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1.  Hypoxemia in patients with COPD: cause, effects, and disease progression 
Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.
doi:10.2147/COPD.S10611
PMCID: PMC3107696  PMID: 21660297
COPD; hypoxia; sleep; inflammation; pulmonary hypertension
2.  Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is a debilitating disease characterized by inflammation-induced airflow limitation and parenchymal destruction. In addition to pulmonary manifestations, patients with COPD develop systemic problems, including skeletal muscle and other organ-specific dysfunctions, nutritional abnormalities, weight loss, and adverse psychological responses. Patients with COPD often complain of dyspnea on exertion, reduced exercise capacity, and develop a progressive decline in lung function with increasing age. These symptoms have been attributed to increases in the work of breathing and in impairments in gas exchange that result from airflow limitation and dynamic hyperinflation. However, there is mounting evidence to suggest that skeletal muscle dysfunction, independent of lung function, contributes significantly to reduced exercise capacity and poor quality of life in these patients. Limb and ventilatory skeletal muscle dysfunction in COPD patients has been attributed to a myriad of factors, including the presence of low grade systemic inflammatory processes, nutritional depletion, corticosteroid medications, chronic inactivity, age, hypoxemia, smoking, oxidative and nitrosative stresses, protein degradation and changes in vascular density. This review briefly summarizes the contribution of these factors to overall skeletal muscle dysfunction in patients with COPD, with particular attention paid to the latest advances in the field.
PMCID: PMC2650609  PMID: 19281080
skeletal muscles; chronic obstructive pulmonary disease; diaphragm; quadriceps; fatigue; disuse; atrophy; smoking; exercise
3.  Chronic obstructive pulmonary disease: an update of treatment related to frequently associated comorbidities 
Chronic obstructive pulmonary disease (COPD) is associated with a pulmonary inflammatory response to inhaled substances, and individuals with COPD often have raised levels of several circulating inflammatory markers indicating the presence of systemic inflammation. Recently, there has been increasing interest in comorbidities associated with COPD such as skeletal muscle dysfunction, cardiovascular disease, osteoporosis, diabetes and lung cancer. These conditions are associated with a similar inflammation-based patho-physiology to COPD, and may represent a lung inflammatory ‘overspill’ to distant organs. Cardiovascular disease is a significant cause of mortality in COPD, and the concepts of an inflammatory link raise the possibility that treatment for one organ may show benefits to comorbidities in other organs. When considering treatment of COPD and its comorbidities, one approach is to target the pulmonary inflammation and hence reduce any ‘overspill’ effect of inflammatory mediators systemically as suggested by response to inhaled corticosteroids. Alternatively, treatment targeted towards comorbid organs may alter features of pulmonary disease as statins, angiotensin-converting enzyme (ACE) inhibitors and peroxisome proliferator-activated receptor (PPAR) agonists may have beneficial effects on COPD by reducing exacerbations and mortality. Newer anti-inflammatory treatments, such as phosphodiesterase 4 (PDE4), nuclear factor(NF)-kB, and p38 mitogen-activated protein kinase (MAPK) inhibitors, are given systemically and may confer benefits to both COPD and its comorbidities. With common inflammatory pathways it might be expected that successful anti-inflammatory therapy in one organ may also influence others. In this review we explore the concepts of systemic inflammation in COPD and current evidence for treatment of its related comorbidities.
doi:10.1177/2040622310370631
PMCID: PMC3513857  PMID: 23251728
angiotensin-converting enzyme inhibitors; anti-inflammatory drugs; chronic obstructive pulmonary disease; comorbidity; peroxisome proliferator-activated receptor agonists; statins; systemic inflammation
4.  Structural and Functional Changes of Peripheral Muscles in Copd Patients 
Purpose of Review
The purpose of this review is to identify new advances in our understanding of skeletal muscle dysfunction in patients with COPD.
Recent findings
Recent studies have confirmed the relevance of muscle dysfunction as an independent prognosis factor in COPD. Animal studies have shed light on the molecular mechanisms governing skeletal muscle hypertrophy/atrophy. Recent evidence in patients with COPD highlighted the contribution of protein breakdown and mitochondrial dysfunction as pathogenic mechanisms leading to muscle dysfunction in these patients.
