Revue des maladies respiratoires最新文献

{"title":"Design of experiments assisted optimization of induced Pluripotent Stem Cell (iPSC) directed differentiation toward airway progenitors","authors":"A. Coeur ,&nbsp;C. Bourdais ,&nbsp;M. Nadaud ,&nbsp;F. Foisset ,&nbsp;C. Urena ,&nbsp;I. Vachier ,&nbsp;S. Assou ,&nbsp;A. Bourdin ,&nbsp;J. De Vos","doi":"10.1016/j.rmr.2025.02.027","DOIUrl":"10.1016/j.rmr.2025.02.027","url":null,"abstract":"<div><div>Primary ciliary dyskinesia (PCD) is a rare genetic disease causing ciliary function impairment and bronchial mucus accumulation among other comorbidities. We assume that the development of an autologous cell and gene therapy using iPSC derived airway progenitors (AP) could restore mucociliary function of PCD patients. Common bottlenecks regarding iPSC differentiation are the persistence of undifferentiated cells and the emergence of unwanted cell types. In a therapeutic context, it can cause uncontrolled cell proliferation or differentiation and reduce the therapy efficiency. iPSC differentiation into AP often leads to the coexistence of hepatic and pulmonary cell lineages. The emergence of hepatic progenitors occurs between the definitive endoderm (DE) and the anterior foregut endoderm (AFE) stages. This key differentiation step relies on the inhibition of the TGF-β and BMP pathways. In our standard protocol (STD), this is performed by removing all cytokines from the differentiation medium. Alternatively, a double inhibition (DI) can be realized by using inhibitors of both pathways.</div><div>A comparison of those two protocols (STD <em>vs</em> DI) showed that DI reduces pluripotency and liver markers expression, improving pulmonary marker expression. Nevertheless, DI leads to increased cell mortality. We chose to optimize DI protocol employing a design of experiments (DOE) approach. Besides, the effect of cell density at the critical step of the protocol has been investigated. To assess the efficiency of the iPSC differentiation, the relative expression of the main airway progenitor biomarker NKX2-1 has been measured by RT-qPCR as well as the expression unwanted cell-types markers. The viability of the cells in the end of the differentiation process has also been assessed.</div><div>The main effects shown by the screening DOE were caused by three variables linked to the transition from DE to AFE stages. Significant effects linked to the last step of differentiation have also been observed. The optimization DOE applied to the three most critical variables allowed significant modeling of the expression of several genes. The best conditions of the optimization DOE allow more than a 2-fold increase of the NKX2-1 expression compared to our STD protocol without compromising cell viability. We further optimize the protocol by passaging cells at a lower density once the AFE stage is reached, allowing a 10-fold increase of the NKX2-1 expression and an even lower expression of unwanted cell type markers.</div><div>The optimized protocol remains to be tested to assess the capacity of these NKX2-1+ lung progenitors to differentiate into bronchial epithelium. Furthermore, a single cell RNA sequencing analysis will be performed to fully characterize the homogeneity of the resulting cells.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 195"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791517","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":"Cystatin M/E, Cathepsin V and Asparaginyl Endopeptidase: New actors of the proteolytic balance in lung fibrosis","authors":"B. Rigoux ,&nbsp;A. David ,&nbsp;R. Allouche ,&nbsp;L. Vanderlynden ,&nbsp;F. Lecaille ,&nbsp;S. Marchand-Adam ,&nbsp;G. Lalmanach ,&nbsp;A. Saidi","doi":"10.1016/j.rmr.2025.02.081","DOIUrl":"10.1016/j.rmr.2025.02.081","url":null,"abstract":"<div><h3>Introduction</h3><div>Idiopathic