Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine

In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially since the advent of the new CFTR modulators which had the potential to correct this protein’s dysfunction in COPD. The CFTR is an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway. Therefore, its abnormal function favours the accumulation of thicker and more viscous secretions, reduces the periciliary layer and mucociliary clearance, and produces inflammation in the airway, as a consequence of a bronchial infection by both bacteria and viruses. Identifying CFTR dysfunction in the context of COPD pathogenesis is key to fully understanding its role in the complex pathophysiology of COPD and the potential of the different therapeutic approaches proposed to overcome this dysfunction. In particular, the potential of the rehydration of mucus and the role of antioxidants and phosphodiesterase inhibitors should be discussed. Additionally, the modulatory drugs which enhance or restore decreased levels of the protein CFTR were recently described. In particular, two CFTR potentiators, ivacaftor and icenticaftor, were explored in COPD. The present review updated the pathophysiology of the complex role of CFTR in COPD and the therapeutic options which could be explored

Triple therapy for COPD: A crude analysis from a systematic review of the evidence

We systematically reviewed the current knowledge on fixed-dose triple therapies for the treatment of chronic obstructive pulmonary disease (COPD), with a specific focus on its efficacy versus single bronchodilation, double fixed dose combinations, and open triple therapies. Articles were retrieved from PubMed, Embase, and Scopus up to 3 August 2018. We selected articles with randomized controlled or crossover design conducted in patients with COPD and published as fulllength articles or scientific letters, evaluating triple therapy combinations in a single or different inhaler, and with efficacy data versus monocomponents, double combinations, or open triple therapies. Our systematic search reported 108 articles, of which 24 trials were finally selected for the analysis. A total of 7 studies with fixed dose triple therapy combinations, and 17 studies with open triple therapies combinations. Triple therapy showed improvements in lung function [trough forced expiratory volume (FEV1) ranging from not significant (NS) to 147 ml], health status using the St. George’s Respiratory Questionnaire [(SGRQ) from NS to 8.8 points], and exacerbations [risk ratio (RR) from NS to 0.59 for all exacerbations] versus single or double therapies with a variability in the response, depending the specific combination, and the comparison group. The proportion of adverse effects was similar between study groups, the exception being the increase in pneumonia for some inhaled corticosteroid (ICS) containing grou

Clinical Audits in Outpatient Clinics for Chronic Obstructive Pulmonary Disease: Methodological Considerations and Workflow

Objectives: Previous clinical audits for chronic obstructive pulmonary disease (COPD) have provided valuable information on the clinical care delivered to patients admitted to medical wards because of COPD exacerbations. However, clinical audits of COPD in an outpatient setting are scarce and no methodological guidelines are currently available. Based on our previous experience, herein we describe a clinical audit for COPD patients in specialized outpatient clinics with the overall goal of establishing a potential methodological workflow.Methods: A pilot clinical audit of COPD patients referred to respiratory outpatient clinics in the region of Andalusia, Spain (over 8 million inhabitants), was performed. The audit took place between October 2013 and September 2014, and 10 centers (20% of all public hospitals) were invited to participate. Cases with an established diagnosis of COPD based on risk factors, clinical symptoms, and a post-bronchodilator FEV1/FVC ratio of less than 0.70 were deemed eligible. The usefulness of formally scheduled regular follow-up visits was assessed. Two different databases (resources and clinical database) were constructed. Assessments were planned over a year divided by 4 three-month periods, with the goal of determining seasonal-related changes. Exacerbations and survival served as the main endpoints.Conclusions: This paper describes a methodological framework for conducting a clinical audit of COPD patients in an outpatient setting. Results from such audits can guide health information systems development and implementation in real-world settings.This study was financially supported by an unrestricted grant from Laboratorios Menarini, SA (Barcelona, Spain)

Expresión diferencial de reactantes de fase aguda en distintos tipos celulares de pacientes con enfermedad pulmonar obstructiva crónica