Summary
Chronic Obstructive Pulmonary Disease (COPD) is a debilitating disease impacting negatively on health status and the functional capacity of patients. COPD goes beyond the lungs and incurs significant systemic effects among which muscle dysfunction/wasting in one of the most important. Muscle dysfunction is a prominent contributor to exercise limitation, healthcare utilization and an independent predictor of morbidity and mortality. Gaining more insight into the molecular mechanisms leading to muscle dysfunction/wasting is key for the development of new and tailored therapeutic strategies to tackle skeletal muscle dysfunction/wasting in COPD patients.
doi:10.1097/MCP.0b013e328336438d
PMCID: PMC2920417  PMID: 20071991
COPD; systemic effects; muscle dysfunction; muscle wasting
5.  Disability in COPD and Chronic Heart Failure Is the Skeletal Muscle the Final Common Pathway? 
Mædica  2013;8(2):206-213.
ABSTRACT
Chronic Obstructive Pulmonary Disease (COPD) and Chronic Heart Failure (CHF), two major causes of worldwide morbidity and mortality have important systemic components, affecting additional tissues, other than the lung or the heart, such as the skeletal muscle. Muscle function (or dysfunction) may not only influence the symptoms that limit exercise, but may contribute directly to the poor exercise performance, health status and increased healthcare utilization.
The present review tries to summarize the muscular abnormalities in COPD and CHF and the mechanisms underlying these alterations, which are strikingly similar, despite the obvious differences concerning the primary impairment in these two chronic diseases.
The muscles therefore represent a potential site to improve patients' functioning level and quality of life of COPD and CHF. Only one practical therapeutic intervention currently exists that can reverse some of the muscle abnormalities observed in COPD and CHF, namely exercise training, which becomes nowadays the "cornerstone" of the whole rehabilitation.
PMCID: PMC3865132  PMID: 24371487
chronic Heart Failure; chronic obstructive pulmonary disease; skeletal muscle; disability; rehabilitation
6.  COPD 
Clinical Evidence  2008;2008:1502.
Introduction
Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Classically, it is thought to be a combination of emphysema and chronic bronchitis, although only one of these may be present in some people with COPD. The main risk factor for the development and deterioration of COPD is smoking.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of maintenance drug treatment in stable COPD? What are the effects of maintenance drug treatment in stable COPD? What are the effects of non-drug interventions in people with stable COPD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alpha1 antitrypsin, antibiotics (prophylactic), anticholinergics (inhaled), beta2 agonists (inhaled), corticosteroids (oral and inhaled), general physical activity enhancement, inspiratory muscle training, maintaining healthy weight, mucolytics, oxygen treatment (long-term domiciliary treatment), peripheral muscle strength training, psychosocial and pharmacological interventions for smoking cessation, pulmonary rehabilitation, and theophylline.
Key Points
The main risk factor for the development and deterioration of chronic obstructive pulmonary disease (COPD) is smoking.
Inhaled anticholinergics and beta2 agonists improve lung function and symptoms and reduce exacerbations in stable COPD compared with placebo. It is unclear whether inhaled anticholinergics or inhaled beta2 agonists are the more consistently effective drug class in the treatment of COPD.Short-acting anticholinergics seem to be associated with a small improvement in quality of life compared with beta2 agonists. Long-acting inhaled anticholinergic drugs may improve lung function compared with long-acting beta2 agonists.Combined treatment with inhaled anticholinergics and beta2 agonists may improve symptoms and lung function and reduce exacerbations compared with either treatment alone, although long-term effects are unknown.
Inhaled corticosteroids reduce exacerbations in COPD and reduce decline in FEV1, but the beneficial effects are small. Oral corticosteroids may improve short-term lung function, but have serious adverse effects. Combined inhaled corticosteroids plus long-acting beta2 agonists improve lung function and symptoms and reduce exacerbations compared with placebo, and may be more effective than either treatment alone.
Long-term domiciliary oxygen treatment may improve survival in people with severe daytime hypoxaemia.
Theophylline may improve lung function compared with placebo, but adverse effects limit their usefulness in stable COPD.
We don't know whether mucolytic drugs, prophylactic antibiotics, or alpha1 antitrypsin improve outcomes in people with COPD compared with placebo.
Combined psychosocial and pharmacological interventions for smoking cessation can slow the deterioration of lung function, but have not been shown to reduce long-term mortality compared with usual care.
Multi-modality pulmonary rehabilitation and exercises can improve exercise capacity in people with stable COPD, but nutritional supplementation has not been shown to be beneficial.
PMCID: PMC2907933  PMID: 19445783
7.  COPD 
Clinical Evidence  2011;2011:1502.
