ERS International congress, Madrid, 2019: Highlights from the General Pneumology Assembly

This article contains highlights and a selection of the scientific advances from the European Respiratory Society's General Pneumology Assembly that were presented at the 2019 European Respiratory Society International Congress in Madrid, Spain. The most relevant topics from the different groups will be discussed, covering a wide range of areas including rehabilitation and chronic care, general practice and primary care and M-health and E-health. In this review, the newest research and actual data as well as award-winning abstracts and highlight sessions will be discussed

Endurance training improves oxygen uptake/demand mismatch, metabolic flexibility and recovery in patients with sickle cell disease

Patients with sickle cell disease (SCD) display lower slope coefficients of the oxygen uptake (V_O2) vs. work rate (W) relationship (delineating an O2 uptake/demand mismatch) and a poor metabolic flexibility. Because endurance training (ET) increases the microvascular network and oxidative enzymes activity including one involved in lipid oxidation, ET might improve the slope coefficient of the V_O2 vs. W curve and the metabolic flexibility of SCD patients. ET may also contribute to improve patient post-exercise cardiopulmonary and metabolic recovery. Fifteen patients with SCD performed a submaximal incremental test on a cycle ergometer before (SIT1) and after (SIT2) 8 weeks of ET. Minute ventilation, ventilation rate (VR), heart rate (HR), V_O2, CO2 production, respiratory exchange ratio, carbohydrate/lipid utilization and partitioning (including %Lipidox) and blood lactate concentration ([lactate]b) were measured during and after SIT1 and SIT2. At baseline, the slope coefficient of the V_O2 vs. W curve positively correlated with total hemoglobin, mean corpuscular hemoglobin and percentage of HbF. After training, the slope coefficient of the V_O2 vs. W curve was significantly higher and the [lactate]b increase was delayed. If patients’ energy metabolism apparently relied largely on carbohydrate sources during SIT1, %Lipidox tended to increase at low exercise intensities during SIT2, supporting a training-induced improvement of metabolic flexibility in patients with SCD. Post-exercise recovery of VR, V_E/V_CO2, HR and [lactate]b was faster after training. We concluded that ET in patients with SCD i) ameliorated the oxygen uptake/demand mismatch, ii) blunted the metabolic inflexibility, and iii) improved post-exercise cardiopulmonary and metabolic responses

Etude du défaut d’adaptation vasculaire au réentrainement à l’effort chez le patient BPCO

