with IPAF was significantly lower in idiopathic pulmonary fibrosis (IPF) than in non-IPF (6.0% vs 24.3%, respectively). During a median observation period of 35 months, patients with IPAF more frequently developed systemic autoimmune diseases and had less frequent acute exacerbation of IIPs than patients with non-IPAF. IPAF diagnosis was significantly associated with better survival and was an independent positive prognostic factor in total and patients with non-IPF. Cluster analysis by similarity of clinical phenotypes identified a cluster in which there was a higher number of women, and patients had more autoimmune features and a better prognosis than other clusters. INTERPRETATION: These observations suggest that some patients with IIP show autoimmune features with distinct characteristics and favourable prognosis. However, we were not able to determine the appropriate therapies for these patients.
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Neumonías Intersticiales Idiopáticas , Enfermedades Pulmonares Intersticiales , Femenino , Humanos , Estudios Prospectivos , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown. METHODS: This 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4â mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide (D LCO) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability. RESULTS: 81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was -300â mL and -123â mL, respectively (difference -178â mL, 95% CI -324--31 mL; p=0.018). Serial change in D LCO, 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups. CONCLUSIONS: Combination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF.
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Acetilcisteína , Fibrosis Pulmonar Idiopática , Acetilcisteína/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Japón , Piridonas/uso terapéutico , Resultado del Tratamiento , Capacidad VitalRESUMEN
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. It has generally been considered a non-Th2-type lung disorder, characterized by progressive airflow limitation with inflammation and emphysema, but its cellular and molecular mechanism remains ill defined, compared with that of asthma characterized by reversible airway obstruction. Here we show a previously unappreciated role for basophils at the initiation phase of emphysema formation in an elastase-induced murine model of COPD in that basophils represent less than 1% of lung-infiltrating cells. Intranasal elastase instillation elicited the recruitment of monocytes to the lung, followed by differentiation into interstitial macrophages (IMs) but rarely alveolar macrophages (AMs). Matrix metalloproteinase-12 (MMP-12) contributing to emphysema formation was highly expressed by IMs rather than AMs, in contrast to the prevailing assumption. Experiments using a series of genetically engineered mice suggested that basophil-derived IL-4, a Th2 cytokine, acted on lung-infiltrating monocytes to promote their differentiation into MMP-12-producing IMs that resulted in the destruction of alveolar walls and led to emphysema development. Indeed, mice deficient for IL-4 only in basophils failed to generate pathogenic MMP-12-producing IMs and hence develop emphysema. Thus, the basophil-derived IL-4/monocyte-derived IM/MMP-12 axis plays a crucial role in emphysema formation and therefore may be a potential target to slow down emphysema progression at the initiation phase of COPD.
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Basófilos/patología , Interleucina-4/metabolismo , Macrófagos Alveolares/patología , Macrófagos/patología , Metaloproteinasa 12 de la Matriz/fisiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/etiología , Animales , Basófilos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Macrófagos/metabolismo , Macrófagos Alveolares/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neutrófilos , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologíaRESUMEN
Multidisciplinary discussion (MDD) requiring close communication between specialists (clinicians, radiologists and pathologists) is the gold standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). However, MDD by specialists is not always feasible because they are often separated by time and location. An online database would facilitate data sharing and MDD. Our aims were to develop a nationwide cloud-based integrated database containing clinical, radiological and pathological data of patients with IIPs along with a web-based MDD system, and to validate the diagnostic utility of web-based MDD in IIPs.Clinical data, high-resolution computed tomography images and lung biopsy slides from patients with IIPs were digitised and uploaded to separate servers to develop a cloud-based integrated database. Web-based MDD was performed using the database and video-conferencing to reach a diagnosis.Clinical, radiological and pathological data of 524 patients in 39 institutions were collected, uploaded and incorporated into the cloud-based integrated database. Subsequently, web-based MDDs with a pulmonologist, radiologist and pathologist using the database and video-conferencing were successfully performed for the 465 cases with adequate data. Overall, the web-based MDD changed the institutional diagnosis in 219 cases (47%). Notably, the MDD diagnosis yielded better prognostic separation among the IIPs than did the institutional diagnosis.This is the first study of developing a nationwide cloud-based integrated database containing clinical, radiological and pathological data for web-based MDD in patients with IIPs. The database and the web-based MDD system that we built made MDD more feasible in practice, potentially increasing accurate diagnosis of IIPs.
