Revue des maladies respiratoires最新文献

{"title":"Involvement of epithelial CD146 in severe asthma","authors":"F. Lepretre ,&nbsp;L. Moreno ,&nbsp;A. Joshkon ,&nbsp;N. Bardin ,&nbsp;M. Blot-Chabaud ,&nbsp;P. Chanez ,&nbsp;D. Gras","doi":"10.1016/j.rmr.2025.02.049","DOIUrl":"10.1016/j.rmr.2025.02.049","url":null,"abstract":"<div><h3>Introduction</h3><div>Asthma is a chronic lung disease affecting 300 million people worldwide, 2-10 % of whom suffer from severe asthma. In asthma, the bronchial epithelium is dysregulated, contributing to the pathophysiology of the disease. CD₁₄₆ is an adhesion molecule that is highly expressed on all the cells from the vascular system, including endothelial cells. It is also expressed by epithelial cells, but its functions in these cells are poorly understood, as is its role in severe asthma. The aim of our study is to elucidate the role of CD₁₄₆ in the bronchial epithelium and its implication in severe asthma.</div></div><div><h3>Methods</h3><div>Bronchial epithelia of healthy controls and severe asthma patients were reconstituted in vitro using air-liquid interface culture. Measurements of CD₁₄₆ expression were made on differentiated epithelium (n<!--> <!-->=<!--> <!-->20 control and 20 severe asthma patients). Then, undifferentiated and differentiated bronchial epithelial cells were sorted based on the expression level of CD₁₄₆. The sorted undifferentiated bronchial epithelial cells were cultured and monitored during the differentiation process until obtention of a fully differentiated epithelium (n<!--> <!-->=<!--> <!-->3). The sorted differentiated bronchial epithelial cells were used to perform RNA-Seq experiments (n<!--> <!-->=<!--> <!-->4).</div></div><div><h3>Results</h3><div>We showed that CD₁₄₆ is highly expressed in severe asthma patients compared to healthy controls both at mRNA and protein levels in differentiated epithelium. Then, we have shown that CD₁₄₆ expression is not ubiquitous in the differentiated bronchial epithelium. Cell sorting and RNA-seq experiments demonstrated that CD₁₄₆ is mostly expressed by the basal epithelial cells in the differentiated epithelium. Finally, morphological analysis revealed that CD₁₄₆ seems to play a role in the bronchial epithelium differentiation process. Indeed, fully differentiated epithelium obtained from CD₁₄₆+ and CD₁₄₆− sorted undifferentiated bronchial epithelial cells were different in morphology and cell composition.</div></div><div><h3>Conclusion</h3><div>Our results suggest that CD₁₄₆ is only expressed by basal cells of the bronchial epithelium and supports an important role in the differentiation of this epithelium. Moreover, we demonstrated that CD₁₄₆is overexpressed in severe asthma, suggesting a possible role of this molecule in this disease notably during repair epithelial process.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 206"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are the behaviors of myogenic progenitors induced by mechanical stretch similar between the human quadriceps and diaphragm?","authors":"E. Lhospice ,&nbsp;G. Hugon ,&nbsp;F. Panaro ,&nbsp;B. Al Taweel ,&nbsp;S. Matecki ,&nbsp;G. Carnac","doi":"10.1016/j.rmr.2025.02.086","DOIUrl":"10.1016/j.rmr.2025.02.086","url":null,"abstract":"<div><h3>Introduction</h3><div>The stretch-induced behaviors of myogenic progenitors from the human diaphragm during mechanical ventilation are poorly understood. In all muscles, following injury, quiescent satellite cells (SCs) become activated, proliferate into myoblasts, and then merge and differentiate to form myotubes. Until now, SC adaptation to injury has been considered similar across various muscles. However, in animal models, transcriptional factors involved in maintaining the quiescent state, such as PAX3 and PAX7, are expressed differently between the diaphragm and quadriceps. In humans, no data currently exist to determine whether differences in stretch-induced behavior of myogenic progenitors during mechanical ventilation exist between these two muscles.