Revue des maladies respiratoires最新文献

{"title":"Uncovering cystic fibrosis patient profiles and exposome associations through unsupervised multidimensional phenotyping","authors":"M. Leemans ,&nbsp;R. Epaud ,&nbsp;P. De Carli ,&nbsp;C. Dehillotte ,&nbsp;L. Lemonnier ,&nbsp;T. Benoussaid ,&nbsp;A. Coman ,&nbsp;I. Coll ,&nbsp;S. Lanone ,&nbsp;E. Audureau","doi":"10.1016/j.rmr.2024.01.038","DOIUrl":"https://doi.org/10.1016/j.rmr.2024.01.038","url":null,"abstract":"<div><h3>Introduction</h3><p>Cystic fibrosis (CF) is a genetic disorder that affects the respiratory and digestive systems. CF patients exhibit considerable variation in their symptoms and disease progression, suggesting complex genotype–phenotype relationships that may involve environmental factors. This study aimed to use unsupervised clustering analyses to identify distinct profiles and trajectories of CF patients, while also assessing their associations with various environmental factors.</p></div><div><h3>Methods</h3><p>Data from the French CF Registry, which covers 90% of CF patients in France and provides comprehensive health information for monitoring and research purposes, were utilized. By employing dimensionality reduction and clustering techniques, such as self-organizing maps (SOMs), reverse graph embedding (DDRTree algorithm, ClinTrajAn), and trajectory analyses (latent class analysis) based on longitudinal lung function tests, patients were grouped based on their clinical characteristics.</p></div><div><h3>Results</h3><p>Preliminary findings revealed the existence of different subgroups among CF children and adult patients, characterized by significant differences in overall health status, decline in lung function, comorbidities, incidence of infections, and exposure to environmental factors like passive smoking. Additionally, the study investigates the connections between CF profiles and air pollution at the geographic level of French departments.</p></div><div><h3>Conclusion</h3><p>Applying clustering techniques to large medical datasets reveals valuable insights into the impact of the environment on the physiological and pathological processes of CF. By uncovering distinct patient profiles, this approach can optimize treatment strategies and improve patient outcomes.</p></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"41 3","pages":"Page 200"},"PeriodicalIF":0.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140160433","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":"Development of succinate-based analogues and formulations against influenza virus infection","authors":"V. Vasseur ,&nbsp;A. Cezard ,&nbsp;A. Caumon ,&nbsp;A. Guillon ,&nbsp;N. Tsapis ,&nbsp;S. Le Poder ,&nbsp;S. Messaoudi ,&nbsp;M. Si-Tahar","doi":"10.1016/j.rmr.2024.01.049","DOIUrl":"https://doi.org/10.1016/j.rmr.2024.01.049","url":null,"abstract":"<div><h3>Introduction</h3><p>One of the top global causes of death worldwide is respiratory viral infections. Among these, influenza virus-related infections cause deadly epidemics and pandemics. Each year, seasonal influenza infects more than 1 billion people (i.e. ∼20% of the world's population) and results in approximately 500,000 deaths. Vaccination efficacy can be impaired by viral intrinsic antigenic drift and the efficiency of drugs targeting directly influenza viruses is largely disputed. Hence, the development of innovative options is required to better treat influenza. In that regard, we recently demonstrated the antiviral activity of succinate (EMBO J., 2022) as well as of “C2”, two host metabolites. In this project, our objectives are to synthesize succinate-derived drugs against influenza viruses, select the best candidates and test them in vitro and in vivo, and finally formulate them into dry powders for direct lung delivery.</p></div><div><h3>Methods</h3><p>A series of compounds are synthesized by a structure-activity relationship strategy. Various chemical modifications will be introduced in the “hit” compound in the aim to identify analogues with high activity and good druggability.</p></div><div><h3>Results</h3><p>A preliminary screening of a short series of commercially available analogues using human bronchial epithelial cells led to the identification of three new active compounds (coined “S1”, “S10” and “S11”). All have an antiviral and anti-inflammatory effect more potent than the natural metabolites succinate and C2. In an in vivo model of influenza pneumonia, mice treated at day 2 post-infection with these analogues resisted better than non-treated or C2-treated animals to a lethal dose of influenza virus (survival rate: 85%, 0%, and 50% respectively).