RESUMEN
Zoledronic acid is an established agent used in the management of metastatic bone disease. The administration of zoledronic acid improves overall survival (OS) of lung cancer patients with bone metastases receiving chemotherapy. However, it is currently unknown whether zoledronic acid-induced fever is associated with OS. The purpose of this study was to examine the association between zoledronic acid-induced fever and prognosis in lung cancer patients with bone metastases. We retrospectively analyzed 98 lung cancer patients with bone metastases who had received zoledronic acid. The end point outcome measure was OS. Multivariate analyses were used to estimate the hazard ratio (HR) for OS due to fever after adjusting for covariates. In multivariate analysis, white blood cell (WBC) count, lactate dehydrogenase (LDH) level, fever, chemotherapy, and hypercalcemia were independent prognostic factors, with HRs of 2.834 for WBC count (<10 × 103/µL vs. ≥10 × 103/µL, p < 0.001), 3.044 for LDH level (<250 vs. ≥250 IU/L, p < 0.001), 0.603 for fever (<37.0 vs. ≥37.0°C, p = 0.039), 0.481 for chemotherapy (chemotherapy not administered vs. administered, p = 0.006), and 2.453 for hypercalcemia (<11.0 vs. ≥11.0 mg/dL, p = 0.001). Zoledronic acid-induced fever was the most important prognostic factor in this cohort of lung cancer patients with bone metastases.
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Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias Óseas/secundario , Difosfonatos/uso terapéutico , Imidazoles/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/patología , Esquema de Medicación , Femenino , Fiebre/complicaciones , Humanos , Estimación de Kaplan-Meier , L-Lactato Deshidrogenasa/metabolismo , Leucocitos/citología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Neutropenia/complicaciones , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Ácido ZoledrónicoRESUMEN
BACKGROUND: Long-acting ß2-agonists (LABA) and leukotriene receptor antagonists (LTRA) are two principal agents that can be added to inhaled corticosteroids (ICS) for patients with asthma that is not adequately controlled by ICS alone. In our previous study, the Gly16Arg genotype of the ß2-adrenergic receptor (ADRB2) gene did not influence the differential bronchodilator effect of salmeterol versus montelukast as an add-on therapy to ICS within 16 weeks of follow-up (the J-Blossom study). METHODS: We examined if genes encoding CYSLTR1, CYSLTR2, PTGER2 or PTGER4 could explain differential responses to salmeterol versus montelukast using the participants of the J-Blossom study. This study included 76 patients with mild-to-moderate asthma. The difference in peak expiratory flow (PEF) (ΔPEF, l/min) after 16 weeks of treatment with salmeterol (ΔPEFsal) versus montelukast (ΔPEFmon) was associated with the genotypes at each of 4 genes. In addition, multivariate analyses were used to identify a gene-gene interaction between ADRB2 gene and each of these 4 genes. RESULTS: Although none of 4 genes were associated with ΔPEFsal-ΔPEFmon in the univariate analyses, multivariate analysis showed that PTGER4 gene, interacting with ADRB2 Gly16Arg, was associated with ΔPEFsal-ΔPEFmon (p=0.0032). CONCLUSION: Our findings suggested that the interactions between two genetic loci at ADRB2 and PTGER4 is important in determining the differential response to salmeterol versus montelukast in patients with chronic adult asthma.
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Acetatos/uso terapéutico , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/genética , Quinolinas/uso terapéutico , Receptores Adrenérgicos beta 2/genética , Subtipo EP4 de Receptores de Prostaglandina E/genética , Xinafoato de Salmeterol/uso terapéutico , Ciclopropanos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , SulfurosRESUMEN
BACKGROUND: MicroRNAs are non-coding small RNAs that regulate expression of target genes by binding to 3' untranslated regions. In this study, we used bronchial epithelial cells to investigate in vitro the role of the microRNA miR-155 in the expression of chemokines associated with airway inflammation. miR-155 has previously been reported to regulate allergic inflammation. METHODS: BEAS-2B bronchial epithelial cells were cultured and transfected with mimic or inhibitor oligonucleotides to overexpress or downregulate miR-155, as confirmed by real-time PCR. Cells were then stimulated with tumor necrosis factor-alpha, interleukin-13 (IL-13), and a double stranded RNA that binds Toll-like receptor 3. Expression and secretion of the chemokines CCL5, CCL11, CCL26, CXCL8, and CXCL10 were then quantified by real-time PCR and ELISA, respectively. Phosphorylation of signal transducer and activator of transcription 6 (STAT6), a target of the IL-13 receptor, was analyzed by ELISA. RESULTS: miR-155 overexpression significantly suppressed IL-13-induced secretion of CCL11 and CCL26. These effects were specific, and were not observed for other chemokines, nor in cells with downregulated miR-155. miR-155 overexpression also suppressed CCL11 and CCL26 mRNA, but did not affect expression of the IL-13 receptor or phosphorylation of STAT6. CONCLUSIONS: miR-155 specifically inhibits IL-13-induced expression of eosinophilic chemokines CCL11 and CCL26 in bronchial epithelial cells, even though the 3'-untranslated region of these genes do not contain a consensus binding site for miR-155.