pulmonary fibrosis (IPF) is a chronic disease with unknown etiology, characterized by progressive and irreversible fibrous thickening in the interstitial spaces of the lung. Alterations in alveolar epithelia induce the TGF-β1-dependent differentiation and proliferation of fibroblasts into myofibroblasts. Extracellular matrix (ECM) overproduction by myofibroblasts causes a dysregulated remodeling in fibrotic foci, which is closely associated with an altered protease/antiprotease balance <span><span>[1]</span></span>. Among proteases involved, some cysteine cathepsins are potent collagenases and elastases which participate in ECM remodeling. During IPF, the cathepsin/cystatin (i.e. endogenous cathepsin inhibitors) balance is impaired in favor of cystatins. The secretion of human Cystatin C (CysC) is upregulated during myodifferentiation, promoting collagen I deposition <span><span>[2]</span></span>. In addition, expression levels of both fibronectin and elastin are altered during fibrogenesis. Accordingly, this led us to investigate the involvement of Cathepsin V (CatV, the most potent human elastase) <span><span>[3]</span></span>, Asparaginyl endopeptidase (AEP) (a.k.a. Legumain (LGMN), participate in extracellular matrix degradation) <span><span>[4]</span></span> and of Cystatin M/E (CysM) (a dual tight-binding inhibitor of both enzymes) <span><span>[5]</span></span>, in the differentiation of human lung fibroblasts.</div></div><div><h3>Methods</h3><div>Characterization of CysC, CysM, CatV and AEP was conducted by immunochemical analysis of control and IPF bronchoalveolar lavage fluid (BALF) and lung biopsies. CCD-19Lu human lung fibroblasts were used as a model of TGF-β1-dependent myodifferentiation to study the regulation of these proteases and cystatins during pulmonary fibrosis. SiRNAs targeting the proteins of interest and the effects on ECM were evaluated as previously. Also, kinetic assays were performed.</div></div><div><h3>Results</h3><div>We observed that CysC and CysM are oversecreted in IPF patients BALF. Similar results were observed in supernatants of TGF-β1-differentiated human lung fibroblasts. Furthermore, silencing of CatV and AEP increased the expression levels of ECM proteins, elastin and fibronectin, respectively.</div></div><div><h3>Conclusion</h3><div>Our data support that CysC and CysM are key molecular players involved in the TGF-β1-dependent myofibrogenesis. Secreted forms could impair both fibronectin degradation and elastinolytic activities of extracellular cysteine proteases. Results obtained from IPF lung biopsies further confirmed this imbalance between protease and cystatins. Since, these proteases are involved in the ECM remodeling, we suggest that this alteration of protease/antiprotease balance may subsequently promote fibrotic phenotype found in IPF.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 222"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791404","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":"Dyspnée et activation cérébrale corticale mesurée par spectroscopie fonctionnelle dans le proche infrarouge au cours d’une épreuve de sevrage de la ventilation mécanique","authors":"G. Kemoun ,&nbsp;D. Jimenez ,&nbsp;M.-C. Nierat ,&nbsp;N. Wattiez ,&nbsp;D. Bachasson ,&nbsp;J. Mayaux ,&nbsp;M. Lecronier ,&nbsp;T. Similowski ,&nbsp;A. Demoule ,&nbsp;M. Dres ,&nbsp;M. Decavèle","doi":"10.1016/j.rmr.2025.02.085","DOIUrl":"10.1016/j.rmr.2025.02.085","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Chez les patients intubés en réanimation, la dyspnée est fréquente et délétère. Sa détection et sa quantification reposent sur les capacités d’auto-évaluation du patient. Or, la moitié des patients en réanimation sont incapable de rapporter leurs symptômes. Les échelles observationnelles, comme la Mechanical Ventilation Respiratory Distress Observation Scale (MV-RDOS), basées sur les changements physiologiques et comportementaux, sont des outils prometteurs pour suspecter la dyspnée chez ces patients. Cependant, elles reposent encore largement sur une évaluation subjective. L’objectif principal de l’étude est de mesurer et de comparer l’évolution de l’activité cérébrale corticale mesurée par spectroscopie fonctionnelle dans le proche infrarouge (fNIRS) entre des patients intubés dyspnéiques et non dyspnéiques au cours d’une épreuve de sevrage ventilatoire.