</p></div><div><h3>Conclusion</h3><p>Our study will pave the way for the development of appropriate “drug-and-devices” that will help to administer these succinate analogues directly into the respiratory tract. This project is funded through an ANR program.</p></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"41 3","pages":"Page 205"},"PeriodicalIF":0.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140160435","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":"Étude de la physiopathologie de la dysfonction chronique du greffon pulmonaire par analyse transcriptomique sur cellule unique d’explants pulmonaires","authors":"P. Halitim ,&nbsp;A. Tissot ,&nbsp;L. Boussamet ,&nbsp;A. Garcia ,&nbsp;C. Fourgeux ,&nbsp;P. Lacoste ,&nbsp;B. Marie ,&nbsp;J. Poschmann ,&nbsp;S. Brouard ,&nbsp;L. Berthelot","doi":"10.1016/j.rmr.2024.01.044","DOIUrl":"https://doi.org/10.1016/j.rmr.2024.01.044","url":null,"abstract":"<div><h3>Introduction</h3><p>La dysfonction chronique du greffon est la complication majeure de la transplantation pulmonaire puisque sa survenue impacte la survie de manière péjorative <span>[1]</span>, <span>[2]</span>. Il est important de progresser dans la connaissance des mécanismes physiopathologiques de cette pathologie afin d’identifier de nouvelles cibles thérapeutiques.</p></div><div><h3>Méthodes</h3><p>Cette étude présente les résultats d’une analyse transcriptomique sur cellule unique d’explants pulmonaires de patients atteints de CLAD (<em>n</em> <!-->=<!--> <!-->2), comparés à des explants de patients atteints de bronchopneumopathie chronique obstructive (<em>n</em> <!-->=<!--> <!-->1), de fibrose pulmonaire idiopathique (<em>n</em> <!-->=<!--> <!-->2) et des donneurs sains (<em>n</em> <!-->=<!--> <!-->2). Les lobes pulmonaires récupérés lors de transplantations ont été dissociés afin de récupérer les cellules. Une analyse transcriptomique sur cellules uniques a ensuite été réalisée sur le Chromium 10X au sein du laboratoire. Après validation des données, une analyse bio-informatique a été réalisée. Les résultats ont été confirmés au niveau protéique par des marquages sur tissus congelés et paraffiné.</p></div><div><h3>Résultats</h3><p>Ce travail révèle l’importance des monocytes et macrophages qui semblent surreprésentés dans le CLAD. Une sous analyse de cette population monocytaire a révélé quatre clusters associés au CLAD. Ils présentaient de manière globale une signature transcriptomique inflammatoire et pro fibrosante avec un profil macrophagique orienté M1. Trois cibles d’intérêts identifiées dans l’analyse transcriptomique sur cellule unique, CXCL10 PTX3 et IFIT3, ont été étudiées sur coupes tissulaires congelées en immunofluorescence. PTX3 était abondamment présent sur les coupes tissulaires provenant de tissus pulmonaires avec CLAD, ce qui renforce l’intérêt porté à cette protéine dans le cadre du CLAD. CXCL10 et IFIT3 n’étaient observés sur aucunes des coupes (<span>Fig. 1</span>).</p></div><div><h3>Conclusion</h3><p>Les monocytes et macrophages associés au CLAD ont une signature transcriptomique particulièrement pro-inflammatoire. Parmi les transcrits d’intérêts exprimés par ces monocytes, PTX3 semble être une cible qui mériterait d’être étudiée davantage dans la dysfonction chronique du greffon afin d’identifier sa place dans sa prise en charge du CLAD.</p></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"41 3","pages":"Pages 202-203"},"PeriodicalIF":0.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140160522","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":"SPHINX31, a SRPK1 inhibitor, regulates the ATR/DNA-PKcs/CHK1 replicative checkpoint to inhibit cell growth in NSCLC cells","authors":"A. Shreim ,&nbsp;M. Rouchette ,&nbsp;N. Zubchuk ,&nbsp;H. Polverche ,&nbsp;D. Auboeuf ,&nbsp;S. Gazzeri ,&nbsp;B. Eymin","doi":"10.1016/j.rmr.2024.01.029","DOIUrl":"https://doi.org/10.1016/j.rmr.2024.01.029","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;p&gt;Lung cancer, including the non-small cell lung carcinoma (NSCLC) histological subtype, is a leading cause of cancer-related death worldwide. Acquisition