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Quimiocinas/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-13/farmacología , MicroARNs/genética , Bronquios , Línea Celular , Quimiocinas/metabolismo , Humanos , Fosforilación , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Mucosa Respiratoria/metabolismo , Factor de Transcripción STAT6/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
AIM: To elucidate the characteristics of patients with asthma who have specific IgE responses to inhaled allergens detected by ImmunoCAP, which is not detectable by MAST-26. METHODS: A total of 168 patients with adult asthma who reside in the Kanto region were recruited. Levels of total serum IgE and allergen specific IgE antibodies towards 14 common inhaled allergens (MAST-26) were measured. Among these samples, 48 patients with no detectable allergen-specific IgE (group A) and 44 patients with strong sensitization to Dermatophagoides farinae (group B) were selected for further assessment of their sensitization to inhaled allergens such as cockroach and moth using ImmunoCAP. RESULTS: In group A, ImmunoCAP detected specific IgE responses to some inhaled allergens in 27.1% of the patients. The strongest predictive factor for the presence of allergen-specific IgE responses detected by ImmunoCAP was elevated levels of total serum IgE (p=0.0007). In group B, the presence of IgE responses specific to cockroach or moth by ImmunoCAP were found in 27.8% or 52.3% of the patients, respectively. The predictive factor for the presence of these positive IgE responses was also elevated levels of total serum IgE (p=0.0003). CONCLUSION: Asthma patients with no detectable specific IgE responses to any inhaled allergens by MAST-26 may be still sensitized to common inhaled allergens, including cockroach and moth. Thus, the presence of allergen-specific IgE responses may be re-assessed by ImmunoCAP in patients with asthma, especially when patients have higher levels of total serum IgE.
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Alérgenos/inmunología , Asma/inmunología , Epítopos/inmunología , Fluoroinmunoensayo/métodos , Técnicas para Inmunoenzimas/métodos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Mediciones Luminiscentes/métodos , Adulto , Anciano , Anciano de 80 o más Años , Animales , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pyroglyphidae/inmunología , Juego de Reactivos para Diagnóstico , Adulto JovenRESUMEN
OBJECTIVE: Interleukin (IL)-32 is a novel cytokine and is involved in the pathogenesis of various inflammatory diseases, including asthma and COPD. However, the regulatory mechanisms of IL-32 expression and its precise pathogenic role remain to be defined. Given that viral infections are known to potentially cause and exacerbate airway inflammation, in this study, we investigated the expression of IL-32 induced by synthetic double-stranded (ds) RNA, and its signaling mechanisms involved. METHODS: Bronchial epithelial cells were stimulated with synthetic dsRNA poly I:C. The levels of IL-32 expression were analyzed using real-time PCR and ELISA. The involvement of transforming growth factor ß-activated kinase 1 (TAK1) and a subunit of nuclear factor-κB (NF-κB), p65 was determined by western blot analyses. TAK1 inhibitor, 5Z-7-Oxozeaenol and NF-κB inhibitor, BAY 11-7082 were added to the culture to identify key signaling events leading to the expression of IL-32. Finally, the effect of short interfering RNAs (siRNAs) targeting TAK1 and p65 was investigated. RESULTS: dsRNA significantly induced IL-32 gene and protein expression, concomitant with activation of TAK1 and p65. Pretreatment of 5Z-7-Oxozeaenol diminished dsRNA-induced phosphorylation of NF-κB. Both 5Z-7-Oxozeaenol and BAY 11-7082 significantly abrogated dsRNA-induced IL-32 production. Moreover, transfection of the cells with siRNAs targeting TAK1 and p65 inhibited the expression of IL-32. CONCLUSIONS: The expression of IL-32 is induced by dsRNA via the TAK1-NF-κB signaling pathway in bronchial epithelial cells. IL-32 is involved in the pathogenesis of airway inflammation, and may be a novel therapeutic target for airway inflammatory diseases.
