RESUMEN

Recent therapeutic advances in the management of asthma have underscored the importance of eosinophilia and the role of pro-eosinophilic mediators such as IL-5 in asthma. Given that a subset of patients with COPD may display peripheral eosinophilia similar to what is observed in asthma, a number of recent studies have implied that eosinophilic COPD is a distinct entity. This review will seek to contrast the mechanisms of eosinophilia in asthma and COPD, the implications of eosinophilia for disease outcome, and review current data regarding the utility of peripheral blood eosinophilia in the management of COPD patients.

Asunto(s)

Asma , Eosinofilia , Enfermedad Pulmonar Obstructiva Crónica , Eosinófilos , Humanos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones

RESUMEN

BACKGROUND: While 30-day readmissions following hospitalization for pneumonia have been well-studied in the elderly, their burden in young adults remains poorly understood. OBJECTIVE: To study patterns of readmissions following hospitalization for pneumonia across age groups and insurance payers. METHODS: In the Nationwide Readmission Database for the years 2013 and 2014 we identified all adults (≥18 years) discharged alive after a hospitalization with the primary diagnosis of pneumonia, and examined rates of readmissions within 30-days of discharge. Using covariates included in the Center for Medicare & Medicaid Services risk-adjustment model for pneumonia readmissions in a multivariable regression model for survey data, we identified predictors of 30-day readmission. RESULTS: We identified 629,939 index pneumonia hospitalizations with a weighted estimate of 1,472,069 nationally. Overall, 16.2% of patients were readmitted within 30 days of their hospitalization for pneumonia, with 30-day readmission rates of 12.4% in the 18-44 year age-group, 16.1% in the 45-64 year age-group, and 16.7% in the ≥65-year age-group. In risk-adjusted analyses, compared with elderly, middle-aged adults were more likely to be readmitted (risk-adjusted OR 1.05, 95% CI 1.03-1.07). Mean cost per readmission was also highest for this age group at $15,976. CONCLUSION: Middle-aged adults experience substantial rates of 30-day readmission that are comparable to those over 65 years of age, with a higher cost per readmission event. Future efforts are needed to identify potential interventions to alleviate the high burden of pneumonia readmissions in middle-aged adults.

Asunto(s)

Bases de Datos Factuales , Modelos Económicos , Readmisión del Paciente , Neumonía , Adolescente , Adulto , Factores de Edad , Anciano , Niño , Preescolar , Costos y Análisis de Costo , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Neumonía/economía , Neumonía/epidemiología , Neumonía/terapia , Estados Unidos/epidemiología

RESUMEN

Eosinophils are involved in the pathogenesis of a number of lung diseases. Recent advances in eosinophil biology have now produced clinically applicable therapies that seek to counter eosinophilia in blood and lungs. This article reviews the basic biology of eosinophils and their role in mediating T-helper 2 cell responses. The current status of anticytokine therapy for eosinophilic lung disease is discussed. A clinical approach to eosinophilic lung disease based on symptoms and radiography is generated. The clinical significance of persistent eosinophilia in lung transplant patients and patients with asthma will receive special emphasis.

Asunto(s)

Eosinófilos/inmunología , Eosinofilia Pulmonar/inmunología , Células Th2/inmunología , Animales , Asma/inmunología , Asma/patología , Asma/terapia , Eosinófilos/patología , Humanos , Trasplante de Pulmón , Eosinofilia Pulmonar/patología , Eosinofilia Pulmonar/terapia , Células Th2/patología