of resistance to therapies such as platinum salts, the gold standard chemotherapy in NSCLC, is one of the major trick supporting patients’ poor prognosis. Deregulation of splicing patterns as well as of some splicing factors and/or their regulators participate in the process of carcinogenesis and lung tumor progression. However, less is known regarding the contribution of RNA splicing defects to lung tumor escape from therapies. Recently, pharmacological inhibitors targeting different components/regulators of the spliceosome machinery have emerged as potential anti-cancer drugs, such as SPHINX31 that inhibits SRPK1, a kinase implicated in splicing regulation through the phosphorylation of various serine/arginine (SR)-rich proteins.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;In order to investigate whether RNA splicing defects contribute to acquired resistance to platinum salts in NSCLC, we have worked in cellular models of resistance derived from NSCLC cell line sub-cultured with increasing concentrations of cisplatin during 4–6 months in order to obtain resistant cells. We treated both the parental and resistant cells with SPHINX31 in order to investigate the role of SRPK1 in cell cycle regulation and apoptosis. Western blot and co-immunoprecipitation assays were used to study the effect of SPHINX31 on the expression/interaction of some ATR signaling pathway components. Then, RNA-seq analysis was performed to predict the potential signaling pathway by which SRPK1 inhibition induces cell death.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;In this study, we demonstrated that SPHINX31 inhibits ATR signaling, the main pathway involved in the management of replicative stress, notably in NSCLC cells with acquired resistance to platinum salts. This leads to cell growth inhibition and enhanced genomic instability. At the molecular level, we demonstrated that SRPK1 is recruited at stalled replication forks upon replicative stress, co-immunoprecipitates with the ATR/ATRIP/TOPBP1 complex and is required for TOPBP1/ATRIP recruitment to chromatin and TOPBP1 nuclear foci formation which contribute to ATR full activation. We further provided evidence that SPHINX31 and SRPK1 regulate the splicing of WIZ, in favor of splice variants involved in ATR activation, thereby identifying both splicing-dependent and -independent functions of SRPK1 by which it controls ATR signaling pathway. Last, we showed that the inhibitory effects of SPHINX31 on ATR are counterbalanced by the activation of DNA-PKcs and we identified a strong synergistic cytotoxic effect of the combination SPHINX31 and DNA-PKcs inhibitor in vitro. We propose that SPHINX31, alone or combined with DNA-PKcs inhibitor, could be benefit for NSCLC patients who relapse after platinum based-chemotherapy (&lt;span&gt;Fig. 1&lt;/span&gt;).&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusio","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"41 3","pages":"Pages 194-195"},"PeriodicalIF":0.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159988","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":"Late response of bronchial epithelium to rhinovirus in severe asthma","authors":"K. Valette ,&nbsp;L. Moreno ,&nbsp;A.S. Payet ,&nbsp;P. Chanez ,&nbsp;D. Gras","doi":"10.1016/j.rmr.2024.01.014","DOIUrl":"https://doi.org/10.1016/j.rmr.2024.01.014","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;p&gt;Alteration of bronchial epithelium is one of the main features of severe asthma. Bronchial epithelial cells (BEC) promote airway inflammation and remodeling leading to chronic symptoms and airway hyperresponsiveness and obstruction. Moreover, BEC are the first line in viral infections, which are the major contributor to asthma exacerbation. However, the consequences of the persisting long-term responses to viral infection of BEC in severe asthma are not fully understood. The aim of our study was to investigate the morphological and functional responses of bronchial epithelium induced by human rhinovirus in acute and late phase post-infection in severe asthma in an ALI culture model.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Primary human bronchial epithelial cells (HBECs) from control (C) (&lt;em&gt;n&lt;/em&gt; &lt;!--&gt;=&lt;!--&gt; &lt;!--&gt;3) and severe asthmatic (SA) (&lt;em&gt;n&lt;/em&gt; &lt;!--&gt;=&lt;!--&gt; &lt;!