Dysfunction In Chronic Obstructive Pulmonary Disease Research Articles

Revisiting airway epithelial dysfunction and mechanisms in chronic obstructive pulmonary disease: Role of mitochondrial damage.

Chronic exposure to environmental hazards causes airway epithelial dysfunction, primarily impaired physical barriers, immune dysfunction, and repair or regeneration. Impairment of airway epithelial function subsequently leads to exaggerated airway inflammation and remodeling, the main features of chronic obstructive pulmonary disease (COPD). Mitochondrial damage has been identified as one of the mechanisms of airway abnormalities in COPD, which is closely related to airway inflammation and airflow limitation. In this review, we evaluate updated evidence for airway epithelial mitochondrial damage in COPD and focus on the role of mitochondrial damage in airway epithelial dysfunction. In addition, the possible mechanism of airway epithelial dysfunction mediated by mitochondrial damage is discussed in detail, and recent strategies related to airway epithelial-targeted mitochondrial therapy are summarized. Results have shown that dysregulation of mitochondrial quality and oxidative stress may lead to airway epithelial dysfunction in COPD. This may result from mitochondrial damage as a central organelle mediating abnormalities in cellular metabolism. Mitochondrial damage mediates pro-cellular senescence effects due to mitochondrial reactive oxygen species, which effectively exacerbate different types of programmed cell death, participate in lipid metabolism abnormalities, and ultimately promote airway epithelial dysfunction and trigger COPD airway abnormalities. These can be prevented by targeting mitochondrial damage factors and mitochondrial transfer. Thus, because mitochondrial damage is involved in COPD progression as a central factor of homeostatic imbalance in airway epithelial cells, it may be a novel target for therapeutic intervention to restore airway epithelial integrity and function in COPD.

The role of pulmonary vascular endothelium in chronic obstructive pulmonary disease (COPD): Does endothelium play a role in the onset and progression of COPD?

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung pathology characterized by persistent airflow limitation and is the third leading cause of death globally. COPD pathophysiology includes both environmental and host risk factors and the presence of comorbidities contributes to its harmful outcome. Cardiovascular disease (CVD) is closely related to COPD and their coexistence is associated with worse outcomes than either condition alone. COPD impairs the cardiovascular system favoring mostly endothelial dysfunction that is a significant COPD prognostic factor at different stages of the disease. The mechanisms promoting endothelial dysfunction in the systemic and/or pulmonary circulation of COPD patients are different and include systemic inflammation, alteration of adhesion and pro-inflammatory molecules, oxidative stress, cellular senescence, and apoptosis. Nevertheless, the role of endothelium in the onset and progression of COPD and CVD is not yet fully understood. Hence, the purpose of this narrative review is to analyze the literature and provide evidence supporting the importance of endothelial dysfunction in COPD.

Mitochondrial Dysfunction and Nanocarrier-Based Treatments in Chronic Obstructive Pulmonary Disease (COPD)

Mitochondrial dysfunction significantly contributes to the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). To treat mitochondrial dysfunction in COPD, novel drug delivery systems (DDS) are needed. In this review, we provide a brief overview of the current understanding of the factors in COPD and highlight the trends in novel nanocarriers/nanoparticles for targeting mitochondrial dysfunction. These drug-encapsulated nanoparticles are still in the early stages of clinical application but represent the most promising system for COPD therapy.

Assessment of left ventricular function in subjects with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is the world's third leading cause of death, posing a significant public health challenge. Heart failure is an important milestone in the natural history of this disease's ever-decreasing course. Cor pulmonale alone is sometimes insufficient to explain the scenario, as many heart failures are refractory even after standard treatment. A possible explanation is involvement of the left ventricle (LV). However, there is currently no consensus on a therapeutic approach to LV dysfunction in COPD. Some previous studies were conducted on COPD patients regardless of the presence or absence of other factors influencing LV function. This study attempted to rule out all known confounding factors/co-morbidities that influence LV function. We discovered that LV diastolic dysfunction was common in subjects at all stages of COPD. We believe that all COPD patients, regardless of stage, should have screening echocardiography.