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Méthodes&lt;/h3&gt;&lt;div&gt;Il s’agit d’une étude physiologique monocentrique prospective. Les patients sous ventilation mécanique invasive depuis plus de 24&lt;!--&gt; &lt;!--&gt;heures et jugés aptes à la réalisation d’une épreuve de sevrage ventilatoire (SBT) ont été inclus. Au cours du SBT étaient mesurées : la dyspnée définie par un score MV-RDOS&lt;!--&gt; &lt;!--&gt;&gt;&lt;!--&gt; &lt;!--&gt;2,6, et la fNIRS sur 24 canaux en regard des cortex frontaux et pariétaux. À partir des signaux fNIRS étaient extraits le taux d’oxyhémoglobine (HbO&lt;sub&gt;2&lt;/sub&gt;) et désoxyhémoglobine ainsi que l’amplitude d’oscillation du signal à divers fréquences correspondant à l’activité myogénique (tonus sympathique), neurogénique (tonus des grosses artères) et métabolique (tonus des petits vaisseaux).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Résultats&lt;/h3&gt;&lt;div&gt;Au total, 12 patients ont été inclus. Sept patients (42 %) étaient dyspnéiques pendant le SBT. La &lt;span&gt;&lt;span&gt;Fig. 1&lt;/span&gt;&lt;/span&gt; représente l’évolution de l’amplitude d’oscillation fréquentielle myogène de l’HbO&lt;sub&gt;2&lt;/sub&gt;en regard de l’aire motrice supplémentaire (AMS) entre les patients dyspnéiques ou non. Il existait une corrélation positive entre le score MV-RDOS et l’élévation de l’HbO&lt;sub&gt;2&lt;/sub&gt;au niveau de l’AMS avec un coefficient de Spearman rho à 0,30 (&lt;em&gt;p&lt;/em&gt; &lt;!--&gt;=&lt;!--&gt; &lt;!--&gt;0,019) et du cortex préfrontal droit (PFD) avec un rho à 0,54 (&lt;em&gt;p&lt;/em&gt; &lt;!--&gt;&lt;&lt;!--&gt; &lt;!--&gt;0,001). Une corrélation positive est également observée entre le score MV-RDOS et l’amplitude des oscillations en regard de l’AMS aux fréquences métaboliques, neurogènes et myogènes, respectivement r&lt;!--&gt; &lt;!--&gt;=&lt;!--&gt; &lt;!--&gt;0,48 (&lt;em&gt;p&lt;/em&gt; &lt;!--&gt;&lt;&lt;!--&gt; &lt;!--&gt;0,001), r&lt;!--&gt; &lt;!--&gt;=&lt;!--&gt; &lt;!--&gt;0,36 (&lt;em&gt;p&lt;/em&gt; &lt;!--&gt;=&lt;!--&gt; &lt;!--&gt;0,005) et r&lt;!--&gt; &lt;!--&gt;=&lt;!--&gt; &lt;!--&gt;0,35 (&lt;em&gt;p&lt;/em&gt; &lt;!--&gt;=&lt;!--&gt; &lt;!--&gt;0,006).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Au cours d’un SBT, les patients dyspnéiques présentent un pattern de perfusion cérébrale, mesurée par la fNIRS, différent des patients non dyspnéiques. Le manque de puissance ne permet probablement pas d’atteindre la significativité statistique.&lt;/div&gt;&lt;/div","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 224"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791408","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":"Implication des protéines polymorphiques épithéliales dans les réponses immunitaires post-transplantation pulmonaire","authors":"J. Milesi ,&nbsp;J. Di Cristofaro ,&nbsp;M. Reynaud-Gaubert ,&nbsp;P. Chanez ,&nbsp;B. Coiffard ,&nbsp;D. Gras","doi":"10.1016/j.rmr.2025.02.030","DOIUrl":"10.1016/j.rmr.2025.02.030","url":null,"abstract":"<div><h3>Introduction</h3><div>La transplantation pulmonaire (TxP) est une option thérapeutique pour les patients en insuffisance respiratoire terminale, bien que la survie soit limitée par des complications immunologiques, notamment les rejets aigus concernant 35 % des patients à 1 an post-TxP. Les cellules épithéliales bronchiques (HBEC) expriment des molécules polymorphiques pouvant être soit des allo-antigènes, soit induire ou réprimer des réactions immunitaires. Elles pourraient ainsi avoir un rôle central dans le devenir post-TxP.