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease associated with exercise intolerance and cardiovascular comorbidities. These elements appear to be closely linked to the structure and function of muscle capillaries but also of upstream arteries. Although exercise training (ET) provide a beneficial effect on vascular function in healthy subjects, this effect appears to be blunt in COPD patients. The aim of this thesis work was thus to understand the impairments of the vascular adaptations to ET in COPD patients. In a first study, we analysed capillary ultrastructure during muscle angiogenesis in COPD patients and healthy sedentary control (HSC) subjects during an ET and demonstrated disturbances in pericyte/capillary interactions in patients. In a second study, we looked for abnormalities of pericyte coverage adaptations during ET-induced angiogenesis in COPD patients, as well as the effect of circulating factors on the determinants of pericyte coverage. We have thus shown a lack of pericyte coverage adaptation during ET-induced angiogenesis after 10 weeks of ET in COPD patients. In addition, we were able to observe that COPD patient’s serum disturbed pericyte recruitment in vitro. In a third study, we investigated the PGC1-α pathway expression and its proangiogenic effectors in the skeletal muscle stimulated with exercise, in patients with COPD and HSC. Through the isolation, differentiation and stimulation of muscle stem cells from muscles of COPD and HSC patients, we have demonstrated an impairment of the raise of PGC1-α expression under electrical pulse stimulation in muscle cells of COPD patients. A reduction in the production of SPP1 by these cells has also been found, limiting their ability to orchestrate capillary maturation. In a fourth study, we were interested in the clinical, functional, cellular and molecular determinants involved in the lack of response of arterial vasoreactivity to ET in COPD patients. To address these questions, we have developed a multicenter clinical study protocol and demonstrated its feasibility. To conclude, this thesis work provided a better understanding of the mechanisms of capillary impairments and blunted angiogenesis in COPD patients. While the alteration in the muscle capillary number appeared to be a late process, we showed a novel and early lack of pericyte coverage in these patients. In addition, we were able to identify some actors potentially at the origin of this impairment: the deleterious circulating factors of the disease and some abnormalities of the skeletal muscle cell. The perspective of this thesis will be to better understand the causes and consequences of the pericyte coverage defect during the skeletal muscle angiogenesis in COPD patients.La broncho-pneumopathie chronique obstructive (BPCO) est une maladie respiratoire chronique associée à une intolérance à l’effort et à des comorbidités cardiovasculaires. Ces éléments apparaissent intimement liés à la structure et la fonction des capillaires sanguins musculaires mais également des artères en amont. Bien que le ré-entrainement à l’effort (REE) ait un effet bénéfique sur la fonction vasculaire chez les sujets sains, cet effet semble émoussé chez les patients BPCO. L’objectif de ces travaux de thèse était ainsi de comprendre les défauts d’adaptation vasculaire chez les patients BPCO en réponse au REE. Dans une première étude, nous avons analysé l’angiogenèse musculaire à l’échelon ultrastructural, chez des patients BPCO et des sujets contrôles sédentaires sains (CSS) au cours d’un REE et avons mis en évidence des défauts d’interaction péricyte/capillaire chez les patients. Dans une deuxième étude, nous avons recherché des anomalies d’adaptation de la couverture péricytaire au cours de l’angiogenèse induite par le REE chez les patients BPCO, ainsi que l’effet de facteurs circulants sur les déterminants de la couverture péricytaire. Nous avons ainsi montré un défaut d’adaptation de la couverture péricytaire durant l’angiogenèse induite par le REE après 10 semaines de REE chez des patients BPCO par rapport à des CSS. De plus, nous avons pu observer que le sérum des patients BPCO perturbait le recrutement péricytaire in vitro. Dans une troisième étude, nous avons étudié l’expression de la voie PGC1-α musculaire et de ses effecteurs pro-angiogéniques, en réponse à une stimulation par l’exercice, chez des patients BPCO et des CSS. Grâce à l’isolement, la différenciation et la stimulation de cellules souches musculaires issues de muscles de patients BPCO et de CSS, nous avons démontré une altération de l’expression de PGC1-α dans les cellules musculaires de patients BPCO sous l’effet d’une stimulation électrique par impulsion. Une réduction de la production de SPP1 par ces cellules a également été trouvée, limitant leur capacité d’orchestration de la maturation capillaire. Dans une quatrième étude nous nous sommes intéressés aux déterminants cliniques, fonctionnels, cellulaires et moléculaires impliqués dans le défaut de réponse de la vasoréactivité artérielle au REE chez le patient BPCO. Pour cela, nous avons mis au point un protocole d’étude clinique multicentrique et démontré sa faisabilité. Au final, ces travaux de thèse ont permis une meilleure compréhension des mécanismes de l’atteinte capillaire et de l’angiogenèse émoussée du patient BPCO. Alors que l’altération du nombre de capillaires sanguins musculaires semblait être un processus tardif, nous avons montré un défaut inédit et précoce de couverture péricytaire chez ces patients. De plus, nous avons pu identifier certains acteurs potentiellement à l’origine de cette altération : les facteurs circulants délétères de la maladie et des anomalies de la cellule musculaire. La perspective de cette thèse sera de mieux comprendre les causes et les conséquences du défaut de couverture péricytaire durant l’angiogenèse musculaire chez le patient BPCO

Etude du défaut d’adaptation vasculaire au réentrainement à l’effort chez le patient BPCO