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Bronquios/metabolismo , Células Epiteliales/metabolismo , Interleucinas/metabolismo , ARN Bicatenario/metabolismo , Bronquios/efectos de los fármacos , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Humanos , Proteínas I-kappa B/metabolismo , Lactonas/farmacología , Quinasas Quinasa Quinasa PAM/metabolismo , FN-kappa B/metabolismo , Nitrilos/farmacología , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Neumonía/metabolismo , Resorcinoles/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Sulfonas/farmacología , Factor de Transcripción ReIA/metabolismoRESUMEN
The expression of IL-17F is seen in the airway of asthmatics and its level is correlated with disease severity. Several studies have demonstrated that IL-17F plays a pivotal role in allergic airway inflammation and induces several asthma-related molecules such as CCL20. IL-17F-induced CCL20 may attract Th17 cells into the airway resulting in the recruitment of additional Th17 cells to enhance allergic airway inflammation. We have recently identified, for the first time, that bronchial epithelial cells are its novel cell source in response to IL-33 via ST2-ERK1/2-MSK1 signaling pathway. The receptor for IL-17F is the heterodimeric complex of IL-17RA and IL-17RC, and IL-17F activates many signaling pathways. In a case-control study of 867 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL-17F gene was associated with asthma. In atopic patients with asthma, prebronchodilator baseline FEV1/FVC values showed a significant association with the H161R variant. Moreover, this variant is a natural antagonist for the wild-type IL-17F. Moreover, IL-17F is involved in airway remodeling and steroid resistance. Hence, IL-17F may play an orchestrating role in the pathogenesis of asthma and may provide a valuable therapeutic target for development of novel strategies.
Asunto(s)
Asma/etiología , Interleucina-17/genética , Interleucina-17/metabolismo , Remodelación de las Vías Aéreas (Respiratorias) , Animales , Asma/tratamiento farmacológico , Asma/metabolismo , Asma/patología , Resistencia a Medicamentos , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Interleucina-17/química , Neutrófilos/inmunología , Neutrófilos/metabolismo , Receptores de Interleucina-17/metabolismo , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Transducción de Señal , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
Pneumonia is a leading cause of death among elderly patients. Although aspiration pneumonia (AP) commonly occurs with aging, its clinical features and outcomes are still uncertain. The aims of this study were to describe the clinical features and outcomes of AP and to assess whether presence of AP affects clinical outcomes in patients with community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP). We retrospectively analyzed patients with CAP and HCAP hospitalized in our institution in Japan from October 2010 to March 2012. We compared clinical features and outcomes between AP and non-AP, and investigated risk factors for recurrence of pneumonia and death. Of 214 consecutive patients, 100 (46.7%) were diagnosed as having aspiration pneumonia. These patients were older and had lower body mass index, more comorbidities, and poorer Eastern Cooperative Oncology Group performance status (ECOG PS) than the patients with non-AP. Patients with AP had more severe disease, required longer hospital stays, and had a frequent recurrence rate of pneumonia and higher mortality. In multivariate analyses, AP, age, and ECOG PS were related to recurrence of pneumonia, and the prognostic factors were CURB-65 score and ECOG PS. AP was not a significant indicator for prognosis but was the strongest risk factor for recurrence of pneumonia. Clinical background and outcomes including recurrence and mortality of AP were obviously different from those of non-AP; therefore AP should be considered as a distinct subtype of pneumonia, and it is important to prevent the recurrence of pneumonia in the patients with AP.