</div></div><div><h3>Methods</h3><div>To address this issue, we purified and characterized human satellite cells from quadriceps and diaphragm biopsies from 11 patients. We then plan to culture these cells on a stretchable PDMS support to develop an in vitro model involving mechanical stress applied to human primary muscle-derived cells. A stretch of 12% of the initial length was applied using a FlexCell apparatus at a frequency of 0.3<!--> <!-->Hz to mimic mechanical ventilation in the ICU as showed in <span><span>Fig. 1</span></span>.</div></div><div><h3>Results</h3><div>Our preliminary results (<em>n</em> <!-->=<!--> <!-->6) show that the Pax7/Pax3 ratio at the myoblast stage, the fusion index, and the surface area at the myotube stage were higher in quadriceps compared to the diaphragm, indicating a higher quality of differentiation (<span><span>Fig. 2</span></span>). In a preliminary exploratory experiment, human diaphragm muscle cells from one patient were subjected to different stretching protocols, varying between 2 and 6 days, initiated at different stages of development. Our first results as indicated in <span><span>Fig. 3</span></span> show that the quadriceps and diaphragm cells tolerate the stretching protocol and can proliferate and differentiate under these conditions.</div></div><div><h3>Conclusion</h3><div>Our preliminary results show that a comparative study between diaphragmatic and quadriceps cells will allow us in the future to assess the sensitivity of these two cell populations to mechanical stress.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 225"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consequences of exacerbation in old rats with emphysema","authors":"Y. Colombani,&nbsp;P.E. Grillet,&nbsp;Y. Rourre,&nbsp;Q. Wynands,&nbsp;C. Roure,&nbsp;L. Alburquerque,&nbsp;F. Lopez,&nbsp;P. Pomies,&nbsp;E. Passerieux,&nbsp;A. Bourdin,&nbsp;O. Cazorla","doi":"10.1016/j.rmr.2025.02.055","DOIUrl":"10.1016/j.rmr.2025.02.055","url":null,"abstract":"<div><h3>Introduction</h3><div>Chronic Obstructive Pulmonary Disease (COPD), is marked by chronic airflow limitation due to small airway obstruction and emphysema, which involves abnormal enlargement of lung air spaces and inflammation-induced tissue destruction. COPD often coexists with cardiovascular diseases, likely due to chronic inflammation. As an age-related disease, COPD's effects are worsened with aging, intensifying both lung and systemic impacts. However, the connection between age-related emphysema and cardiac issues remains unclear, indicating a need for more research on how aging affects COPD's impact on cardiovascular health.</div></div><div><h3>Methods</h3><div>Old male Wistar rats (18 months old, <em>n</em> <!-->=<!--> <!-->9 control, 5 ELA-LPS) received weekly intra-tracheal instillations of elastase (ELA) over 4 weeks at a dose of 10<!--> <!-->U. I to induce emphysema. In the fourth week, alongside elastase, bacterial lipopolysaccharide (LPS) derived from <em>E.</em> <em>coli</em> O55 B: 5 was delivered to mimic a bacterial exacerbation. We evaluated pulmonary, cardiac and muscular functions using various in-vivo and ex-vivo methods, including cardiorespiratory tests on a treadmill, whole-body plethysmography and echocardiography. The results in aged animals were compared with those from young animals (6–7 weeks-old).</div></div><div><h3>Results</h3><div>Preliminary results revealed significant alteration in cardiac systolic function, along by morphological changes in the left ventricular posterior wall during systole and diastole, compared to the young emphysema model, where a correlation between emphysema and diastolic dysfunction was noted. Unexpectedly, there was a trend of improvement in respiratory parameters, including Peak Inspiratory Flow, Peak Expiratory Flow, and tidal volume. The cardiorespiratory performance test showed a trend towards reduced O₂ consumption and decreased exercise capacity, consistent with aging patterns. Then, the assessment of lung elastic properties (ex vivo pressure-volume curve) indicated a greater loss of pulmonary elasticity compared to the young emphysematous model. Additionally, ex vivo endurance and force tests on the soleus muscle showed a tendency toward reduced muscle endurance and strength, aligning with the findings from the treadmill test.