RESUMEN
Epithelial to mesenchymal transition (EMT) is a process whereby epithelial cells undergo transition to a mesenchymal phenotype and contribute directly to fibrotic disease. Recent studies support a role for EMT in cutaneous fibrotic diseases including scleroderma and hypertrophic scarring, although there is limited data on the cytokines and signalling mechanisms regulating cutaneous EMT. We investigated the ability of TGF-ß and TNF-α, both overexpressed in cutaneous scleroderma and central mediators of EMT in other epithelial cell types, to induce EMT in primary keratinocytes and studied the signalling mechanisms regulating this process. TGF-ß induced EMT in normal human epidermal keratinocytes (NHEK cells), and this process was enhanced by TNF-α. EMT was characterised by changes in morphology, proteome (down-regulation of E-cadherin and Zo-1 and up-regulation of vimentin and fibronectin), MMP secretion and COL1α1 mRNA expression. TGF-ß and TNF-α in combination activated SMAD and p38 signalling in NHEK cells. P38 inhibition with SB203580 partially attenuated EMT, whereas SMAD inhibition using SB431542 significantly inhibited EMT and also reversed established EMT. These data highlight the retained plasticity of adult keratinocytes and support further studies of EMT in clinically relevant in vivo models of cutaneous fibrosis and investigation of SMAD inhibition as a potential therapeutic intervention.
Asunto(s)
Transición Epitelial-Mesenquimal , Queratinocitos/citología , Proteínas Smad/antagonistas & inhibidores , Proteínas Smad/metabolismo , Benzamidas/química , Colágeno/metabolismo , Citocinas/metabolismo , Dioxoles/química , Regulación hacia Abajo , Células Epidérmicas , Fibronectinas/metabolismo , Fibrosis/metabolismo , Humanos , Metaloproteinasas de la Matriz/metabolismo , Proteínas Recombinantes/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Vimentina/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Airway inflammation and pulmonary disease are heterogeneous phenotypes in cystic fibrosis (CF) patients, even among patients with the same cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Endothelin, a proinflammatory peptide and smooth muscle agonist, is increased in CF airways, potentially contributing to the pulmonary phenotype. Four cohorts of CF patients were screened for variants in endothelin pathway genes to determine whether any of these variants associated with pulmonary function. An initial cohort of 808 CF patients homozygous for the common CF mutation, DeltaF508, showed significant association for polymorphisms in the endothelin receptor A gene, EDNRA (P = 0.04), but not in the related endothelin genes (EDN1, EDN2, EDN3, or EDNRB) or NOS1, NOS2A, or NOS3. Variants within EDNRA were examined in three additional cohorts of CF patients, 238 patients from Seattle, WA, 303 from Ireland and the U.K., and 228 from Cleveland, OH, for a total of 1,577 CF patients. The three additional groups each demonstrated a significant association between EDNRA 3'-untranslated region (UTR) variant rs5335 and pulmonary function (P = 0.002). At the molecular level, single nucleotide primer extension assays suggest that the effect of the variants is quantitative. EDNRA mRNA levels from cultured primary tracheal smooth muscle cells are greater for the allele that appears to be deleterious to lung function than for the protective allele, suggesting a mechanism by which increased receptor function is harmful to the CF airway. Finally, cell proliferation studies using human airway smooth muscle cells demonstrated that cells homozygous for the deleterious allele proliferate at a faster rate than those homozygous for the protective allele.
Asunto(s)
Fibrosis Quística/genética , Fibrosis Quística/patología , Predisposición Genética a la Enfermedad , Músculo Liso/metabolismo , Músculo Liso/patología , Polimorfismo de Nucleótido Simple/genética , Receptor de Endotelina A/genética , Adulto , Alelos , Línea Celular , Proliferación Celular , Estudios de Cohortes , Fibrosis Quística/fisiopatología , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Músculo Liso/fisiopatología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor de Endotelina A/metabolismo , Reproducibilidad de los Resultados , Pruebas de Función Respiratoria , Tráquea/patología , Adulto JovenRESUMEN
BACKGROUND: In cystic fibrosis (CF) airways excessive levels of serine trypsin-like proteases (TLPs) activate the epithelial sodium channel (ENaC) resulting in airways dehydration and promotion of mucus secretion. Despite this the relationship of TLP activity and clinical outcome has not been studied. METHODS: We analysed supernatant (sol) prepared from CF sputum from adult CF patients in two study cohorts (29 and 33 samples, respectively). Protease activities were determined by measuring the hydrolysis of peptide-based substrates or by ELISA. Lung function was assessed by spirometry (FEV1). Mortality data was retrospectively obtained and time in months until death or transplantation used for subsequent survival analysis. RESULTS: TLP activity inversely correlated with percent predicted FEV1 (r = -0.4, p = 0.03) and was greater in individuals who did not survive beyond 5-years from the time of sample collection. A Kaplan-Meier analysis demonstrated significantly reduced survival (p = 0.04) for individuals with high TLP activity [hazard ratio (HR) of 7.21 per log unit TLP activity (p = 0.03)]. In contrast, neutrophil elastase displayed no significant associations with lung function or patient survival. Similar findings were evident in the second study cohort. CONCLUSIONS: Sputum TLP activity may represent a novel non-invasive biomarker and/or therapeutic target for CF lung disease.