Incident low muscle mass is associated with greater lung disease and lower circulating leptin in a tobacco-exposed longitudinal cohort

BackgroundMuscle loss is prevalent in chronic obstructive pulmonary disease (COPD). Prior studies evaluating musculoskeletal dysfunction in COPD have focused on individuals with baseline low muscle mass. Currently, there is limited data evaluating clinical characteristics and outcomes associated with progression to incident low muscle mass in a tobacco-exposed cohort of individuals with baseline normal muscle mass.MethodsWe evaluated 246 participants from a single-center longitudinal tobacco-exposed cohort with serial spirometry, thoracic imaging, dual energy x-ray absorptiometry (DXA) measurements, walk testing, and plasma adipokine measurements. DXA-derived fat free mass index (FFMI) and appendicular skeletal mass index (ASMI) were used as surrogates for muscle mass. Participants with incident low muscle mass (LM) at follow-up were characterized by FFMI < 18.4 kg/m2 in males and < 15.4 kg/m2 in females and/or ASMI < 7.25 kg/m2 in males and < 5.67 kg/m2 in females.ResultsTwenty-five (10%) participants progressed to incident low muscle mass at follow-up. At baseline, the LM subgroup had greater active smoking prevalence (60% v. 38%, p = 0.04), lower FFMI (17.8 ± 1.7 kg/m2 v. 19.7 ± 2.9 kg/m2, p = 0.002), lower ASMI (7.3 ± 0.9 kg/m2 v. 8.2 ± 1.2 kg/m2, p = 0.0003), and lower plasma leptin (14.9 ± 10.1 ng/mL v. 24.0 ± 20.9 ng/mL, p = 0.04). At follow-up, the LM subgroup had higher COPD prevalence (68% v. 43%, p = 0.02), lower FEV1/FVC (0.63 ± 0.12 v. 0.69 ± 0.12, p = 0.02), lower %DLco (66.5 ± 15.9% v. 73.9 ± 16.8%, p = 0.03), and higher annual rate of FFMI decline (-0.17 kg/m2/year v. -0.04 kg/m2/year, p = 0.006). There were no differences in age, gender distribution, pack years smoking history, or walk distance.ConclusionsWe identified a subgroup of tobacco-exposed individuals with normal baseline muscle mass who progressed to incident DXA-derived low muscle mass. This subgroup demonstrated synchronous lung disease and persistently low circulating leptin levels. Our study suggests the importance of assessing for muscle loss in conjunction with lung function decline when evaluating individuals with tobacco exposure.

LncRNA H19 Contributes to Smoke-Related Chronic Obstructive Pulmonary Disease by Targeting miR-181/PDCD4 Axis

Chronic obstructive pulmonary disease (COPD) kills more than 3 million people worldwide every year. Despite progress in the treatment of symptoms and prevention of acute exacerbations, few advances have been made to ameliorate disease progression or affect mortality. Exercise plays a positive role in the prevention and treatment of diaphragm dysfunction in COPD, and the changes in diaphragm structure and function induced by exercise are closely related to the regulation of oxidative stress. But the mechanism remains unclear. So the aim of this study was to reveal the therapeutic mechanism of exercise to COPD using both in vivo and in vitro experiments. In this study, cigarette smoke (CS) induced COPD mice model, treadmill aerobic training for COPD mice were constructed and cigarette smoke extract (CSE) induced bronchial epithelial cells (BECs) model were used for COPD study. Bioinformatics analysis, luciferase reporting analysis, and RT-qPCR detection were used to clarify the interacted relationship among lncRNA, miRNA, and mRNA. ROS, inflammatory cytokines expression, and EMT relative protein α-SMA were detected using immunofluorescence and ELISA detection. The result shows that exercise ameliorates COPD induced lung injury by inhibit ROS, inflammation, and epithelial-mesenchymal transition (EMT) relative protein α-SMA expression. RT-qPCR detection shows that lnc-H19 expression was increased in lung tissues of COPD mice. Exercise decreased COPD induced lnc-H19 expression. Downregulation lnc-H19 inhibits COPD mediated lung injury. Bioinformatics analysis and luciferase reporting analysis confirmed that miR-181 and PDCD4 were downstream targets of lnc-H19. Upregulation of PDCD4 or downregulation of miR-181 reversed the protective effect of si-lnc-H19 to BECs after exposure to CSE. In conclusion, lncRNA H19 contributes to smoke-related chronic obstructive pulmonary disease by targeting miR-181/PDCD4 Axis.