--&gt;4), cultured in air–liquid interface (ALI), were infected with Rhinovirus A16 (RV-A16) at the apical pole. The virus was removed four hours after infection. Differences in term of viral replication, cytotoxicity (measured by LDH activity), epithelium cohesion (TEER measurement) and antiviral response was assessed at the acute phase (until 4&lt;!--&gt; &lt;!--&gt;days) and at the late phase (until 14&lt;!--&gt; &lt;!--&gt;days) post-infection (dpi).&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;RV-A16 replication increased during the acute phase then decreased during the late phase, without difference between control and severe asthmatic. Cytotoxicity was slightly induced by RV-A16 infection only in the acute phase with no difference observed between control and severe asthmatic (fold induction compared to MOCK: 10.4 and 11.7 for C and SA respectively at 4 dpi). Epithelium cohesion is damaged by RV-A16 in severe asthmatics at the late phase whereas it is strengthened in controls (Fold induction compared to MOCK: 1.12 and 0.62 for C and SA respectively at 14 dpi). RV-A16 induced secretion of several antiviral defense peptides (IFNλ2-3, IFNλ1, IFNβ, IFNα2) and inflammatory mediators (CCL5, CXCL10, IL 33, TSLP) over the first week post-infection, with different kinetic and intensities between control and severe asthmatic. IL-33 and TSLP secretion is significantly more induced in severe asthmatic than in control (&lt;em&gt;P&lt;/em&gt; &lt;!--&gt;&lt;&lt;!--&gt; &lt;!--&gt;0.05). Antiviral and proinflammatory mediator's secretion returns to baseline at 14 dpi in both severe asthmatics and controls, but declines more rapidly in severe asthmatics.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;The antiviral response is different in terms of profile and intensity between control and severe asthmatic, both in the acute and late phases. The virus induces alteration of epithelium cohesion in severe asthmatics, suggesting a defect in cellular events normally induced by injury. Then, an altered response of HBECs in severe asthma, illustrated by the increased secretion of epithelial alarmins IL-33 and TSLP, could contribute to increased disease su","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"41 3","pages":"Pages 187-188"},"PeriodicalIF":0.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140160086","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":"MicroRNA-155 differentially regulates IL-13Rα1 and IL-13Rα2 expression and signaling that drives abnormal epithelial cells functions in severe asthma","authors":"M. Klein ,&nbsp;P.A. Gagnon ,&nbsp;M. Salem ,&nbsp;M. Rouabhia ,&nbsp;J. Chakir","doi":"10.1016/j.rmr.2024.01.015","DOIUrl":"https://doi.org/10.1016/j.rmr.2024.01.015","url":null,"abstract":"<div><h3>Rationale</h3><p>Asthma is a chronic airway disease characterized by a prevailing type 2 inflammation and airway remodeling. In asthma, microRNA-155 (miR-155) is known to increase in innate and adaptive immune cells and is associated with disease severity. However, little is known about its role in lung structural cells.</p></div><div><h3>Objectives</h3><p>This study investigated the expression of miR-155 and its regulatory role on IL-13 receptors and function in bronchial epithelial cells (BEC) isolated from healthy and severe asthmatic donors.</p></div><div><h3>Methods</h3><p>BECs isolated from healthy donors and severe asthma patients were stimulated with IL-13. MiR-155 expression and release were measured by RT-PCR in BECs and in their derived exosomes. Modulation of miR-155 in BECs was performed using transfection of miR-155 inhibitor and miR-155 mimic. MUC5AC, IL-8 and EOTAXIN-1 expression were measured by RT-PCR and BECs repair process was assessed by wound healing assay. IL-13Rα1 and IL-13Rα2 expression and downstream pathways were evaluated by western blot.</p></div><div><h3>Main results</h3><p>Severe asthma BECs showed an increased expression and exosomal release of miR-155 at baseline and amplified following IL-13 stimulation. Additionally, they expressed more IL-13Rα1 and less IL-13Rα2 than healthy BECs. IL-13Rα1 but not IL-13Rα2 induced miR-155 expression. Following miR-155 overexpression, BECs expressed more MUC5AC, IL-8 and EOTAXIN-1 through IL-13Rα1/SOCS1/STAT6 pathway and harbored a delayed repair process with a downregulated IL-13α2/ERK1/2/c-Jun signaling.