Asunto(s)
Infecciones Comunitarias Adquiridas/patología , Infección Hospitalaria/patología , Neumonía por Aspiración/patología , Neumonía/patología , Factores de Edad , Anciano , Anciano de 80 o más Años , Infecciones Comunitarias Adquiridas/mortalidad , Comorbilidad , Infección Hospitalaria/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Japón/epidemiología , Masculino , Neumonía/mortalidad , Neumonía por Aspiración/mortalidad , Pronóstico , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Long-acting ß2-agonists and leukotriene receptor antagonists are two principal agents that can be added to inhaled corticosteroids (ICS) for patients with asthma that is not adequately controlled by ICS alone. The Gly16Arg genotype of the ß2-adrenergic receptor (ADRB2) gene may influence the bronchodilator effects of ß2-agonists. We hypothesized that differential responses to long-acting ß2-agonists or leukotriene receptor antagonists might be determined partly by the Gly16Arg polymorphism in Japanese asthma patients. MATERIALS AND METHODS: This randomized, genotype-stratified, two-period crossover study included 80 patients with mild-to-moderate asthma (35 Arg/Arg and 45 Gly/Gly individuals). The primary study outcome was the difference in peak expiratory flow (ΔPEF) (ΔPEF, l/min) by genotype after 16 weeks of treatment with salmeterol (ΔPEFsal) or montelukast (ΔPEFmon). In addition, multivariate analyses were used to identify independent factors that were predictive of responses to each treatment. RESULTS: The mean ΔPEFsal-ΔPEFmon was 19.3±46.6 among Arg/Arg individuals and 16.8±51.5 among Gly/Gly individuals, indicating that the Gly16Arg genotype did not influence the differential bronchodilator effect of the two agents. Multivariate analysis showed that higher peripheral eosinophil counts were associated with better response to salmeterol (P<0.05). CONCLUSION: The Gly16Arg genotype did not influence the differential bronchodilator effect of salmeterol or montelukast as an add-on therapy to ICS within 16 weeks of follow-up. Higher peripheral eosinophil counts may be associated with better responses to salmeterol in combination with ICS.
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Acetatos/administración & dosificación , Albuterol/análogos & derivados , Asma/genética , Quinolinas/administración & dosificación , Receptores Adrenérgicos beta 2/genética , Administración por Inhalación , Corticoesteroides/administración & dosificación , Adulto , Albuterol/administración & dosificación , Asma/tratamiento farmacológico , Asma/patología , Ciclopropanos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Xinafoato de Salmeterol , SulfurosRESUMEN
The purpose of the present study was to report cases of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-naïve patients carrying a mutation associated with acquired resistance to the drug. Gene alterations in 77 lung carcinoma patients were analyzed by collecting and studying curette lavage fluid at the time of diagnosis. PCRs were performed to amplify mutation hotspot regions in EGFR genes. The PCR products were direct-sequenced and the mutations confirmed by resequencing using different primers. Case 1 was a 78-year-old Japanese male diagnosed with stage IB lung adenocarcinoma who was found to have two EGFR mutations, G719S and L747S. Case 2 was a 73-year-old Japanese male diagnosed with stage IV squamous cell lung carcinoma and bone metastasis who had the EGFR mutation, L747S. Case 3 was an 82-year-old Japanese male diagnosed with hyponatremia due to inappropriate secretion of antidiuretic hormone and stage IIIB small cell lung carcinoma (SCLC) who had the EGFR mutation, L747S. Thus, the EGFR mutation L747S associated with acquired EGFR-TKI resistance was detected in two non-small cell lung carcinoma (NSCLC) patients and one SCLC patient, none of whom had ever received EGFR-TKI. The patients were current smokers with stages at diagnosis ranging from IB to IV, and their initial tumors contained resistant clones carrying L747S. L747S may be associated with primary resistance. To the best of our knowledge, this study is the first report of an EGFR mutation associated with resistance to EGFR-TKI in SCLC patients. The early detection of EGFR-TKI resistance mutations may be beneficial in making treatment decisions for lung carcinoma patients, including those with SCLC.
