Phosphodiesterase isoforms and cAMP compartments in the development of new therapies for obstructive pulmonary diseases.

The second messenger molecule 3'5'-cyclic adenosine monophosphate (cAMP) imparts several beneficial effects in lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). While cAMP is bronchodilatory in asthma and COPD, it also displays anti-fibrotic properties that limit fibrosis. Phosphodiesterases (PDEs) metabolize cAMP and thus regulate cAMP signaling. While some existing therapies inhibit PDEs, there are only broad family specific inhibitors. The understanding of cAMP signaling compartments, some centered around lipid rafts/caveolae, has led to interest in defining how specific PDE isoforms maintain these signaling microdomains. The possible altered expression of PDEs, and thus abnormal cAMP signaling, in obstructive lung diseases has been poorly explored. We propose that inhibition of specific PDE isoforms can improve therapy of obstructive lung diseases by amplifying specific cAMP signals in discreet microdomains.

Role of CD38/cADPR signaling in obstructive pulmonary diseases.

The worldwide socioeconomical burden associated with chronic respiratory diseases is substantial. Enzymes involved in the metabolism of nicotinamide adenine dinucleotide (NAD) are increasingly being implicated in chronic airway diseases. One such enzyme, CD38, utilizes NAD to produce several metabolites, including cyclic ADP ribose (cADPR), which is involved in calcium signaling in airway smooth muscle (ASM). Upregulation of CD38 in ASM caused by exposure to cytokines or allergens leads to enhanced calcium mobilization by agonists and the development of airway hyperresponsiveness (AHR) to contractile agonists. Glucocorticoids and microRNAs can suppress CD38 expression in ASM, whereas cADPR antagonists such as 8Br-cADPR can directly antagonize intracellular calcium mobilization. Bronchodilators act via CD38-independent mechanisms. CD38-dependent mechanisms could be developed for chronic airway diseases therapy.

Intratracheal GLP-1 receptor agonist treatment up-regulates mucin via p38 and exacerbates emphysematous phenotype in mucus hypersecretory obstructive lung diseases.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone that stimulates glucose-mediated insulin production by pancreatic beta cells. It is also associated with protective effects in multiple tissues. GLP-1 receptor is highly expressed in pulmonary tissue, hinting possible pulmonary delivery of GLP-1 drugs. However, little is known about the role of GLP-1 signaling in the lung, especially in mucus hypersecretory obstructive lung diseases. Here, we showed that treatment with exendin-4, a clinically available GLP-1 receptor agonist, up-regulates mucin expression in normal airway epithelial cells and in the lung of normal mice, indicating mucus stimulatory effect of GLP-1 under physiological condition. Exendin-4 also increased mucin expression in in vitro cellular and in vivo murine models of obstructive lung diseases via the activation of p38 MAP kinase. Notably, mucin induction in vivo exacerbated key pulmonary abnormalities including emphysematous phenotypes, implying that GLP-1 signaling in the lung is detrimental under pulmonary obstructive condition. Another GLP-1 receptor agonist liraglutide had similar induction of mucin. Together, our studies not only demonstrate novel physiological and pathological roles of GLP-1 in the lung but may also caution against the clinical use of inhaled GLP-1 receptor agonists in the patients with obstructive lung diseases.

Lack of IL-1 Receptor Signaling Reduces Spontaneous Airway Eosinophilia in Juvenile Mice with Muco-Obstructive Lung Disease.