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease associated with exercise intolerance and cardiovascular comorbidities. These elements appear to be closely linked to the structure and function of muscle capillaries but also of upstream arteries. Although exercise training (ET) provide a beneficial effect on vascular function in healthy subjects, this effect appears to be blunt in COPD patients. The aim of this thesis work was thus to understand the impairments of the vascular adaptations to ET in COPD patients. In a first study, we analysed capillary ultrastructure during muscle angiogenesis in COPD patients and healthy sedentary control (HSC) subjects during an ET and demonstrated disturbances in pericyte/capillary interactions in patients. In a second study, we looked for abnormalities of pericyte coverage adaptations during ET-induced angiogenesis in COPD patients, as well as the effect of circulating factors on the determinants of pericyte coverage. We have thus shown a lack of pericyte coverage adaptation during ET-induced angiogenesis after 10 weeks of ET in COPD patients. In addition, we were able to observe that COPD patient’s serum disturbed pericyte recruitment in vitro. In a third study, we investigated the PGC1-α pathway expression and its proangiogenic effectors in the skeletal muscle stimulated with exercise, in patients with COPD and HSC. Through the isolation, differentiation and stimulation of muscle stem cells from muscles of COPD and HSC patients, we have demonstrated an impairment of the raise of PGC1-α expression under electrical pulse stimulation in muscle cells of COPD patients. A reduction in the production of SPP1 by these cells has also been found, limiting their ability to orchestrate capillary maturation. In a fourth study, we were interested in the clinical, functional, cellular and molecular determinants involved in the lack of response of arterial vasoreactivity to ET in COPD patients. To address these questions, we have developed a multicenter clinical study protocol and demonstrated its feasibility. To conclude, this thesis work provided a better understanding of the mechanisms of capillary impairments and blunted angiogenesis in COPD patients. While the alteration in the muscle capillary number appeared to be a late process, we showed a novel and early lack of pericyte coverage in these patients. In addition, we were able to identify some actors potentially at the origin of this impairment: the deleterious circulating factors of the disease and some abnormalities of the skeletal muscle cell. The perspective of this thesis will be to better understand the causes and consequences of the pericyte coverage defect during the skeletal muscle angiogenesis in COPD patients.La broncho-pneumopathie chronique obstructive (BPCO) est une maladie respiratoire chronique associée à une intolérance à l’effort et à des comorbidités cardiovasculaires. Ces éléments apparaissent intimement liés à la structure et la fonction des capillaires sanguins musculaires mais également des artères en amont. Bien que le ré-entrainement à l’effort (REE) ait un effet bénéfique sur la fonction vasculaire chez les sujets sains, cet effet semble émoussé chez les patients BPCO. L’objectif de ces travaux de thèse était ainsi de comprendre les défauts d’adaptation vasculaire chez les patients BPCO en réponse au REE. Dans une première étude, nous avons analysé l’angiogenèse musculaire à l’échelon ultrastructural, chez des patients BPCO et des sujets contrôles sédentaires sains (CSS) au cours d’un REE et avons mis en évidence des défauts d’interaction péricyte/capillaire chez les patients. Dans une deuxième étude, nous avons recherché des anomalies d’adaptation de la couverture péricytaire au cours de l’angiogenèse induite par le REE chez les patients BPCO, ainsi que l’effet de facteurs circulants sur les déterminants de la couverture péricytaire. Nous avons ainsi montré un défaut d’adaptation de la couverture péricytaire durant l’angiogenèse induite par le REE après 10 semaines de REE chez des patients BPCO par rapport à des CSS. De plus, nous avons pu observer que le sérum des patients BPCO perturbait le recrutement péricytaire in vitro. Dans une troisième étude, nous avons étudié l’expression de la voie PGC1-α musculaire et de ses effecteurs pro-angiogéniques, en réponse à une stimulation par l’exercice, chez des patients BPCO et des CSS. Grâce à l’isolement, la différenciation et la stimulation de cellules souches musculaires issues de muscles de patients BPCO et de CSS, nous avons démontré une altération de l’expression de PGC1-α dans les cellules musculaires de patients BPCO sous l’effet d’une stimulation électrique par impulsion. Une réduction de la production de SPP1 par ces cellules a également été trouvée, limitant leur capacité d’orchestration de la maturation capillaire. Dans une quatrième étude nous nous sommes intéressés aux déterminants cliniques, fonctionnels, cellulaires et moléculaires impliqués dans le défaut de réponse de la vasoréactivité artérielle au REE chez le patient BPCO. Pour cela, nous avons mis au point un protocole d’étude clinique multicentrique et démontré sa faisabilité. Au final, ces travaux de thèse ont permis une meilleure compréhension des mécanismes de l’atteinte capillaire et de l’angiogenèse émoussée du patient BPCO. Alors que l’altération du nombre de capillaires sanguins musculaires semblait être un processus tardif, nous avons montré un défaut inédit et précoce de couverture péricytaire chez ces patients. De plus, nous avons pu identifier certains acteurs potentiellement à l’origine de cette altération : les facteurs circulants délétères de la maladie et des anomalies de la cellule musculaire. La perspective de cette thèse sera de mieux comprendre les causes et les conséquences du défaut de couverture péricytaire durant l’angiogenèse musculaire chez le patient BPCO

Response to Electrostimulation Is Impaired in Muscle Cells from Patients with Chronic Obstructive Pulmonary Disease

