La suppression de p16INK4a favorise la régénération pulmonaire grâce à un interrupteur lipogénique des fibroblastes

La régénération des poumons est essentielle pour la récupération après un dommage et /ou pour améliorer le déclin de la fonction associée au vieillissement. Cependant, jusqu'à présent, les thérapies utilisant les progeniteurs endogènes ont échoué dans les maladies pulmonaires chroniques. L'induction de l'inhibiteur du cycle cellulaire p16INK4A peut limiter la capacité du poumon à se régénérer et son inhibition peut être un moyen de promouvoir la capacité des progéniteurs alvéolaires à se renouveler et à se différencier. Nous montrons ici que l'expression de p16INK4A est augmentée dans le sang de cordon des nouveau-nés prématurés. Cette surexpression persiste dans le sang de survivants du dysplasie bronchopulmonaire âgés de 7 à 15 ans. Deux modèles murins d'alvéologenèse ont été utilisés pour comprendre les mécanismes impliqués: l'hyperoxie précoce (de J3 à J14) mimant la DBP et ses séquelles et la pneumonectomie. Chez les souris, p16INK4a augmente dans les fibroblastes pulmonaires après l'hyperoxie et ceci persiste à l'age adulte. Nous montrons que la suppression ou la clairance des cellules surexprimant p16INK4a à l'aide d'un modèle transgénique améliore l'alvéolisation et restaure un poumon normal à l'âge adulte. De même, la néo-alvéolisation a augmenté après la pneumonectomie chez des souris déficientes en p16INK4a. Ce phénomène était associé à une synthèse augmentée de lipides neutres et à la différenciation des lipofibroblastes. Enfin, l'induction de lipofibroblastes avec un agoniste de PPARγ rétablit aussi l'architecture alvéolaire une fois que l'hypoalvéolisation induite par l'hypoxie a été établie. Nous proposons ici la possibilité de promouvoir la régénération du poumon dans deux modèles différents grâce à la modulation de p16INK4a et à son rôle dans la niche des cellules souches, notamment par la différenciation des lipofibroblastes. Globalement, ces données suggèrent que l'activation des lipofibroblastes pourrait être utilisée pour favoriser la régénération pulmonaire.Lung regeneration is critical for recovering after damage and/or to ameliorate declining function associated with aging. However, until now, endogenous regenerative therapies have failed to succeed in chronic lung diseases. The induction of the cell cycle inhibitor p16INK4A may limit the ability of the lung to regenerate and its inhibition may be a way to promote alveolar progenitors ability to self-renewal and differentiation. Here we show that p16INK4A expression was increased in cord blood of preterm infants, this overexpression persisted in blood of 7 to 15 years old BPD survivors. Two models of alveologenesis were used concurrently: post hyperoxia mimicking BPD with adult sequelae and pneumonectomy. In mice, p16INK4a was increased in lung fibroblasts after, both post nataly and at the stage of adult sequelae. We show that p16INK4a deletion or clearance of p16 INK4a positive cells using an INK-ATTAC transgenic model increased secondary septation and alveolization and restored a normal lung in mice exposed to hyperoxia at adulthood. Similarly, neoalveolization was increased after pneumonectomy in p16INK4a deficient mice. This phenomenon was associated with the promotion of neutral lipids synthesis and lipofibroblasts differentiation. Finally, induction of lipofibroblasts with a PPARγ agonist restore the alveolar architecture once hypoxia induced hypoalveolization was established.Here we provide the possibility to promote lung regeneration in two different models thanks to the modulation of p16INK4a and its role in the stem cell niche especially through lipofibroblasts differentiation. Altogether these data suggest that lipofibroblasts activation may be used to promote lung regeneration

The Non-Paced 3-Minute Sit-to-Stand Test: Feasibility and Clinical Relevance for Pulmonary Rehabilitation Assessment

Pulmonary rehabilitation (PR) improves health-related quality-of-life (HRQoL) in individuals with chronic obstructive pulmonary disease (COPD), notably by increasing exercise tolerance. Easy-to-implement sit-to-stand tests can facilitate the assessment of exercise tolerance in routine practice. This retrospective study conducted in a real-life setting was designed to describe the non-paced 3-min sit-to-stand test (3-STST) and to evaluate its relationship with HRQoL (VQ11 questionnaire) to identify the determinants of 3-STST performance and to analyze the evolution of 3-STST performance and HRQoL over the course of a community-based PR program. Seventy-one COPD patients (age 69 ± 10 years old; 51% with GOLD spirometric stages III–IV) were included. Mean ± SD 3-STST performance at the initial PR assessment was 43 ± 15 repetitions. This performance was significantly associated with HRQoL and other indicators of clinical severity (lung function, dyspnea, and functional capacities). During the multivariate analysis, younger age, exertional dyspnea with mMRC ≤ 1, and better HRQoL were significantly associated with better 3-STST performance. From the initial to second PR assessment, changes in 3-STST performance were significantly associated with changes in HRQoL. This study provides evidence that the non-paced 3-STST is feasible and might be clinically relevant in the assessment of patients with COPD referred for community-based PR. This test deserves to be prospectively validated