</div></div><div><h3>Méthodes</h3><div>Un modèle de culture cellulaire reproduisant l’épithélium bronchique en interface air/Liquide in vitro en condition standard et pro-inflammatoire (stimulation avec TNFa ou poly IC) a été utilisé. Nous avons réalisé une analyse transcriptomique par séquençage des ARN totaux (RNAseq) afin de déterminer les gènes codant pour des protéines polymorphiques transmembranaires (BEPM). L’analyse ontologique du panel de gènes identifiés a été faite à l’aide des bases de données GO et KEGG. L’influence des incompatibilités polymorphiques sur le devenir post-TxP a été évaluée en utilisant la cohorte LARA. Une sélection des gènes d’intérêt en TxP a été faite (ALCAM, EGFR, CD₁₄₆, CD₆₈, HLA-F, THBD et MICA) et leur expression protéique à la surface des HBEC a été montrée par cytométrie.</div></div><div><h3>Résultats</h3><div>L’analyse RNAseq a permis d’identifier 916 séquences codantes réparties en 282 gènes, hors système HLA. L’analyse ontologique a mis en évidence que les processus biologiques d’adhésion cellulaire et d’entrée intracellulaire étaient les plus représentés. Les BEPM sont également impliquées dans des voies de signalisation immunitaires, telles que JAK-STAT, ou encore la cytotoxicité des cellules NK (<span><span>Figure 1</span></span>). Au-delà du nombre d’incompatibilités polymorphiques, c’est leur nature qui semble influencer le devenir post-TxP. L’expression de des gènes tels que ALCAM, EGFR, CD₁₄₆, CD₆₈et HLA-F, déjà décrite dans les HBEC, a été confirmée à la surface des HBEC. Cependant, il s’agit de la première mise en évidence de l’expression de THBD et MICA à la surface des HBEC.</div></div><div><h3>Conclusion</h3><div>Nos résultats suggèrent que les HBEC, au-delà de leur rôle de barrière physique, participent activement aux réponses immunitaires post-TxP par l’expression de BEPM polymorphiques. Ces protéines pourraient servir de biomarqueurs pour identifier les patients à risque de rejet aigu compte tenu de leur variabilité inter-individuelle. Les études futures incluront l’évaluation de l’influence des immunosuppresseurs sur l’expression des BEPM et l’analyse des profils génétiques pour affiner la prédiction du rejet. À long terme, la détection d’anticorps dirigés contre ces BEPM pourrait constituer un test diagnostic ou une cible thérapeutique potentielle.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Pages 196-197"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791450","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 du remodelage épithélial dans l’asthme sévère par approche de séquençage sur cellule unique","authors":"E. Redman ,&nbsp;M. Fierville ,&nbsp;D. Gras ,&nbsp;K. Valette ,&nbsp;P. Porracciolo ,&nbsp;S. Leroy ,&nbsp;M. Couralet ,&nbsp;P. Chanez ,&nbsp;P. Barbry ,&nbsp;LE. Zaragosi","doi":"10.1016/j.rmr.2025.02.033","DOIUrl":"10.1016/j.rmr.2025.02.033","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Dans l’asthme, l’épithélium des voies respiratoires est l’objet d’une inflammation chronique conduisant à un remodelage qui se caractérise par une diminution des cellules multiciliées et une hyperplasie des cellules à mucus. Ce remodelage peut être induit par l’interleukine 13 (IL-13) dans l’asthme de type 2, mais les effets de cette cytokine sur des épithéliums de donneurs sains et d’asthmatiques sévères n’ont encore jamais été comparés. De plus, les événements cellulaires et moléculaires permettant la régénération de l’épithélium dans ce contexte restent inexplorés. Ainsi, l’objectif de cette étude était d’identifier les acteurs clés du remodelage pathologique de l’épithélium des voies respiratoires dans l’asthme sévère.