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Nube Computacional , Manejo de Datos/organización & administración , Neumonías Intersticiales Idiopáticas/diagnóstico , Comunicación Interdisciplinaria , Anciano , Biopsia , Bases de Datos Factuales , Diagnóstico Diferencial , Femenino , Humanos , Neumonías Intersticiales Idiopáticas/mortalidad , Japón/epidemiología , Masculino , Persona de Mediana Edad , Patólogos , Pautas de la Práctica en Medicina , Neumólogos , Radiólogos , Análisis de Supervivencia , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Periostin is an established biomarker of Th2 immune response and fibrogenesis. Recent research has indicated that periostin plays an important role in the pathogenesis of idiopathic interstitial pneumonias. To clarify the relationship between periostin and pathogenesis in chronic bird-related hypersensitivity pneumonitis (HP) and to reveal the usefulness of serum periostin levels in diagnosing and managing chronic bird-related HP. METHODS: We measured serum periostin in 63 patients with chronic bird-related HP, 13 patients with idiopathic pulmonary fibrosis, and 113 healthy volunteers. We investigated the relationship between serum periostin and clinical parameters, and evaluated if the baseline serum periostin could predict the prognosis. RESULTS: Serum periostin was significantly higher in patients with chronic bird-related HP compared to the healthy volunteers. In chronic bird-related HP, serum periostin had significant positive correlations with serum KL-6 levels, the CD4/CD8 ratio in bronchoalveolar lavage fluid, and fibrosis score on HRCT, and a significant negative correlation with the diffusing capacity of the lungs for carbon monoxide. Chronic bird-related HP patients with serum periostin levels exceeding ≥92.5 ng/mL and ≥89.5 ng/mL had a significantly worse prognosis and significantly higher frequency of acute exacerbation, respectively. Higher serum periostin (92.5 ng/mL or higher; binary response for serum periostin) was an independent prognostic factor in multivariate analysis. CONCLUSIONS: Serum periostin may reflect the extent of lung fibrosis and play an important role in pathogenesis of chronic bird-related HP. Elevated serum periostin could be a predictor of prognosis in patients with chronic bird-related HP.
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Pulmón de Criadores de Aves/sangre , Pulmón de Criadores de Aves/patología , Moléculas de Adhesión Celular/sangre , Anciano , Biomarcadores/sangre , Biomarcadores/metabolismo , Pulmón de Criadores de Aves/inmunología , Pulmón de Criadores de Aves/fisiopatología , Líquido del Lavado Bronquioalveolar/inmunología , Moléculas de Adhesión Celular/metabolismo , Femenino , Humanos , Fibrosis Pulmonar Idiopática/sangre , Estimación de Kaplan-Meier , Pulmón/patología , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Mucina-1/sangre , PronósticoRESUMEN
A man in his 60's with interstitial pneumonitis who was previously admitted to another hospital was transferred to our hospital for further investigations 6 years prior to an acute exacerbation. Given his history of avian contact, the presence of antibodies specific to avian antigen, and a positive result of the inhalation provocation test using pigeon dropping extracts, he was diagnosed with bird-related hypersensitivity pneumonitis (BRHP). As such, we instructed the patient to avoid exposure to avian antigen, and regularly measured the level of avian antigen in dust samples collected from his household environment. Despite avoiding the stimulus, corticosteroids and immunosuppressants were needed in view of progression of dyspnea after approximately five to six years. Four months after immunosuppressant therapy began, the patient suffered an acute exacerbation of BRHP and died. At this time, we found that the level of avian antigen was much higher than baseline. We suggest that exposure to high level of avian antigen is one cause of an acute exacerbation of BRHP.