Previous studies demonstrated spontaneous type 2 airway inflammation with eosinophilia in juvenile Scnn1b (sodium channel, non-voltage-gated 1, ß-subunit)-transgenic (Scnn1b-Tg) mice with muco-obstructive lung disease. IL-1 receptor (IL-1R) signaling has been implicated in allergen-driven airway disease; however, its role in eosinophilic inflammation in muco-obstructive lung disease remains unknown. In this study, we examined the role of IL-1R signaling in the development of airway eosinophilia and type 2 inflammation in juvenile Scnn1b-Tg mice. We determined effects of genetic deletion of Il1r1 (IL-1 receptor type I) on eosinophil counts, transcript levels of key type 2 cytokines, markers of eosinophil activation and apoptosis, and tissue morphology in lungs of Scnn1b-Tg mice at different time points during neonatal development. Furthermore, we measured endothelial surface expression of intercellular adhesion molecule 1 (ICAM-1), an integrin involved in eosinophil transendothelial migration, and determined effects of eosinophil depletion using an anti-IL-5 antibody on lung morphology. Lack of IL-1R reduced airway eosinophilia and structural lung damage, but it did not reduce concentrations of type 2 cytokines and associated eosinophil activation in Scnn1b-Tg mice. Structural lung damage in Scnn1b-Tg mice was also reduced by eosinophil depletion. Lack of IL-1R was associated with reduced expression of ICAM-1 on lung endothelial cells and reduced eosinophil counts in lungs from Scnn1b-Tg mice. We conclude that IL-1R signaling is implicated in airway eosinophilia independent of type 2 cytokines in juvenile Scnn1b-Tg mice. Our data suggest that IL-1R signaling may be relevant in the pathogenesis of eosinophilic airway inflammation in muco-obstructive lung diseases, which may be mediated in part by ICAM-1-dependent transmigration of eosinophils into the lungs.

The role of elastin-derived peptides in human physiology and diseases.

Once considered as inert, the extracellular matrix recently revealed to be biologically active. Elastin is one of the most important components of the extracellular matrix. Many vital organs including arteries, lungs and skin contain high amounts of elastin to assure their correct function. Physiologically, the organism contains a determined quantity of elastin from the early development which may remain physiologically constant due to its very long half-life and very low turnover. Taking into consideration the continuously ongoing challenges during life, there is a physiological degradation of elastin into elastin-derived peptides which is accentuated in several disease states such as obstructive pulmonary diseases, atherosclerosis and aortic aneurysm. These elastin-derived peptides have been shown to have various biological effects mediated through their interaction with their cognate receptor called elastin receptor complex eliciting several signal transduction pathways. In this review, we will describe the production and the biological effects of elastin-derived peptides in physiology and pathology.

Respiratory complications of metabolic disease in the paediatric population: A review of presentation, diagnosis and therapeutic options.

Inborn errors of metabolism (IEMs) whilst individually rare, as a group constitute a field which is increasingly demands on pulmonologists. With the advent of new therapies such as enzyme replacement and gene therapy, early diagnosis and treatment of these conditions can impact on long term outcome, making their timely recognition and appropriate investigation increasingly important. Conversely, with improved treatment, survival of these patients is increasing, with the emergence of previously unknown respiratory phenotypes. It is thus important that pulmonologists are aware of and appropriately monitor and manage these complications. This review aims to highlight the respiratory manifestations which can occur. It isdivided into conditions resulting primarily in obstructive airway and lung disease, restrictive lung disease such as interstitial lung disease or pulmonary alveolar proteinosis and pulmonary hypertension, whilst acknowledging that some diseases have the potential to cause all three. The review focuses on general phenotypes of IEMs, their known respiratory complications and the basic metabolic investigations which should be performed where an IEM is suspected.

Fractional exhaled nitric oxide in preterm-born subjects: A systematic review and meta-analysis.

BACKGROUND: Decreased lung function is common in preterm-born survivors. Increased fractional exhaled nitric oxide (FeNO) appears to be a reliable test for eosinophillic airway inflammation especially in asthma. We, systematically, reviewed the literature to compare FeNO levels in preterm-born children and adults who did or did not have chronic lung disease of prematurity (CLD) in infancy with term-born controls. METHODS: We searched eight databases up to February 2018. Studies comparing FeNO levels in preterm-born subjects (<37 weeks' gestation) in childhood and adulthood with and without (CLD) with term-born subjects were identified and extracted by two reviewers. Data were analysed using Review Manager v5.3. RESULTS: From 6042 article titles, 183 full articles were screened for inclusion. Nineteen studies met the inclusion criteria. Seventeen studies compared FeNO levels in preterm- and term-born children and adults; 11 studies (preterm n = 640 and term n = 4005) were included in a meta-analysis. The mean FeNO concentration difference between the preterm-born and term-born group was -0.74 (95% CI -1.88 to 0.41) ppb. For the six studies reporting data on CLD (preterm n = 204 and term n = 211) the mean difference for FeNO levels was -2.82 (95% CI -5.87 to 0.22) ppb between the preterm-born CLD and term-born groups. CONCLUSIONS: Our data suggest that preterm born children with and without CLD have similar FeNO levels to term-born children suggesting an alternative mechanism to eosinophilic inflammation for symptoms of wheezing and airway obstruction observed in preterm-born subjects.