</div></div><div><h3>Conclusion</h3><div>This multidisciplinary approach seeks to deepen our understanding of the age-related aspects of COPD-emphysema and its broader impact on human health. Initial results are promising, showing that aged rats exhibit a more severe phenotype than younger ones. Once confirmed, the underlying causes of these age-related dysfunctions compared to younger animals need to be determined to provide valuable insights into associated cardiac disorders.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 209"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of cigarette smoke on inflammatory effect of Quinolinic acid during influenza infection","authors":"G. Pamart,&nbsp;O. Le Rouzic,&nbsp;M. Pichavant,&nbsp;P. Gosset,&nbsp;O. Poulain-Godefroy","doi":"10.1016/j.rmr.2025.02.064","DOIUrl":"10.1016/j.rmr.2025.02.064","url":null,"abstract":"<div><h3>Introduction</h3><div>La bronchopneumopathie chronique obstructive (BPCO) se caractérise par une inflammation chronique et une obstruction des voies respiratoires principalement dues à l’exposition au tabac. Les patients atteints de BPCO développent fréquemment des exacerbations principalement causées par des infections, souvent virales, associées à une inflammation pulmonaire, une progression de la maladie et une augmentation de la mortalité. La voie métabolique du tryptophane, permettant la formation de NAD (Nicotinamide Adénine Dinucléotide) est également affectée par la fumée de cigarette (CS) entraînant une modification de la production de l’acide quinolinique (QA), un métabolite possédant des propriétés immunomodulatrices dont les taux sont altérés chez les patients atteints de BPCO.</div></div><div><h3>Méthode</h3><div>Notre objectif est de déterminer le rôle potentiel de la voie du tryptophane, et plus particulièrement de QA, au cours des exacerbations de la BPCO. La production de QA et l’expression des enzymes de la voie des kynurénines ont été mesurées chez des souris C57Bl6 après une semaine d’infection par le virus de la grippe H₃N2 (MOI 0,5). Des cellules épithéliales bronchiques (BEAS 2B) et des macrophages humains ont également été exposés à QA (100<!--> <!-->μM) 1 heure avant une infection par H₃N2. Les réponses antivirales et inflammatoires ont été évaluées 6 et 24<!--> <!-->heures après l’infection par RT-qPCR et dosage ELISA des cytokines.</div></div><div><h3>Résultats</h3><div>L’infection virale a stimulé l’expression de certaines enzymes de la voie des kynurénines 24<!--> <!-->h après l’infection viral, et à augmenter la concentration de QA au sein du tissu pulmonaire. La préexposition à QA augmente l’expression génique de molécules antivirales telles que IFNb et Mx1 24<!--> <!-->heures après l’infection dans les cellules BEAS 2B mais à moduler la réponse antivirale dans les macrophages en stimulant l’IFNb, mais en diminuant l’expression des récepteurs TLR. QA a également modulé l’inflammation des macrophages en stimulant l’expression et la sécrétion de molécules telles que IL6, IL8, TNFa ou encore CXCL1.</div></div><div><h3>Conclusion</h3><div>L’infection grippale induit la voie des kynurénines, et augmente la concentration de l’acide quinolinique, qui semble impacter la réponse inflammatoire et antivirale de l’épithélium respiratoire et des macrophages, suggérant son rôle au cours des exacerbations de la BPCO.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 213"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kcnk3 deficiency aggravates right ventricular dysfunction induced by pulmonary artery banding","authors":"K. El Jekmek ,&nbsp;M. Gourmelon ,&nbsp;A. Saint-Martin Willer ,&nbsp;M. Dutheil ,&nbsp;V. Capuano ,&nbsp;O. Mercier ,&nbsp;D. Montani ,&nbsp;F. Antigny","doi":"10.1016/j.rmr.2025.02.020","DOIUrl":"10.1016/j.rmr.2025.02.020","url":null,"abstract":"<div><h3>Introduction</h3><div>Right ventricular failure (RVF) is characterized by the inability of the right ventricle (RV) to maintain adequate blood flow and is the major predictor of mortality in pulmonary arterial hypertension (PAH). PAH is defined by a mean pulmonary arterial pressure greater than 20<!--> <!