Asunto(s)
Fibrosis Quística , Serina Endopeptidasas/metabolismo , Esputo/metabolismo , Adulto , Biomarcadores/metabolismo , Pruebas de Química Clínica/métodos , Fibrosis Quística/metabolismo , Fibrosis Quística/mortalidad , Fibrosis Quística/fisiopatología , Canales Epiteliales de Sodio/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas/métodos , Transporte Iónico/fisiología , Masculino , Reproducibilidad de los Resultados , Pruebas de Función Respiratoria/métodos , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/fisiopatología , Análisis de SupervivenciaRESUMEN
BACKGROUND: Antimicrobial susceptibility testing (AST) is a cornerstone of infection management in cystic fibrosis. However, there is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment. It has been suggested there is a need for careful consideration of current AST use by the CF community. METHODS: We engaged a group of experts consisting of pulmonary (adult and pediatric) and infectious disease clinicians, microbiologists, and pharmacists representing a broad international experience. We conducted an iterative systematic survey (Delphi) to determine and quantify consensus regarding key questions facing CF clinicians in the use of respiratory culture results including what tests to order, when to obtain them, and how to act upon the results of the testing. RESULTS: Consensus was reached for many questions but there was not universal agreement to the questions that were addressed. There were some differences with respect to cultures obtained for surveillance compared to when there is clinical worsening. Areas of general consensus include when and how respiratory cultures should be performed, what information should be reported, and when AST should be performed. A key finding is that clinical response to treatment is used to guide treatment decisions rather than AST results. CONCLUSIONS: Recommendations are presented regarding questions related to microbiology testing for patients with CF. We have also offered recommendations for priority research questions.
Asunto(s)
Antibacterianos/uso terapéutico , Fibrosis Quística , Farmacorresistencia Bacteriana , Pruebas de Sensibilidad Microbiana/métodos , Utilización de Procedimientos y Técnicas , Adulto , Antibacterianos/clasificación , Niño , Consenso , Vías Clínicas/normas , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/microbiología , Técnica Delphi , Humanos , Cooperación Internacional , Selección de Paciente , Resultado del TratamientoRESUMEN
BACKGROUND: Improved lung function and fewer pulmonary exacerbations (PEx) were observed with lumacaftor/ivacaftor (LUM/IVA) in patients with cystic fibrosis homozygous for F508del. It is unknown whether PEx reduction extends to patients without early lung function improvement. METHODS: Post hoc analyses of pooled phase 3 data (NCT01807923, NCT01807949) categorized LUM/IVA-treated patients by percent predicted forced expiratory volume in 1â¯s (ppFEV1) change from baseline to day 15 into threshold categories (absolute change ≤0 vs >0; relative change <5% vs ≥5%) and compared PEx rates vs placebo. RESULTS: LUM (400â¯mg q12h)/IVA (250â¯mg q12h)-treated patients (nâ¯=â¯369) experienced significantly fewer PEx vs placebo, regardless of threshold category. With LUM/IVA, PEx rate per patient per year was 0.60 for those with absolute change in ppFEV1â¯>â¯0 and 0.85 for those with absolute change ≤0 (respective rate ratios vs placebo [95% CI]: 0.53 [0.40-0.69; Pâ¯<â¯.0001], 0.74 [0.55-0.99; Pâ¯=â¯.04]). CONCLUSIONS: LUM/IVA significantly reduced PEx, even in patients without early lung function improvement.
