Complex urban atmosphere alters alveolar stem cells niche properties and drives lung fibrosis.

There is growing evidence suggesting that urban pollution has adverse effects on lung health. However, how urban pollution affects alveolar mesenchymal and epithelial stem cell niches remains unknown. This study aimed to determine how complex representative urban atmospheres alter alveolar stem cell niche properties. Mice were placed in an innovative chamber realistically simulating the atmosphere of a megalopolis, or "clean air," for 7 days. Lungs were collected, and fibroblasts and epithelial cells (EpCAM+) were isolated. Proliferative capacities of fibroblasts were tested by population doubling levels (PDL), and microarray analyses were performed. Fibroblasts and EpCAM+ cells from exposed, nonexposed, or naive mice were cocultured in organoid assays to assess the stem cell properties. Collagen deposition (Sirius red), lipofibroblasts (ADRP, COL1A1), myofibroblasts (αSMA), alveolar type 2 cells (AT2, SFTPC+), and alveolar differentiation intermediate cell [ADI, keratin-8-positive (KRT8+)/claudin-4-positive (CLDN4+)] markers were quantified in the lungs. Fibroblasts obtained from mice exposed to urban atmosphere had lower PDL and survival and produced fewer and smaller organoids. Microarray analysis showed a decrease of adipogenesis and an increase of genes associated with fibrosis, suggesting a lipofibroblast to myofibroblast transition. Collagen deposition and myofibroblast number increased in the lungs of urban atmosphere-exposed mice. AT2 number was reduced and associated with an increase in ADI cells KRT8+/CLDN4+. Furthermore, EpCAM+ cells from exposed mice also produced fewer and smaller organoids. In conclusion, urban atmosphere alters alveolar mesenchymal stem cell niche properties by inducing a lipofibroblast to myofibroblast shift. It also results in alveolar epithelial dysfunction and a fibrotic-like phenotype.NEW & NOTEWORTHY Urban pollution is known to have major adverse effects on lung health. To assess the effect of pollution on alveolar regeneration, we exposed adult mice to a simulated high-pollution urban atmosphere, using an innovative CESAM simulation chamber (Multiphase Atmospheric Experimental Simulation Chamber, https://cesam.cnrs.fr/). We demonstrated that urban atmosphere alters alveolar mesenchymal stem cell niche properties by inducing a lipofibroblast to myofibroblast shift and induces alveolar epithelial dysfunction.

Identification of factors impairing exercise capacity after severe COVID-19 pulmonary infection: a 3-month follow-up of prospective COVulnerability cohort.

BACKGROUND: Patient hospitalized for coronavirus disease 2019 (COVID-19) pulmonary infection can have sequelae such as impaired exercise capacity. We aimed to determine the frequency of long-term exercise capacity limitation in survivors of severe COVID-19 pulmonary infection and the factors associated with this limitation. METHODS: Patients with severe COVID-19 pulmonary infection were enrolled 3 months after hospital discharge in COVulnerability, a prospective cohort. They underwent cardiopulmonary exercise testing, pulmonary function test, echocardiography, and skeletal muscle mass evaluation. RESULTS: Among 105 patients included, 35% had a reduced exercise capacity (VO2peak < 80% of predicted). Compared to patients with a normal exercise capacity, patients with reduced exercise capacity were more often men (89.2% vs. 67.6%, p = 0.015), with diabetes (45.9% vs. 17.6%, p = 0.002) and renal dysfunction (21.6% vs. 17.6%, p = 0.006), but did not differ in terms of initial acute disease severity. An altered exercise capacity was associated with an impaired respiratory function as assessed by a decrease in forced vital capacity (p < 0.0001), FEV1 (p < 0.0001), total lung capacity (p < 0.0001) and DLCO (p = 0.015). Moreover, we uncovered a decrease of muscular mass index and grip test in the reduced exercise capacity group (p = 0.001 and p = 0.047 respectively), whilst 38.9% of patients with low exercise capacity had a sarcopenia, compared to 10.9% in those with normal exercise capacity (p = 0.001). Myocardial function was normal with similar systolic and diastolic parameters between groups whilst reduced exercise capacity was associated with a slightly shorter pulmonary acceleration time, despite no pulmonary hypertension. CONCLUSION: Three months after a severe COVID-19 pulmonary infection, more than one third of patients had an impairment of exercise capacity which was associated with a reduced pulmonary function, a reduced skeletal muscle mass and function but without any significant impairment in cardiac function.

Overexpression of Spock2 in mice leads to altered lung alveolar development and worsens lesions induced by hyperoxia.

SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 (SPOCK2) was previously associated with genetic susceptibility to bronchopulmonary dysplasia in a French population of very preterm neonates. Its expression increases during lung development and is increased after exposure of rat pups to hyperoxia compared with controls bred in room air. To further investigate the role of SPOCK2 during lung development, we designed two mouse models, one that uses a specific anti-Spock2 antibody and one that reproduces the hyperoxia-induced Spock2 expression with a transgenic mouse model resulting in a conditional and lung-targeted overexpression of Spock2. When mice were bred under hyperoxic conditions, treatment with anti-Spock2 antibodies significantly improved alveolarization. Lung overexpression of Spock2 altered alveolar development in pups bred in room air and worsened hyperoxia-induced lesions. Neither treatment with anti-Spock2 antibody nor overexpression of Spock2 was associated with abnormal activation of matrix metalloproteinase-2. These two models did not alter the expression of known players in alveolar development. This study brings strong arguments for the deleterious role of SPOCK2 on lung alveolar development especially after lung injury, suggesting its role in bronchopulmonary dysplasia susceptibility. These effects are not mediated by a deregulation in metalloproteases activity and in expression of factors essential to normal alveolarization. The balance between types 1 and 2 epithelial alveolar cells may be involved.

[Natural history of COPD: evolution of concepts]. / Histoire naturelle de la BPCO : évolution des concepts.

NATURAL HISTORY OF COPD: EVOLUTION OF CONCEPTS. Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease responsible for significant morbidity and mortality. The natural history of this disease is complex. The first cause is tobacco smoke exposure, followed by exposure to biomass smoke and occupational exposure to inhaled toxic substances. Genetic predisposing factors are known as the alpha-1-antitrypsin deficiency. The involvement of respiratory events in childhood in the genesis of the disease is also increasingly described. The decline of the different respiratory trajectories can be accelerated in COPD. The phenotypes of this disease also have a role in the evolution of respiratory function over time and their descriptions can modulate the therapeutic management in this disease.

HISTOIRE NATURELLE DE LA BPCO: ÉVOLUTION DES CONCEPTS. La bronchopneumopathie chronique obstructive (BPCO) est une maladie respiratoire chronique fréquente et responsable d'une morbi-mortalité importante. La compréhension de l'histoire naturelle de cette pathologie a évolué ces dernières années. La première cause de BPCO est le tabagisme, suivi de l'exposition à la fumée de biomasse et de l'exposition professionnelle à des toxiques inhalés. Des facteurs de prédisposition génétique sont connus, comme le déficit en alpha-1-antitrypsine. L'implication d'événements respiratoires au cours de l'enfance dans la genèse de la maladie est également de plus en plus décrite. Le déclin des différentes trajectoires de la fonction respiratoire peut être accéléré en cas de BPCO. Les phénotypes de cette maladie jouent aussi un rôle dans l'évolution de la fonction respiratoire au cours du temps et leur description peut moduler la prise en charge thérapeutique de cette maladie.

[COPD exacerbations]. / Exacerbations de BPCO.

COPD EXACERBATIONS. COPD exacerbations, characterized by an acute worsening of dyspnea and/or cough and sputum volume beyond daily variations, are a public health issue because of their frequency, the number of hospitalizations and the high rate of recurrence. Because of non-specific symptoms, differential diagnoses must be ruled out. Additional tests are rarely necessary, and treatment is outpatient, except in severe cases (respiratory distress, severity of COPD, socio-economic conditions). Increased bronchodilator treatment, and sometimes antibiotic and/or systemic corticosteroid therapy, are the main measures to be introduced and should be systematically reassessed. After an exacerbation, the aim is to optimize follow-up and treatment, to prevent recurrences.

EXACERBATIONS DE BPCO. Les exacerbations de bronchopneumopathie chronique obstructive (EBPCO), caractérisées par une aggravation aiguë de la dyspnée et/ou de la toux et du volume de l'expectoration au-delà des variations quotidiennes, constituent un enjeu de santé publique du fait de leur fréquence, du nombre d'hospitalisations et du taux élevé de récidives. L'absence de spécificité des symptômes impose d'éliminer les diagnostics différentiels. Les examens complémentaires sont rarement nécessaires, et le traitement est ambulatoire hormis en cas de signes de gravité (détresse respiratoire, sévérité de la BPCO, conditions socio-économiques). La majoration du traitement bronchodilatateur, parfois une antibiothérapie et/ou une corticothérapie systémique sont les principales mesures à instaurer et doivent faire l'objet d'une réévaluation systématique. Après une exacerbation, l'optimisation du suivi et du traitement a pour objectif la prévention d'une récidive.

Combined effects of smoking and HIV infection on the occurrence of aging-related manifestations.

Both HIV-1 infection and smoking may contribute to the development of ageing-related manifestations affecting the prognosis of people living with HIV, but it is unclear whether HIV and smoking exert their effects independently or interact by potentiating each other. We conducted a cross-sectional study in 192 people living with HIV aged- and gender-matched with 192 HIV-uninfected controls, assessing the relative effect of HIV-1/smoking status on lung function (FEV1), bone mineral density (BMD), appendicular skeletal muscle mass index (ASMI), aortic pulse-wave velocity (PWV), insulin resistance (HOMA-IR) and renal function. In both unadjusted and adjusted analyses, FEV1, BMD and ASMI significantly differed according to smoking/HIV status, with the worst parameters found in HIV-1 infected patients currently smoking, and BMD and ASMI decreased to a lesser extent in HIV-1 infected patients formerly smoking (> 10 pack-years). Values in people living with HIV with < 10 pack-years exposure were of similar magnitude to those from controls. Regarding PWV, HOMA-R and eGFR, no significant differences were found, with the exception of eGFR values which were globally lower in HIV-1 infected patients. In conclusion HIV infection and smoking acted synergistically and were associated with a wasting phenotype combining muscle mass and bone mineral reduction.Clinical Trial Registration (registrar, website, and registration number), where applicable: CPP 10-023, 09-027, 10-034.