Introduction
Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Classically, it is thought to be a combination of emphysema and chronic bronchitis, although only one of these may be present in some people with COPD. The main risk factor for the development and deterioration of COPD is smoking.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of maintenance drug treatment in stable COPD? What are the effects of smoking cessation interventions in people with stable COPD? What are the effects of non-drug interventions in people with stable COPD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 119 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alpha1 antitrypsin, antibiotics (prophylactic), anticholinergics (inhaled), beta2 agonists (inhaled), corticosteroids (oral and inhaled), general physical activity enhancement, inspiratory muscle training, nutritional supplementation, mucolytics, oxygen treatment (long-term domiciliary treatment), peripheral muscle strength training, psychosocial and pharmacological interventions for smoking cessation, pulmonary rehabilitation, and theophylline.
Key Points
The main risk factor for the development and deterioration of chronic obstructive pulmonary disease (COPD) is smoking.
Inhaled anticholinergics and beta2 agonists improve lung function and symptoms and reduce exacerbations in stable COPD compared with placebo. It is unclear whether inhaled anticholinergics or inhaled beta2 agonists are the more consistently effective drug class in the treatment of COPD.Short-acting anticholinergics seem to be associated with a small improvement in quality of life compared with beta2 agonists. Long-acting inhaled anticholinergics may improve lung function compared with long-acting beta2 agonists.Combined treatment with inhaled anticholinergics plus beta2 agonists may improve symptoms and lung function and reduce exacerbations compared with either treatment alone, although long-term effects are unknown.
Inhaled corticosteroids reduce exacerbations in COPD and reduce decline in FEV1, but the beneficial effects are small. Oral corticosteroids may improve short-term lung function, but have serious adverse effects. Combined inhaled corticosteroids plus long-acting beta2 agonists improve lung function, symptoms, and health-related quality of life, and reduce exacerbations compared with placebo, and may be more effective than either treatment alone.
Long-term domiciliary oxygen treatment may improve survival in people with severe daytime hypoxaemia.
Theophylline may improve lung function compared with placebo, but adverse effects limit its usefulness in stable COPD.
We don't know whether mucolytic drugs, prophylactic antibiotics, or alpha1 antitrypsin improve outcomes in people with COPD compared with placebo.
Combined psychosocial and pharmacological interventions for smoking cessation can slow the deterioration of lung function, but have not been shown to reduce long-term mortality compared with usual care.
Multi-modality pulmonary rehabilitation can improve exercise capacity, dyspnoea, and health-related quality of life in people with stable COPD; general physical exercises and peripheral muscle training can improve exercise capacity; inspiratory muscle training may improve lung function and exercise capacity; but nutritional supplementation has not been shown to be beneficial.
PMCID: PMC3275305  PMID: 21639960
8.  Factors contributing to muscle wasting and dysfunction in COPD patients 
Many patients with chronic obstructive pulmonary disease (COPD) suffer from exercise intolerance. In about 40% of the patients exercise capacity is limited by alterations in skeletal muscle rather than pulmonary problems. Indeed, COPD is often associated with muscle wasting and a slow-to-fast shift in fiber type composition resulting in weakness and an earlier onset of muscle fatigue, respectively. Clearly, limiting muscle wasting during COPD benefits the patient by improving the quality of life and also the chance of survival. To successfully combat muscle wasting and remodeling during COPD a clear understanding of the causes and mechanisms is needed. Disuse, hypoxemia, malnutrition, oxidative stress and systemic inflammation may all cause muscle atrophy. Particularly when systemic inflammation is elevated muscle wasting becomes a serious complication. The muscle wasting may at least partly be due to an increased activity of the ubiquitin proteasome pathway and apoptosis. However, it might well be that an impaired regenerative potential of the muscle rather than the increased protein degradation is the crucial factor in the loss of muscle mass during COPD with a high degree of systemic inflammation. Finally, we briefly discuss the various treatments and rehabilitation strategies available to control muscle wasting and fatigue in patients with COPD.