Respiratory rehabilitation for Covid-19 related persistent dyspnoea: A one-year experience

International audienceBackground: Growing consideration is emerging regarding the burden of persisting sequelae after SARS-CoV-2 infection. Out-patients exhibiting long Covid may benefit from ambulatory rehabilitation which is, to date, poorly documented. Methods: A longitudinal follow-up over a one-year period was conducted in two ambulatory rehabilitation structures in order to describe the characteristics of real-life patients referred with Covid-19 sequelae and their evolution over the course of rehabilitation. Results: 39 consecutive patients were included from April 1st, 2020 to April 1st, 2021. Patients were middle-aged (48 ± 15yr), without comorbidities, and mostly mild to moderate SARS-CoV-2 infection (25(64%) not requiring hospitalisation). Rehabilitation referral was considered with a median delay of 73[34–178] days after disease onset. Most prevalent symptoms were dyspnoea (n = 35(90%)) and fatigue (n = 30(77%)). Hyperventilation syndrome was highly frequent (n = 12(34%)). 29(74%) patients presented with prolonged functional sequelae, which was associated with younger age (43 ± 14 vs. 50 ± 10yr; p = 0.002), greater prevalence of hyperventilation syndrome (n = 12(41%) vs. 0(0%); p = 0.255) and poorer quality of life (VQ-11; 31 ± 10 vs. 23 ± 9; p = 0.030). Over the course of rehabilitation, exertional dyspnoea, 6-min walking distance, 3-min sit-to-stand test, hyperventilation syndrome prevalence and quality of life significantly improved. Conclusion: Hyperventilation is frequent in long Covid and may explain persistent dyspnoea as well as altered quality of life. Our data support screening of hyperventilation syndrome and functional impairment in mild Covid-19 out-patients as both of these components may improve with ambulatory rehabilitation

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

Pulmonary rehabilitation after severe exacerbation of COPD: a nationwide population study

Abstract Background Acute exacerbations of chronic obstructive pulmonary disease (COPD) lead to a significant reduction in quality of life and an increased mortality risk. Current guidelines strongly recommend pulmonary rehabilitation (PR) after a severe exacerbation. Studies reporting referral for PR are scarce, with no report to date in Europe. Therefore, we assessed the proportion of French patients receiving PR after hospitalization for COPD exacerbation and factors associated with referral. Methods This was a national retrospective study based on the French health insurance database. Patients hospitalized in 2017 with COPD exacerbation were identified from the exhaustive French medico-administrative database of hospitalizations. In France, referral to PR has required as a stay in a specialized PR center or unit accredited to provide multidisciplinary care (exercise training, education, etc.) and admission within 90 days after discharge was assessed. Multivariate logistic regression was used to assess the association between patients’ characteristics, comorbidities according to the Charlson index, treatment, and PR uptake. Results Among 48,638 patients aged ≥ 40 years admitted for a COPD exacerbation, 4,182 (8.6%) received PR within 90 days after discharge. General practitioner’s (GP) density (number of GPs for the population at regional level) and PR center facilities (number of beds for the population at regional level) were significantly correlated with PR uptake (respectively r = 0.64 and r = 0.71). In multivariate analysis, variables independently associated with PR uptake were female gender (aOR 1.36 [1.28–1.45], p < 0.0001), age (p < 0.0001), comorbidities (p = 0.0013), use of non-invasive ventilation and/or oxygen therapy (aOR 1.52 [1.41–1.64], p < 0.0001) and administration of long-acting bronchodilators (p = 0.0038). Conclusion This study using the French nationally exhaustive health insurance database shows that PR uptake after a severe COPD exacerbation is dramatically low and must become a high-priority management strategy