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Alveolitis Alérgica Extrínseca , Pulmón de Criadores de Aves , Animales , Antígenos , Columbidae , Polvo , Humanos , MasculinoRESUMEN
Fibroblast growth factor receptor 1 (FGFR1) amplification has been identified in 10-20% of patients with squamous non-small-cell lung cancer. Preclinical models showed promising activity of specific FGFR inhibitors, but early clinical trials showed that only a small fraction of patients with FGFR1-amplified lung cancer responded to FGFR inhibitors. These unsatisfactory results were partly explained by heterogeneous amplicons around the 8p11 genomic region, leading to false-positive amplification results. Furthermore, discrepancies in the gene amplification and protein expression of FGFR1 were also reported. In this study, we identified the roles of alternative receptor tyrosine kinases (RTKs) in FGFR1-amplified lung cancer. These alternative RTKs dominantly activate phosphoinositide 3-kinase-AKT signaling and also mitigate sustained inhibition of mitogen-activated protein kinase signaling by FGFR inhibitors. The rebound activation of extracellular signal-regulated kinase phosphorylation was associated with sensitivity to the drugs. Combinatorial inhibition of alternative RTKs and FGFR1 was required to suppress both AKT and extracellular signal-regulated kinase phosphorylation and to induce key pro-apoptotic proteins BIM and p53 upregulated modulator of apoptosis (PUMA). Furthermore, even in FGFR inhibitor-sensitive NCI-H1581 lung cancer cells, MET-expressing clones were already detectable at a very low frequency before resistance induction. Selection of these pre-existing subclones resulted in FGFR inhibitor resistance because of the activation of AKT and extracellular signal-regulated kinase by MET signaling that was mediated by GRB2 associated binding protein 1 (GAB1). These results suggest that incomplete suppression of key survival signals led to intrinsic and acquired resistance to FGFR inhibitors. Our results may help explain the low clinical response rates to FGFR inhibitors in FGFR1-amplified lung cancer.
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Amplificación de Genes/genética , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinasas/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Amplificación de Genes/efectos de los fármacos , Células HCT116 , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: Avian antigen is a common cause of hypersensitivity pneumonitis (HP). Inhalation challenge with pigeon serum and pigeon dropping extract (PDE) elicits a hypersensitivity reaction in patients with bird-related hypersensitivity pneumonitis (BRHP), but the antigenic components in these materials have yet to be fully elucidated. METHOD: Pigeon serum, pigeon intestine homogenates, and PDE were immunoblotted with serum samples from 8 patients with BRHP, 2 patients with summer-type HP, 2 patients with humidifier lung, and 3 healthy volunteers. Among the protein spots found in both pigeon serum and PDE, those that reacted with sera from BRHP patients were identified by mass spectrometry. Immunoassays using recombinant protein were performed to confirm the antigenicity of the identified protein. Cytokine production by peripheral blood mononuclear cells (PBMCs) stimulated with recombinant protein was also assessed. RESULTS: Immunoglobulin lambda-like polypeptide-1 (IGLL-1) was identified from all spots on 2-DE immunoblots of both pigeon serum and PDE. The BRHP patients exhibited higher levels of serum IgG antibody against the recombinant IGLL-1 (rIGLL-1) compared to the control subjects, as well as a stronger PBMCs proliferative response to rIGLL-1. Cytokine production by PBMCs from BRHP patients after rIGLL-1 exposure indicated that the protein could induce Th1 prone immune responses: an increase in TNF-α and an absence of elevated IL-10 production. CONCLUSIONS: Pigeon IGLL-1 was identified as the BRHP antigen present in both pigeon serum and PDE.
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Antígenos/inmunología , Pulmón de Criadores de Aves/inmunología , Columbidae/sangre , Columbidae/inmunología , Heces , Adulto , Anciano , Animales , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND AND OBJECTIVE: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is recognized as an important cause of mortality. AE has also been reported in patients with other interstitial lung diseases such as idiopathic non-specific interstitial pneumonia (NSIP) and interstitial pneumonia associated with collagen vascular disease (CVD). Current therapies such as high-dose corticosteroid with immunosuppressive agents have provided little benefit for AE. Direct hemoperfusion (DHP) with a polymyxin B-immobilized fibre column (PMX) was originally developed for the treatment of endotoxaemia. Recent clinical reports have suggested beneficial effects of PMX-DHP treatment on patients with AE. In this study, we evaluated the effectiveness and safety of PMX-DHP treatment for patients with AE. METHODS: The clinical records of patients with AE admitted to our intensive care unit between 2006 and 2015 were retrospectively reviewed. RESULTS: Of 54 patients with AE identified from clinical records, 24 were treated with PMX-DHP and 30 were treated without PMX-DHP. The peripheral white blood cell count was significantly decreased (P < 0.001) and the PaO2 /FiO2 (P/F) ratio was significantly improved after PMX-DHP (P = 0.032). While no significant difference was found in the survival proportion between patients treated with and without PMX-DHP, the prognosis of patients with dermatomyositis was significantly improved with the treatment (P = 0.045). Among the PMX-DHP-treated patients, those who received the treatment within 3 days of AE onset tended to have a better prognosis (P = 0.026). CONCLUSION: The early induction of PMX-DHP treatment may improve the prognosis of patients with AE, especially those with dermatomyositis.