The role of muscle-specific MicroRNAs in patients with chronic obstructive pulmonary disease and skeletal muscle dysfunction.

Skeletal muscle dysfunction is a systematic manifestation of chronic obstructive pulmonary disease (COPD), which is manifested through the changes in the respiratory and peripheral muscle fiber types, reducing muscle strength and endurance, and muscle atrophy. Muscle dysfunction limits the daily mobility, negatively affects the quality of life, and may increase the patient's risk of mortality. MicroRNAs (miRNAs) as the regulators of gene expression, plays an important role in modulating skeletal muscle dysfunction in COPD by regulating skeletal muscle development (proliferation, differentiation), protein synthesis and degradation, inflammatory response, and metabolism. In particular, muscle-specific miRNAs (myomiRs) may play an important role in this process, although the different expression levels of myomiRs in COPD and skeletal muscle dysfunction and the mechanisms underlying their role remain unclear. In this paper, we review the differential expression of the myomiRs in COPD to identify myomiRs that play a role in skeletal muscle dysfunction in COPD. We further explore their possible mechanisms and action in order to provide new ideas for the prevention and treatment of the skeletal muscle dysfunction in COPD.

Dysregulated myokines and signaling pathways in skeletal muscle dysfunction in a cigarette smoke-induced model of chronic obstructive pulmonary disease.

Skeletal muscle dysfunction is an important extrapulmonary comorbidity of chronic obstructive pulmonary disease (COPD). Muscle-derived cytokines (myokines) play important roles in skeletal muscle growth and function, but their contributions to skeletal muscle dysfunction in COPD have not been fully understood. In the current study, by using a well-established mouse model of COPD with skeletal muscle dysfunction, we found that the expressions of Fndc5 (fibronectin type III domain-containing protein 5, the precursor of irisin) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) were decreased, while myostatin (Mstn), phosphorylated extracellular regulated kinase (p-Erk1/2), and p-Smad3 expressions were upregulated in skeletal muscles from cigarette smoke-exposed mice and in cigarette smoke extract (CSE)-stimulated C2C12 myotubes. Treatment with Smad3 or Erk1/2 inhibitors partially restored the expression of Fndc5 in CSE-stimulated C2C12 myotubes. Taken together, CSE exposure, by upregulation of p-Erk1/2, promoted the expression of Mstn, which further inhibited Fndc5 expression by the p-Smad3/PGC-1α pathway, revealing a novel regulating mechanism of myokines in the pathogenesis of skeletal muscle comorbidities of COPD.

Diaphragm Dysfunction and Rehabilitation Strategy in Patients With Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) affects the whole body and causes many extrapulmonary adverse effects, amongst which diaphragm dysfunction is one of the prominent manifestations. Diaphragm dysfunction in patients with COPD is manifested as structural changes, such as diaphragm atrophy, single-fibre dysfunction, sarcomere injury and fibre type transformation, and functional changes such as muscle strength decline, endurance change, diaphragm fatigue, decreased diaphragm mobility, etc. Diaphragm dysfunction directly affects the respiratory efficiency of patients and is one of the important pathological mechanisms leading to progressive exacerbation of COPD and respiratory failure, which is closely related to disease mortality. At present, the possible mechanisms of diaphragm dysfunction in patients with COPD include systemic inflammation, oxidative stress, hyperinflation, chronic hypoxia and malnutrition. However, the specific mechanism of diaphragm dysfunction in COPD is still unclear, which, to some extent, increases the difficulty of treatment and rehabilitation. Therefore, on the basis of the review of changes in the structure and function of COPD diaphragm, the potential mechanism of diaphragm dysfunction in COPD was discussed, the current effective rehabilitation methods were also summarised in this paper. In order to provide direction reference and new ideas for the mechanism research and rehabilitation treatment of diaphragm dysfunction in COPD.