International audienceAmong the comorbidities associated with chronic obstructive pulmonary disease (COPD), skeletal muscle weakness and atrophy are known to affect patient survival rate. In addition to muscle deconditioning, various systemic and intrinsic factors have been implicated in COPD muscle dysfunction but an impaired COPD muscle adaptation to contraction has never been extensively studied. We submitted cultured myotubes from nine healthy subjects and nine patients with COPD to an endurance-type protocol of electrical pulse stimulation (EPS). EPS induced a decrease in the diameter, covered surface and expression of MHC1 in COPD myotubes. Although the expression of protein degradation markers was not affected, expression of the protein synthesis marker mTOR was not induced in COPD compared to healthy myotubes after EPS. The expression of the differentiation markers p16INK4a and p21 was impaired, while expression of Myf5 and MyoD tended to be affected in COPD muscle cells in response to EPS. The expression of mitochondrial biogenesis markers PGC1α and MFN2 was affected and expression of TFAM and COX1 tended to be reduced in COPD compared to healthy myotubes upon EPS. Lipid peroxidation was increased and the expression of the antioxidant enzymes SOD2 and GPx4 was affected in COPD compared to healthy myotubes in response to EPS. Thus, we provide evidence of an impaired response of COPD muscle cells to contraction, which might be involved in the muscle weakness observed in patients with COPD

Cellular interplay in skeletal muscle regeneration and wasting: insights from animal models

Abstract Skeletal muscle wasting, whether related to physiological ageing, muscle disuse or to an underlying chronic disease, is a key determinant to quality of life and mortality. However, cellular basis responsible for increased catabolism in myocytes often remains unclear. Although myocytes represent the vast majority of skeletal muscle cellular population, they are surrounded by numerous cells with various functions. Animal models, mostly rodents, can help to decipher the mechanisms behind this highly dynamic process, by allowing access to every muscle as well as time‐course studies. Satellite cells (SCs) play a crucial role in muscle regeneration, within a niche also composed of fibroblasts and vascular and immune cells. Their proliferation and differentiation is altered in several models of muscle wasting such as cancer, chronic kidney disease or chronic obstructive pulmonary disease (COPD). Fibro‐adipogenic progenitor cells are also responsible for functional muscle growth and repair and are associated in disease to muscle fibrosis such as in chronic kidney disease. Other cells have recently proven to have direct myogenic potential, such as pericytes. Outside their role in angiogenesis, endothelial cells and pericytes also participate to healthy muscle homoeostasis by promoting SC pool maintenance (so‐called myogenesis–angiogenesis coupling). Their role in chronic diseases muscle wasting has been less studied. Immune cells are pivotal for muscle repair after injury: Macrophages undergo a transition from the M1 to the M2 state along with the transition between the inflammatory and resolutive phase of muscle repair. T regulatory lymphocytes promote and regulate this transition and are also able to activate SC proliferation and differentiation. Neural cells such as terminal Schwann cells, motor neurons and kranocytes are notably implicated in age‐related sarcopenia. Last, newly identified cells in skeletal muscle, such as telocytes or interstitial tenocytes could play a role in tissular homoeostasis. We also put a special focus on cellular alterations occurring in COPD, a chronic and highly prevalent respiratory disease mainly linked to tobacco smoke exposure, where muscle wasting is strongly associated with increased mortality, and discuss the pros and cons of animal models versus human studies in this context. Finally, we discuss resident cells metabolism and present future promising leads for research, including the use of muscle organoids

Interactive whiteboard use in clinical reasoning sessions to teach diagnostic test ordering and interpretation to undergraduate medical students

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Plasma ratio of angiopoietin-2 to angiopoietin-1 is a biomarker of vascular impairment in chronic obstructive pulmonary disease patients

International audienceChronic obstructive pulmonary disease (COPD) patients have an increased risk of cardiovascular disease. Muscle biopsies have revealed that the muscle vasculature in COPD patients was characterized by a capillary rarefaction with reduced pericyte coverage. Thus, an imbalance of the plasma Angiopoietin-1 / Angiopoietin-2 (Ang2/Ang1) ratio could constitute a non-invasive marker of the muscle vascular impairment. In 14 COPD patients (65.5±5.1-year-old) and 7 HC (63.3±5.8-year-old), plasma samples were obtained at 3 time-points: before, after 5 weeks (W5), and after 10 weeks (W10) of exercise training. COPD patients showed a muscle capillary rarefaction at baseline with a reduced capillary coverage at W5 and W10. The plasma Ang2/Ang1 ratio was significantly higher in COPD patients vs. HC during the training (Group: p=0.01). The plasma Ang2/Ang1 ratio was inversely correlated with the pericyte coverage index regardless of the time period W0 (r=−0.51; p=0.02), W5 (r=−0.48; p=0.04), and W10 (r=−0.61; p<0.01). Last, in ECFC/MSC co-cultures exposed to the W10 serum from COPD patients and HC, the plasma Ang2/Ang1 at W10 were inversely correlated with calponin staining (r=−0.64. p=0.01 and r= 0.71. p<0.01, Fig. 1B), in line with a role of this plasma Ang2/Ang1 in the MSC differentiation into pericytes. Altogether, plasma Ang2/Ang1 ratio could constitute a potential marker of the vascular impairment in COPD patients