RESUMEN
BACKGROUND: Viral infection can exacerbate asthma by inducing the accumulation of inflammatory cells in the airway. We have previously reported that double-stranded RNA (dsRNA), a viral product and ligand of the Toll-like receptor-3 (TLR3), activates the transcription factors NF-κB and IRF-3 and upregulates the expression of inflammatory chemokines in airway epithelial cells. Here, we examined the effects of the glucocorticoid fluticasone propionate (FP) on the expression of the inflammatory chemokines CCL5, CXCL8 and CXCL10. METHODS: The airway epithelial cell line BEAS-2B was used for this study. Expression of CCL5, CXCL8 and CXCL10 mRNA and protein was quantified by real-time PCR and ELISA assay, respectively. To examine the association of FP with the physiology of chemokine production, we included several methods. Nuclear translocation of transcription factors was determined by performing Western blot analysis. Histone deacetylase (HDAC) activity in nuclear extracts was measured using a colorimetric assay. Stability of the chemokine mRNAs was examined in cells incubated with actinomycin D. The activities of the CCL5 promoter and the transcription factors NF-κB and IRF-3 were assessed using luciferase reporter assays. RESULTS: Treatment of BEAS-2B cells with FP significantly and dose-dependently (10(-9) to 10(-6)M) inhibited dsRNA-induced expression of CCL5, CXCL8 and CXCL10 protein and mRNA, but did not affect mRNA stability. FP also significantly inhibited dsRNA-stimulated CCL5 promoter activity. However, FP had no effect on the activity of HDAC or the nuclear translocation of NF-κB and IRF-3. CONCLUSIONS: FP inhibits the dsRNA-stimulated expression of inflammatory chemokines in airway epithelial cells. FP may act by inhibiting chemokine transcription through an as yet unidentified mechanism.
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Androstadienos/farmacología , Antialérgicos/farmacología , Asma/genética , Quimiocinas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Mediadores de Inflamación , Asma/metabolismo , Asma/virología , Línea Celular , Núcleo Celular/metabolismo , Quimiocina CCL5/genética , Quimiocinas/biosíntesis , Fluticasona , Histona Acetiltransferasas/metabolismo , Humanos , Poli I-C/farmacología , Regiones Promotoras Genéticas , Transporte de Proteínas/efectos de los fármacos , Estabilidad del ARN/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción/metabolismo , Activación Transcripcional/efectos de los fármacosRESUMEN
Histopathological samples are commonly used for molecular testing to detect both oncogenes and tumor-suppressor genes in lung cancer. The purpose of this study was to determine the efficacy of using curette lavage fluid for molecular testing to detect EGFR, KRAS and P53 mutations in lung cancer patients. Samples were obtained from 77 lung cancer patients by bronchoscopy at the time of diagnosis, collected by scraping the site of the primary tumor lesion with a curette. DNA was extracted from cells in the curette lavage fluid, and PCRs were performed to amplify mutation hot spot regions in the EGFR, KRAS and P53 genes. The PCR products were direct-sequenced to detect mutations of each gene. The reference sequence of each gene was obtained from GenBank. Overall, 27% (21 of 77) were found with EGFR mutations, 1% (1 of 77) with KRAS mutations, and 36% (28 of 77) with P53 mutations. KRAS mutations were not detected in patients harboring mutations in either EGFR or P53. P53 mutations were identified in 38% (8 of 21) of the patients with EGFR mutations, all of who had advanced lung cancer. Of these patients, a 62-year-old female current smoker was given EGFR-TKI as third-line therapy, with no improvement in clinical symptoms or results of radiographic examination. Multivariate analysis indicated that P53 mutation rates in advanced-stage lung cancer were significantly higher than those in early-stage lung cancer (P=.017). In contrast, EGFR mutation rates were not significantly associated with staging. L747S in EGFR, described as a mutation associated with secondary resistance to EGFR-TKI, was detected in three patients who had never received EGFR-TKI, including one SCLC patient. It is possible to analyze EGFR, KRAS and P53 mutations using curette lavage fluid collected from lung cancer patients. This is useful when sufficient amounts of tumor samples cannot be obtained. Data from the current study suggest that EGFR mutations in concert with P53 mutations accelerate cancer development and lead to evolution of therapeutic resistance.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas/genética , Proteína p53 Supresora de Tumor/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Líquido del Lavado Bronquioalveolar , Broncoscopía , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Legrado , Análisis Mutacional de ADN , Resistencia a Antineoplásicos , Femenino , Humanos , Modelos Logísticos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación Missense , Proteínas Proto-Oncogénicas p21(ras) , Eliminación de SecuenciaRESUMEN
A 74-year-old Japanese man with myelodysplastic syndrome (MDS) received chemotherapy with azacitidine. From the second day after starting the administration, he complained of fever, cough and shortness of breath. Chest roentgenography and computed tomography showed consolidations and ground-glass opacities. His symptoms grew from worse to life-threatening. We diagnosed him with azacitidine-induced pneumonitis and began administering corticosteroids. Thereafter, his symptoms and radiographic abnormalities improved. Azacitidine is a hypomethylating agent that improves the survival of MDS patients. Although this drug is commonly well tolerated and rarely causes severe lung injury, it is important to consider the potentially serious adverse effects of azacitidine-induced pneumonitis.