La presente Tesis Doctoral se enmarca en el estudio de la enfermedad pulmonar obstructiva crónica (EPOC) como enfermedad pulmonar con repercusión sistémica y se basa en el estudio de la expresión celular diferencial de marcadores inflamatorios inespecíficos haciendo un especial hincapié en la importancia de los reactantes de fase aguda. Con objeto de centrar la exposición de la metodología y poder valorar adecuadamente los resultados, iniciaremos el presente trabajo realizando una revisión de la situación actual del tema. En concreto, revisaremos los siguientes apartados: · EPOC. Concepto actual. Donde se revisarán los aspectos principales del concepto actual de la enfermedad, así como su estadificación funcional. · Conceptos básicos sobre su diagnóstico y detección en pacientes con factores de riesgo. · Epidemiología de la EPOC. Haciendo especial énfasis en la prevalencia, mortalidad y morbilidad. · Patogenia. Datos sobre la patogenia de la enfermedad, donde se discutirán los principales tipos celulares implicados en su génesis. · Importancia de la inflamación sistémica. Evaluación de la importancia de la inflamación sistémica dentro del nuevo marco conceptual de la EPOC como enfermedad sistémica. · Reactantes de fase aguda mayores. Importancia de los reactantes de fase aguda como parte de la inflamación sistémica y base de nuestro estudio. Existe producción de RFA por el tejido pulmonar siendo ésta diferente según el territorio y el tipo celular analizado y variando entre pacientes con EPOC frente a fumadores sanos, de manera que su síntesis se encuentra relacionada con la presencia de la enfermedad. Objetivos OBJETIVOS PRINCIPALES 1. Explorar la existencia de una expresión génica de RFA en sujetos sanos y comparala con los pacientes con EPOC. 2. Comparar la expresión génica de PCR y AAS en el tejido bronquial y en parénquima de pulmón humano. 3. Determinar la expresión de PCR y AAS en células epiteliales, macrófagos y fibroblastos pulmonares humanos. 4. Comparar la expresión génica de RFA en dichos grupos celulares entre pacientes con EPOC frente a fumadores sanos

Agudizaciones frecuentes o persistentes: identificando el problema real

Peer reviewe

Understanding of COPD among final-year medical students.

Several previous studies have shown a suboptimal level of understanding of COPD among different population groups. Students in their final year of Medicine constitute a population that has yet to be explored. The evaluation of their understanding provides an opportunity to establish strategies to improve teaching processes. The objective of the present study is to determine the current level of understanding of COPD among said population. A cross-sectional observational study was done using digital surveys given to medical students in their final year at the Universidad de Sevilla. Those surveyed were asked about demographic data, smoking habits as well as the clinical manifestation, diagnosis and treatment of COPD. Of the 338 students contacted, responses were collected from 211 of them (62.4%). Only 25.2% had an accurate idea about the concept of the disease. The study found that 24.0% of students were familiar with the three main symptoms of COPD. Tobacco use was not considered a main risk factor for COPD by 1.5% of students. Of those surveyed, 22.8% did not know how to spirometrically diagnose COPD. Inhaled corticosteroids were believed to be part of the main treatment for this disease among 51.0% of the students. Results show that 36.4% of respondents believed that home oxygen therapy does not help COPD patients live longer. Only 15.0% considered the Body-mass index, airflow Obstruction, Dyspnea, and Exercise (BODE) index to be an important parameter for measuring the severity of COPD. Giving up smoking was not believed to prevent worsening COPD among 3.4% of students surveyed. Almost half of students (47.1%) did not recommend that those suffering from COPD undertake exercise. The moderate level of understanding among the population of medical students in their final year shows some strengths and some shortcomings. Teaching intervention is required to reinforce solid knowledge among this population

Cellular mechanisms involved in the pathogenesis of airway remodeling in chronic lung disease

