Carmen Calero

Clinical applications of coenzyme Q10.

Coenzyme Q10 (CoQ10) or ubiquinone was known for its key role in mitochondrial bioenergetics as electron and proton carrier; later studies demonstrated its presence in other cellular membranes and in blood plasma, and extensively investigated its antioxidant role. These two functions constitute the basis for supporting the clinical indication of CoQ10. Furthermore, recent data indicate that CoQ10 affects expression of genes involved in human cell signalling, metabolism and transport and some of the effects of CoQ10 supplementation may be due to this property. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, ageing-related oxidative stress and carcinogenesis processes, and also a secondary effect of statin treatment. Many neurodegenerative disorders, diabetes, cancer, fibromyalgia, muscular and cardiovascular diseases have been associated with low CoQ10 levels. CoQ10 treatment does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ10 absorption and tissue distribution. Oral CoQ10 treatment is a frequent mitochondrial energizer and antioxidant strategy in many diseases that may provide a significant symptomatic benefit.

Symptom variability in COPD: a narrative review

Chronic obstructive pulmonary disease (COPD) has traditionally been considered an inexorably progressive disease, associated with a constant increase of symptoms that occur as the forced expiratory volume in 1 second (FEV1) worsens, only intermittently interrupted by exacerbations. However, this paradigm has been challenged in recent decades by the available evidence. Recent studies have pointed out that COPD-related symptoms are not consistently perceived by patients in the same way, showing not only seasonal variation, but also changes in symptom perception during a week or even within a single day. According to the available data, patients experience the biggest increase in respiratory symptoms during the first hours of the early morning, followed by the nighttime. This variation over time is of considerable importance, since it impacts on daily life activities and health-related quality of life, as measured by a recently developed ad hoc questionnaire. Additionally, recent clinical trials have suggested that the use of rapid-onset long-acting bronchodilators may have an impact on morning symptoms, despite their current use as maintenance treatment for a determined period. Although this hypothesis is to be validated in future long-term clinical trials comparing fast-onset versus slow-onset inhaled drugs in COPD, it may bring forward a new concept of long-term bronchodilator therapy. At the present time, the two available long-acting, fast-onset bronchodilators used in the treatment of COPD are formoterol and the recently marketed indacaterol. Newer drugs have also been shown to have a rapid onset of action in preclinical studies. Health care professionals caring for COPD patients should consider this variation in the perception of symptoms during their clinical interview as a potential new target in the long-term treatment plan.

C-reactive protein and serum amyloid a overexpression in lung tissues of chronic obstructive pulmonary disease patients: a case-control study.

Background. Although researchers have consistently demonstrated systemic inflammation in chronic obstructive pulmonary disease (COPD), its origin is yet unknown. We aimed to compare the lung bronchial and parenchymal tissues as potential sources of major acute-phase reactants in COPD patients and resistant smokers. Methods. Consecutive patients undergoing elective surgery for suspected primary lung cancer were considered for the study. Patients were categorized as COPD or resistant smokers according to their spirometric results. Lung parenchyma and bronchus sections distant from the primary lesion were obtained. C-reactive protein (CRP) and serum amyloid A (SAA1, SAA2 and SAA4) gene expressions were evaluated by RT-PCR. Protein levels were evaluated in paraffin embedded lung tissues by immunohistochemistry and in serum samples by nephelometry. Results. Our study included 85 patients with COPD and 87 resistant smokers. In bronchial and parenchymal tissues, both CRP and SAA were overexpressed in COPD patients. In the bronchus, CRP, SAA1, SAA2, and SA4 gene expressions in COPD patients were 1.89-fold, 4.36-fold, 3.65-fold, and 3.9-fold the control values, respectively. In the parenchyma, CRP, SAA1, and SAA2 gene expressions were 2.41-, 1.97-, and 1.76-fold the control values, respectively. Immunohistochemistry showed an over-stained pattern of these markers on endovascular cells of COPD patients. There was no correlation with serum protein concentration. Conclusions. These results indicate an overexpression of CRP and SAA in both bronchial and parenchymal tissue in COPD, which differs between both locations, indicating tissue/cell type specificity. The endothelial cells might play a role in the production of theses markers.