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Azacitidina/efectos adversos , Azacitidina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Neumonía/inducido químicamente , Corticoesteroides/uso terapéutico , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Humanos , Japón , Masculino , Neumonía/diagnóstico , Neumonía/tratamiento farmacológico , Resultado del TratamientoRESUMEN
In recent years, many novel nontuberculous mycobacterial species have been discovered through genetic analysis. Mycobacterium massiliense and M. bolletii have recently been identified as species separate from M. abscessus. However, little is known regarding their clinical and microbiological differences in Japan. We performed a molecular identification of stored M. abscessus clinical isolates for further identification. We compared clinical characteristics, radiological findings, microbiological findings, and treatment outcomes among patients with M. abscessus and M. massiliense lung diseases. An analysis of 102 previous isolates of M. abscessus identified 72 (71%) M. abscessus, 27 (26%) M. massiliense, and 3 (3%) M. bolletii isolates. Clinical and radiological findings were indistinguishable between the M. abscessus and M. massiliense groups. Forty-two (58%) patients with M. abscessus and 20 (74%) patients with M. massiliense infections received antimicrobial treatment. Both the M. abscessus and M. massiliense groups showed a high level of resistance to all antimicrobials, except for clarithromycin, kanamycin, and amikacin. However, resistance to clarithromycin was more frequently observed in the M. abscessus than in the M. massiliense group (16% and 4%, respectively; P = 0.145). Moreover, the level of resistance to imipenem was significantly lower in M. abscessus isolates than in M. massiliense isolates (19% and 48%, respectively; P = 0.007). The proportions of radiological improvement, sputum smear conversion to negativity, and negative culture conversion during the follow-up period were higher in patients with M. massiliense infections than in those with M. abscessus infections. Patients with M. massiliense infections responded more favorably to antimicrobial therapy than those with M. abscessus infections.
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Infecciones por Mycobacterium/microbiología , Infecciones por Mycobacterium/patología , Mycobacterium/aislamiento & purificación , Mycobacterium/patogenicidad , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/patología , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Femenino , Humanos , Japón , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mycobacterium/clasificación , Infecciones por Mycobacterium/tratamiento farmacológico , Neumonía Bacteriana/tratamiento farmacológico , Radiografía , Esputo/microbiología , Resultado del TratamientoRESUMEN
We investigated the potential role of IL-17A in the induction of granulocyte colony-stimulating factor (G-CSF), a critical granulopoietic growth factor, in human renal proximal tubular epithelial cells. Human renal proximal tubular cells (HK-2, ATCC) were used to characterize the effects of IL-17A or IL-17F on G-CSF production, using ELISA, real-time RT-PCR, and immunoblotting. The cell surface expression of IL-17 receptors (IL-17Rs) was analyzed by flow cytometry. IL-17A stimulation of proximal tubular cells led to a dose- and time-dependent increase in secreted G-CSF. This effect was dependent on mRNA transcription and protein translation. Real-time RT-PCR demonstrated that G-CSF mRNA expression reached a maximum level at 6 h following IL-17A stimulation and that this increase was dose dependent. Both IL-17RA and IL-17RC were expressed on proximal tubular cells. IL-17A also enhanced TNF-α- or IL-1ß-mediated G-CSF secretion from cells. Additionally, IL-17A induced MAPK (ERK1/2 but not p38 MAPK or JNK) activation, and pharmacological inhibitors of MEK1/2 (U0126) but not of p38 MAPK (SB203580) or JNK (SP600125), significantly blocked the IL-17A-mediated G-CSF release. We demonstrated the potential ability of IL-17A to induce G-CSF in renal proximal tubular cells. It is proposed that IL-17A may play an important role in neutrophil transmigration and activation via stimulation of G-CSF in tubular injury.