Muscle-Bone Crosstalk in Chronic Obstructive Pulmonary Disease.

Sarcopenia and osteoporosis are common musculoskeletal comorbidities of chronic obstructive pulmonary disease (COPD) that seriously affect the quality of life and prognosis of the patient. In addition to spatially mechanical interactions, muscle and bone can also serve as endocrine organs by producing myokines and osteokines to regulate muscle and bone functions, respectively. As positive and negative regulators of skeletal muscles, the myokines irisin and myostatin not only promote/inhibit the differentiation and growth of skeletal muscles, but also regulate bone metabolism. Both irisin and myostatin have been shown to be dysregulated and associated with exercise and skeletal muscle dysfunction in COPD. During exercise, skeletal muscles produce a large amount of IL-6 which acts as a myokine, exerting at least two different conflicting functions depending on physiological or pathological conditions. Remarkably, IL-6 is highly expressed in COPD, and considered to be a biomarker of systemic inflammation, which is associated with both sarcopenia and bone loss. For osteokines, receptor activator of nuclear factor kappa-B ligand (RANKL), a classical regulator of bone metabolism, was recently found to play a critical role in skeletal muscle atrophy induced by chronic cigarette smoke (CS) exposure. In this focused review, we described evidence for myokines and osteokines in the pathogenesis of skeletal muscle dysfunction/sarcopenia and osteoporosis in COPD, and proposed muscle-bone crosstalk as an important mechanism underlying the coexistence of muscle and bone diseases in COPD.

Rehabilitation Effects of Acupuncture on the Diaphragm Dysfunction in Chronic Obstructive Pulmonary Disease: A Systematic Review.

IntroductionDiaphragm dysfunction is a significant extrapulmonary effect in chronic obstructive pulmonary disease (COPD), which is manifested by changes in diaphragm structure and reduced diaphragm strength. Acupuncture is a traditional rehabilitation technique in China, which has been used in rehabilitation for COPD. But whether acupuncture can improve the diaphragm function of COPD patients remains to be verified.ObjectiveThe objective of this study was to evaluate the rehabilitation effects of acupuncture on diaphragm dysfunction in patients with COPD.MethodsThe authors retrieved in CNKI, VIP, SinoMed, PubMed, Ebsco, Web of Science, from inception to November 2020, for relevant randomized control trials. Two researchers independently screened the articles and extracted the data. The quality of the included studies was evaluated by Physiotherapy Evidence Database scale. The primary outcome measures were maximal inspiratory pressure and the scale for accessory respiratory muscle mobilization, the secondary outcome measures were pulmonary function-related indicators and arterial blood gas indicators.ResultsNine articles were finally obtained. Seven studies added acupuncture to standard treatment for patients with diaphragm dysfunction in COPD and found statistically significant changes in the maximum inspiratory pressure and the scale for accessory respiratory muscle mobilization. Two studies have proved that use acupuncture combined with other Traditional Chinese Medicine methods in the rehabilitation for COPD can effectively improve the diaphragm strength and diaphragmatic motor performance. Seven studies showed that acupuncture has obvious improvement in pulmonary ventilation function. Seven studies reported significant differences in arterial blood gas pre- to post-intervention.ConclusionThis systematic review found that acupuncture can effectively enhance the diaphragm strength, relieve respiratory muscle fatigue, it can also play a promoting role in improving lung function, hypoxia, and carbon dioxide retention, as well as preventing and alleviating respiratory failure. The generalizability of these results is limited by the design of the included studies.