PMCID: PMC2695204  PMID: 18229567
COPD; muscle wasting; systemic inflammation; rehabilitation; muscle function
9.  Hyperinflation and its management in COPD 
Chronic obstructive pulmonary disease (COPD) is characterized by poorly reversible airflow limitation. The pathological hallmarks of COPD are inflammation of the peripheral airways and destruction of lung parenchyma or emphysema. The functional consequences of these abnormalities are expiratory airflow limitation and dynamic hyperinflation, which then increase the elastic load of the respiratory system and decrease the performance of the respiratory muscles. These pathophysiologic features contribute significantly to the development of dyspnea, exercise intolerance and ventilatory failure. Several treatments may palliate flow limitation, including interventions that modify the respiratory pattern (deeper, slower) such as pursed lip breathing, exercise training, oxygen, and some drugs. Other therapies are aimed at its amelioration, such as bronchodilators, lung volume reduction surgery or breathing mixtures of helium and oxygen. Finally some interventions, such as inspiratory pressure support, alleviate the threshold load associated to flow limitation. The degree of flow limitation can be assessed by certain spirometry indexes, such as vital capacity and inspiratory capacity, or by other more complexes indexes such as residual volume/total lung capacity or functional residual capacity/total lung capacity. Two of the best methods to measure flow limitation are to superimpose a flow–volume loop of a tidal breath within a maximum flow–volume curve, or to use negative expiratory pressure technique. Likely this method is more accurate and can be used during spontaneous breathing. A definitive definition of dynamic hyperinflation is lacking in the literature, but serial measurements of inspiratory capacity during exercise will document the trend of end-expiratory lung volume and allow establishing relationships with other measurements such as dyspnea, respiratory pattern, exercise tolerance, and gas exchange.
PMCID: PMC2707802  PMID: 18044095
COPD; flow limitation; dynamic hyperinflation; treatment; exercise
10.  Systems biology coupled with label-free high-throughput detection as a novel approach for diagnosis of chronic obstructive pulmonary disease 
Respiratory Research  2009;10(1):29.
Chronic obstructive pulmonary disease (COPD) is a treatable and preventable disease state, characterised by progressive airflow limitation that is not fully reversible. Although COPD is primarily a disease of the lungs there is now an appreciation that many of the manifestations of disease are outside the lung, leading to the notion that COPD is a systemic disease. Currently, diagnosis of COPD relies on largely descriptive measures to enable classification, such as symptoms and lung function. Here the limitations of existing diagnostic strategies of COPD are discussed and systems biology approaches to diagnosis that build upon current molecular knowledge of the disease are described. These approaches rely on new 'label-free' sensing technologies, such as high-throughput surface plasmon resonance (SPR), that we also describe.
doi:10.1186/1465-9921-10-29
PMCID: PMC2678087  PMID: 19386108
11.  Nutritional Aspects of Chronic Obstructive Pulmonary Disease 
It is clear that being underweight is a poor prognostic sign in chronic obstructive pulmonary disease (COPD). It is also clear that undernutrition is at least in part associated with the severity of airflow obstruction. While both weight and body mass index are useful screening tools in the initial nutritional evaluation, fat-free mass (FFM) may be a better marker of undernutrition in patients with COPD. The causes of cachexia in patients with COPD are multifactorial and include decreased oral intake, the effect of increased work of breathing due to abnormal respiratory mechanics, and the effect of chronic systemic inflammation. Active nutritional supplementation in undernourished patients with COPD can lead to weight gain and improvements in respiratory muscle function and exercise performance. However, long-term effects of nutritional supplementation are not clear. In addition, the optimal type of nutritional supplementation needs to be explored further. The role of novel forms of treatment, such as androgens or appetite stimulants designed to increase FFM, also needs to be further studied. Thus, in the absence of definitive data, it cannot be said that long-term weight gain, either using enhanced caloric intake, with or without anabolic steroids or appetite stimulants, offers survival or other benefits to patients with COPD. However, there are indications from single-center trials that this is an avenue well worth exploring.
doi:10.1513/pats.200707-092ET
PMCID: PMC2645329  PMID: 18453365
chronic obstructive pulmonary disease; nutrition; cachexia; testosterone; megace
12.  Effects of peripheral neuropathy on exercise capacity and quality of life in patients with chronic obstructive pulmonary diseases 
Introduction
Chronic obstructive pulmonary diseases (COPD) have some systemic effects including systemic inflammation, nutritional abnormalities, skeletal muscle dysfunction, and cardiovascular, skeletal and neurological disorders. Some studies have reported the presence of peripheral neuropathy (PNP) at an incidence of 28-94% in patients with COPD. Our study aimed to identify whether PNP affects exercise performance and quality of life in COPD patients.
Material and methods
Thirty mild-very severe patients with COPD (male/female = 29/1, mean age = 64 ±10 years) and 14 normal subjects (male/female = 11/5, mean age = 61 ±8 years) were included in the present study. All subjects underwent pulmonary function testing (PFT), cardiopulmonary exercise testing, electroneuromyography and short form 36 (SF-36).