Effects of a human microenvironment on the differentiation of human myoblasts

International audienceMyogenic differentiation mechanisms are generally assessed using a murine cell line placed in low concentrations of an animal-derived serum. To more closely approximate in vivo pathophysiological conditions, recent studies have combined the use of human muscle cells with human serum. Nevertheless, the in vitro studies of the effects of a human microenvironment on the differentiation process of human myoblasts require the identification of the culture conditions that would provide an optimal and reproducible differentiation process of human muscle cells. We assessed the differentiation variability resulting from the use of human myoblasts and serums from healthy subjects by measuring the myotube diameter, fusion index and surface covered by myotubes. We showed the preserved cell-dependent variability of the differentiation response of myoblasts cultured in human serums compared to FBS. We found that using a pool of serums reduced the serum-dependent variability of the myogenic response compared to individual serums. We validated our methodology by showing the atrophying effect of pooled serums from COPD patients on healthy human myotubes. By replacing animal-derived tissues with human myoblasts and serums, and by validating the sensitivity of cultured human muscle cells to a pathological microenvironment, this human cell culture model offers a valuable tool for studying the role of the microenvironment in chronic disease

Application of a force-velocity-endurance model to cycling, rowing and running locomotion.

International audienceIntroduction. The production of force during brief maximal effort is limited by a force-velocity relation-ship, which is characterized by a negative linear function and determined by the theoretical maximum force (F0)and velocity (V0) [1]. For longer efforts, the intensity-duration relationship has been described mathematicallyby an asymptotic decay function, with the critical intensity being the asymptote [3]. The force and velocityproduced during an exercise can be modified by changing the cadence during cycling, for example, which altersthe intensity-duration relationship [4]. As the effort is prolonged, changes in force and velocity capacities mayoccur differently. To account for the influence of the force-velocity and intensity relationships on each other, wedeveloped a three-dimensional model that describes the force production capacity as a function of velocity andtime, F (v, t). In addition, we designed a test to determine the F (v, t) relationship for an individual based on a3-min all-out interspersed with a stop-start sprint (IFLET test) [2]. The aim of this study was to evaluate theparameters of the F (v, t) relationship for various types of human locomotion (cycling, rowing and running) andto compare the parameters obtained for different populations based on their training status.Methods. The IFLET test was administered to 49 participants across cycling, rowing, and running. Dur-ing cycling, 21 moderately active individuals who were not cyclists (NC), 19 subelite trained cyclists (SC), andnine elite cyclists (EC) participated. Twelve elite rowers participated for the rowing task and 16 U21 eliterugby players participated for running locomotion. The test involved a 3- minute all-out effort, with conditionschanging every 30s to assess the force-velocity relationship at a specific point in time. During cycling, this wasachieved by suddenly blocking the flywheel, while in rowing, a motor replaced the flywheel and was controlledto produce varying force-velocity conditions. During running, the test was conducted in shuttle mode, whichrequired participants to start sprinting at zero speed. The force-velocity-time data recorded or computed duringthe various locomotions was fitted to the F (v, t) model’s parameters to obtain the initial force (F0i ), velocity(V0i ), critical force (F0c ), and velocity (V0c ) capacities, as well as the time constant (τ ).Results and discussion. The goodness of fit of the model from experimental data was excellent for alllocomotion (all r2 > 0.93). Considering the group effect for cycling task locomotion, no difference was observedfor V0c (NC : 58.9 ± 12.3 %; SC : 59.3 ± 9.7 %; EC: 55.7 ± 6.3 %). However, all groups were statisticallydifferent in terms of F0c (NC : 51.4 ± 11.2 %; SC : 64.2 ± 7.3 %; EC: 71.6 ± 10.4 %).Conclusions and perspectives. This is the first time a model has been developed that simultaneouslyconsiders both velocity and time to describe the force capacity. This model accurately fits the experimental dataobtained from the IFLET test, which is a 3-minute all-out sprint exercise interspersed with different locomotiontypes, such as running, cycling, or rowing. The applications of this approach are numerous and can be used inthe evaluation of physical capacities as well as for performance enhancement through training or optimizationof human-material interactions