-->mmHg at rest and is characterized by increased pulmonary vascular resistance, leading to right heart failure. Currently, no treatments specifically target RVF in PAH. However, slowing down the progression of RVF could delay the need for double lung transplantation and reduce PAH-related mortality. Loss-of-function mutations in the KCNK3 (Potassium channel subfamily K⁺ member 3) gene, which encodes the potassium channel known as TASK-1 (TWIK-related acid-sensitive K⁺ channel 1), have been identified in PAH patients. Our team has recently shown that KCNK3 dysfunction is involved in pulmonary vascular remodeling and contributes to the development of PAH <span><span>[1]</span></span>. They also demonstrated that reduced function and expression of KCNK3 is a hallmark of RV hypertrophy and dysfunction associated with pulmonary hypertension <span><span>[2]</span></span>.</div><div>Our objective was to investigate whether the Kcnk3 deficiency exacerbates RV remodeling in a rat model of RV dysfunction induced independently of pulmonary vascular remodeling.</div></div><div><h3>Methods</h3><div>To address this, we subjected male and female Kcnk3-deficient rats (WT, heterozygous, and homozygous) to chronic RV pressure overload by pulmonary artery banding (PAB). 4 weeks after surgery, we analyzed the consequence of Kcnk3-deficiency on RV remodeling by performing echocardiography, right heart catheterization, and RV histology.</div></div><div><h3>Results</h3><div>Our results show that rats (males and females) subjected to PAB developed RV hypertrophy and RV dysfunction. In male homozygous Kcnk3-deficient rats, PAB led to an exacerbation of RV hypertrophy, RV dilatation, and a more pronounced increase in RV systolic pressure compared to WT-PAB rats. In contrast, no difference was observed in male heterozygous Kcnk3-deficient rats compared to WT-PAB male rats. Interestingly, RV dysfunction and hypertrophy were unchanged in female homozygous Kcnk3-deficient rats subjected to PAB compared to WT-PAB female rats.</div></div><div><h3>Conclusion</h3><div>In conclusion, our results suggest that KCNK3 dysfunction is a crucial event in the physiopathology of RV failure. Further studies are needed to understand underlying molecular and cellular mechanisms and to investigate sex differences linked to Kcnk3-deficiency in these experimental conditions.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Pages 191-192"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined cellular and gene therapy to treat primary ciliary dyskinesia","authors":"C. Bourdais ,&nbsp;M. Nadaud ,&nbsp;A. Coeur ,&nbsp;F. Foisset ,&nbsp;E. Ahmed ,&nbsp;I. Vachier ,&nbsp;A. Bourdin ,&nbsp;S. Assou ,&nbsp;J. De Vos","doi":"10.1016/j.rmr.2025.02.026","DOIUrl":"10.1016/j.rmr.2025.02.026","url":null,"abstract":"<div><div>Primary Ciliary Dyskinesia (PCD) is a genetic disease caused by mutations that alter cilia beating, including in the respiratory airways. This results in poor mucus clearance, severe morbidity, and increased mortality. We hypothesized that bronchial cilia beating can be restored using genetically corrected iPSC differentiated into air - liquid interface bronchial epithelium model (iALI) for autologous cell therapy. We have previously demonstrated that corrected cells derived from a PCD patient iPS line can be differentiated into iALI with functional ciliary beating. The current aim of the project is to evaluate the engraftment potential of these corrected cells and their ability to repair the pathological model post-engraftment. Several key issues need to be addressed identifying competent cells for bronchial engraftment, exploring various strategies to pre-treat the bronchial epithelium, and assessing the recovery of the ciliary beating recovery to assure bronchial repair.</div><div>Our team has established the differentiation of iPSCs into iALI. We have generated a PCD patient iPSC line using Sendai viruses, a corresponding CRISPR/Cas9 corrected cell line, as well a wild-type iPSC line and its CRISPR/Cas9 mutated counterpart. We also generated a GFP-iPSC line that expresses the fluorescent GFP protein under the human elongation factor 1 alpha promoter (EF1a), which allows us to track the engraftment of GFP-labeled bronchial stem cells in both control and mutated iALI models. Our results suggest that lung progenitors at the ventralized anterior foregut endoderm stage could be the most efficient cells for engraftment. Their self-renewal capability and ability to differentiate into various cell types of the bronchial epithelium are promising for developing a long-term and effective therapy. Regarding bronchial erosion, we found that promoting cell engraftment is crucial due to the barrier function of the intact bronchial epithelium and the lack of selective advantage of corrected cells. Various chemical and enzymatic strategies have shown potential, but their safety for in-vivo use needs further assessment. Furthermore, GFP-expressing engrafted cells displaying cilia suggest successful differentiation into ciliated cells, though functional recovery still requires confirmation.