Results
Peak oxygen uptake (PeakVO2) was lower in COPD patients (1.15 ±0.53 l/min) than healthy subjects (2.02 ±0.46 l/min) (p = 0.0001). There was no PNP in healthy subjects while 16 (53%) of the COPD patients had PNP. Forced expiratory volume in 1 s (FEV1) and PeakVO2 were significantly different between patients with PNP and those without (p = 0.009, p = 0.03 respectively). Quality of life of patients with PNP was lower than that of patients without PNP (p < 0.05).
Conclusions
The present study demonstrates the exercise limitation in COPD patients with PNP. Thus, presence of PNP has a poor effect on exercise capacity and quality of life in patients with COPD. Furthermore, treatment modalities for PNP can be recommended to these patients in order to improve exercise capacity and quality of life.
doi:10.5114/aoms.2012.28557
PMCID: PMC3361042  PMID: 22662003
chronic obstructive pulmonary diseases; peripheral neuropathy; exercise capacity; quality of life
13.  Cardiovascular Function in Pulmonary Emphysema 
BioMed Research International  2013;2013:184678.
Chronic obstructive pulmonary disease (COPD) and chronic cardiovascular disease, such as coronary artery disease, congestive heart failure, and cardiac arrhythmias, have a strong influence on each other, and systemic inflammation has been considered as the main linkage between them. On the other hand, airflow limitation may markedly affect lung mechanics in terms of static and dynamic hyperinflation, especially in pulmonary emphysema, and they can in turn influence cardiac performance as well. Skeletal mass depletion, which is a common feature in COPD especially in pulmonary emphysema patients, may have also a role in cardiovascular function of these patients, irrespective of lung damage. We reviewed the emerging evidence that highlights the role of lung mechanics and muscle mass impairment on ventricular volumes, stroke volume, and stroke work at rest and on exercise in the presence of pulmonary emphysema. Patients with emphysema may differ among COPD population even in terms of cardiovascular function.
doi:10.1155/2013/184678
PMCID: PMC3866814  PMID: 24369007
14.  Glucocorticoid insensitivity as a future target of therapy for chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal and chronic inflammatory response in the lung that underlies the chronic airflow obstruction of the small airways, the inexorable decline of lung function, and the severity of the disease. The control of this inflammation remains a key strategy for treating the disease; however, there are no current anti-inflammatory treatments that are effective. Although glucocorticoids (GCs) effectively control inflammation in many diseases such as asthma, they are less effective in COPD. The molecular mechanisms that contribute to the development of this relative GC-insensitive inflammation in the lung of patients with COPD remain unclear. However, recent studies have indicated novel mechanisms and possible therapeutic strategies. One of the major mechanisms proposed is an oxidant-mediated alteration in the signaling pathways in the inflammatory cells in the lung, which may result in the impairment of repressor proteins used by the GC receptor to inhibit the transcription of proinflammatory genes. Although these studies have described mechanisms and targets by which GC function can be restored in cells from patients with COPD, more work is needed to completely elucidate these and other pathways that may be involved in order to allow for more confident therapeutic targeting. Given the relative GC-insensitive nature of the inflammation in COPD, a combination of therapies in addition to a restoration of GC function, including effective alternative anti-inflammatory targets, antioxidants, and proresolving therapeutic strategies, is likely to provide better targeting and improvement in the management of the disease.
PMCID: PMC2939685  PMID: 20856829
inflammation; oxidative stress; histone deacetylase; phosphoinositol 3-kinase; p38 mitogen-activated protein kinase
15.  Models of chronic obstructive pulmonary disease 
Respiratory Research  2004;5(1):18.
Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.
doi:10.1186/1465-9921-5-18
PMCID: PMC533858  PMID: 15522115
Chronic obstructive pulmonary disease; COPD; asthma; animal; mice; rat; guinea pig; tobacco smoke; nitrogen dioxide; sulfur dioxide
16.  Skeletal Muscle Strength and Endurance in Recipients of Lung Transplants 
Purpose: Exercise limitation in recipients of lung transplant may be a result of abnormalities in the skeletal muscle. However, it is not clear whether these abnormalities are merely a reflection of the changes observed in the pretransplant condition. The purpose of this paper was to compare thigh muscle volume and composition, strength, and endurance in lung transplant recipients to people with chronic obstructive pulmonary disease (COPD).
Methods: Single lung transplant recipients (n=6) and people with COPD (n=6), matched for age, sex, and BMI participated in the study. Subjects underwent MRI to determine muscle size and composition, lower extremity strength testing and an isometric endurance test of the quadriceps.
Results: Lung transplant recipients had similar muscle volumes and intramuscular fat infiltration of their thigh muscles and similar strength of the quadriceps and hamstrings to people with COPD who had not undergone transplant. However, quadriceps endurance tended to be lower in transplant recipients compared to people with COPD (15 ± 7 seconds in transplant versus 31 ± 12 seconds in COPD, p = 0.08).