RESUMEN

Previous study of transgenic mice with long-term expression of pleiomorphic adenoma gene-like 2 (PLAGL2), a surfactant protein C (SP-C) transactivator, in type II cells showed the manifestation of centrilobular emphysema in vivo. Since emphysema is an independent risk factor for bronchogenic carcinoma, we hypothesized that the mouse lungs with induced PLAGL2-expression had increased incidences in developing lung adenocarcinoma. To test the hypothesis, mouse lungs were examined for the presence of tumors. Male mice with induced PLAGL2-expression in the lungs were more vulnerable to tumorigenesis than female mice (p<0.05). Epithelial cells expressing pro-SP-C and Clara cell secretory protein (CCSP) at the terminal bronchioles and the bronchoalveolar duct junction (BADJ) were increased in the induced transgenic mice, suggesting a role of PLAGL2 in expanding SP-C expression cells. Co-expression of TTF-1, pro-SP-C and CD133 (a stem-cell marker) in cancer and distal airway epithelial cells indicated that both cells were derived from common progenitors. This result supported a common-cell-origin mechanism for the comorbid diseases - emphysema and lung cancer. Furthermore, a public lung cancer gene expression profiling database was examined to determine the relevance of PLAGL2 expression and lung adenocarcinoma in humans. Patients with high PLAGL2 expression in lung tumors were readily found. Female patients (N=218) with low PLAGL2 expression (the lowest quartile of total patients) at the early-stage of disease had better prognosis in survival. Male patients, on the other hand, had no such correlation. Generally, their survival rate was significantly poorer than of female patients. Taken together, our data suggested a pathological role of PLAGL2 in lung adenocarcinoma development and a preferable prognosis of low PLAGL2 expression in female patients.

Asunto(s)

Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiología , Proteínas de Unión al ADN/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/epidemiología , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Antígeno AC133 , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Comorbilidad , Proteínas de Unión al ADN/genética , Femenino , Glicoproteínas/genética , Glicoproteínas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Transgénicos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Péptidos/genética , Péptidos/metabolismo , Pronóstico , Enfisema Pulmonar/mortalidad , Enfisema Pulmonar/patología , Proteína C Asociada a Surfactante Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/metabolismo , Proteínas de Unión al ARN/genética , Mucosa Respiratoria , Riesgo , Factores Sexuales , Análisis de Supervivencia , Factores de Transcripción/genética , Carga Tumoral

RESUMEN

Emphysema and bronchitis are major components of chronic obstructive pulmonary disease (COPD). Pleomorphic adenoma gene like-2 (PLAGL2), a zinc finger DNA-binding protein, is a transcription factor of the surfactant protein C (SP-C) promoter. Using an inducible transgenic mouse model, PLAGL2 and SP-C were ectopically expressed in lung epithelial cells of terminal bronchiole including the bronchoalveolar duct junction (BADJ), where only few cells express both genes under normal conditions. Ectopic PLAGL2 was also expressed in alveolar type II cells of induced mice. The overexpression of PLAGL2 was associated with the development of air space enlargement in the distal airways of adult mice. Defective alveolar septa and degraded airway fragments were found in the lesions of emphysematous lungs, indicating chronic airway destruction. Female mice were particularly sensitive to the effects of PLAGL2 overexpression with more dramatic emphysematous changes compared with male mice. In addition, analysis of the respiratory system mechanics in the mice indicated that the induction of PLAGL2 resulted in a significant increase in respiratory system compliance. Both TdT-mediated dUTP nick end labeling (TUNEL) and caspase-3 analyses showed that apoptotic activity was increased in epithelial cells within the emphysematous lesions as well as at the BADJ. Our results indicate that increased cell injury and/or death could be caused directly by the upregulation of PLAGL2 downstream gene, bNip3, a preapoptotic molecule that dimerizes with Bcl-2, or indirectly by the aberrant expression of SP-C-induced endoplasmic reticulum stress in epithelial cells. Finally, increased expression of PLAGL2 in alveolar epithelial cells correlated with the development of emphysema in the lung of COPD patients. In summary, our data from both animal and human studies support a novel pathogenic role of PLAGL2 in pulmonary emphysema, a critical aspect of severe COPD.

Asunto(s)

Bronquiolos/patología , Proteínas de Unión al ADN/metabolismo , Epitelio/patología , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales/metabolismo , Alveolos Pulmonares/patología , Enfisema Pulmonar/metabolismo , Proteína C Asociada a Surfactante Pulmonar/metabolismo , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Anciano , Animales , Bronquiolos/metabolismo , Bronquiolos/fisiopatología , Muerte Celular , Células Epiteliales/metabolismo , Células Epiteliales/patología , Epitelio/metabolismo , Femenino , Humanos , Rendimiento Pulmonar/fisiología , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/patología , Enfisema Pulmonar/fisiopatología , Transgenes