Growth of home respiratory equipment from 2006 to 2019 and cost control by health policies.

BACKGROUND: Home respiratory equipment (HRE) designed for the management of chronic respiratory failure includes oxygen therapy (O2), noninvasive ventilation (NIV) and mechanical insufflation-exsufflation (MI-E). The growth of the number of patients treated by HRE, the prevalence and the associated costs in France have not been determined. METHODS: The French open access national health insurance aggregated data was used to estimate the evolution of theses parameters from 2006 to 2019. RESULTS: The number of patients treated by HRE increased by 117% between 2006 and 2019, reaching a total of 245,896 patients (367/100,000). Prescriptions for O2, NIV, and MI-E increased by 88%, 189% and 162%, respectively. In 2019, 139,323 patients received long-term home O2 alone (208/100,000) with a 13% decrease for liquid O2 compared to a 44% increase for O2 concentrator. The number of patients treated by portable oxygen concentrator increased by 509% over the last 5 years. In 2019, 96,126 patients received NIV (144/100,000) and 97% of these patients were treated by NIV for less than 12 h/day. A total of 9,158 patients were treated by MI-E in 2019 (13.6/100,000). Despite the global increase in the number of patients, health costs decreased from 9% to 8% of total medical device spending in 2019 due to adjustment of health policies, such as a reduction of reimbursement rates. CONCLUSION: Our results highlighted the high rate of HRE prescription, but with cost control as a result of adapted health policies.

Feasibility of a Hypoxic Challenge Test Under Noninvasive Ventilation Versus Oxygen in Neuromuscular Patients with Chronic Respiratory Insufficiency.

Ribeiro Baptista, Bruno, Morgane Faure, Gimbada Benny Mwenge, Capucine Morelot-Panzini, Christian Straus, Thomas Similowski, and Jésus Gonzalez-Bermejo. Feasibility of a hypoxic challenge test under noninvasive ventilation versus oxygen in neuromuscular patients with chronic respiratory insufficiency. High Alt Med Biol. 22:346-350, 2021. Background: The British Thoracic Society recommendations suggest that all patients with an oxygen saturation (SpO2) <85% during a hypoxic challenge test (HCT) should receive supplemental oxygen during air travel. However, neuromuscular patients already using ventilatory support are a specific population and noninvasive ventilation (NIV) during a flight could be an alternative to oxygen for hypoxemia correction, through the augmentation of ventilation. Methods: We conducted a comparative, observational study of neuromuscular patients with chronic respiratory failure, requiring nocturnal mechanical ventilation, who were planning to take a flight. HCT was performed with a ventilated canopy placed over the patient's head or the patient's home ventilator. The positive threshold value chosen for the HCT was <90% SpO2. Results: HCTs were performed on 13 adults with neuromuscular diseases using their home ventilator. Among them, 11 had a positive HCT. For all patients with a positive test, hypoxemia was corrected (SpO2 to >90%) by oxygen therapy (+9 [6-12]%, p = 0.0029). Patient's home ventilator also significantly increased the SpO2 by 8 [7-12]% (p = 0.016). Correction of SpO2 during the HCT was not different between oxygen and NIV. NIV was associated with a significant decrease in pressure, end tidal, carbon dioxide (PetCO2) (-10 [-16 to -7.5] mmHg, p = 0.04). Conclusions: The performance of an adapted HCT in home-ventilated patients with a neuromuscular pathology may be useful in a personalized treatment plan for air travel. NIV can be a new alternative to oxygen therapy for neuromuscular patients planning to take a flight.

Beclin-1 increases with obstructive sleep apnea severity.

Obstructive 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.

Pulmonary arterial hypertension in patient treated for multiple sclerosis with 4-aminopyridine.

4-Aminopyridine (4-AP) is a recent treatment indicated to improve walking in patient with multiple sclerosis. We report the first case of pulmonary arterial hypertension (PAH) that we attribute to the use of 4-AP. A 64-year-old woman with multiple sclerosis presented with dyspnea. After excluding other secondary causes of pulmonary hypertension, a diagnosis of severe PAH due to 4-AP was made based on right heart catheterization. History revealed that the dyspnea began with the initiation of 4-AP. After discontinuation of 4-AP therapy and initiation of ambrisentan and tadalafil, dyspnea and pulmonary arterial pressure have improved significantly and one specific PAH treatment was stopped. 4-AP is an outward rectifying potassium channel blocker with a vasoconstrictor effect in animal's pulmonary artery. According to the chronological sequence of events, the lack of other etiology, and its pharmacological plausibility, 4-AP is highly suspected to have induced our patient's PAH.