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Antibacterianos/uso terapéutico , Progresión de la Enfermedad , Hemoperfusión/métodos , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/terapia , Polimixina B/uso terapéutico , Anciano , Terapia Combinada , Femenino , Humanos , Recuento de Leucocitos , Enfermedades Pulmonares Intersticiales/mortalidad , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVE: Lobar and temporal histological variability in chronic bird-related hypersensitivity pneumonitis (BRHP) has not been clearly elucidated. This study was designed to evaluate the spatio-temporal histopathological variability in chronic BRHP. METHODS: Fifty-two patients with chronic BRHP who underwent a surgical lung biopsy (SLB) between 1992 and 2008 were evaluated. The histopathological characteristics of the lung biopsy specimens were classified by the 2002 American Thoracic Society/European Respiratory Society (ATS/ERS) consensus classification of idiopathic interstitial pneumonias (IIPs). Autopsy specimens from seven patients were also evaluated to examine the serial changes from SLB to autopsy. RESULTS: In a study of lobar histological variability based on the findings of SLB, 7 patients were diagnosed with cellular nonspecific interstitial pneumonia (NSIP) pattern, 16 with fibrotic NSIP pattern, 20 with fibrotic NSIP pattern and usual interstitial pneumonia (UIP) (discordant UIP) pattern and 9 with UIP (concordant UIP) pattern. In a study of sequential changes, specimens of SLBs with fibrotic NSIP pattern changed to a bronchiolocentric interstitial pneumonia (BIP) pattern or UIP pattern. CONCLUSION: Interlobar and intralobar histological variability is present in chronic BRHP. In several patients with chronic BRHP, a fibrotic NSIP pattern may be an early lesion that progresses to a UIP pattern.
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Pulmón de Criadores de Aves/patología , Neumonías Intersticiales Idiopáticas/patología , Exposición por Inhalación/efectos adversos , Pulmón/patología , Anciano , Animales , Autopsia , Biopsia , Pulmón de Criadores de Aves/inmunología , Aves , Lavado Broncoalveolar , Femenino , Humanos , Neumonías Intersticiales Idiopáticas/inmunología , Masculino , PronósticoRESUMEN
BACKGROUND: Pulmonary granulomas are sometimes resected because they resemble lung cancer and false-positive findings come through from positron emission tomography (PET) using 18fluorine-fluorodeoxyglucose (18F-FDG). Mycobacterial infection is a common cause of granulomas. OBJECTIVE: The purpose of this study was to evaluate the radiopathological features and the methods for identifying mycobacterial infections in granulomatous nodules resected from the lung. METHODS: Thirty-five solitary lesions resected because of suspected lung cancer were enrolled, including 22 nonfungal granulomatous lesions and 13 benign lesions as controls. The radiological, microbiological, and histological findings were reviewed. To identify mycobacterial infection, immunohistochemical (IHC) staining, IS6110 polymerase chain reaction (PCR), and real-time PCR for the detection of Mycobacterium tuberculosis (TB) were performed using formalin-fixed and paraffin-embedded tissue specimens. The correlations between the radiopathological features and the median maximum standardized uptake value (SUVmax) of 18F-FDG PET were also evaluated. RESULTS: Mycobacteria were isolated from the cultures of 10 of the granulomatous lesions, including TB from 2 and Mycobacterium avium complex from 8. The mean size of the nodules in the culture-positive group was significantly larger than that of those in the culture-negative group (30.5 ± 13.1 vs. 15.1 ± 6.3 mm, p = 0.003). IHC stainings were positive in 15 granulomas. Eight granulomas were positive in IS6110 PCR, and 7 of them were also positive in real-time PCR. SUVmax was ≥2.5 in all of the PCR-positive granulomas. CONCLUSION: The most frequent cause of granulomatous lesions was mycobacterial infection. It seemed that the culture result was associated with nodule size and that the results of IS6110 were associated with 18F-FDG-uptake.
