Diaphragm In Chronic Obstructive Pulmonary Disease Research Articles

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.

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.

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Introduction: Redundant diaphragm describes a condition, usually resulting from bilateral phrenic nerve palsy, leading to the inability of the diaphragm to contract during respiration. It has also been described as a result of post-surgical, iatrogenic injuries where mediastinal shifts from paradoxical diaphragm movement can worsen respiratory distress. In the latter group, early recognition and treatment with surgical diaphragm plication reduces the duration of mechanical ventilation, morbidity, and ICU stay especially in pediatric patients. Redundant diaphragm has been hypothesized in advanced Chronic Obstructive Pulmonary Disease (COPD). There is conflicting literature on prevalence of diaphragm dysfunction attributed to direct effect on lung volume changes on diaphragm. Possible mechanisms for redundant diaphragm in COPD include phrenic neuropathy from chronic steroid use or direct muscle changes from chronic hyperinflation. Studies have shown myofibre atrophy, impaired fiber contractility with remodeling in the diaphragm in advanced COPD. Use of muscle ultrasound has made bedside visualization of the diaphragm possible in critically ill patients. Ultrasound can be used to evaluate diaphragm thickness, change in thickness with respiration, excursion amplitude and paradoxical movements with respiration. Feasibility of expeditious bedside ultrasound is uncovering unique phenomenon that may help understand natural history of diaphragm changes seen in COPD. We present a case of redundant diaphragm visualized using ultrasound in a patient with advanced COPD. An 88-year old female with chronic kidney disease was admitted with right basal ganglia and temporal lobe infarcts. On hospital day 2, the patient had acute respiratory failure from aspiration, requiring intubation. Patient was noted to have tachypnea (Rate 35)and acutely increased work of breathing using accessory muscles while on ventilator settings SIMV, FiO2 100%, PEEP 8 cm H2O. Chest x-ray showed pulmonary edema with hyperinflation, suggesting severe COPD. Bedside diaphragm ultrasound in mid axillary line in the zone of apposition showed visible diaphragm separating the thorax and abdomen, with lack of thickening during respiration. Fasciculations were seen in diaphragm muscle but descending lung shadows were not visualized corresponding to diaphragm movements signifying passive movements of diaphragm with positive pressure changes during mechanical ventilation. Abnormal attachment of the diaphragm was visualized on both liver and spleen windows with adhesions seen at the zone of apposition. Ineffective movements were also suspected based on fluttering of diaphragm around incidental splenic accessory lobe without any splenic movements seen. All changes were captured on video using ultrasound. Her hospital course was complicated by worsening hypoxia and hypotension and evolution of septic and cardiogenic shock, leading to her death on hospital day 4. The emerging interest in the use of bedside ultrasonography in real time in critically ill patients may uncover unique phenomena like a redundant diaphragm. Visualization of the diaphragm for changes in thickness and pattern of movements in acute respiratory distress can help uncover natural history of disease and help provide newer perspectives to pathophysiology of respiratory muscle dysfunction in critical illness.

Atrophy and hypertrophy signalling of the quadriceps and diaphragm in COPD

BackgroundFactors involved in the regulation of muscle mass in chronic obstructive pulmonary disease (COPD) are still poorly understood. Comparing the signalisation involved in muscle mass regulation between two muscles with...

Diaphragm Muscle Fiber Dysfunction in Chronic Obstructive Pulmonary Disease

Inspiratory muscle weakness in patients with chronic obstructive pulmonary disease (COPD) is of major clinical relevance; maximum inspiratory pressure generation is an independent determinant of survival in severe COPD. Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered of pathologic nature. Although the fiber-type shift toward oxidative type I fibers in COPD diaphragm is regarded as beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness. The reduced diaphragm force generation at single-fiber level is associated with loss of myosin content. Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury. The current Pulmonary Perspective postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force-generating capacity of diaphragm fibers in patients with COPD. Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients do not appear to be limited in their daily-life activities. Therefore, investigating in vivo diaphragm function in mild to moderate COPD should be the focus of future research. Treatment of diaphragm dysfunction in COPD is complex because its etiology is unclear, but recent findings show promise for the use of proteasome inhibitors in syndromes associated with muscle wasting, such as the diaphragm in COPD.