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Méthodes&lt;/h3&gt;&lt;div&gt;L’étude a porté sur des épithéliums reconstitués in vitro, dans un modèle de culture à interface air-liquide, à partir de biopsies bronchiques issues de donneurs sains ou souffrant d’asthme sévère. Après 8 (J&lt;sub&gt;8&lt;/sub&gt;) ou 22&lt;!--&gt; &lt;!--&gt;jours (J&lt;sub&gt;22&lt;/sub&gt;) de traitement apical par IL-13, les épithéliums ont été analysés par imagerie confocale et séquençage d’ARN sur cellule unique. Une deuxième mesure a été réalisée deux semaines après retrait de l’IL-13 afin de mimer la résolution de l’inflammation locale. L’implication de deux gènes dans le remodelage épithélial a été plus particulièrement étudiée après leur invalidation par CRISPR-Cas9 et analyse par séquençage d’ARN sur cellule unique.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Résultats&lt;/h3&gt;&lt;div&gt;Plus de 260 000 cellules issues de 9 donneurs sains et 11 donneurs asthmatiques sévères ont été étudiées. Les épithéliums d’asthmatiques sévères ont présenté, à l’état de base, une hyperplasie des cellules basales et un défaut de différenciation cellulaire avec l’expression luminale des kératines &lt;em&gt;KRT5&lt;/em&gt;, &lt;em&gt;KRT6A&lt;/em&gt; et &lt;em&gt;KRT16&lt;/em&gt;. L’IL-13 a induit, dans les épithéliums d’asthmatiques sévères, un remodelage en deux temps avec initialement (J&lt;sub&gt;8&lt;/sub&gt;) une hyperplasie des cellules à mucus, suivie d’une hyperplasie des cellules basales à J&lt;sub&gt;22&lt;/sub&gt;. Deux semaines après le retrait de l’IL-13, les capacités de récupération entre les cellules saines et les cellules d’asthmatiques sévères sont apparues similaires. Des analyses de suivi par microscopie confocale et d’inférence de trajectoires cellulaires ont identifié une population de cellules hybrides exprimant à la fois des marqueurs de cellules multiciliées (&lt;em&gt;FOXJ&lt;/em&gt;&lt;sub&gt;&lt;em&gt;1&lt;/em&gt;&lt;/sub&gt;) et de cellules à mucus (&lt;em&gt;SPDEF&lt;/em&gt;), dont l’origine semble être les cellules multiciliées. Notre analyse transcriptomique a dressé une liste de gènes susceptibles de réguler le remodelage épithélial. L’effet de l’invalidation par CRISPR-Cas9 de deux de ces gènes, &lt;em&gt;EHF&lt;/em&gt; et &lt;em&gt;GATA3&lt;/em&gt;, a été évalué par séquençage d’ARN sur cellule unique.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Cette étude met en évidence des défauts de différenciation des cellules épithéliales d’","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 198"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791453","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":"Prior viral respiratory infections affect the immune response against a mouse-adapted strain of sars-cov-2 and modulate disease severity in mice","authors":"C. Gourzones,&nbsp;M. Hologne,&nbsp;M. Pathammavong,&nbsp;L. Gillet","doi":"10.1016/j.rmr.2025.02.059","DOIUrl":"10.1016/j.rmr.2025.02.059","url":null,"abstract":"<div><div>Successive pulmonary infections shape the lung's immune landscape, influencing future immune responses to other pathogens. This phenomenon has been particularly evident in the context of SARS-CoV-2 infections, where some patients experienced only mild symptoms, while others required intensive care or succumbed to the virus. While many studies have examined the impact of comorbidities, few have explored the role of patients’ infection histories. In this study, we aimed to investigate how prior exposure to different respiratory viruses affects the pathogenesis of SARS-CoV-2 using preclinical models. Specifically, C57BL/6 mice were either pre-infected or not with a mouse-adapted strain of influenza (PR8), mouse adenovirus 1 (MAV1), Murid Herpesvirus 4 (MuHV4), or