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Granuloma/microbiología , Infecciones por Mycobacterium/diagnóstico , Nódulo Pulmonar Solitario/microbiología , Anciano , Femenino , Granuloma/diagnóstico por imagen , Granuloma/patología , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium/diagnóstico por imagen , Infecciones por Mycobacterium/patología , Infecciones del Sistema Respiratorio/diagnóstico por imagen , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/patología , Nódulo Pulmonar Solitario/diagnóstico por imagen , Nódulo Pulmonar Solitario/patologíaRESUMEN
Developmental processes of hematopoietic cells are orchestrated by transcriptional networks. GATA-1, the founding member of the GATA family of transcription factors, has been demonstrated to play crucial roles in the differentiation of erythroid cells, magakaryocytes, eosinophils, and mast cells. However, the role of GATA-1 in basophils remains elusive. Here we show that basophils abundantly express Gata1 mRNAs, and that siRNA-mediated knockdown of Gata1 resulted in impaired production of IL-4 by basophils in response to the stimulation with IgE plus antigens. ΔdblGATA mice that carry the mutated Gata1 promoter and are widely used for functional analysis of eosinophils owing to their selective loss of eosinophils showed a decreased number of basophils with reduced expression of Gata1 mRNAs. The number of basophil progenitors in bone marrow was reduced in these mice, and the generation of basophils from their bone marrow cells in culture with IL-3 or thymic stromal lymphopoietin was impaired. ΔdblGATA basophils responded poorly ex vivo to stimulation with IgE plus antigens compared with wild-type basophils as assessed by degranulation and production of IL-4 and IL-6. Moreover, ΔdblGATA mice showed impaired responses in basophil-mediated protective immunity against intestinal helminth infection. Thus, ΔdblGATA mice showed numerical and functional aberrancy in basophils in addition to the known deficiency of eosinophils. Our findings demonstrate that GATA-1 plays a key role in the generation and function of basophils and underscore the need for careful distinction of the cell lineage responsible for each phenotype observed in ΔdblGATA mice.
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Basófilos/inmunología , Diferenciación Celular/inmunología , Factor de Transcripción GATA1/metabolismo , Células Madre Hematopoyéticas/inmunología , Animales , Basófilos/metabolismo , Cartilla de ADN/genética , Citometría de Flujo , Factor de Transcripción GATA1/genética , Técnicas de Silenciamiento del Gen , Células Madre Hematopoyéticas/citología , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) occurs in 10%-30% of patients with RA, and interstitial lung disease (ILD) is associated with increased mortality in up to 10% of patients with RA. The pathogenesis of RA-ILD is virtually unknown. The aim of this study is to investigate the proteins related to UIP pattern by comparing to OP pattern in RA-ILD using proteome analysis of bronchoalveolar lavage fluid (BALF). METHODS: Proteomic differences in BALF were compared between the UIP pattern and OP pattern by examining BALF from 5 patients with the UIP pattern and 7 patients with the OP pattern by two-dimensional gel electrophoresis and mass spectrometry. RESULTS: In individual comparisons of BALF samples, the levels of the protein gelsolin and Ig kappa chain C region were significantly higher in the UIP pattern than in the OP pattern. In contrast, the levels of α-1 antitrypsin, CRP, haptoglobin ß, and surfactant protein A (isoform number 5) were all significantly higher in the OP pattern than in the UIP pattern. Gelsolin was cleaved into two fragments, a C-terminal half and N-terminal half, and the levels of both were significantly higher in the UIP pattern than in the OP pattern. CONCLUSIONS: Fragmented gelsolins may be associated with the pathogenesis of fibrosis in RA-ILD.