Increasing complexity and interactions of oxidative stress in chronic respiratory diseases: An emerging need for novel drug delivery systems.

Oxidative stress is intensely involved in enhancing the severity of various chronic respiratory diseases (CRDs) including asthma, chronic obstructive pulmonary disease (COPD), infections and lung cancer. Even though there are various existing anti-inflammatory therapies, which are not enough to control the inflammation caused due to various contributing factors such as anti-inflammatory genes and antioxidant enzymes. This leads to an urgent need of novel drug delivery systems to combat the oxidative stress. This review gives a brief insight into the biological factors involved in causing oxidative stress, one of the emerging hallmark feature in CRDs and particularly, highlighting recent trends in various novel drug delivery carriers including microparticles, microemulsions, microspheres, nanoparticles, liposomes, dendrimers, solid lipid nanocarriers etc which can help in combating the oxidative stress in CRDs and ultimately reducing the disease burden and improving the quality of life with CRDs patients. These carriers improve the pharmacokinetics and bioavailability to the target site. However, there is an urgent need for translational studies to validate the drug delivery carriers for clinical administration in the pulmonary clinic.

Combination of urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate for the treatment of inflammatory lung diseases: An in vitro study.

This in vitro study evaluated, for the first time, the safety and the biological activity of a novel urea-crosslinked hyaluronic acid component and sodium ascorbyl phosphate (HA-CL - SAP), singularly and/or in combination, intended for the treatment of inflammatory lung diseases. The aim was to understand if the combination HA-CL - SAP had an enhanced activity with respect to the combination native hyaluronic acid (HA) - SAP and the single SAP, HA and HA-CL components. Sample solutions displayed pH, osmolality and viscosity values suitable for lung delivery and showed to be not toxic on epithelial Calu-3 cells at the concentrations used in this study. The HA-CL - SAP displayed the most significant reduction in interleukin-6 (IL-6) and reactive oxygen species (ROS) levels, due to the combined action of HA-CL and SAP. Moreover, this combination showed improved cellular healing (wound closure) with respect to HA - SAP, SAP and HA, although at a lower rate than HA-CL alone. These preliminary results showed that the combination HA-CL - SAP could be suitable to reduce inflammation and oxidative stress in lung disorders like acute respiratory distress syndrome, asthma, emphysema and chronic obstructive pulmonary disease, where inflammation is prominent.

Tiotropium bromide exerts anti-inflammatory effects during resistive breathing, an experimental model of severe airway obstruction.

INTRODUCTION: Resistive breathing (RB), a hallmark of obstructive airway diseases, is characterized by strenuous contractions of the inspiratory muscles that impose increased mechanical stress on the lung. RB is shown to induce pulmonary inflammation in previous healthy animals. Tiotropium bromide, an anticholinergic bronchodilator, is also shown to exert anti-inflammatory effects. The effect of tiotropium on RB-induced pulmonary inflammation is unknown. METHODS: Adult rats were anesthetized, tracheostomized and breathed spontaneously through a two-way non-rebreathing valve. Resistances were connected to the inspiratory and/or expiratory port, to produce inspiratory resistive breathing (IRB) of 40% or 50% Pi/Pi,max (40% and 50% IRB), expiratory resistive breathing (ERB) of 60% Pe/Pe,max (60% ERB) or combined resistive breathing (CRB) of both 40% Pi/Pi,max and 60% Pe/Pe,max (40%/60% CRB). Tiotropium aerosol was inhaled prior to RB. After 6 h of RB, mechanical parameters of the respiratory system were measured and bronchoalveolar lavage (BAL) was performed. IL-1ß and IL-6 protein levels were measured in lung tissue. Lung injury was estimated histologically. RESULTS: In all, 40% and 50% IRB increased macrophage and neutrophil counts in BAL and raised IL-1ß and IL-6 lung levels, tissue elasticity, BAL total protein levels and lung injury score. Tiotropium attenuated BAL neutrophil number, IL-1ß, IL-6 levels and lung injury score increase at both 40% and 50% IRB. The increase in macrophage count and protein in BAL was only reversed at 40% IRB, while tissue elasticity was not affected. In all, 60% ERB raised BAL neutrophil count and total protein and reduced macrophage count. IL-1ß and IL-6 levels and lung injury score were increased. Tiotropium attenuated these alterations, except for the decrease in macrophage count and the increase in total protein level. In all, 40%/60% CRB increased macrophage and neutrophil count in BAL, IL-1ß and IL-6 levels, tissue elasticity, total protein in BAL and histological injury score. Tiotropium attenuated the aforementioned alterations. CONCLUSION: Tiotropium inhalation attenuates RB-induced pulmonary inflammation.

Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease.

NSCLC is a leading cause of morbidity and mortality worldwide. It includes adeno- and squamous cell carcinoma. In the background, COPD and smoking play a vital role in development of NSCLC. Local progression and metastasis of NSCLC has been associated with various mechanisms, but in particular by a process called epithelial mesenchymal transition (EMT), which is implicated in COPD pathogenesis. In this study, we have investigated whether expression of EGFR (activation marker) and S100A4, vimentin and N-cadherin (as EMT) is different both in central and leading edge of NSCLC and to what extent related to EMT activity of both small and large airways, stage and differentiation of NSCLC. We have investigated EMT biomarkers (S100A4, vimentin, and N-cadherin), an epithelial activation marker (EGFR) and a vascularity marker (Type-IV collagen) in surgically resected tissue from patients with NSCLC (adeno- and squamous cell carcinoma), and compared them with expression in the corresponding non-tumorous airways. EGFR, S100A4, vimentin, N-cadherin expression was higher in tumor cells located at the peripheral leading edge of NSCLC when compared with centrally located tumor cells of same subjects (P < 0.01). Type-IV collagen-expressing blood vessels were also more at the leading edge in comparison with central parts of NSCLC. EGFR and S100A4 expression was related to differentiation status (P < 0.05) and TNM stage (P < 0.05) of NSCLC. Moreover, EMT markers in the leading edge were significantly related to airway EMT activity, while peripheral edge vascularity of squamous cell carcinoma only was significantly related to large airway Rbm vascularity (P < 0.05). EGFR- and EMT-related protein expression was markedly high in the peripheral leading edge of NSCLCs and related to tumor characteristics associated with poor prognosis. The relationships between EMT-related tumor biomarker expression and those in the airway epithelium and Rbm provide a background for utility of airway changes in clinical settings.

Expiratory Snoring Predicts Obstructive Pulmonary Disease in Patients with Sleep-disordered Breathing.

RATIONALE: Sleep-disordered breathing and chronic obstructive pulmonary disease are two common conditions that may present concomitantly. The effects of chronic obstructive pulmonary disease on the polysomnographic manifestation of sleep-disordered breathing have not been studied. OBJECTIVES: We hypothesized that the presence of airflow obstruction could be predicted by the presence of expiratory upper airway narrowing during sleep in patients with sleep-disordered breathing. METHODS: Ninety-three patients with sleep-disordered breathing (19 men; age, 51.6 yr; body mass index, 40.1 kg/m(2); apnea-hypopnea index, 37.4 events/h) were observed. Every patient had an in-lab polysomnography study and complete pulmonary function tests. Sleep and respiratory events were scored using American Academy of Sleep Medicine recommended scoring criteria. Expiratory snoring events were identified on polysomnography using microphone sensor and/or pressure flow sensor in each patient. The FEV1/FVC ratio less than 70 was used to define the presence of airflow obstruction. MEASUREMENTS AND MAIN RESULTS: The proportion analysis demonstrated that patients with expiratory snoring have 11 times higher odds of having evidence of lower airway obstruction, defined as FEV1/FVC less than 70 (odds ratio [OR], 11.03; P < 0.001), whereas smokers have increased odds by 13 times (OR, 13.18; P < 0.001). Spearman correlation analysis showed that FEV1 was positively related to mean SaO2 (P < 0.05) and negatively related to expiratory snoring, smoking, 3% oxygen desaturation index, 2% oxygen desaturation index, and age (P < 0.05). Epworth sleepiness scale, sex, and body mass index did not have any association with FEV1. The multiple logistic regression analysis demonstrated that chronic obstructive pulmonary disease (FEV1/FVC < 70) correlated significantly with expiratory snoring and smoking (OR, 11.76; confidence interval, 3.23-42.83; and OR, 9.95; confidence interval, 2.67-37.09), respectively. The multiple linear regression analysis revealed that the linear combination of mean SaO2 and expiratory snoring (P < 0.05) predicted FEV1. However, age and 2% oxygen desaturation index did not predict FEV1. CONCLUSIONS: The presence of expiratory snoring predicts obstructive airway disorders. Patients with expiratory snoring and low mean oxygen saturation during sleep should be carefully assessed for pulmonary disorders such as asthma and chronic obstructive pulmonary disease.