</div><div>In conclusion, the engraftment of corrected lung progenitors into eroded bronchial epithelium appears to be a promising therapeutic strategy to PCD. Next step of the project involves developing this therapy for in-vivo application, assessing its safety and efficacy in an immunodeficient mini-pig model.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Pages 194-195"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic analysis of pulmonary fibrosis associated with lung cancer reveals dysregulation of the apoptotic pathway","authors":"C. Guillois ,&nbsp;H. Cazier ,&nbsp;E. Guenzi ,&nbsp;A. Chassac ,&nbsp;P. Mordant ,&nbsp;G. Zalcman ,&nbsp;A. Mailleux ,&nbsp;B. Crestani ,&nbsp;A. Cazes ,&nbsp;G. Chevreux ,&nbsp;N. Poté","doi":"10.1016/j.rmr.2025.02.072","DOIUrl":"10.1016/j.rmr.2025.02.072","url":null,"abstract":"<div><h3>Introduction</h3><div>Pulmonary fibrosis (PF), especially idiopathic pulmonary fibrosis, is associated with a high risk of lung cancer (LC), but the mechanisms of carcinogenesis remains poorly understood. Combining Liquid Chromatography Mass Spectrometry (LC-MS/MS) and Mass Spectrometry Imaging (MSI), we compared the proteome of fibrotic areas from PF tissue samples with and without LC to identify altered signaling pathways.</div></div><div><h3>Methods</h3><div>34 Formalin Fixed Paraffin-Embedded (FFPE) surgical samples from patients with PF with LC (LC+, <em>n</em> <!-->=<!--> <!-->17) and without LC (LC−, <em>n</em> <!-->=<!--> <!-->17) were included. For each case, a representative FFPE block was selected for downstream analyses. After macrodissection of fibrotic areas, whole protein extracts were analyzed by LC-MS/MS. MSI was performed on tissue section after tryptic digestion, on selected regions of interest within fibrotic areas. <em>In silico</em> tryptic digestion of peptides of interest was further performed, and spatial localization of these peptides was visualized on ion maps.</div></div><div><h3>Results</h3><div>By LC-MS/MS analysis, we identified 72 out of 4901 proteins significantly differentially expressed between fibrotic areas of LC- and LC+ samples (<em>P</em> <!-->&lt;<!--> <!-->0.001). Pathway analysis suggested the involvement of oxidative stress metabolism and apoptosis, with significant downregulation of two mitochondrial proteins (BAX, Frataxin), known to activate apoptosis, in fibrotic areas adjacent to LC. After <em>in silico</em> tryptic digestion of BAX protein, MSI analysis revealed at least 2 unique peptides per protein that were significantly underexpressed in LC+ fibrotic areas. Complementary ion map analysis showed a specific expression of these mitochondrial peptides within metaplastic epithelial cells ligning honeycomb cysts.</div></div><div><h3>Conclusion</h3><div>Using an original proteomic approach integrating LC-MS/MS and MSI, we show that, in patients with PF, fibrotic areas have distinct proteomic profiles depending on the presence of LC. Fibrotic areas adjacent to LC exhibit a significant downregulation of pro-apoptotic mitochondrial proteins. Interestingly, spatial analysis by MSI show that these proteins are expressed by metaplastic epithelial cells within fibrotic areas, suggesting that dysregulation of apoptosis in these cells might be involved in lung carcinogenesis in patients with PF.