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Artritis Reumatoide/complicaciones , Gelsolina/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/metabolismo , Anciano , Secuencia de Aminoácidos , Líquido del Lavado Bronquioalveolar/química , Femenino , Gelsolina/química , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico , Enfermedades Pulmonares Intersticiales/diagnóstico , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteoma , Proteómica/métodosRESUMEN
BACKGROUND: Mycobacterium avium complex (MAC) pulmonary disease (PD) is often difficult and complicated to diagnose or to discriminate from follicular bronchitis, bronchiectasis, or other conditions associated with rheumatoid arthritis (RA) lung in the clinical setting. OBJECTIVE: We investigated whether a serologic test for anti-glycopeptidolipid (GPL) antibody was useful for distinguishing MAC-PD from RA lung in diagnosis. METHODS: Serum IgA antibody to MAC-specific GPL core antigen was measured by an enzyme immunoassay. Antibody levels were measured in sera from 14 RA patients with MAC-PD (RA + MAC), 20 RA patients with bronchial or bronchiolar lesions without MAC-PD (RA w/o MAC), 20 RA patients without pulmonary lesions (RA only), and 25 healthy volunteers (HV). RESULTS: The levels of serum anti-GPL antibodies were higher in the RA + MAC group than in the RA w/o MAC, RA-only, and HV groups (2.87 ± 2.83 vs. 0.50 ± 0.45, 0.31 ± 0.24, and 0.38 ± 0.10 U/ml, respectively; p < 0.001). With the cutoff point in receiver-operating characteristic analysis set at 0.7 U/ml, the serologic test differentiated RA + MAC from RA w/o MAC with a sensitivity of 100% and specificity of 90%. CONCLUSIONS: This serologic test for anti-GPL antibody is useful for diagnosing MAC-PD in RA.
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Artritis Reumatoide/diagnóstico , Enfermedades Pulmonares/diagnóstico , Infección por Mycobacterium avium-intracellulare/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Pruebas SerológicasRESUMEN
An 85-year-old man with dementia first visited our hospital 5 years ago, complaining of hemoptysis. He was hospitalized 2 years later owing to fever, cough, and dyspnea. A chest computed tomography scan showed infiltration with a cavity in the left upper lobe. He was diagnosed with nontuberculous mycobacterial lung infection on the basis of the presence of acid-fast bacilli in the sputum and repeated bronchoalveolar lavage specimens; however, we were unable to identify the isolate by DNA-DNA hybridization. Although his general condition had slightly improved after treatment initiation, intermittent chemotherapy owing to the adverse effects of the drugs and dementia led to rapid disease progression and death. After his death, the isolated mycobacterium was identified as Mycobacterium kyorinense by sequence analysis of the hsp 65 and rpoB genes.
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Enfermedades Pulmonares/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Anciano de 80 o más Años , Resultado Fatal , Estudios de Seguimiento , Humanos , MasculinoRESUMEN
PURPOSE: The purpose of this study was to identify prognostic genes by integrated microarray analysis between comparative genomic hybridization and gene expression with laser microdissection in non-small cell lung cancer (NSCLC). METHODS: Integrated microarray analysis in 11 lung adenocarcinomas was performed, and several genes were identified. Among them, neural precursor cell-expressed developmentally down-regulated 4-like (NEDD4L) was chosen for further characterization. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to explore the clinicopathological significance of NEDD4L expression in 84 NSCLC patients. RESULTS: 18q was more frequently lost in advanced lung cancer. Therefore, we selected the NEDD4L gene, located on chromosome 18q, for which reduced expression was significantly correlated with copy number loss. NEDD4L mRNA expression in paired tumor/normal samples from 79 cases of lung cancer was evaluated using real-time PCR analysis. NEDD4L mRNA expression was significantly lower in tumor tissues than in normal lung tissues (p < 0.0001). Clinicopathological factors, such as excessive smoking history, histological grade (moderately and poorly), T stage (T2-4), lymph node metastasis, and pathological stage (stage II-IV), were significantly associated with low NEDD4L expression (p < 0.05). In the low expression group, prognoses were significantly poorer than in the high expression group (p < 0.05). CONCLUSIONS: Low NEDD4L expression may be a marker of prognosis. This is the first report to describe NEDD4L expression in NSCLC. NEDD4L may be considered a key gene in the progression of NSCLC, and its expression is likely affected by genomic alterations.