The Microenvironment of Lung Cancer and Therapeutic Implications.

The tumor microenvironment (TME) represents a milieu that enables tumor cells to acquire the hallmarks of cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. Concerted interactions between genetically altered tumor cells and genetically stable intratumoral stromal cells result in an "activated/reprogramed" stroma that promotes carcinogenesis by contributing to inflammation, immune suppression, therapeutic resistance, and generating premetastatic niches that support the initiation and establishment of distant metastasis. The lungs present a unique milieu in which tumors progress in collusion with the TME, as evidenced by regions of aberrant angiogenesis, acidosis and hypoxia. Inflammation plays an important role in the pathogenesis of lung cancer, and pulmonary disorders in lung cancer patients such as chronic obstructive pulmonary disease (COPD) and emphysema, constitute comorbid conditions and are independent risk factors for lung cancer. The TME also contributes to immune suppression, induces epithelial-to-mesenchymal transition (EMT) and diminishes efficacy of chemotherapies. Thus, the TME has begun to emerge as the "Achilles heel" of the disease, and constitutes an attractive target for anti-cancer therapy. Drugs targeting the components of the TME are making their way into clinical trials. Here, we will focus on recent advances and emerging concepts regarding the intriguing role of the TME in lung cancer progression, and discuss future directions in the context of novel diagnostic and therapeutic opportunities.

Secretoglobin and Transferrin Expression in Bronchoalveolar Lavage Fluid of Horses with Chronic Respiratory Disease.

BACKGROUND: Lower expression of secretoglobin and transferrin has been found in the bronchoalveolar lavage fluid (BALF) of a small number of horses with experimentally induced signs of recurrent airway obstruction (RAO) compared to healthy controls. HYPOTHESIS/OBJECTIVES: Secretoglobin and transferrin BALF expression will be similarly decreased in horses with naturally occurring clinical signs of RAO and in horses with experimentally induced clinical signs of RAO as compared to healthy controls and intermediate in horses with inflammatory airway disease (IAD). ANIMALS: Recurrent airway obstruction-affected and control horses were subjected to an experimental hay exposure trial to induce signs of RAO. Client-owned horses with a presumptive diagnosis of RAO and controls from the same stable environments were recruited. METHODS: Pulmonary function and BALF were evaluated from control and RAO-affected research horses during an experimental hay exposure trial (n = 5 in each group) and from client-owned horses (RAO-affected horses, n = 17; IAD-affected horses, n = 19; healthy controls, n = 5). The concentrations of secretoglobin and transferrin in BALF were assessed using Western blots. RESULTS: Naturally occurring and experimentally induced RAO horses had similar decreases in BALF transferrin expression, but secretoglobin expression was most decreased in naturally occurring RAO. Secretoglobin and transferrin expression were both lower in BALF of RAO-affected horses than in IAD-affected and control horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Secretoglobin and transferrin expression is decreased in BALF of RAO-affected horses after both experimental and natural exposure. Secretoglobin and transferrin likely play clinically relevant roles in the pathophysiology of RAO, and may thus be used as biomarkers of the disease.

Different approaches in the treatment of obstructive pulmonary diseases.