Apoptotic microtubules delimit an active caspase free area in the cellular cortex during the execution phase of apoptosis

Apoptotic microtubule network (AMN) is organized during apoptosis, forming a cortical structure beneath plasma membrane, which has an important role in preserving cell morphology and plasma membrane permeability. The aim of this study was to examine the role of AMN in maintaining plasma membrane integrity during the execution phase of apoptosis. We demonstrated in camptothecin-induced apoptosis in H460 cells that AMN delimits an active caspase free area beneath plasma membrane that permits the preservation of cellular cortex and transmembrane proteins. AMN depolymerization in apoptotic cells by a short exposure to colchicine allowed active caspases to reach the cellular cortex and cleave many key proteins involved in plasma membrane structural support, cell adhesion and ionic homeostasis. Cleavage of cellular cortex and plasma membrane proteins, such as α-spectrin, paxilin, focal adhesion kinase (FAK), E-cadherin and integrin subunit β4 was associated with cell collapse and cell detachment. Otherwise, cleavage-mediated inactivation of calcium ATPase pump (PMCA-4) and Na+/Ca2+ exchanger (NCX) involved in cell calcium extrusion resulted in calcium overload. Furthermore, cleavage of Na+/K+ pump subunit β was associated with altered sodium homeostasis. Cleavage of cell cortex and plasma membrane proteins in apoptotic cells after AMN depolymerization increased plasma permeability, ionic imbalance and bioenergetic collapse, leading apoptotic cells to secondary necrosis. The essential role of caspase-mediated cleavage in this process was demonstrated because the concomitant addition of colchicine that induces AMN depolymerization and the pan-caspase inhibitor z-VAD avoided the cleavage of cortical and plasma membrane proteins and prevented apoptotic cells to undergo secondary necrosis. Furthermore, the presence of AMN was also critical for proper phosphatidylserine externalization and apoptotic cell clearance by macrophages. These results indicate that AMN is essential to preserve an active caspase free area in the cellular cortex of apoptotic cells that allows plasma membrane integrity during the execution phase of apoptosis.

Exacerbations or complications? Redefining the concepts in COPD.

To the Editor: Chronic inflammatory diseases such as inflammatory bowel disease, multiple sclerosis or rheumatoid arthritis are characterised by continuing inflammation, which is frequently of unknown origin. From a pathophysiological perspective, all of these conditions share common features including the presence of organ-specific inflammation, the occurrence of a systemic inflammatory response, and episodic peaks in inflammation. The latter may lead to an increase in the severity of the disease or its signs and symptoms (known as bouts, crisis or exacerbations), ultimately requiring treatment modifications. Exacerbations are deemed to be an intrinsic feature of chronic inflammatory disorders and part of their natural history (1–3). In contrast, patients with chronic inflammatory diseases may frequently experience comorbid transient acute disorders (generally of known origin) that may significantly complicate the clinical picture as well. Despite their impact on the total inflammatory load, such episodes are not necessarily considered part of the natural history of the disease and are referred to as complications. Some examples of complications include the occurrence of acute diarrhoea in patients with inflammatory bowel disease, cerebrovascular events in patients with multiple sclerosis, and septic arthritis in patients with rheumatoid arthritis. The differentiation between exacerbations and complications in patients with chronic inflammatory diseases is clinically relevant because of therapeutic implications and potential prognostic impact. Chronic obstructive pulmonary disease (COPD) shares several features with other chronic inflammatory diseases. Although COPD undoubtedly has a multifaceted aetiology, tobacco use is widely considered to be its major risk factor. However, the higher inflammatory load observed in COPD patients as compared with non-COPD smokers has no obvious origin. As in other chronic inflammatory conditions, COPD patients may experience transient increases in symptoms associated with a higher inflammatory load. Although such episodes are generally known as exacerbations, controversy still exists on their exact definition as well as their differentiation from other acute respiratory conditions that may complicate COPD. According to international guidelines, a COPD exacerbation is defined as ‘an acute event characterised by a worsening of the patient’s respiratory symptoms that is beyond day to day variations and leads to a change in medication’ (4). Despite its wide use, there has been considerable debate as to the definition of COPD exacerbations (5). For example, it is well known that COPD patients may suffer from acute pulmonary embolism (PE). If the traditional definition is followed, PE should be considered as an exacerbation of COPD as it would lead to a sustained worsening of symptoms beyond normal day to day variations and may warrant a change in medication. However, such worsening is clearly unrelated to COPD pathophysiology because PE is a distinct clinical entity with its own specific risk factors (6). In this scenario, it is conceivable that PE episodes should be considered as a complication – rather than an exacerbation – of COPD. Conversely, it should be also acknowledged that PE may also be a cause of COPD exacerbations (7), generating further classification controversy. Another similar example is provided by community acquired pneumonia (CAP). Patients with COPD are known to be at an increased risk for developing acute CAP, a condition which can in turn lead to symptoms worsening and need of treatment changes. Although CAP may fulfil the definition of an exacerbation (8), it is an infectious process that has no obvious correlation with COPD pathophysiology. One may also argue that episodes of acute infectious bronchitis are generally considered as COPD exacerbations with antibiotic therapy assuming a prominent role (9). Although CAP and acute bronchitis differ in terms of infection sites, the contention that a bronchial infection should be considered an exacerbation whereas a parenchymal infection should not is not clear or doesn’t seem to be coherent. Moreover, as the presence of lung condensations is frequently reported in patients discharged with a diagnosis of COPD exacerbations (10), the confusion will escalate. Another interesting example is provided by inhaled steroids, which may decrease the number of exacerbations but can in turn increase the number of lung infections (11). Consequently, infections and COPD should be considered as comorbid conditions (12). Beyond semantics, an infective cause of COPD worsening should guide the clinician towards an appropriate targeted therapy. As in other chronic inflammatory conditions, it is paramount to make a clear distinction between COPD exacerbations and complications. In this scenario, we propose that any of these acute events that is not directly related to COPD pathophysiology should be considered as a complication. By contrast, an exacerbation should indicate any episode of increased bronchial inflammation which reflects these respiratory inflammatory bouts associated with the natural expression of the disease.