RESUMEN

Pleomorphic adenoma gene like-2 (PLAGL2), a developmentally regulated and stress inducible zinc finger protein can be post-translationally modified by small ubiquitin-like modifier peptide (SUMO-1); and SUMOylation attenuates PLAGL2 activity on the interactive promoter. Since PLAGL2 was a transactivator of the surfactant protein-C (SP-C) promoter, we hypothesized that SUMOylation down-regulated PLAGL2-activated SP-C promoter activity. Unexpectedly, the SUMO-conjugating enzyme Ubc9 enhanced, rather than reduced, PLAGL2 activated promoter activity but did not affect TTF-1 activation of the promoter. Ubc9 mutant (Ubc9-C93S) defective in SUMO-conjugating activity also enhanced PLAGL2-driven promoter activity suggesting that the stimulatory effect of Ubc9 on SP-C promoter activation was independent of its enzymatic function. PLAGL2 mutants without the K250 and/or K269 SUMOylation sites did not further improve PLAGL2 programmed transcription nor did they abolish Ubc9 enhanced promoter activity supporting the SUMOylation-independent mechanism. Chromatin immunoprecipitation (ChIP) assay demonstrated the association of PLAGL2 and Ubc9 with the SP-C promoter in vivo. Taken together, our data suggests that Ubc9 can function as a co-factor of PLAGL2, uncoupling from its enzymatic activity, to mediate PLAGL2 interactive SP-C promoter activity.

Asunto(s)

Proteínas de Unión al ADN/metabolismo , Proteína C Asociada a Surfactante Pulmonar/genética , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Activación Transcripcional , Enzimas Ubiquitina-Conjugadoras/metabolismo , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Humanos , Pulmón/metabolismo , Regiones Promotoras Genéticas , Proteína SUMO-1/metabolismo

RESUMEN

Cobalt is a transition metal which can substitute for iron in the oxygen-sensitive protein and mimic hypoxia. Cobalt was known to be associated with the development of lung disease. In this study, when lung cells were exposed to hypoxia-induced by CoCl(2) at a sub-lethal concentration (100 microM), their thyroid transcription factor-1 (TTF-1) expression was greatly reduced. Under this condition, SP-B promoter activity was down-regulated, but SP-C promoter remained active. Therefore, we hypothesized that other factor(s) besides TTF-1 might contribute to the modulation of SP-C promoter in hypoxic lung cells. Pleomorphic adenoma gene like-2 (PLAGL2), a previously identified TTF-1-independent activator of the SP-C promoter, was not down-regulated, nor increased, within those cells. Its cellular location was redistributed from the cytoplasm to the nucleus. Chromatin immunoprecipitation (ChIP) and quantitative RT-PCR analyses demonstrated that nuclear PLAGL2 occupied and transactivated the endogenous SP-C promoter in lung cells. Thereby, through relocating and accumulating of PLAGL2 inside the nucleus, PLAGL2 interacted with its target genes for various cellular functions. These results further suggest that PLAGL2 is an oxidative stress responding regulator in lung cells.

Asunto(s)

Hipoxia de la Célula/fisiología , Proteínas de Unión al ADN/metabolismo , Pulmón/metabolismo , Regiones Promotoras Genéticas , Proteína B Asociada a Surfactante Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/genética , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Hipoxia de la Célula/genética , Línea Celular , Cobalto/farmacología , Regulación hacia Abajo/efectos de los fármacos , Humanos , Pulmón/citología , Pulmón/efectos de los fármacos , Ratones , Estrés Oxidativo/efectos de los fármacos , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/genética

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is an adult-onset, lethal, scarring lung disease of unknown etiology. Some individuals with IPF have a familial disorder that segregates as a dominant trait with incomplete penetrance. Here we used linkage to map the disease gene in two families to chromosome 5. Sequencing a candidate gene within the interval, TERT, revealed a missense mutation and a frameshift mutation that cosegregated with pulmonary disease in the two families. TERT encodes telomerase reverse transcriptase, which together with the RNA component of telomerase (TERC), is required to maintain telomere integrity. Sequencing the probands of 44 additional unrelated families and 44 sporadic cases of interstitial lung disease revealed five other mutations in TERT. A heterozygous mutation in TERC also was found in one family. Heterozygous carriers of all of the mutations in TERT or TERC had shorter telomeres than age-matched family members without the mutations. Thus, mutations in TERT or TERC that result in telomere shortening over time confer a dramatic increase in susceptibility to adult-onset IPF.