Role of inner mitochondrial protein OPA1 in mitochondrial dysfunction by tobacco smoking and in the pathogenesis of COPD

BackgroundChronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are linked to several mitochondrial alterations. Cigarette smoke (CS) alters the structure and function of mitochondria. OPA1 is the main inner mitochondrial GTPase responsible for the fusion events. OPA1 undergoes proteolytic cleavage from long to short forms during acute stress and mitophagy. However, the exact role of OPA1 isoforms and related proteins during CS-induced mitophagy and COPD is not clear. MethodsLung tissues from non-smokers, smokers, COPD and IPF were used to determine the relative expression of OPA1 and related proteins. Additionally, we used mouse lungs from chronic (6 months) CS exposure to evaluate the status of OPA1. Primary lung fibroblasts from normal and COPD patients and naked mole rat (NMR) lung fibroblasts, human fetal lung fibroblast (HFL1), mouse embryonic fibroblast from wild type (WT), OPA1−/−, MFN1 and MFN2−/− were used to determine the effect of CS on OPA1 isoforms. Various mitochondrial fusion promoters/activators (BGP-15, leflunomide, M1) and fission inhibitor (DRP1) were used to determine their effect on OPA1 status and cigarette smoke extract (CSE)-induced lung epithelial (BEAS2B) cell damage, respectively. Seahorse flux analyzer was used to determine the effect of these compounds in BEAS2B cells with and without CSE exposure. FindingsShort OPA1 isoforms were predominantly detected and significantly increased in COPD subjects. Acute CSE treatment in various cell lines except NMR was found to increase the conversion of long to short OPA1 isoforms. CSE treatment significantly increased mitochondrial stress-related protein SLP2 in all the cells used. OPA1 interacting partners like prohibitins (PHB1 and 2) were also altered depending on the CS exposure. Finally, BGP-15 and leflunomide treatment were able to preserve the long OPA1 isoform in cells treated with CSE. Interpretation/conclusionThe long OPA1 isoform along with SLP2 and prohibitins play a crucial role in CS-induced lung damage, causing mitophagy/mitochondrial dysfunction in COPD, which may be used as a novel therapeutic target in COPD.

Effect of Oxidative Stress on Diaphragm Dysfunction and Exercise Intervention in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) can cause extrapulmonary injury such as diaphragm dysfunction. Oxidative stress is one of the main factors causing diaphragm dysfunction in COPD. Exercise plays a positive role in the prevention and treatment of diaphragm dysfunction in COPD, and the changes in diaphragm structure and function induced by exercise are closely related to the regulation of oxidative stress. Therefore, on the basis of the review of oxidative stress and the changes in diaphragm structure and function in COPD, this article analyzed the effects of exercise on oxidative stress and diaphragm dysfunction in COPD and explored the possible mechanism by which exercise improves oxidative stress. Studies have found that diaphragm dysfunction in COPD includes the decline of muscle strength, endurance, and activity. Oxidative stress mainly affects the structure and function of the diaphragm in COPD through protein oxidation, protease activation and calcium sensitivity reduction. The effects of exercise on oxidative stress level and diaphragm dysfunction may differ depending on the intensity, duration, and style of exercise. The mechanism of exercise on oxidative stress in the diaphragm of COPD may include improving antioxidant capacity, reducing oxidase activity and improving mitochondrial function.

Correlation Between 2D Strain and Classic Echocardiographic Indices in the Diagnosis of Right Ventricular Dysfunction in COPD.