Conclusions: Recipients of lung transplant showed similar changes in muscle size and strength as people with COPD, however muscle endurance tended to be lower in people with lung transplants. Impairments in muscle endurance may reflect the effects of immunosuppressant medications on skeletal muscle in people with lung transplant.
PMCID: PMC2845229  PMID: 20467503
lung transplant; muscle function; MRI
17.  The Epidemiology of Vascular Dysfunction Relating to Chronic Obstructive Pulmonary Disease and Emphysema 
Cor pulmonale has long been described in very severe chronic obstructive pulmonary disease (COPD) and emphysema. Cross-sectional results from population-based studies show that left ventricular filling and a variety of vascular measures in the systemic circulation are abnormal in preclinical COPD and emphysema and that a predominant vascular change in COPD and emphysema is endothelial and microvascular dysfunction. These findings suggest that pulmonary vascular changes may occur early in COPD and emphysema and might contribute to pathogenesis. However, longitudinal epidemiologic studies with direct measures of the pulmonary vasculature are lacking; therefore, inferences are limited at present. New imaging-based approaches to the assessment of the pulmonary vasculature are applicable to epidemiologic studies and may help in defining the relationship of pulmonary vascular damage to progression of COPD and emphysema. These measures may also provide imaging-based surrogate markers, and novel therapeutics targeted to the pulmonary vasculature might reduce symptoms and improve function in these common diseases.
doi:10.1513/pats.201101-008MW
PMCID: PMC3359073  PMID: 22052931
chronic obstructive pulmonary disease; pulmonary emphysema; pulmonary hypertension; vascular disease; pulmonary vasculature
18.  Pathogenesis of hyperinflation in chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable lung disease characterized by airflow limitation that is not fully reversible. In a significant proportion of patients with COPD, reduced lung elastic recoil combined with expiratory flow limitation leads to lung hyperinflation during the course of the disease. Development of hyperinflation during the course of COPD is insidious. Dynamic hyperinflation is highly prevalent in the advanced stages of COPD, and new evidence suggests that it also occurs in many patients with mild disease, independently of the presence of resting hyperinflation. Hyperinflation is clinically relevant for patients with COPD mainly because it contributes to dyspnea, exercise intolerance, skeletal muscle limitations, morbidity, and reduced physical activity levels associated with the disease. Various pharmacological and nonpharmacological interventions have been shown to reduce hyperinflation and delay the onset of ventilatory limitation in patients with COPD. The aim of this review is to address the more recent literature regarding the pathogenesis, assessment, and management of both static and dynamic lung hyperinflation in patients with COPD. We also address the influence of biological sex and obesity and new developments in our understanding of hyperinflation in patients with mild COPD and its evolution during progression of the disease.
doi:10.2147/COPD.S38934
PMCID: PMC3933347  PMID: 24600216
chronic obstructive pulmonary disease; hyperinflation; expiratory flow limitation; operational lung volumes
19.  Non-volitional assessment of skeletal muscle strength in patients with chronic obstructive pulmonary disease 
Thorax  2003;58(8):665-669.
Background: Although quadriceps weakness is well recognised in chronic obstructive pulmonary disease (COPD), the aetiology remains unknown. In disabled patients the quadriceps is a particularly underused muscle and may not reflect skeletal muscle function as a whole. Loss of muscle function is likely to be equally distributed if the underlying pathology is a systemic abnormality. Conversely, if deconditioning and disuse are the principal aetiological factors, weakness would be most marked in the lower limb muscles.
Methods: The non-volitional technique of supramaximal magnetic stimulation was used to assess twitch tensions of the adductor pollicis, quadriceps, and diaphragm muscles (TwAP, TwQ, and TwPdi) in 22 stable non-weight losing COPD patients and 18 elderly controls.
Results: Mean (SD) TwQ tension was reduced in the COPD patients (7.1 (2.2) kg v 10.0 (2.7) kg; 95% confidence intervals (CI) -4.4 to -1.4; p<0.001). Neither TwAP nor TwPdi (when corrected for lung volume) differed significantly between patients and controls (mean (SD) TwAP 6.52 (1.90) N for COPD patients and 6.80 (1.99) N for controls (95% CI -1.5 to 0.97, p=0.65; TwPdi 23.0 (5.6) cm H2O for COPD patients and 23.5 (5.2) cm H2O for controls (95% CI -4.5 to 3.5, p=0.81).