</p></div><div><h3>Conclusions</h3><p>MiR-155 is overexpressed in severe asthma BECs and contributes to modulate IL-13Rα1 and IL-13Rα2 expression favoring mucin and eosinophils recruitment to detriment of airway repair. These results contribute to a better understanding of miR-155 role in the abnormal behavior of severe asthma BECs.</p></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"41 3","pages":"Page 188"},"PeriodicalIF":0.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140160087","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;A. Nasri ,&nbsp;F. Foisset ,&nbsp;I. Vachier ,&nbsp;A. Bourdin ,&nbsp;S. Assou ,&nbsp;J. De Vos","doi":"10.1016/j.rmr.2024.01.007","DOIUrl":"https://doi.org/10.1016/j.rmr.2024.01.007","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;p&gt;Primary ciliary dyskinesia (PCD) is a genetic disease caused by mutations that alter cilia beating, including in the respiratory airways, resulting in impaired mucus clearance and severe morbidity as well as increased mortality. We hypothesized that we could restore bronchial cilia beating with genetically corrected iPSC differentiated into bronchial progenitors.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Our project aims to assess the ability of a corrected iPSC line to functionally repair pathological models in vitro. We generated a PCD patient iPSC line reprogrammed using Sendai viruses, and the 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 expressing the fluorescent GFP protein under the human elongation factor 1 alpha promoter (EF1a), allowing us to study the engraftment ability of GFP bronchial stem cells on a control epithelium model. To assess the efficiency of different bronchial progenitors to engraft a bronchial epithelium, we used our previously published air–liquid interface bronchial epithelium model (iALI).&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;One main issue is to identify the competent cell type for regeneration of the adult bronchial epithelium. Indeed, there are several cell types constituting the bronchial epithelium, as well as several developmentally bronchial progenitor cells that could be considered. Our iALI differentiation process mimics the embryonic development and thus the iALI model may provide any cell type from the definitive endoderm to the mature bronchial epithelium. Our results suggest that lung progenitors at the ventralized anterior foregut endoderm stage, could be the most efficient cells for engraftment. Besides, their self-renewal ability and their capacity to differentiate into the different cell type spectrum of the bronchial epithelium are promising for the development of a long-term and efficient therapy. The second issue for bronchial epithelium cell replacement would be to determine the best strategy to erode the bronchi prior to cell therapy. Such an erosion is considered necessary to promote cell engraftment because of the barrier function of the intact bronchial epithelium and the lack of selection advantage from the corrected cells. To this end, we compared mechanical, chemical and enzymatic erosion strategies on the iALI model. Our results suggest a better efficiency with enzymatic erosion, showing a homogeneous detachment of the cells and a better engraftment of cells from the GFP-iPSC line.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;In conclusion, engraftment of corrected lung progenitors to enzymatically eroded bronchial epithelium seems to be a promising therapeutic strategy to treat PCD. Future experiments will refine the best condition regarding enzymatic solution (concentration, time exposure) and graft cell number to assure functional recovery of the mucociliary clearance.&lt;/p&gt;","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"41 3","pages":"Page 184"},"PeriodicalIF":0.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140160152","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 maturation et les fonctions de l’éosinophile dans l’asthme sévère","authors":"B. Hugo ,&nbsp;E. Coralie ,&nbsp;R. Morgane ,&nbsp;B. François-Xavier ,&nbsp;L. Gervaise ,&nbsp;H. Dorian ,&nbsp;S. Vincent","doi":"10.1016/j.rmr.2024.01.008","DOIUrl":"https://doi.org/10.1016/j.rmr.2024.01.008","url":null,"abstract":"<div><h3>Introduction</h3><p>L’asthme est une pathologie bronchique caractérisée par une hyperréactivité bronchique, un remodelage tissulaire et une inflammation chronique. Nos travaux ont montré que la GTPase Rac était activée au sein des éosinophiles dans un modèle murin d’asthme allergique sévère. Notre objectif est d’évaluer le rôle de la protéine Rac dans la maturation et la dégranulation des éosinophiles.