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Células Epiteliales/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/biosíntesis , Interleucina-17/farmacología , Túbulos Renales Proximales/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Humanos , Interleucina-1beta/farmacología , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Fosforilación/efectos de los fármacos , Receptores de Interleucina-17/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
IL-17F plays a crucial role in airway inflammatory diseases including asthma, but its function has not been fully elucidated. CCL20 is also involved in allergic airway inflammation, while its regulatory mechanisms remain to be defined. To further identify a novel role of IL-17F, the expression of CCL20 by IL-17F in bronchial epithelial cells and the signaling mechanisms involved were investigated. Bronchial epithelial cells were stimulated with IL-17F, and the levels of CCL20 gene and protein measured, with the effects of the addition of various kinase inhibitors and siRNAs also investigated. IL-17F significantly induced the expression of CCL20 gene and protein. Pretreatment with inhibitors for MEK1/2, Raf1 and MSK1, and overexpression of a Raf1 dominant-negative mutant significantly diminished IL-17F-induced CCL20 production. Moreover, transfection of the siRNAs targeting MSK1, p90RSK, and CREB blocked CCL20 expression. These findings suggest that IL-17F is able to induce CCL20 via Raf1-MEK1/2-ERK1/2-MSK1/p90RSK-CREB signaling pathway in bronchial epithelial cells. The IL-17F/CCL20 axis may be a novel pharmacological target for asthma.
RESUMEN
We investigated the role of IL-17 family members IL-17A and IL-17F in the induction of chemokines in mouse cultured mesangial cells (SV40 MES 13 cells). We evaluated the expression of the chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) by ELISA and real-time RT-PCR (Q-PCR). Activation of MAPK was assessed by immunoblotting. IL-17RA and IL-17RC were inhibited by small interfering RNA (siRNA). We found that IL-17A or IL-17F stimulation of mesangial cells led to both a dose- and time-dependent increase in MCP-1 and MIP-2 release. This effect was dependent on mRNA transcription and protein translation. Both also enhanced TNF-alpha- and IL-1beta-mediated MCP-1 and MIP-2 release in the cells. Additionally, we observed that IL-17A and IL-17F induced MAPK (p38 MAPK, ERK1/2, and JNK) activation and that pharmacological inhibitors of p38 MAPK (SB203580) and ERK1/2 (U0126), but not JNK (SP600125), blocked the IL-17A/IL-17F-mediated MCP-1 and MIP-2 release. Mesangial cells expressed IL-17RA and IL-17RC, and the IL-17A-mediated MCP-1 and MIP-2 release was significantly blocked by soluble IL-17RA. Furthermore, inhibition of either IL-17RA or IL-17RC expression via siRNA led to significant reduction of IL-17A/IL-17F-stimulated chemokine production. We conclude that IL-17A and IL-17F induce the production of chemokines MCP-1 and MIP-2 via MAPK pathways (p38 MAPK and ERK1/2), as well as mRNA transcription and protein translation and have synergistic effects with TNF-alpha and IL-1beta in cultured mesangial cells.
Asunto(s)
Quimiocinas/metabolismo , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Células Mesangiales/enzimología , Células Mesangiales/inmunología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Western Blotting , Línea Celular , Quimiocina CCL2/metabolismo , Quimiocina CXCL2/metabolismo , Quimiocinas/genética , Activación Enzimática , Ensayo de Inmunoadsorción Enzimática , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Células Mesangiales/efectos de los fármacos , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Reacción en Cadena de la Polimerasa , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , ARN Mensajero/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Proteínas Recombinantes/metabolismo , Factores de Tiempo , Transcripción Genética , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: This study investigated the variations in the clinical efficacy and drug cost following the introduction of the Asthma Prevention and Management Guidelines in Japan (JGL2003). METHODS: The medical charts of fifty outpatients treated continuously for asthma, aged 16-50 years, from October 2002 to October 2004 at Showa University Hospital were analyzed for physicians' compliance with asthma guidelines, symptom severity, episodes in various occasions, prescriptions and drug costs. RESULTS: Physicians' compliance with the guidelines, which were defined as the number of patient visits treated in conformity with the JGL over the total number of patient visits, was found to be high before (89.4%) and after (90.3%) the introduction of JGL2003, without a statistical difference. On the other hand, the distribution of asthma symptom severity varied significantly (P<0.0001). Fewer patients were recognized as having more severe asthma symptoms after the introduction of JGL2003. Significantly more patients with severe asthma symptoms were detected in the physicians' noncompliant group than in the compliant group (P<0.0001). The number of patients prescribed with oral corticosteroids, long-acting beta2-agonists containing patches, long-acting oral beta2-agonists, short-acting inhaled beta2-agonists, sustained-released theophylline and leukotriene receptor antagonists decreased after the introduction of JGL2003. Furthermore, the total annual drug cost per patient decreased significantly by an average of 16,259 yen (P=0.006). CONCLUSIONS: The JGL2003 was judged to have improved criteria, which thus resulted in the high compliance of physicians with the guidelines, in the remission of asthma symptoms and in the reduction in the total annual drug cost per patient.