PurposeThis study aims to define which of the right ventricular myocardial deformation indices best correlates with the classic echocardiographic measurements and indices of right ventricular (RV) dysfunction in patients with stable chronic obstructive pulmonary disease (COPD).Patients and MethodsNinety-one patients with stable COPD underwent clinical evaluation, spirometry, a 6-minute walk test, and echocardiographic examination. Patients were divided into two groups: “with RV dysfunction” (≥1 classic parameter) and “without RV dysfunction”. We used speckle tracking to estimate myocardial deformation. For all analyses, results were considered significant if p < 0.05.ResultsThe mean age across all participants was 65 ± 9 years, with 53% (48/91) being male. Patients in the group with RV dysfunction were able to walk shorter distances and had higher estimated right ventricular systolic pressure (RVSP) and mean pulmonary arterial pressure (mPAP). The RV free wall longitudinal strain (RVFWLS) was the only deformation indices that showed a significant correlation with all classic measurements and indices in the diagnosis of RV dysfunction (Wald test, 10.24; p < 0.01; odds ratio, 1.61). In the ROC curve analysis, the absolute value <20% was the lowest cut-off point of this index for detection of RV dysfunction (AUC = 0.93, S: 95.8%, and E: 88%).ConclusionIn COPD patients, RVFWLS is the myocardial deformation index that best correlates with classic echocardiographic parameters for the diagnosis of RV dysfunction using <20% as a cut-off point.

Presence or Absence of Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease is Associated With Distinct Phenotypes

IntroductionReduced skeletal muscle function and cognitive performance are common extrapulmonary features in Chronic Obstructive Pulmonary Disease (COPD) but their connection remains unclear. Whether presence or absence of skeletal muscle dysfunction in COPD patients is linked to a specific phenotype consisting of reduced cognitive performance, comorbidities and nutritional and metabolic disturbances needs further investigation. MethodsThirty-seven patients with COPD (grade II–IV) were divided into two phenotypic cohorts based on the presence (COPD dysfunctional, n=25) or absence (COPD functional, n=12) of muscle dysfunction. These cohorts were compared to 28 healthy, age matched controls. Muscle strength (dynamometry), cognitive performance (Trail Making Test and STROOP Test), body composition (Dual-energy X-Ray Absorptiometry), habitual physical activity, comorbidities and mood status (questionnaires) were measured. Pulse administration of stable amino acid tracers was performed to measure whole body production rates. ResultsPresence of muscle dysfunction in COPD was independent of muscle mass or severity of airflow obstruction but associated with impaired STROOP Test performance (p=0.04), reduced resting O2 saturation (p=0.003) and physical inactivity (p=0.01), and specific amino acid metabolic disturbances (enhanced leucine (p=0.02) and arginine (p=0.06) production). In contrast, COPD patients with normal muscle function presented with anxiety, increased fat mass, plasma glucose concentration, and metabolic syndrome related comorbidities (hypertension and dyslipidemia). ConclusionCOPD patients with muscle dysfunction show characteristics of a cognitive – metabolic impairment phenotype, influenced by the presence of hypoxia, whereas those with normal muscle function present a phenotype of metabolic syndrome and mood disturbances.

Blood-Flow–Restricted Strength Training Combined With High-Load Strength and Endurance Training in Pulmonary Rehabilitation for COPD: A Case Report

The purpose of this report is to describe the case of a patient with chronic obstructive pulmonary disease (COPD) who was load compromised and being referred for outpatient pulmonary rehabilitation. Low-load blood flow restriction strength training (LL-BFRT) was applied to prepare for and increase tolerability of subsequently applied high-load strength training (HL-ST). A 62-year-old woman with COPD GOLD 2 B presented with severe breathlessness. Lower limb strength was severely reduced while functional exercise capacity was preserved. The patient was severely load compromised and had high risk to be intolerant of the high training loads required to trigger the desired adaptations. LL-BFRT was applied during the first 12 training sessions and HL-ST in the subsequent 12 training sessions of the rehabilitation program. Endurance training on a cycle ergometer was performed throughout the program. Symptom burden in the COPD Assessment test was reduced by 6 points (40%). Lower limb strength improved by 95.3Nm (521%) and 88.4Nm (433%) for the knee extensors and by 33.8Nm (95%) and 56Nm (184%) for the knee flexors, respectively. Functional exercise capacity improved by 44m (11%) in the 6-Minute Walk Test and 14 repetitions (108%) in the 1-minute sit-to stand test. The patient did not experience any adverse events related to the exercise training. Clinically relevant changes were observed in both strength-related functional and self-reported outcomes. The achievements translated well into daily living and enabled functioning according to the patients' desires. LL-BFRT was reported to be well tolerated and implementable into an outpatient pulmonary rehabilitation program. The description of this case encourages the systematic investigation of LL-BFRT in COPD. LL-BFRT has the potential to increase benefits as well as tolerability of strength training in pulmonary rehabilitation. Consideration of the physiological changes achieved through LL-BFRT highlights potential in targeting peripheral muscle dysfunction in COPD.