the pneumonia virus of mice (PVM). One month later, the mice were infected with a mouse-adapted strain of SARS-CoV-2 (MA30) <span><span>[1]</span></span>. Our findings revealed that mice pre-infected with MuHV4, MAV1, and PVM exhibited varying levels of protection against MA30 infection and disease, whereas those pre-infected with PR8 were sicker and had a lower survival rate. Using an Olink® cytokine quantification assay on bronchoalveolar lavage fluid (BALF) collected 4 and 8 days post-MA30 infection, we observed significant differences in the levels and kinetics of BALF cytokines. The most severely affected mice showed increased concentrations of pro-inflammatory cytokines, while those protected exhibited an early cytokine signature associated with protection. Additionally, these observations were linked to variations in leukocyte infiltrates, particularly myeloid cells, in the lungs. In conclusion, our results underscore that a history of respiratory virus infections dramatically influences the outcome of subsequent SARS-CoV-2 infections.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 211"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791719","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":"Effects of perinatal exposure to nanoparticles on lung function","authors":"T. Bellil ,&nbsp;L. Plantade ,&nbsp;B. Costes ,&nbsp;R. Souktani ,&nbsp;J. Rose ,&nbsp;S. Bellusci ,&nbsp;A. Aissat ,&nbsp;S. Lanone ,&nbsp;Y. Watanabe","doi":"10.1016/j.rmr.2025.02.047","DOIUrl":"10.1016/j.rmr.2025.02.047","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Nanoparticles (NP) are materials with 3 dimensions between 1 and 100&lt;!--&gt; &lt;!--&gt;nm Due to their physico-chemical characteristics, they can be found in many daily products. In particular, Titanium dioxide (TiO&lt;sub&gt;2&lt;/sub&gt;) NP are widely used in industry in many applications owing to their large range of properties (ultraviolet absorption, antimicrobial effect, food brightening and whitening agent etc.). This raises questions about their potential effect on health, particularly in the perinatal period, when the developing organism is more vulnerable to environmental stressors. Indeed, in mice models, TiO&lt;sub&gt;2&lt;/sub&gt;NP administered to pregnant or lactating mice can reach the fetus, crossing the placental barrier via the bloodstream, or the offspring after translocation in the breastmilk. Our goal is to better understand the perinatal toxicity of TiO&lt;sub&gt;2&lt;/sub&gt;NP on lung development and function, by studying two distinct TiO&lt;sub&gt;2&lt;/sub&gt;NP with different sizes and crystalline phases.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Pregnant and/or lactating C57BL/6&lt;!--&gt; &lt;!--&gt;J mice were exposed to 10&lt;!--&gt; &lt;!--&gt;nm anatase (Ti10) and 21&lt;!--&gt; &lt;!--&gt;nm anatase/rutile (P25) NP by intra-tracheal instillation (100&lt;!--&gt; &lt;!--&gt;μg of NP) once a week, during the gestation and/or the lactation. The pulmonary phenotype of the offspring was analyzed on juvenile and adult mice weighed every week from D&lt;sub&gt;9&lt;/sub&gt;to D&lt;sub&gt;60&lt;/sub&gt;. The pulmonary function was measured by two techniques: whole-body plethysmography (VivoFlow®), a non-invasive technique on awake mice that measures respiratory times and the FlexiVent® system, an invasive technique on anesthetized mice that evaluates lung mechanical properties.