Advances in drug formulation, inhalation device design and disease management are generating new opportunities for patients suffering from obstructive pulmonary diseases. This article provides a comprehensive review of the different promising pulmonary drug delivery technologies in the treatment of obstructive pulmonary diseases, particularly with regard to the treatment of asthma and chronic pulmonary diseases (COPD), which are increasing day by day due to increasing environmental pollution and its harmful and toxic contaminants. In the recent years, a better knowledge has been gained regarding the mechanism of action of glucocorticoids and how they suppress the chronic inflammation. New etiology has been brought into light regarding the inactivity of glucocorticoids in some patients having asthma and COPDs even though the inflammatory genes are triggered by similar molecules in both the diseases. This new knowledge has given a new platform to improve glucocorticoids and their resistance also how other combination therapy can be used for these diseases. It has also led to the quest for improving and developing other alternatives such as anti-leukotriene agents, muscarinic inhibitors, combination therapy, as well as biologic immune-modulators in the treatment of the different pulmonary diseases. Several new combinations of glucocorticoids are available in the global market for the use in pulmonary diseases especially asthma although their availability fluctuates between continents. There has been several studies done regarding the variation of effectiveness of the different inhaled glucocorticoids and hence it is important to take into consideration the different delivery systems and the methods which are used to treat the patients.

Mecanismos patogénicos en la enfermedad pulmonar obstructiva crónica causada por exposición a humo de biomasa / Pathogenic Mechanisms in Chronic Obstructive Pulmonary Disease Due to Biomass Smoke Exposure

Las tasas de mortalidad y morbilidad de la enfermedad pulmonar obstructiva crónica (EPOC) han aumentado mundialmente de forma significativa durante las últimas décadas. A pesar de que el humo de tabaco se sigue considerando el principal factor etiopatogénico para el desarrollo de la enfermedad, se estima que entre una tercera y una cuarta parte de los pacientes con EPOC son no fumadores. De todos los factores de riesgo que pueden incrementar la probabilidad de sufrir EPOC en estos sujetos se ha propuesto al humo de biomasa como uno de los más importantes, afectando sobre todo a mujeres y a niños de países emergentes. Aunque existen numerosas evidencias epidemiológicas que relacionan la exposición al humo de biomasa con efectos nocivos para la salud, todavía no se conocen bien los mecanismos celulares y moleculares específicos mediante los cuales este contaminante puede suponer una noxa para los sistemas respiratorio y cardiovascular. En esta revisión se recogen los mecanismos patogénicos propuestos hasta la fecha que sitúan al humo de biomasa como uno de los principales factores de riesgo para la EPOC

Chronic obstructive pulmonary disease (COPD) mortality and morbidity have increased significantly worldwide in recent decades. Although cigarette smoke is still considered the main risk factor for the development of the disease, estimates suggest that between 25% and 33% of COPD patients are nonsmokers. Among the factors that may increase the risk of developing COPD, biomass smoke has been proposed as one of the most important, affecting especially women and children in developing countries. Despite the epidemiological evidence linking exposure to biomass smoke with adverse health effects, the specific cellular and molecular mechanisms by which this pollutant can be harmful for the respiratory and cardiovascular systems remain unclear. In this article we review the main pathogenic mechanisms proposed to date that make biomass smoke one of the major risk factors for COPD

Transforming growth factor-ß superfamily in obstructive lung diseases. more suspects than TGF-ß alone.

Asthma and chronic obstructive pulmonary disease are respiratory disorders and a major global health problem with increasing incidence and severity. Genes originally associated with lung development could be relevant in the pathogenesis of chronic obstructive pulmonary disease/asthma, owing to either an early-life origin of adult complex diseases or their dysregulation in adulthood upon exposure to environmental stressors (e.g., smoking). The transforming growth factor (TGF)-ß superfamily is conserved through evolution and is involved in a range of biological processes, both during development and in adult tissue homeostasis. TGF-ß1 has emerged as an important regulator of lung and immune system development. However, considerable evidence has been presented for a role of many of the other ligands of the TGF-ß superfamily in lung pathology, including activins, bone morphogenetic proteins, and growth differentiation factors. In this review, we summarize the current knowledge on the mechanisms by which activin, bone morphogenetic protein, and growth differentiation factor signaling contribute to the pathogenesis of obstructive airway diseases.