Conclusions: The strength of the adductor pollicis muscle (and the diaphragm) is normal in patients with stable COPD whereas quadriceps strength is substantially reduced. Disuse may be the principal factor in the development of skeletal muscle weakness in COPD, but a systemic process preferentially affecting the proximal muscles cannot be excluded.
doi:10.1136/thorax.58.8.665
PMCID: PMC1746754  PMID: 12885979
20.  Skeletal muscle dysfunction in chronic obstructive pulmonary disease 
Respiratory Research  2001;2(4):216-224.
It has become increasingly recognized that skeletal muscle dysfunction is common in patients with chronic obstructive pulmonary disease (COPD). Muscle strength and endurance are decreased, whereas muscle fatigability is increased. There is a reduced proportion of type I fibers and an increase in type II fibers. Muscle atrophy occurs with a reduction in fiber cross-sectional area. Oxidative enzyme activity is decreased, and measurement of muscle bioenergetics during exercise reveals a reduced aerobic capacity. Deconditioning is probably very important mechanistically. Other mechanisms that may be of varying importance in individual patients include chronic hypercapnia and/or hypoxia, nutritional depletion, steroid usage, and oxidative stress. Potential therapies include exercise training, oxygen supplementation, nutritional repletion, and administration of anabolic hormones.
doi:10.1186/rr60
PMCID: PMC59579  PMID: 11686887
exercise; lung diseases; muscle; nutrition disorder; obstructive; rehabilitation; skeletal
21.  Polyunsaturated fatty acids improve exercise capacity in chronic obstructive pulmonary disease 
Thorax  2005;60(5):376-382.
Background: Muscle wasting and decreased muscle oxidative capacity commonly occur in patients with chronic obstructive pulmonary disease (COPD). Polyunsaturated fatty acids (PUFA) have been shown to mediate several inflammatory and metabolic pathways which may be involved in the pathogenesis of muscle impairment in COPD. The aim of this study was to investigate the effect of PUFA modulation on systemic inflammation, reversal of muscle wasting, and functional status in COPD.
Methods: Eighty patients with COPD (57 men) with forced expiratory volume in 1 second (FEV1) 37.3 (13.8)% predicted received 9 g PUFA or placebo daily in a double blind randomised fashion during an 8 week rehabilitation programme. Body composition (bioelectrical impedance), functional capacity (lung function, incremental cycle ergometry test, submaximal cycle test, isokinetic quadriceps strength) and inflammatory markers (C-reactive protein (CRP), interleukin (IL)-6 and tumour necrosis factor (TNF)-α) were assessed at baseline and after 8 weeks.
Results: Both groups had similar increases in weight, fat-free mass (FFM), and muscle strength. The peak load of the incremental exercise test increased more in the PUFA group than in the placebo group (difference in increase 9.7 W (95% CI 2.5 to 17.0), p = 0.009) even after adjustment for FFM. The duration of the constant work rate test also increased more in patients receiving PUFA (difference in increase 4.3 min (95% CI 0.6 to 7.9), p = 0.023). The positive effects of PUFA could not be attributed to a decrease in systemic levels of CRP, IL-6 and TNF-α.
Conclusions: This is the first study to show beneficial effects of PUFA on exercise capacity in patients with COPD.
doi:10.1136/thx.2004.030858
PMCID: PMC1758900  PMID: 15860712
22.  Airway Epithelial Stem Cells and the Pathophysiology of Chronic Obstructive Pulmonary Disease 
Characteristic pathologic changes in chronic obstructive pulmonary disease (COPD) include an increased fractional volume of bronchiolar epithelial cells, fibrous thickening of the airway wall, and luminal inflammatory mucus exudates, which are positively correlated with airflow limitation and disease severity. The mechanisms driving general epithelial expansion, mucous secretory cell hyperplasia, and mucus accumulation must relate to the effects of initial toxic exposures on patterns of epithelial stem and progenitor cell proliferation and differentiation, eventually resulting in a self-perpetuating, and difficult to reverse, cycle of injury and repair. In this review, current concepts in stem cell biology and progenitor–progeny relationships related to COPD are discussed, focusing on the factors, pathways, and mechanisms leading to mucous secretory cell hyperplasia and mucus accumulation in the airways. A better understanding of alterations in airway epithelial phenotype in COPD will provide a logical basis for novel therapeutic approaches.