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Pages 217-218"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact de l’activation de la GTPase Rac dans la dégranulation des éosinophiles au cours de l’asthme sévère","authors":"H. Bergereau ,&nbsp;D. Hassoun ,&nbsp;Q. Marquant ,&nbsp;M. Rousselle ,&nbsp;A. Magnan ,&nbsp;G. Loirand ,&nbsp;V. Sauzeau","doi":"10.1016/j.rmr.2025.02.032","DOIUrl":"10.1016/j.rmr.2025.02.032","url":null,"abstract":"<div><h3>Introduction</h3><div>L’asthme est une pathologie chronique caractérisée par une inflammation exacerbée, une hyperréactivité bronchique et un remodelage des voies aériennes. Récemment, nous avons démontré que la GTPase Rac est activée au sein des éosinophiles dans un modèle murin d’asthme sévère. Notre objectif a été d’identifier le rôle de Rac dans la fonction principale des éosinophiles au cours de l’asthme : la dégranulation.</div></div><div><h3>Méthodes</h3><div>Les cellules progénitrices hématopoïétiques provenant de la moelle osseuse de souris sont mises en culture en présence de Stem Cell Factor (SCF) et de Fms-Like Tyrosine kinase 3 (FLT3-L) pour induire leur expansion. Au 4^e jour de culture, l’ajout d’interleukine 5 permet la différenciation des cellules progénitrices en éosinophiles. In vitro, la dégranulation des éosinophiles est induite par le Platelet Activating Factor (PAF). Le trafic des granules de sécrétion a été analysé par immunofluorescence et par microscopie électronique. Les voies de signalisation intracellulaire ont été analysées par western-blot.</div></div><div><h3>Résultats</h3><div>Nous avons observé que le traitement des éosinophiles au PAF induit une libération d’éosinophile peroxydase (EPX) mais également une activation de la protéine Rac. L’inhibition pharmacologique de Rac (A41, 10-5<!--> <!-->M) prévient la libération d’EPX des éosinophiles murins et également des éosinophiles humains. Par immunofluorescence et microscopie électronique, nous avons observé que l’activation de Rac par le PAF joue un rôle majeur dans la migration des granules de sécrétion du cytoplasme vers la membrane plasmique des éosinophiles, aboutissant à la libération des médiateurs cytotoxiques. Par une approche biochimique, nous avons démontré que l’activation de Rac par le PAF favorise la formation du complexe protéique Rac/PLCß2 (phospholipase<!--> <!-->C ß2) permettant la production d’IP3 et ainsi l’augmentation de la concentration calcique intracellulaire nécessaire à la dégranulation. Pour valider in vivo le rôle de Rac dans les éosinophiles, nous avons développé un modèle expérimental d’asthme sévère allergique. Nous avons observé que la libération d’EPX par les cellules inflammatoires présentes dans les poumons des souris asthmatiques est inhibée par l’A41.</div></div><div><h3>Conclusions</h3><div>Nos résultats démontrent que la dégranulation des éosinophiles induite par le PAF au cours de l’asthme est dépendante de l’activation de Rac. Ainsi, la GTPase apparaît comme une nouvelle cible thérapeutique d’intérêt pour lutter contre l’inflammation au cours de l’asthme allergique.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Pages 197-198"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact de la matrice extracellulaire sur le canal mécanosensible PIEZO1 dans les cellules musculaires lisses pulmonaires","authors":"A. Leriche ,&nbsp;A. Gaubert ,&nbsp;C. Guibert ,&nbsp;T. Ducret ,&nbsp;JF. Quignard","doi":"10.1016/j.rmr.2025.02.021","DOIUrl":"10.1016/j.rmr.2025.02.021","url":null,"abstract":"<div><h3>Introduction</h3><div>L’hypertension pulmonaire est une pathologie caractérisée par un remodelage important des artères intra-pulmonaires ayant pour conséquence d’augmenter le travail cardiaque conduisant à la mort. Dans cette pathologie, les contraintes mécaniques exercées sur les cellules musculaires lisses vasculaires sont modifiées. Ces contraintes mécaniques sont perçues par des canaux ioniques membranaires mécano-sensibles tels que Piezo1 qui convertissent les différents stimuli mécaniques en influx calcique et en réponses biologiques. La rigidité de la matrice extracellulaire est une contrainte mécanique majeure et elle augmente au cours de la pathologie. Nous avons investigué les effets de la rigidité matricielle sur l’activité de Piezo1.</div></div><div><h3>Méthodes</h3><div>Des cellules musculaires lisses d’artères intra-pulmonaires ont été cultivées sur des hydrogels Bola Bis Urée (BBU) de différentes rigidités (1 à 10 KPa). Cette matrice synthétique ne contient pas de protéines pouvant interagir avec des récepteurs membranaires. La concentration calcique intracellulaire et le potentiel transmembranaire ont été mesurés grâce aux sondes fluorescentes Cal520® et FLIPR®. La prolifération cellulaire a été estimé avec CyQUANT®.