ФИЗИЧЕСКАЯ СЛАБОСТЬ КАК ФЕНОТИП ХОБЛ

Chronic obstructive pulmonary disease (COPD) is an important cause of disability and premature death. The Global Strategy for the Diagnosis, Management and Prevention of COPD (GOLD) gives much attention to pulmonary rehabilitation programs including training of the muscles of the upper extremities and of respiratory muscles, which, in turn, permits to reliably reduce severity of clinical manifestations, to improve the quality of life, reduce the need for specialized medical care including outpatient visits to a doctor and the rate of exacerbations and hospitalizations for the given disease. One of the main problems of patients with this pathology is the syndrome of physical weakness. In these patients, disorders occur both in respiratory muscles and in mus-cles of the extremities, which reduces tolerance to physical exercise with the result of a consider-able impairment of the quality of life. Muscles of the lower extremities suffer to a higher extent than respiratory muscles and muscles of the upper extremities. According to foreign data, the cause of physical weakness is skeletal muscle dysfunction which leads not only to exercise intol-erance, but is also a predictor of increased mortality in COPD. Factors that contribute to muscle dysfunction are similar to those observed in a stable course of COPD: a significant role of nutritive support, hypercapnia, hypoxemia, electrolyte disorders, systemic inflammation. These factors may play a role of a triggering mechanism for a cascade of local inflammatory reactions and metabolic disorders that may induce different clinical effects including development of muscle dysfunction. At the moment, the problem of physical weakness as a consequence of muscle dysfunction in COPD deserves special study in order to effectively manage patients with this pathology in real clinical practice. Given the importance of the problem, a number of researchers have identified a separate phenotype of physical weakness in COPD. Identification of molecular mechanisms participating in muscle dysfunction, in loss of muscle mass and in disorders in anabolism will permit to elaborate new therapeutic goals in future.

Ebselen prevents cigarette smoke-induced gastrointestinal dysfunction in mice.

Gastrointestinal (GI) dysfunction is a common comorbidity of chronic obstructive pulmonary disease (COPD) for which a major cause is cigarette smoking (CS). The underlying mechanisms and precise effects of CS on gut contractility, however, are not fully characterised. Therefore, the aim of the present study was to investigate whether CS impacts GI function and structure in a mouse model of CS-induced COPD. We also aimed to investigate GI function in the presence of ebselen, an antioxidant that has shown beneficial effects on lung inflammation resulting from CS exposure. Mice were exposed to CS for 2 or 6 months. GI structure was analysed by histology and immunofluorescence. After 2 months of CS exposure, ex vivo gut motility was analysed using video-imaging techniques to examine changes in colonic migrating motor complexes (CMMCs). CS decreased colon length in mice. Mice exposed to CS for 2 months had a higher frequency of CMMCs and a reduced resting colonic diameter but no change in enteric neuron numbers. Ten days cessation after 2 months CS reversed CMMC frequency changes but not the reduced colonic diameter phenotype. Ebselen treatment reversed the CS-induced reduction in colonic diameter. After 6 months CS, the number of myenteric nitric-oxide producing neurons was significantly reduced. This is the first evidence of colonic dysmotility in a mouse model of CS-induced COPD. Dysmotility after 2 months CS is not due to altered neuron numbers; however, prolonged CS-exposure significantly reduced enteric neuron numbers in mice. Further research is needed to assess potential therapeutic applications of ebselen in GI dysfunction in COPD.