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Perinatal exposure to P25 induced a decrease in body weight for both males and females from D&lt;sub&gt;16&lt;/sub&gt;until D&lt;sub&gt;60&lt;/sub&gt;. Ti10 exposure induced a decrease in body weight for males from D&lt;sub&gt;32&lt;/sub&gt;and a transient increase in females from D&lt;sub&gt;16&lt;/sub&gt;to D&lt;sub&gt;37&lt;/sub&gt;. In juvenile mice, perinatal exposure to P25 and Ti10 NP induced abnormalities in respiratory parameters with no change in lung mechanical properties. Indeed, P25 gestational exposure induced a decrease of tidal volume wheareas Ti10 exposure induced an increase of tidal volume. At the adult age, only P25 exposure provoked male specific modifications on the mechanical properties characterized by a decrease of inspiratory capacity and forced vital capacity.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;TiO&lt;sub&gt;2&lt;/sub&gt;NP maternal exposure had an impact on the offspring, while this impact is different for the 2 NP tested. Ti10 exposure induced transient changes on the body weight and on the respiratory parameters that do not last until the adult age. On the other hand, P25 exposure provoked a permanent decrease in body weight, induced transient abnormalities of the respiratory parameters in juvenile mice and lung mechanical defects at the adult age.","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 205"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791794","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":"Chronic ozone induces lung inflammation through NLRP6-dependent activation of pyroptosis pathways in pneumocytes","authors":"A. Gombault,&nbsp;S. Huot-Marchand,&nbsp;C. Véront,&nbsp;S. Carignon,&nbsp;VFJ. Quesniaux,&nbsp;B. Ryffel,&nbsp;P. Broz,&nbsp;N. Riteau,&nbsp;I. Couillin","doi":"10.1016/j.rmr.2025.02.035","DOIUrl":"10.1016/j.rmr.2025.02.035","url":null,"abstract":"<div><h3>Introduction</h3><div>Environmental air pollutants including ozone cause severe lung injury and aggravate respiratory diseases such as asthma and COPD. Ozone is a major air pollutant causing pulmonary inflammation evolving into lung emphysema and/or fibrosis in mice exposed to ozone but the mechanisms are not well understood. Innate immune sensors such as nucleotide-oligomerization domain-like receptors (NLRs) are able to form cytosolic complexes named inflammasomes that mediate inflammatory cytokines production and immunological cell death. Among NLRs, NLRP3 was shown to be involved in establishment of lung inflammation to ozone. However, the role of NLRP6, another NLR in involved in inflammasome scaffold, like NLRP6 in ozone-induced lung pathologies is unknown.</div></div><div><h3>Methods</h3><div>Using a 6 weeks model of chronic ozone exposure in mice, we explored the role of the innate receptor NLRP6 in the context of immunological cell death, in ozone exposure-associated pulmonary inflammation.</div></div><div><h3>Results</h3><div>We found that Nlrp6 deficiency dampens airway and lung inflammation with reduced neutrophils, eosinophils influx and production of associated chemokines/cytokines including Th2 response, remodeling factor production, collagen deposition and fibrosis in response to chronic ozone exposure. Interestingly, we observed increased NLRP6 expression in bronchial epithelial cells, pneumocytes and infiltrating macrophages in lung tissue and airway macrophages upon chronic ozone exposure. Mechanistically, we report that chronic ozone promotes NLRP6-mediated caspase-1- and caspase11-dependent gasdermin D activation in alveolar type 1 pneumocytes suggesting NLRP6 inflammasome drives lung inflammation. Moreover, gasdermin D deficiency leads to reduced pulmonary inflammation after chronic ozone exposure. Mice deficient for NLRP6 in alveolar epithelial cells display reduced inflammation with impaired caspase-1/11 and gasdermin D activation in lungs, which confirms NLRP6-driven inflammation in these cells. Finally, we found that caspase-3Casp3/8 and gasdermin E activation depends on NLRPlrp6.</div></div><div><h3>Conclusion</h3><div>In conclusion we provide the first evidence that NLRP6 is a key player in chronic ozone pulmonary inflammation associated with the induction of both gasdermin-D and gasdermin E-dependent pyroptosisimmunogenic cell death.