</p></div><div><h3>Méthodes</h3><p>Les éosinophiles étudiés ont été obtenus par différenciation de cellules médullaires issues de moelles osseuses de souris. Les niveaux de Rac-GTP ont été évalués au cours de la maturation cellulaire par cytométrie en flux et western blot. Sur le plan fonctionnel, la dégranulation des éosinophiles est induite in vitro par le <em>platelet activating factor</em> (PAF) et évaluée par la mesure de l’activité peroxidase et RNase.</p></div><div><h3>Résultats</h3><p>Le protocole de différenciation des cellules médullaire permet d’obtenir des cultures cellulaires contenant 95 % d’éosinophiles. Au cours de cette différenciation, le niveau de Rac actif (Rac-GTP) augmente significativement (j4 0,6 vs j11 2,7, <em>p</em> <!-->=<!--> <!-->0,03). Par cytométrie en flux, nous avons déterminé que cette élévation concerne principalement les éosinophiles. Nous avons observé que le PAF entraîne la dégranulation des éosinophiles en culture avec une libération d’éosinophile péroxidase et de RNases. Cette dégranulation s’accompagne d’une augmentation de l’activation de Rac. L’inhibition pharmacologique de Rac génère une accumulation des granules au niveau de la membrane plasmique et prévient la dégranulation in vitro (diminution de 74 %, <em>p</em> <!-->=<!--> <!-->0,002) et sur des lysats pulmonaires de modèles d’asthme sévère.</p></div><div><h3>Conclusions</h3><p>Nos résultats mettent en évidence que l’activation de Rac participe à la maturation et à la dégranulation des polynucléaires éosinophiles. Rac apparaît comme une nouvelle cible thérapeutique dans l’asthme allergique pour lutter contre l’inflammation.</p></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"41 3","pages":"Pages 184-185"},"PeriodicalIF":0.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140160153","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":"Identification of a host metabolite with both antiviral and anti-inflammatory properties that protects against influenza virus-driven morbidity and mortality","authors":"A. Cezard ,&nbsp;D. Brea ,&nbsp;V. Vasseur ,&nbsp;L. Gonzalez ,&nbsp;B. Da-Costa ,&nbsp;R. Le Goffic ,&nbsp;D. Fouquenet ,&nbsp;T. Baranek ,&nbsp;C. Paget ,&nbsp;A. Guillon ,&nbsp;M. Si-Tahar","doi":"10.1016/j.rmr.2024.01.051","DOIUrl":"https://doi.org/10.1016/j.rmr.2024.01.051","url":null,"abstract":"<div><h3>Introduction</h3><p>Influenza is an acute respiratory immunopathology resulting from the intrinsic pathogenicity of influenza A (IAV) and B (IBV) viruses, added to an inflammatory host response, which in excess, is deleterious. Influenza is a major public health issue, causing 500,000 deaths per year and a considerable socioeconomic burden. Frequent vaccine escape and emerging antiviral resistance spur innovative research on host-directed therapy against influenza. In that regard, some host metabolites have emerged as potent immuno-regulatory molecules.</p></div><div><h3>Methods</h3><p>We recently characterized mitochondria-derived succinate as a major antiviral metabolite (EMBO J., 2022). Here, we extended those findings by screening the effect of other host metabolites on influenza virus infection, using human bronchial epithelial cells. Among these metabolites, we focused on one mitochondria-derived metabolite (coined here “C2”) and evaluated its anti-inflammatory and antiviral activity using complementary approaches, such as immunological and qRT-PCR assays, reverse genetics, western-blotting, flow cytometry and confocal microscopy techniques.</p></div><div><h3>Results</h3><p>We found that C2 has a major antiviral activity by preventing the expression of viral mRNA and protein, and the subsequent multiplication of both influenza A and B virus strains. Next, we observed that C2 alleviates the inflammatory cascades triggered by influenza virus and other inflammatory stimuli, including the inflammatory cytokine TNFα. We further showed in a mouse model of influenza pneumonia that C2 decreases the viral load, the leukocyte recruitment into the airspaces, the secretion of inflammatory mediators and the damage of lung tissues. As a result, mice treated at day 2 post-infection with C2 resist better than non-treated animals to a lethal dose of influenza virus (survival rate: 70% and 0%, respectively).