Association Between Systemic and Pulmonary Vascular Dysfunction in COPD.

IntroductionIn chronic obstructive pulmonary disease (COPD), endothelial dysfunction and stiffness of systemic arteries may contribute to increased cardiovascular risk. Pulmonary vascular disease (PVD) is frequent in COPD. The association between PVD and systemic vascular dysfunction has not been thoroughly evaluated in COPD.MethodsA total of 108 subjects were allocated into four groups (non-smoking controls, smoking controls, COPD without PVD and COPD with PVD). In systemic arteries, endothelial dysfunction was assessed by flow-mediated dilation (FMD) and arterial stiffness by pulse wave analysis (PWA) and pulse wave velocity (PWV). PVD was defined by a mean pulmonary artery pressure (PAP) ≥25 mmHg at right heart catheterization or by a tricuspid regurgitation velocity >2.8 m/s at doppler echocardiography. Biomarkers of inflammation and endothelial damage were assessed in peripheral blood.ResultsFMD was lower in COPD patients, with or without PVD, compared to non-smoking controls; and in patients with COPD and PVD compared to smoking controls. PWV was higher in COPD with PVD patients compared to both non-smoking and smoking controls in a model adjusted by age and the Framingham score; PWV was also higher in patients with COPD and PVD compared to COPD without PVD patients in the non-adjusted analysis. FMD and PWV correlated significantly with forced expiratory volume in the first second (FEV1), diffusing capacity for carbon monoxide (DLCO) and systolic PAP. FMD and PWV were correlated in all subjects.DiscussionWe conclude that endothelial dysfunction of systemic arteries is common in COPD, irrespective if they have PVD or not. COPD patients with PVD show increased stiffness and greater impairment of endothelial function in systemic arteries. These findings suggest the association of vascular impairment in both pulmonary and systemic territories in a subset of COPD patients.

Presence or Absence of Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease is Associated With Distinct Phenotypes

IntroductionReduced skeletal muscle function and cognitive performance are common extrapulmonary features in Chronic Obstructive Pulmonary Disease (COPD) but their connection remains unclear. Whether presence or absence of skeletal muscle dysfunction in COPD patients is linked to a specific phenotype consisting of reduced cognitive performance, comorbidities and nutritional and metabolic disturbances needs further investigation. MethodsThirty-seven patients with COPD (grade II–IV) were divided into two phenotypic cohorts based on the presence (COPD dysfunctional, n=25) or absence (COPD functional, n=12) of muscle dysfunction. These cohorts were compared to 28 healthy, age matched controls. Muscle strength (dynamometry), cognitive performance (Trail Making Test and STROOP Test), body composition (Dual-energy X-Ray Absorptiometry), habitual physical activity, comorbidities and mood status (questionnaires) were measured. Pulse administration of stable amino acid tracers was performed to measure whole body production rates. ResultsPresence of muscle dysfunction in COPD was independent of muscle mass or severity of airflow obstruction but associated with impaired STROOP Test performance (p=0.04), reduced resting O2 saturation (p=0.003) and physical inactivity (p=0.01), and specific amino acid metabolic disturbances (enhanced leucine (p=0.02) and arginine (p=0.06) production). In contrast, COPD patients with normal muscle function presented with anxiety, increased fat mass, plasma glucose concentration, and metabolic syndrome related comorbidities (hypertension and dyslipidemia). ConclusionCOPD patients with muscle dysfunction show characteristics of a cognitive – metabolic impairment phenotype, influenced by the presence of hypoxia, whereas those with normal muscle function present a phenotype of metabolic syndrome and mood disturbances.