Activation of the Ubiquitin–Proteasome Pathway in the Diaphragm in Chronic Obstructive Pulmonary Disease

Studies show that the myosin content of the diaphragm in patients with mild to moderate chronic obstructive pulmonary disease (COPD) is reduced, compromising diaphragm contractile performance. The mechanisms for reduced contractile protein content are unknown. In the present study we hypothesized that the loss of contractile protein content is associated with activation of the ubiquitin-proteasome pathway in the diaphragm of patients with mild to moderate COPD. Proteolytic activity of isolated 20S proteasomes was determined in diaphragm biopsies from patients with and without COPD (predicted mean FEV1, 66 and 93%, respectively). In addition, we determined 20S proteasome subunit C8 protein levels by means of Western blotting, ubiquitin-ligase mRNA levels by means of real-time polymerase chain reaction, and caspase-3 activity by determining the hydrolysis of fluorogenic substrates. The 20S proteasome activity was about threefold increased in the diaphragm of patients with COPD. C8 protein levels were not significantly different between COPD and non-COPD diaphragm, indicating increased specific activity of individual proteasomes, rather than an increased number of proteasomes. mRNA levels of the muscle-specific ubiquitin-ligase MAFbx were significantly higher in diaphragm from patients with COPD compared with patients without COPD. Caspase-3-mediated cleavage of actomyosin complexes is considered an initial step in muscle wasting, yielding fragments that can be degraded by the ubiquitin-proteasome pathway. In line with the increased ubiquitin-proteasome activity, caspase-3 activity was higher in diaphragm homogenates from patients with COPD. The present study is the first to demonstrate increased activity of the ubiquitin-proteasome pathway in COPD diaphragm. Importantly, these changes occur in patients with only mild to moderate COPD (Global Initiative for Chronic Obstructive Lung Disease stage I/II).

Passive properties of the diaphragm in COPD

Structural adaptations that occur in the diaphragm muscle of patients with chronic obstructive pulmonary disease (COPD), namely an increase in type I fibers and a decrease in type II fibers, have been explored in terms of the active contractile properties of the diaphragm. The aim of this study was to test the passive properties of the diaphragm by measuring the force response of relaxed diaphragm muscle fibers to stretching to determine the effect of COPD on these properties. Costal diaphragm biopsies were taken from patients with COPD and from controls with normal pulmonary function. From these biopsies, titin expression was assessed in diaphragm homogenates by gel electrophoresis, and the restoring force was measured by incremental stretching of single fibers in the relaxed state and measuring the force response to stretching. A quadratic model was used to illustrate the relationship between restoring force and muscle fiber length, and it revealed that COPD fibers generate significantly lower restoring forces than control fibers as judged by the area under the force-length curve. Furthermore, this finding applies to both type I and type II fibers. Gel electrophoresis revealed different titin isoforms in COPD and controls, consistent with the conclusion that COPD results not only in a change in muscle fiber-type distribution but in a structural change in the titin molecule in all muscle fiber types within the diaphragm. This may assist the muscle with the energetic changes in the length of the diaphragm required during breathing in COPD.

Increased injury and intramuscular collagen of the diaphragm in COPD: autopsy observations

Evidence for diaphragm injury in people with chronic obstructive pulmonary disease (COPD) has been reported, although the extent of injury and collagen accumulation post mortem have not previously been examined. In addition, it is not known whether the amount of injury and collagen are different in key regions of the diaphragm. The cross-sectional area of collagen and the percentage of abnormal myofibres in the post mortem diaphragm and psoas major were determined by computer-assisted image analysis of stained cross-sections of the diaphragm for collagen with picrosirius red and with haematoxylin and eosin for morphology. In the midcostal diaphragm of six subjects with COPD and six subjects with no significant respiratory disease, the COPD diaphragm displayed a greater cross-sectional area of collagen and percentage of abnormal myofibres (collagen: 24.2+/-1.0 versus 18.6+/-1.1%; injury: 28.4+/-7.2 versus 12.0+/-1.3%). In 18 patients with various respiratory conditions, the midcostal diaphragm displayed more collagen and abnormal myofibres than the crural diaphragm, while both costal and crural diaphragms displaying more collagen and abnormal myofibres than psoas major. This study reveals extensive injury and collagen accumulation in the chronic obstructive pulmonary diseased diaphragm, and reveals a regional pattern of injury and intramuscular collagen which may correspond to variations in diaphragm loading.