</p></div><div><h3>Conclusion</h3><p>We reveal that C2 is a host metabolite with anti-viral and anti-inflammatory properties that protect against influenza pneumonia. Our results open new avenues for the development of a C2-based treatment of influenza virus infection.</p></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"41 3","pages":"Page 206"},"PeriodicalIF":0.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140160437","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":"Mucosal administration of an immunotherapy provides long-term protection against a bacterial respiratory infection","authors":"A. Pitiot ,&nbsp;M. Ferreira ,&nbsp;C. Parent ,&nbsp;C. Boisseau ,&nbsp;M. Cortes ,&nbsp;L. Bouvart ,&nbsp;C. Paget ,&nbsp;N. Heuzé-Vourc’h ,&nbsp;T. Sécher","doi":"10.1016/j.rmr.2024.01.059","DOIUrl":"https://doi.org/10.1016/j.rmr.2024.01.059","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;p&gt;Acute and chronic respiratory infections are one of the first causes of death worldwide, especially for young children and elderly people. Their threat on human health has significantly increased over the last few years, due to the emergence of new viruses and the increase of antimicrobial multi-resistant strains of bacteria. Therapeutic antibodies (Ab) have proven their efficacy in infection prevention and control. Their administration inside the airways, rather than through parenteral route, allows to potentiate their therapeutic index against respiratory infections. The mode of action of anti-infectious Ab relies mainly on direct neutralization of the pathogen, and the recruitment of effectors immune cells facilitating its elimination. However, some studies suggest an immunomodulator role of therapeutic antibodies. Thus, this project aimed at making a proof-of-concept of mAb-mediated long-term immune protection after mucosal administration during a pulmonary bacterial infection and deciphering the mechanisms underlying this effect.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;We used a mouse model of &lt;em&gt;Pseudomonas aeruginosa&lt;/em&gt; (&lt;em&gt;P. aeruginosa&lt;/em&gt;) lung infection, resembling to human acute pneumonia. The primary infection was treated using a neutralizing anti-&lt;em&gt;P. aeruginosa&lt;/em&gt; mAb delivered through the airways. To investigate long-term protection, mice surviving primary infection were challenged a month later, at a time when circulating/local mAb had disappeared, once again with &lt;em&gt;P. aeruginosa&lt;/em&gt;. Local and systemic humoral and cellular immune responses were analyzed thereafter.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;Thanks to the, previously presented, model, we have shown that beyond a rapid and efficient containment of a lethal primo infection, an antibacterial Ab, administered in the airways, can interact with the mucosal immune system to develop a long-term immunity, protecting against a secondary infection. Results obtained in vitro and in vivo indicate an essential contribution of immune complexes, formed between the bacteria and the antibody, in the induction of an antibacterial humoral response. This humoral response, persistent, is protective against the pathogenic bacteria. The long-term immunity thus seems to be dependent on both the amount of immune complexes, but also the presence of a local inflammation during the primo infection. Interestingly, the long-term immune response also offers a partial protection against a secondary infection by a heterologous strain of &lt;em&gt;P. aeruginosa&lt;/em&gt;.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;Complementary studies will be needed to identify all cellular and molecular actors implicated in this long-term protection. Nevertheless, our results suggest that a mucosal administration of an Ab enables the neutralization of a bacterial infection and ensures a long-term protection against a reinfection. This immunomodulatory characteristic of inhaled antibacterial Ab opens new pe","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"41 3","pages":"Page 210"},"PeriodicalIF":0.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140160473","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}