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Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Dosificación de Gen/genética , Neoplasias Pulmonares/genética , Ubiquitina-Proteína Ligasas/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/secundario , Estudios de Casos y Controles , Hibridación Genómica Comparativa , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Captura por Microdisección con Láser , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Ubiquitina-Proteína Ligasas Nedd4 , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de SupervivenciaRESUMEN
BACKGROUND: Recent research has suggested that the Th1 and Th2 chemokine/cytokine axis contributes to the development of chronic hypersensitivity pneumonitis (HP). Acute exacerbations (AE) are significant factors in the prognosis of chronic HP. Little is known, however, about these biomarkers in association with AE in chronic HP patients. METHODS: Fifty-six patients with chronic HP were evaluated, including 14 patients during episodes of AE. Th1 mediators (C-X-C chemokine ligand [CXCL]10 and interferon [IFN]-γ), Th2 mediators (C-C chemokine ligand [CCL]17, interleukin-4, and interleukin-13), and pro-fibrotic mediator (transforming growth factor [TGF]-ß) were measured to evaluate the mediators as predictors of AE. C-C chemokine receptor (CCR)4 (receptor for CCL17)-positive lymphocytes were quantified in lung specimens. RESULTS: Serum CCL17 levels at baseline independently predicted the first episode of AE (HR, 72.0; 95% CI, 5.03-1030.23; p = 0.002). AE was significantly more frequent in the higher-CCL17 group (≥285 pg/ml) than in the lower-CCL17 group (<285 pg/ml) (log-rank test, p = 0.0006; 1-year incidence: higher CCL17 vs. lower CCL17, 14.3% vs. 0.0%). Serum CCL17 levels and CCR4-positive cells during episodes of AE were increased from the baseline (p = 0.01 and 0.031). CONCLUSIONS: Higher serum concentrations of CCL17 at baseline may be predictive of AE in patients with chronic HP, and CCL17 may contribute to the pathology of AE by inducing the accumulation of CCR4-positive lymphocytes in the lungs.
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Alveolitis Alérgica Extrínseca/sangre , Biomarcadores/sangre , Quimiocina CCL17/sangre , Adulto , Anciano , Anciano de 80 o más Años , Alveolitis Alérgica Extrínseca/diagnóstico , Alveolitis Alérgica Extrínseca/patología , Líquido del Lavado Bronquioalveolar , Recuento de Células , Enfermedad Crónica , Citocinas/sangre , Femenino , Humanos , Pulmón/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Receptores CCR4/biosíntesis , Balance Th1 - Th2RESUMEN
BACKGROUND: The purpose of this study was to evaluate the feasibility and compliance of adjuvant chemotherapy of S-1 plus carboplatin for patients with completely resected non-small cell lung cancer (NSCLC) of pathological stage IB-IIIB. METHODS: S-1 was given orally at a dose of 80 mg/m²/day for 2 weeks, followed by a 2-week period of no treatment. Carboplatin was given intravenously on day 8 at an area under the curve of 6. This regimen was repeated for four to six 28-day courses. RESULTS: Seventeen patients were enrolled in this study. Fourteen of them completed at least 4 cycles of chemotherapy. Nine patients had grade 2 and three patients had grade 3 thrombocytopenia, respectively. Severe nonhematologic toxicities were uncommon. Treatment was delayed in a few patients because of prolonged thrombocytopenia. CONCLUSION: We concluded that the regimen was feasible and tolerable for patients with completely resected NSCLC as adjuvant chemotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Ácido Oxónico/uso terapéutico , Tegafur/uso terapéutico , Anciano , Antineoplásicos/efectos adversos , Área Bajo la Curva , Carboplatino/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioterapia Adyuvante , Combinación de Medicamentos , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Ácido Oxónico/efectos adversos , Curva ROC , Tegafur/efectos adversos , Trombocitopenia/etiología , Resultado del TratamientoRESUMEN
BACKGROUND: Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease induced by the inhalation of a variety of antigens. Patients with chronic HP often have a family history of pulmonary fibrosis. This strongly suggests that both genetic and environmental factors play an important role in the pathogenesis of chronic HP. OBJECTIVES: We aimed to investigate the epidemiology and clinical features of chronic HP patients with a family history of pulmonary fibrosis. METHODS: We retrospectively reviewed the clinical information of 114 cases diagnosed with chronic HP with insidious onset between 1992 and 2009. RESULTS: Twenty cases (17.5%) were identified as having a family history of pulmonary fibrosis. All of these patients had lived apart from their afflicted relatives for at least several decades. The familial cases were younger than the nonfamilial cases at onset (57.5 ± 9.6 vs. 64.0 ± 7.0 years old, p = 0.008). The predicted vital capacity percentage and partial pressure of oxygen in arterial blood gas were significantly higher in the familial cases. There were no differences between the 2 groups in gender, smoking history, bronchoalveolar lavage fluid profile, radiologic findings or other clinical features. CONCLUSIONS: We found a familial clustering in patients with chronic HP. Various factors including genetic susceptibility to pulmonary fibrosis and environmental factors may contribute to the development of familial chronic HP.