Increased levels of soluble ICAM-1 in chronic obstructive pulmonary disease and resistant smokers are related to active smoking

AIM Serum ICAM-1 (sICAM-1) is known to be a smoking-associated inflammatory marker, but data in chronic obstructive pulmonary disease (COPD) are lacking. PATIENTS & METHODS A total of 142 COPD cases (48 active smokers) and 55 controls (41 active smokers) were consecutively enrolled in this cross-sectional study. The peripheral blood concentrations of sICAM-1, IL-8 (CXCL8), CRP and serum amyloid A (SAA) were determined by ELISA. RESULTS CRP and SAA (log-scale) were elevated in the patients with COPD compared with the control subjects (p = 0.005 for CRP and p = 0.024 for SAA). sICAM-1 was associated with active smoking when corrected for age, gender, the presence of COPD, inhaled corticosteroid use, BMI and forced expiratory volume in 1 s as covariates. CONCLUSION The present study confirms an association between sICAM-1 levels and active smoking in a group of COPD and non-COPD active smokers.

Mortality from cystic fibrosis in Europe: 1994-2010.

To date, available mortality trends due to cystic fibrosis (CF) have been limited to the analysis of certain countries in different parts of the world showing that mortality trends have been constantly decreasing. However, no studies have examined Europe as a whole. The present study aims to analyze CF mortality trends by gender within the European Union (EU) and to quantify potential years of life lost (PYLL).

Results from an Audit Feedback Strategy for Chronic Obstructive Pulmonary Disease In-Hospital Care: A Joint Analysis from the AUDIPOC and European COPD Audit Studies