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

Chronic obstructive pulmonary disease (COPD) is a worldwide prevalent respiratory disease mainly caused by tobacco smoke exposure. COPD is now considered as a systemic disease with several comorbidities. Among them, skeletal muscle dysfunction affects around 20% of COPD patients and is associated with higher morbidity and mortality. Although the histological alterations are well characterized, including myofiber atrophy, a decreased proportion of slow-twitch myofibers, and a decreased capillarization and oxidative phosphorylation capacity, the molecular basis for muscle atrophy is complex and remains partly unknown. Major difficulties lie in patient heterogeneity, accessing patients’ samples, and complex multifactorial process including extrinsic mechanisms, such as tobacco smoke or disuse, and intrinsic mechanisms, such as oxidative stress, hypoxia, or systemic inflammation. Muscle wasting is also a highly dynamic process whose investigation is hampered by the differential protein regulation according to the stage of atrophy. In this review, we report and discuss recent data regarding the molecular alterations in COPD leading to impaired muscle mass, including inflammation, hypoxia and hypercapnia, mitochondrial dysfunction, diverse metabolic changes such as oxidative and nitrosative stress and genetic and epigenetic modifications, all leading to an impaired anabolic/catabolic balance in the myocyte. We recapitulate data concerning skeletal muscle dysfunction obtained in the different rodent models of COPD. Finally, we propose several pathways that should be investigated in COPD skeletal muscle dysfunction in the future

Beclin-1 increases with obstructive sleep apnea severity

International audienceObstructive sleep apnea is a common chronic disorder that leads to chronic intermittent hypoxia described as an important factor contributing to the pathogenesis of OSA-related comorbidities. Besides, recent data suggest that intermittent hypoxia can induce adaptative cardiovascular pathways inducing a relative resistance to ischemic insults. Adaptative pathways induced by hypoxia could implicate autophagic processes and Beclin-1, one of the first mammalian autophagy effectors. Thus, activation of autophagy could protect against cardiovascular events in patients with OSA and could be considered as biomarker of a better prognosis

Relationship between blood eosinophils, clinical characteristics, and mortality in patients with COPD

International audienceIn patients with COPD, there is controversy regarding the association of blood eosinophil (Eos) levels with 1) exacerbation frequency and 2) the effect of inhaled corticosteroids for prevention of exacerbations. To determine whether Eos define subgroups of patients exhibiting attributes of COPD clinical phenotypes, we compared clinical features and mortality rates in COPD patients from the Initiatives BPCO French cohort categorized using different thresholds of blood Eos levels. The following data were collected at inclusion: medical and smoking history, occupational exposures, dyspnea, cough and sputum production, exacerbations in the previous year, history of allergy and asthma, nasal symptoms, body mass index, St George Respiratory Questionnaire (SGRQ) total score, post-bronchodilator spirometry, comorbidities, and medications. Three-year survival between groups was compared using Kaplan–Meier analysis. Three sets of analyses were performed to compare patients with ≥2% versus <2%, ≥3% versus <3%, and ≥4% versus <4% Eos. Eos was available in 458 patients (mean age: 62 years, 72% male, mean forced expiratory volume in 1 second: 51% pred), including 235 patients with Eos ≥2% (49%), 149 with Eos ≥3% (33%), and 90 with Eos ≥4% (20%). For all cutoffs, there was no difference between Eos+ and Eos- groups in univariate analyses except for diabetes and SGRQ score (more frequent and more impaired, respectively, in lower Eos categories). In particular, there was no difference in exacerbation rate, history of asthma, or three-year survival. In conclusion, regardless of the cutoff, Eos+ COPD patients exhibited no specific characteristic in terms of symptoms, lung function, exacerbation rate, and prognosis. These findings suggest that the association of higher Eos with exacerbations reported in previous studies could be population specific, which does not support generalizing the use of Eos as a biomarker for COPD phenotyping

Burden and Characteristics of Severe Chronic Hypoxemia in a Real-World Cohort of Subjects with COPD

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Relationship between gender and survival in a real-life cohort of patients with COPD

International audienceBackground: Although COPD affects both men and women, its prevalence is increasing more rapidly in women.Disease outcomes appear different among women with more frequent dyspnea and anxiety or depression but whetherthis translates into a different prognosis remains to be determined. Our aim was to assess whether the greater clinicalimpact of COPD in women was associated with differences in 3-year mortality rates.Methods: In the French Initiatives BPCO real-world cohort, 177 women were matched up to 458 menon age (within 5-year intervals) and FEV1 (within 5% predicted intervals). 3-year mortality rate and survival were analyzed. Univariate andmultivariate logistic regression analyses were performed.Results: For a given age and level of airflow obstruction, women with COPD had more severe dyspnea, lower BMI, andwere more likely to exhibit anxiety. Nevertheless, three-year mortality rate was comparable among men and women,respectively 11.2 and 10.8%. In a multivariate model, the only factors significantly associated with mortality were dyspneaand malnutrition but not gender.Conclusion: Although women with COPD experience higher levels of dyspnea and anxiety than men at comparablelevels of age and FEV1, these differences do not translate into variations in 3-year mortality rates