Asunto(s)
Aminofenoles/uso terapéutico , Aminopiridinas/uso terapéutico , Benzodioxoles/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Volumen Espiratorio Forzado/fisiología , Pulmón/fisiopatología , Quinolonas/uso terapéutico , Adolescente , Adulto , Anciano , Niño , Fibrosis Quística/fisiopatología , Progresión de la Enfermedad , Método Doble Ciego , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: The causes of subfertility in women with CF though multifactorial are not well described. Our aim in this study was to determine the prevalence and factors associated with female subfertility among women with CF. METHODS: A retrospective multinational study from 11 CF centers in 5 countries (Israel, France, Spain, Italy, UK) including women with CF was undertaken. Sub/infertility was defined as not achieving a spontaneous pregnancy after one year of unprotected sexual intercourse. Data including genetics, pancreatic insufficiency (PI), prevalence of diabetes (CFRD), lung function, nutritional status measured by body mass index (BMI), sputum bacterial colonization, and rate of pulmonary exacerbations were collected from patients' files. RESULTS: Out of 605 women, 241 attempted pregnancy. Of these, 84 (35%) had subfertility, and 67 of them eventually became pregnant. Females attempting conception were older but had better pulmonary function and nutrition compared to those who did not. In a multivariate analysis, PI (OR 1.9 [1.03-3.5], pâ¯=â¯.04) and older age (OR 3.9 [2.1-7.3] pâ¯<â¯.0001) were associated with subfertility. Lung function, BMI, CFRD, Presence of two class I-III mutations and number of exacerbations in the year prior to fertility attempts were not associated with subfertility. CONCLUSIONS: The prevalence of subfertility among women with CF (35%) is higher than the expected 5-15% subfertility in the general population. Older age and pancreatic insufficiency are associated with subfertility in women with CF.
Asunto(s)
Fibrosis Quística/complicaciones , Insuficiencia Pancreática Exocrina/complicaciones , Infertilidad Femenina/epidemiología , Infertilidad Femenina/etiología , Adulto , Factores de Edad , Femenino , Humanos , Prevalencia , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Smoking cessation is the primary disease modifying intervention for chronic obstructive pulmonary disease (COPD). SETTING: A Regional Respiratory Centre (RRC) out-patient department in Northern Ireland. METHODS: A randomised controlled trial (RCT) evaluated the effectiveness of brief advice alone or accompanied by individual nurse support or group support facilitated by nurses. Smoking status was biochemically validated and stage of change, nicotine addiction and dyspnoea were recorded at 2, 3, 6, 9 and 12 months. PARTICIPANTS: Ninety-one cigarette smokers with COPD were enrolled in the study (mean age 61 years, 47 female). RESULTS: After 12 months cessation rates were not significantly different between groups (p=0.7), but all groups had a significant reduction in their nicotine addiction (p=0.03-0.006). No changes in subjects' motivation or dyspnoea were detected over the 12 months. CONCLUSION: Patients with COPD were unable to stop smoking regardless of the type of support they received. Harm reduction may be a more appropriate goal than complete cessation for intractable smokers and nurses must evaluate their role in this arena.
Asunto(s)
Rol de la Enfermera/psicología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Cese del Hábito de Fumar/métodos , Prevención del Hábito de Fumar , Apoyo Social , Análisis de Varianza , Femenino , Estudios de Seguimiento , Reducción del Daño , Humanos , Masculino , Persona de Mediana Edad , Motivación , Irlanda del Norte , Relaciones Enfermero-Paciente , Investigación en Evaluación de Enfermería , Educación del Paciente como Asunto/organización & administración , Grupos de Autoayuda/organización & administración , Índice de Severidad de la Enfermedad , Fumar/psicología , Cese del Hábito de Fumar/psicología , Resultado del TratamientoRESUMEN
OBJECTIVES: We aimed to determine if beliefs about treatment, clinical factors and quality of life predicted adherence to treatment in patients with bronchiectasis. METHODS: We recruited participants with confirmed bronchiectasis to a one-year study. We calculated adherence to treatment using medication possession ratios and self-report. Baseline Beliefs about Medicines, clinical, demographic and Quality of Life Questionnaire-Bronchiectasis data were collected. We used logistic regression to determine predictors of adherence to treatment during the subsequent year. RESULTS: Seventy-five participants were recruited. Beliefs about harm, age and total number of prescribed medications were predictors of adherence to inhaled antibiotics. Concerns about medication, age and Quality of Life Questionnaire-Bronchiectasis Treatment Burden were predictors of adherence to other respiratory medicines. Beliefs about necessity of airway clearance and age were predictors of adherence to airway clearance. CONCLUSION: Beliefs about treatment, age, number of prescribed medications and perceived treatment burden predicted subsequent adherence in bronchiectasis, thereby, providing potential targets for future interventions in this population. Clinicians can use these data to identify patients with bronchiectasis who might be at risk of non-adherence i.e. those who are younger, have concerns about medications, who do not think airway clearance is necessary or who are prescribed numerous medications.