[Background] Airway epithelial cells and lung fibroblasts play an important role in the development of chronic lung disease, but the exact mechanisms responsible have not been clarified. Our objective was to investigate the involvement of these cells in the inflammatory response associated to chronic lung disease.[Methods] Human lung fibroblasts and airway epithelial cells were challenged with Interleukin-1β and hypoxia, and with inhibitory (simvastatin) stimuli of the inflammatory response. Expression of markers of local inflammation ((IL-8, monocyte chemoattractant protein-1 (MCP-1), factor-κB1 (NF-κB1)), systemic inflammation ((C-reactive protein (CRP) and serum amyloid A (SAA)) and proteases matrix metalloproteinase (MMP) 9 and 12 were assessed by PCR and ELISA. Apoptosis/necrosis was analyzed by flow cytometry.[Results] Our results showed that the lung fibroblasts had a higher expression of local and systemic inflammation and protease activity markers when they were treated with IL-1β compared to airway epithelial cells. Under hypoxic conditions, we observed a decrease in systemic inflammation in lung fibroblasts, which was further attenuated by simvastatin.[Conclusion] The lung fibroblasts seem to be the main initially stimulated cells that could potentially trigger the inflammatory response, and be responsible for the eventual onset of chronic lung disease. The involvement of IL-1ß stimulation in systemic inflammatory and proteinase imbalance biomarkers is higher in lung fibroblasts. Apoptosis is not a predominant mechanism in these cells.This study was financially supported by grants from the Instituto de Salud Carlos III, Ministerio de Economía (PI12/01576) and from the Sociedad Española de Neumología y Cirugía Torácica (094/2013).Peer reviewe

Evaluation of lung parenchyma, blood vessels, and peripheral blood lymphocytes as a potential source of acute phase reactants in patients with COPD

[Background] Previous studies have shown that the arterial wall is a potential source of inflammatory markers in COPD. Here, we sought to compare the expression of acute phase reactants (APRs) in COPD patients and controls both at the local (pulmonary arteries and lung parenchyma) and systemic (peripheral blood leukocytes and plasma) compartments.[Methods] Consecutive patients undergoing elective surgery for suspected primary lung cancer were eligible for the study. Patients were categorized either as COPD or control group based on the spirometry results. Pulmonary arteries and lung parenchyma sections, peripheral blood leukocytes, and plasma samples were obtained from all participants. Gene expression levels of C-reactive protein (CRP) and serum amyloid A (SAA1, SAA2, and SAA4) were evaluated in tissue samples and peripheral blood leukocytes by reverse transciption-PCR. Plasma CRP and SAA protein levels were measured by enzyme-linked immunosorbent assays. Proteins were evaluated in paraffin-embedded lung tissues by immunohistochemistry.[Results]A total of 40 patients with COPD and 62 controls were enrolled. We did not find significant differences in the gene expression between COPD and control group. Both CRP and SAA were overexpressed in the lung parenchyma compared with pulmonary arteries and peripheral blood leukocytes. The expression of SAA was significantly higher in the lung parenchyma than in the pulmonary artery (2-fold higher for SAA1 and SAA4, P=0.015 and P<0.001, respectively; 8-fold higher for SAA2, P<0.001) and peripheral blood leukocytes (16-fold higher for SAA1, 439-fold higher for SAA2, and 5-fold higher for SAA4; P<0.001). No correlation between plasma levels of inflammatory markers and their expression in the lung and peripheral blood leukocytes was observed.[Conclusions] The expression of SAA in lung parenchyma is higher than in pulmonary artery and peripheral blood leukocytes. Notably, no associations were noted between lung expression of APRs and their circulating plasma levels, making the leakage of inflammatory proteins from the lung to the bloodstream unlikely. Based on these results, other potential sources of systemic inflammation in COPD (eg, the liver) need further scrutiny.The authors thank the HUVR-IBiS Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobanco PT13/0010/0056) for the assessment and technical support provided. This study was financially supported by grants from Fundación de Neumología y Cirugía Torácica del Sur (Neumosur) No. 4/2012 and from the Instituto de Salud Carlos III, Ministerio de Economía (PI12/01576)