Titin and Diaphragm Dysfunction in Chronic Obstructive Pulmonary Disease

Recently, we have shown that Ca2+-activated force generation in diaphragm single fibers is impaired in patients with mild to moderate chronic obstructive pulmonary disease (COPD). For optimal active-force generation, the passive elasticity provided by titin is indispensable. In the present study, we determined the passive-tension-length relations of single fibers of patients with mild to moderate COPD, hypothesizing that passive-elastic properties of diaphragm fibers are compromised. Passive-tension-length relations were determined in diaphragm fibers from patients with and without COPD (predicted mean FEV1, 76 and 102%, respectively). In diaphragm homogenates titin expression was studied at the protein level by gel electrophoresis and at the transcript level by using a novel titin exon microarray. Diaphragm fibers from patients with COPD generate less passive tension on stretch. Titin content in the diaphragm did not differ between patients with and without COPD. However, titin exon transcript studies revealed up-regulation of seven exons, which code for spring elements in the elastic segment rich in proline, glutamate, valine, and lysine. Immunofluorescence analysis indicated elevated protein expression of the up-regulated splice variant in the COPD diaphragm. Simulation studies on titin molecules including the amino acids encoded by the seven up-regulated exons predicted reduced passive-tension generation on molecule stretch. Passive-tension generation of diaphragm single fibers is reduced in patients with COPD. Our results suggest that alternative splicing of the titin gene, resulting in increased length of the elastic segment rich in proline, glutamate, valine, and lysine, is involved. Interestingly, these changes occur already in patients with mild to moderate COPD.

Adaptation of the diaphragm and the vastus lateralis in mild-to-moderate COPD

The chronology of diaphragm and vastus lateralis adaptation in chronic obstructive pulmonary disease (COPD) has not been studied. The hypothesis of this study was that muscle changes would occur earlier in the diaphragm than in the vastus lateralis in COPD, a finding that would suggest that local factors would be more important than systemic factors in determining the muscle phenotypic expression, at least in mild-to-moderate disease. The adaptation of the vastus lateralis and diaphragm muscles was evaluated in patients with mild-to-moderate COPD and in subjects with normal pulmonary function. In both groups, the oxidative potential and the number of lipofuscin inclusions were higher in the diaphragm than in the vastus lateralis. Compared to control, the diaphragm in COPD had a higher oxidative capacity and a higher proportion of type I fibres, with a reciprocal decrease in type IIA fibres, while there was no difference in diaphragmatic cross sectional areas, capillarisation and lipofuscin inclusions. No significant differences were found in the vastus lateralis from both groups. In conclusion, these data indicate that the diaphragm in controls and in chronic obstructive pulmonary disease has a higher oxidative potential than the vastus lateralis, and that muscle adaptation occurs earlier in the diaphragm than in the vastus lateralis in mild-to-moderate chronic obstructive pulmonary disease.

The Diaphragm in COPD

Chronic obstructive pulmonary disease (COPD) is characterized by increased resistance to airflow, air trapping, and hyperinflation of the lungs. The increased resistance to airflow increases the wo...

Circulating T cell subsets in the Lambert-Eaton myasthenic syndrome.

Peripheral blood T cell subsets were measured using monoclonal antibodies and a fluorescence activated cell sorter in 15 untreated patients with Lambert-Eaton myasthenic syndrome (nine with small cell carcinoma, one undifferentiated epithelial tumour (ca-LEMS], five with no demonstrable tumour (non-ca-LEMS), 10 age-matched healthy controls and 10 patients with small cell carcinoma without neurological disease. OKT8+ (suppressor/cytotoxic) T cells were significantly decreased in ca-LEMS compared with non-ca LEMS (p less than 0.001) ca-controls (p less than 0.01) and healthy controls (p less than 0.001). In one patient depressed OKT8+ T cells antedated clinically evident tumour by five months. OKT3+ (total) and OKT4+ (helper) T cells were similar in ca-LEMS, non-ca LEMS and controls. The mechanism underlying the loss of circulating OKT8+ T cells in ca-LEMS is unknown, but these changes may help to predict the presence of carcinoma in this disease.