Asunto(s)
Antibacterianos/administración & dosificación , Bronquiectasia/tratamiento farmacológico , Conocimientos, Actitudes y Práctica en Salud , Cumplimiento de la Medicación , Calidad de Vida , Administración por Inhalación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: There is uncertainty about the most important indicators of pulmonary exacerbations in CF. METHODS: Two parallel Delphi surveys in 13 CF centres (UK and Ireland). Delphi 1: 31 adults with CF, ≥ one exacerbation over 12 months. Delphi 2: 38 CF health professionals. Rounds 1 and 2 participants rated their level of agreement with statements relating to indicators of exacerbation; Round 3 participants rated the importance of statements which were subsequently placed in rank order. RESULTS: Objective measurements were of higher importance to health professionals. Feelings of increased debility were rated most important by adults with CF. CONCLUSIONS: There were clear differences in perspectives between the two groups as to the most important indicators of an exacerbation. This highlights that CF health professionals should take more cognisance of specific signs and symptoms reported by adults with CF, especially since these may be a precursor to an exacerbation.
Asunto(s)
Fibrosis Quística/fisiopatología , Progresión de la Enfermedad , Personal de Salud , Pulmón/fisiopatología , Adulto , Estudios Transversales , Técnica Delphi , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Medición de Riesgo , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Reino Unido , Adulto JovenRESUMEN
BACKGROUND: Inhaled antibiotics are standard of care for persons with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infection. APT-1026 (levofloxacin inhalation solution, LIS) is fluoroquinolone in development. We compared the safety and efficacy of LIS to tobramycin inhalation solution (TIS) in persons ≥12 years old with CF and chronic P. aeruginosa infection. METHODS: This multinational, randomized (2:1), non-inferiority study compared LIS and TIS over three 28-day on/off cycles. Day 28 FEV(1) % predicted relative change was the primary endpoint. Time to exacerbation and patient-reported quality of life were among secondary endpoints. RESULTS: Baseline demographics for 282 subjects were comparable. Non-inferiority was demonstrated (1.86% predicted mean FEV(1) difference [95% CI -0.66 to 4.39%]). LIS was well-tolerated, with dysgeusia (taste distortion) as the most frequent adverse event. CONCLUSIONS: LIS is a safe and effective therapy for the management of CF patients with chronic P. aeruginosa infection.
Asunto(s)
Antibacterianos/administración & dosificación , Fibrosis Quística/tratamiento farmacológico , Levofloxacino/administración & dosificación , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa , Tobramicina/administración & dosificación , Administración por Inhalación , Adolescente , Adulto , Enfermedad Crónica , Fibrosis Quística/microbiología , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Infecciones por Pseudomonas/complicaciones , Calidad de Vida , Resultado del Tratamiento , Adulto JovenAsunto(s)
Enfermedad Crónica/terapia , Fibrosis Quística/complicaciones , Farmacorresistencia Bacteriana/efectos de los fármacos , Infecciones del Sistema Respiratorio , Antibacterianos/uso terapéutico , Programas de Optimización del Uso de los Antimicrobianos/métodos , Programas de Optimización del Uso de los Antimicrobianos/organización & administración , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/fisiopatologíaAsunto(s)
Alveolitis Alérgica Extrínseca/etiología , Terapias Complementarias/efectos adversos , Intoxicación por Setas/complicaciones , Enfermedades Profesionales/etiología , Alveolitis Alérgica Extrínseca/epidemiología , Alveolitis Alérgica Extrínseca/prevención & control , Industria de Procesamiento de Alimentos , Salud Global , Humanos , Incidencia , Intoxicación por Setas/epidemiología , Intoxicación por Setas/prevención & control , Rol de la Enfermera , Enfermedades Profesionales/epidemiología , Enfermedades Profesionales/prevención & control , Salud Laboral , Factores de RiesgoRESUMEN
A microbiological study was undertaken to assess the risk of infection to a CF patient from a collection of pet reptiles, particularly atypical mycobacteria. This study helped to verify that the reptiles under the care of the CF patient did not harbour bacterial organisms that would normally be pathogenic to CF patients. However, the chronic carriage of Pseudomonas aeruginosa and other pathogens in the CF patient may constitute a greater risk of infection to the animals being handled. Therefore, we recommend stringent infection control precautions by CF patients and their pets, particularly adherence to hand washing and disinfection, when handling the animals, their litter or when working with their immediate environment, to potentially minimize the spread of bacterial and other pathogens from animal to human and vice versa. Detailed risk assessments therefore need to be undertaken by clinicians and veterinarians to detail working models that protect both animals and patients from pathogens originating from the other.