Background Clinical audits have emerged as a potential tool to summarize the clinical performance of healthcare over a specified period of time. However, the effectiveness of audit and feedback has shown inconsistent results and the impact of audit and feedback on clinical performance has not been evaluated for COPD exacerbations. In the present study, we analyzed the results of two consecutive nationwide clinical audits performed in Spain to evaluate both the in-hospital clinical care provided and the feedback strategy. Methods The present study is an analysis of two clinical audits performed in Spain that evaluated the clinical care provided to COPD patients who were admitted to the hospital for a COPD exacerbation. The first audit was performed from November–December 2008. The feedback strategy consisted of personalized reports for each participant center, the presentation and discussion of the results at regional, national and international meetings and the creation of health-care quality standards for COPD. The second audit was part of a European study during January and February 2011. The impact of the feedback strategy was evaluated in term of clinical care provided and in-hospital survival. Results A total of 94 centers participated in the two audits, recruiting 8,143 admissions (audit 1∶3,493 and audit 2∶4,650). The initially provided clinical care was reasonably acceptable even though there was considerable variability. Several diagnostic and therapeutic procedures improved in the second audit. Although the differences were significant, the degree of improvement was small to moderate. We found no impact on in-hospital mortality. Conclusions The present study describes COPD hospital care in Spanish hospitals and evaluates the impact of peer-benchmarked, individually written and group-oral feedback strategy on the clinical outcomes for treating COPD exacerbations. It describes small to moderate improvements in the clinical care provided to COPD patients with no impact on in-hospital mortality.

Differential expression of C-Reactive protein and Serum amyloid A in different cell types in the lung tissue of chronic obstructive pulmonary disease patients

BackgroundChronic systemic inflammatory syndrome has been implicated in the pathobiology of extrapulmonary manifestations of chronic obstructive pulmonary disease (COPD). We aimed to investigate which cell types within lung tissue are responsible for expressing major acute-phase reactants in COPD patients and disease-free (“resistant”) smokers.MethodsAn observational case–control study was performed to investigate three different cell types in surgical lung samples of COPD patients and resistant smokers via expression of the C-reactive protein (CRP) and serum amyloid A (SAA1, SAA2 and SAA4) genes. Epithelial cells, macrophages and fibroblasts from the lung parenchyma were separated by magnetic microbeads (CD326, CD14 and anti-fibroblast), and gene expression was evaluated by RT-PCR.ResultsThe sample consisted of 74 subjects, including 40 COPD patients and 34 smokers without disease. All three cell types were capable of synthesizing these biomarkers to some extent. In fibroblasts, gene expression analysis of the studied biomarkers demonstrated increased SAA2 and decreased SAA1 in patients with COPD. In epithelial cells, there was a marked increase in CRP, which was not observed in fibroblasts or macrophages. In macrophages, however, gene expression of these markers was decreased in COPD patients compared to controls.ConclusionsThese results provide novel information regarding the gene expression of CRP and SAA in different cell types in the lung parenchyma. This study revealed differences in the expression of these markers according to cell type and disease status and contributes to the identification of cell types that are responsible for the secretion of these molecules.

Expression of aquaporins in bronchial tissue and lung parenchyma of patients with chronic obstructive pulmonary disease

BackgroundAquaporins AQP1 and AQP5 are highly expressed in the lung. Recent studies have shown that the expression of these proteins may be mechanistically involved in the airway inflammation and in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the expression of AQP1 and AQP5 in the bronchial tissue and the lung parenchyma of patients with COPD and COPD-resistant smokers.MethodsUsing a case–control design, we selected a group of 15 subjects with COPD and 15 resistant smokers (smokers without COPD) as a control, all of whom were undergoing lung resection surgery due to a lung neoplasm. We studied the expression of AQP1 and AQP5 in the bronchial tissue and the lung parenchyma by means of immunohistochemistry and reverse-transcription real-time polymerase chain reaction. Tissue expression of AQP1 and AQP5 was semi-quantitatively assessed in terms of intensity and expression by immunohistochemistry using a 4-point scale ranging from 0 (none) to 3 (maximum).ResultsThere were no significant differences in gene expression between COPD patients and resistant smokers both in the bronchial tissue and in the lung parenchyma. However, AQP1 gene expression was 2.41-fold higher in the parenchyma of smokers with COPD compared to controls, whereas the AQP5 gene showed the opposite pattern, with a 7.75-fold higher expression in the bronchus of smokers with COPD compared with controls. AQP1 and AQP5 proteins were preferentially expressed in endothelial cells, showing a higher intensity for AQP1 (66.7% of cases with an intensity of 3, and 93.3% of subjects with an extension of 3 among patients with COPD). Subtle interstitial disease was associated with type II pneumocyte hyperplasia and an increased expression of AQP1.ConclusionsThis study provides pilot observations on the differences in AQP1 and AQP5 expression between COPD patients and COPD-resistant smokers. Our findings suggest a potential role for AQP1 in the pathogenesis of COPD.