doi:10.1513/pats.200605-117SF
PMCID: PMC2647659  PMID: 17065380
epithelium; hyperplasia; metaplasia; mucus hypersecretion; stem cells
23.  Eosinophilic airway inflammation in COPD 
Chronic obstructive pulmonary disease is a common condition and a major cause of mortality. COPD is characterized by irreversible airflow obstruction. The physiological abnormalities observed in COPD are due to a combination of emphysema and obliteration of the small airways in association with airway inflammation. The predominant cells involved in this inflammatory response are CD8+ lymphocytes, neutrophils, and macrophages. Although eosinophilic airway inflammation is usually considered a feature of asthma, it has been demonstrated in large and small airway tissue samples and in 20%–40% of induced sputum samples from patients with stable COPD. This airway eosinophilia is increased in exacerbations. Thus, modifying eosinophilic inflammation may be a potential therapeutic target in COPD. Eosinophilic airway inflammation is resistant to inhaled corticosteroid therapy, but does respond to systemic corticosteroid therapy, and the degree of response is related to the intensity of the eosinophilic inflammation. In COPD, targeting treatment to normalize the sputum eosinophilia reduced the number of hospital admissions. Whether controlling eosinophilic inflammation in COPD patients with an airway eosinophilia will modify disease progression and possibly alter mortality is unknown, but warrants further investigation.
PMCID: PMC2706606  PMID: 18046901
COPD; sputum eosinophilia; corticosteroids
24.  Budesonide/formoterol combination in COPD: a US perspective 
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease of the lung caused primarily by exposure to cigarette smoke. Clinically, it presents with progressive cough, sputum production, dyspnea, reduced exercise capacity, and diminished quality of life. Physiologically, it is characterized by the presence of partially reversible expiratory airflow limitation and hyperinflation. Pathologically, COPD is a multicomponent disease characterized by bronchial submucosal mucous gland hypertrophy, bronchiolar mucosal hyperplasia, increased luminal inflammatory mucus, airway wall inflammation and scarring, and alveolar wall damage and destruction. Management of COPD involves both pharmacological and nonpharmacological approaches. Bronchodilators and inhaled corticosteroids are recommended medications for management of COPD especially in more severe disease. Combination therapies containing these medications are now available for the chronic management of stable COPD. The US Food and Drug Administration, recently, approved the combination of budesonide/formoterol (160/4.5 μg; Symbicort™, AstraZeneca, Sweden) delivered via a pressurized meter dose inhaler for maintenance management of stable COPD. The combination also is delivered via dry powder inhaler (Symbicort™ and Turbuhaler™, AstraZeneca, Sweden) but is not approved for use in the United States. In this review, we evaluate available data of the efficacy and safety of this combination in patients with COPD.
doi:10.2147/COPD.S4215
PMCID: PMC2962302  PMID: 21037960
inhaled steroid; bronchodilator; β2-agonist; lung function; quality of life; COPD exacerbations
25.  Alterations in Skeletal Muscle Cell Homeostasis in a Mouse Model of Cigarette Smoke Exposure 
PLoS ONE  2013;8(6):e66433.
Background
Skeletal muscle dysfunction is common in chronic obstructive pulmonary disease (COPD), a disease mainly caused by chronic cigarette use. An important proportion of patients with COPD have decreased muscle mass, suggesting that chronic cigarette smoke exposure may interfere with skeletal muscle cellular equilibrium. Therefore, the main objective of this study was to investigate the kinetic of the effects that cigarette smoke exposure has on skeletal muscle cell signaling involved in protein homeostasis and to assess the reversibility of these effects.
Methods
A mouse model of cigarette smoke exposure was used to assess skeletal muscle changes. BALB/c mice were exposed to cigarette smoke or room air for 8 weeks, 24 weeks or 24 weeks followed by 60 days of cessation. The gastrocnemius and soleus muscles were collected and the activation state of key mediators involved in protein synthesis and degradation was assessed.
Results
Gastrocnemius and soleus were smaller in mice exposed to cigarette smoke for 8 and 24 weeks compared to room air exposed animals. Pro-degradation proteins were induced at the mRNA level after 8 and 24 weeks. Twenty-four weeks of cigarette smoke exposure induced pro-degradation proteins and reduced Akt phosphorylation and glycogen synthase kinase-3β quantity. A 60-day smoking cessation period reversed the cell signaling alterations induced by cigarette smoke exposure.
Conclusions
Repeated cigarette smoke exposure induces reversible muscle signaling alterations that are dependent on the duration of the cigarette smoke exposure. These results highlights a beneficial aspect associated with smoking cessation.
doi:10.1371/journal.pone.0066433
PMCID: PMC3682961  PMID: 23799102

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