Deterioro cognitivo, estado nutricional y perfil clínico en la enfermedad pulmonar obstructiva crónica / Cognitive impairment, nutritional satus and clinical profile in chronic obstructive pulmonary disease

Introducción: La enfermedad pulmonar obstructiva crónica (EPOC) es una enfermedad progresiva, cuya prevalencia aumenta con la edad. Se caracteriza por su elevado número de comorbilidades, entre ellas el deterioro cognitivo, que ha ido adquiriendo gran relevancia clínica en los últimos años. Factores como la función pulmonar, la hipoxemia, la hipercapnia o las exacerbaciones contribuyen al deterioro de las funciones cognitivas. Se ha incluido el estado nutricional como un factor más que presentándose en la EPOC, contribuya también al deterioro de la funciones cognitivas. Objetivo: Evidenciar la relación entre el deterioro cognitivo, el estado nutricional y el perfil clínico de los pacientes que ingresan por exacerbación aguda de EPOC (EAEPOC). Metodología: Ciento diez sujetos hospitalizados por EAEPOC, divididos en dos grupos según su estado nutricional y evaluación a su ingreso de deterioro cognitivo, estado nutricional y perfil clínico. Resultados: Diferencias significativas entre grupos de estado nutricional en las variables antropométricas (sexo e IMC), capacidad funcional (Índice de Barthel y escala de Actividades de la Vida Diaria) calidad de vida (Euroqol-5D y SGRQ), calidad de sueño (Pittsburgh), estado de ánimo (HAD) y deterioro cognitivo (MoCa atención, MoCa abstracción). (p<0.05). Conclusión: Las funciones cognitivas se ven afectadas en pacientes EPOC con un estado nutricional alterado, en comparación con aquellos con un estado nutricional normal. El deterioro nutricional es un factor que contribuye al deterioro de las funciones cognitivas en este tipo de pacientes; en concreto al deterioro de la atención y la capacidad de abstracción (AU)

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease with a prevalence that increases with the aging of the subject. It presents a high prevalence of comorbidities, such as cognitive decline, which is gaining great clinical relevance in recent years. Factors such as pulmonary function, hypoxemia, hypercapnia or exacerbations contribute to the decline of cognitive functions. The nutritional status has been added to these factors as contributing to cognitive function decline when presenting in COPD. Objective: To evidence the relationship between cognitive decline, nutritional status and the clinical profile of patients admitted because of an acute exacerbation of COPD (AECOPD). Methods: 110 subjects hospitalized because of COPD, divided in two groups according to their nutritional status and assessment of cognitive decline at admittance, nutritional status and clinical profile. Results: Significant differences between groups concerning nutritional status in anthropometric variables (sex and IMC), functional ability (Barthel index and Daily Life Activities Scale), quality of life (Euroqol- 5D y SGRQ), sleep quality (Pittsburgh), mood (HAD) and cognitive decline (MoCa attention, MoCa abstraction). (p<0.05). Conclusion: Cognitive function is affected in COPD patients with an altered nutritional status when compared to those with a normal nutritional status. The nutritional decline is a factor contributing to the impairment of cognitive functions in this kind of patients, particularly a decline in attention and abstraction ability (AU)

A-kinase anchoring proteins: cAMP compartmentalization in neurodegenerative and obstructive pulmonary diseases.

The universal second messenger cAMP is generated upon stimulation of Gs protein-coupled receptors, such as the ß2 -adreneoceptor, and leads to the activation of PKA, the major cAMP effector protein. PKA oscillates between an on and off state and thereby regulates a plethora of distinct biological responses. The broad activation pattern of PKA and its contribution to several distinct cellular functions lead to the introduction of the concept of compartmentalization of cAMP. A-kinase anchoring proteins (AKAPs) are of central importance due to their unique ability to directly and/or indirectly interact with proteins that either determine the cellular content of cAMP, such as ß2 -adrenoceptors, ACs and PDEs, or are regulated by cAMP such as the exchange protein directly activated by cAMP. We report on lessons learned from neurons indicating that maintenance of cAMP compartmentalization by AKAP5 is linked to neurotransmission, learning and memory. Disturbance of cAMP compartments seem to be linked to neurodegenerative disease including Alzheimer's disease. We translate this knowledge to compartmentalized cAMP signalling in the lung. Next to AKAP5, we focus here on AKAP12 and Ezrin (AKAP78). These topics will be highlighted in the context of the development of novel pharmacological interventions to tackle AKAP-dependent compartmentalization.