Asunto(s)
Asma/tratamiento farmacológico , Costos de los Medicamentos , Adhesión a Directriz , Adolescente , Adulto , Asma/economía , Asma/fisiopatología , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina , Prescripciones/economía , Resultado del TratamientoRESUMEN
A new family of cytokines, the interleukin (IL)-17 family, has recently been defined, which reveals unique functions and distinct ligand-receptor signaling systems. This family contains six members, IL-17 (also called IL-17A), IL17B, IL-17C, IL-17D, IL-17E (IL-25) and IL-17F. The IL-17F gene was discovered in 2001, and is located on chromosome 6p12. Notably, among this family, IL-17F has been well characterized both in vitro and in vivo, and has been shown to have a pro-inflammatory role in asthma. IL-17F is clearly expressed in the airway of asthmatics and its expression level is correlated with disease severity. Moreover, a coding region variant (H161R) of the IL-17F gene is inversely associated with asthma and encodes an antagonist for the wild-type IL-17F. IL-17F is able to induce several cytokines, chemokines and adhesion molecules in bronchial epithelial cells, vein endothelial cells, fibroblasts and eosinophils. IL-17F utilizes IL-17RA and IL-17RC as its receptors, and activates the MAP kinase related pathway. IL-17F is derived from several cell types such as Th17 cells, mast cells and basophils, and shows a wide tissue expression pattern including lung. Overexpression of IL-17F gene in the airway of mice is associated with airway neutrophilia, the induction of many cytokines, an increase in airway hyperreactivity, and mucus hypersecretion. Hence, IL-17F may have a crucial role in allergic airway inflammation, and have important therapeutic implications in asthma.
Asunto(s)
Asma/inmunología , Citocinas/metabolismo , Interleucina-17/metabolismo , Receptores de Citocinas/metabolismo , Subgrupos de Linfocitos T/inmunología , Animales , Asma/genética , Humanos , Interleucina-17/genética , Ratones , Polimorfismo Genético , Transducción de Señal/inmunologíaRESUMEN
Osteopontin (OPN) is a secreted phosphoglycoprotein with a wide range of functions, and is involved in various pathophysiological conditions. However, the role of OPN in IgE and Th2-associated allergic responses remains incompletely defined. The aim of this study was to elucidate the role of OPN in systemic allergen sensitization in mice. When compared with OPN(+/+) mice, significantly increased levels of OVA-induced IgE were found in OPN(-/-) mice. OPN(-/-) DC demonstrated an increased capacity to enhance Th2 cytokine production in CD4+ T cells from sensitized OPN(+/+) mice. Furthermore, significantly reduced levels of IL-12p70 expression were seen in LPS-stimulated OPN(-/-) DC as compared with the WT DC, and the reduction was reversible by the addition of recombinant OPN (rOPN). rOPN was able to suppress OVA-induced IL-13 production in the cultures of CD4 and OPN(-/-) DC, but this inhibitory activity was neutralized by the addition of anti-IL-12 Ab. In addition, administration of rOPN in vivo suppressed OVA-specific IgE production; however, this suppressive effect was abrogated in IL-12-deficient mice. These results indicate that DC-derived OPN plays a regulatory role in the development of systemic allergen sensitization, which is mediated, at least in part, through the production of endogenous IL-12.