Asunto(s)

Fibrosis Pulmonar/enzimología , Fibrosis Pulmonar/patología , Telomerasa/genética , Telomerasa/metabolismo , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación/genética , Linaje , Fibrosis Pulmonar/genética , Alineación de Secuencia , Telomerasa/química , Telómero/genética

RESUMEN

Surfactant protein-B (SP-B) and -C (SP-C) are small hydrophobic surfactant proteins that maintain surface tension in alveoli. Both SP-B and SP-C are regulated by a key factor, thyroid transcription factor-1 (TTF-1), in lung cells. Previously, we identified a 26-kDa, TTF-1-associated protein (TAP26) that was shown to interact with TTF-1 and enhance TTF-1-transactivated SP-B promoter activity. In this study, we hypothesized that TAP26 could also serve as a co-activator of the SP-C promoter. Using the chromatin immunoprecipitation assay (ChIP), we demonstrated that TAP26 was not only a component of the SP-B promoter, but was also a component of the SP-C promoter complex in lung cells. TAP26 could synergistically stimulate TTF-1-activated SP-B and SP-C promoter activities in H441 cells (a lung adenocarcinoma cell). However, in MLE12 cells (a murine lung type II cell), only SP-B, but not SP-C, promoter activity was improved by TAP26 in a concentration-dependent manner. This result indicated that the TTF-1/TAP26 complex-activated SP-C promoter activity was already optimized in MLE12 cells and that the response of the SP-C promoter to the complex was different from that of the SP-B promoter. Via promoter mutation analysis, adjacent TTF-1 binding sites within the proximal promoter region of SP-C were found to be essential for TTF-1/TAP26-enhanced SP-C promoter activity. Thus, a dimerized complex structure was needed for advanced promoter activity. This result also provided a molecular mechanism by which both the SP-B and SP-C promoters could be differentially regulated by the same complex.

Asunto(s)

Pulmón/metabolismo , Proteínas Nucleares/metabolismo , Proteína B Asociada a Surfactante Pulmonar/metabolismo , Proteína C Asociada a Surfactante Pulmonar/metabolismo , Factores de Transcripción/metabolismo , Animales , Células Cultivadas , Humanos , Ratones , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/genética , Proteína B Asociada a Surfactante Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/genética , Factor Nuclear Tiroideo 1 , Factores de Transcripción/genética

RESUMEN

Expression of surfactant protein (SP)-C occurs principally in type II pneumocytes located in the distal lung alveolae. SP-C expression is thought to be primarily regulated by thyroid transcription factor (TTF)-1 and its associated proteins interacting with a previously defined promoter region between -197 and -158 in mice. We screened a human lung cDNA library using a modified yeast one-hybrid system and identified pleiomorphic adenoma gene-like (PLAGL)-2, a ubiquitously expressed zinc finger protein, as a transfactor of the SP-C promoter. The PLAGL2 DNA-binding site was located in the SP-C promoter proximal region close to the TTF-1 sites. This site was demonstrated to be functional by use of electrophoresis mobility shift assay, mutagenesis analysis, and transfection studies. PLAGL2 bound to DNA via its N-terminus zinc fingers and activated the SP-C promoter in a TTF-1-independent manner. Both human and mouse SP-C promoters, but not the SP-B promoter, could be activated by PLAGL2 in transfected human embryonic kidney-293 (HEK293) cells as well as in murine type II (MLE12) cells. The expression of PLAGL2 in isolated human embryonic lung type II cells and its transactivation activity on the SP-C promoter suggest that PLAGL2 may modulate SP-C expression during lung development.

Asunto(s)

Proteínas de Unión al ADN/metabolismo , Regiones Promotoras Genéticas , Surfactantes Pulmonares/metabolismo , Proteínas de Unión al ARN/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos/genética , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Células Cultivadas , Proteínas de Unión al ADN/genética , Ensayo de Cambio de Movilidad Electroforética , Genes Reporteros/genética , Humanos , Ratones , Datos de Secuencia Molecular , Proteínas Nucleares , Proteínas de Unión al ARN/genética , Factor Nuclear Tiroideo 1 , Factores de Transcripción/genética , Levaduras/metabolismo

Asunto(s)

Medicina Interna/tendencias , Medicina/tendencias , Especialización , Competencia Clínica , Educación Médica , Predicción , Humanos , Medicina Interna/educación , Medicina Interna/normas , Medicina/normas , Objetivos Organizacionales , Sociedades Médicas , Estados Unidos