</div></div><div><h3>Résultats</h3><div>Une forte rigidité matricielle (10<!--> <!-->kPa) augmente l’expression de Piezo1. Elle induit une diminution l’amplitude et un ralentissement de la cinétique des signaux calciques intracellulaires après stimulation de Piezo1 par son agoniste Yoda1. Par contre, cette forte rigidité augmente l’activité basale de Piezo1 induisant une augmentation de la concentration calcique intracellulaire basale. Elle induit aussi une dépolarisation cellulaire liée à Piezo1. L’augmentation de la rigidité induit une augmentation de la prolifération cellulaire mais qui est indépendante de Piezo1.</div></div><div><h3>Conclusion</h3><div>Ainsi la rigidité matricielle pourrait jouer un rôle de stimulus mécanique sur Piezo1 entraînant une altération de son activité en adéquation avec le contexte d’hypertension pulmonaire.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 192"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation locale des lymphocytes B dans la fibrose pulmonaire idiopathique","authors":"Y. Bertrand ,&nbsp;T. Planté-Bordeneuve ,&nbsp;L. Schmit ,&nbsp;M. Lecocq ,&nbsp;C. Pilette ,&nbsp;A. Froidure","doi":"10.1016/j.rmr.2025.02.075","DOIUrl":"10.1016/j.rmr.2025.02.075","url":null,"abstract":"<div><h3>Introduction</h3><div>La fibrose pulmonaire idiopathique (FPI) est une pathologie interstitielle sévère, caractérisée par un remodelage hétérogène du tissu pulmonaire distal. Il a été observé que des agrégats lymphoïdes s’accumulaient dans le tissu fibreux mais également que les taux élevés d’IgA, ainsi que de facteur d’activation des lymphocytes B (BAFF) dans le sérum des patients étaient corrélés à une baisse de la survie. De plus, des auto-anticorps circulants dirigés contre des cibles variées ont été identifiés dans le sérum et le lavage bronchoalvéolaire (LBA) des patients FPI. Toutefois, à l’heure actuelle, l’activation locale des lymphocytes B (LyB), leur distribution et leur environnement restent encore à caractériser dans la FPI.</div></div><div><h3>Méthodes</h3><div>Des immunomarquages sur des lames FFPE de biopsies et d’explants FPI ont été réalisés pour marquer l’IgA, BAFF, CD 19, XBP1, proSP-C, et Krt5. Un dosage de BAFF et APRIL a été effectué dans le LBA et le sérum d’individus FPI et contrôles. Des tests d’immunofluorescence HEp2 ont été réalisés dans les LBA des mêmes individus pour évaluer la présence d’anticorps auto-réactifs d’isotype IgA.</div></div><div><h3>Résultats</h3><div>Les agrégats de lymphocytes B sont observables dans les régions remodelées du parenchyme pulmonaire. On observe que les lymphocytes B sont présents non seulement dans ces agrégats mais également à un niveau sub-épithélial, à proximité de structures ectopiques (proSP-C⁺ et Krt5⁺). Un marquage modéré de BAFF est visible au niveau de ces structures. Toutefois, l’on ne détecte pas de différence dans les taux circulants de BAFF ni d’APRIL entre les individus FPI et contrôle. On n’observe pas non plus de différence significative entre l’intensité de la fluorescence des HEp2 entre ces deux groupes. L’intensité de la fluorescence des anticorps auto-réactifs corrèle avec le taux d’APRIL dans le LBA des individus FPI.</div></div><div><h3>Conclusion</h3><div>Cette étude met en évidence plusieurs localisations des lymphocytes B au sein du tissu remodelé. On observe non seulement leur présence dans les agrégats lymphoïdes mais également sous les structures épithéliales ectopiques. Ces structures sont également positivement marquées pour BAFF, ce qui suggère une potentielle stimulation de la production d’anticorps ainsi qu’un class-switch favorisé localement vers l’IgA. Dans les LBA, on observe la présence d’auto-anticorps dont les taux corrèlent avec ceux de APRIL. Ces résultats suggèrent que, pour une sous-population de patients, une suractivation locale des lymphocytes B avec une production d’auto-anticorps serait déjà présente au moment du diagnostic.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 219"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}