</div></div>","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 199"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791871","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":"Rôle du récepteur GPRX dans la dysplasie bronchopulmonaire","authors":"D. Benfarhone ,&nbsp;CM. Pilard ,&nbsp;I. Gauthereau ,&nbsp;C. Bouchet ,&nbsp;P. Esteves ,&nbsp;E. Dumas-de-la-Roque ,&nbsp;V. Freund-Michel ,&nbsp;C. Guibert ,&nbsp;G. Cardouat","doi":"10.1016/j.rmr.2025.02.022","DOIUrl":"10.1016/j.rmr.2025.02.022","url":null,"abstract":"<div><h3>Introduction</h3><div>La dysplasie bronchopulmonaire (DBP) est une pathologie des nouveau-nés prématurés, qui se caractérise par une altération du développement pulmonaire distal notamment une hypoalvéolisation et un défaut d’angiogenèse. Le récepteur couplé aux protéines G d’adhésion GPRX pourrait être impliqué dans les altérations du développement vasculaire pulmonaire caractéristiques de la DBP. En effet, différentes études suggèrent que ce récepteur régule l’intégrité de l’endothélium vasculaire et l’angiogenèse. En revanche, son rôle dans le développement de la DBP est inconnu.</div></div><div><h3>Méthodes</h3><div>Dans un premier temps, nous avons travaillé sur un modèle de ratons atteints de DBP, induite par une exposition à l’hyperoxie (14<!--> <!-->jours, 90 % d’O₂). La compliance pulmonaire a été évaluée par pléthysmographie invasive. L’alvéolisation, la densité vasculaire et l’expression de GPRX ont été évaluées par immunohistochimie et western-blotting. Dans un second temps, l’expression de GPRX a été évaluée par immunohistochimie et western-blotting sur des poumons fœtaux. Enfin, dans un dernier temps, nous avons travaillé sur des cellules endothéliales fœtales cultivées en conditions de normoxie ou d’hyperoxie (48<!--> <!-->h, 60 % d’O₂), un modèle mimant la DBP in vitro. L’expression de GPRX a été évaluée par western-blotting. La fonctionnalité du récepteur, son rôle dans l’activation des voies pro-angiogéniques et la migration cellulaire ont été évalués par imagerie calcique, western-blotting et inserts de culture Transwell en réponse à son peptide activateur : le peptide GAPX (500<!--> <!-->μM).</div></div><div><h3>Résultats</h3><div>In et ex vivo, les ratons atteints de DBP présentent une diminution de la compliance pulmonaire, une hypoalvéolisation et une diminution de la densité vasculaire. De plus, le récepteur GPRX est exprimé au niveau de l’endothélium vasculaire et son expression est diminuée en condition pathologique. Ex vivo, GPRX est exprimé dans l’endothélium vasculaire pulmonaire fœtal et son expression augmente au cours du développement pulmonaire. In vitro, l’expression et la fonctionnalité de GPRX sont diminuées en condition d’hyperoxie. Enfin, la stimulation de GRPX avec le peptide GAPX permet d’activer les voies de signalisation pro-angiogéniques situées en aval du récepteur, ainsi que la migration cellulaire.</div></div><div><h3>Conclusion</h3><div>Cette étude a permis de mieux caractériser la localisation, l’expression et la fonctionnalité du récepteur GPRX en conditions contrôle ou pathologique (DBP). L’expression et la fonctionnalité du récepteur semblent diminuées en condition pathologique, ce qui pourrait alors contribuer au défaut d’angiogenèse caractéristique de la DBP.</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":"143791500","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":"Using dual energy CT Scans to analyse blood perfusion compensation following resection of cancerous lobes","authors":"M. Puig ,&nbsp;A. Gille ,&nbsp;S. Bommart ,&nbsp;A. Bourdin ,&nbsp;N. Molinari ,&nbsp;K. Hireche ,&nbsp;M. Morand","doi":"10.1016/j.rmr.2025.02.023","DOIUrl":"10.1016/j.rmr.2025.02.023","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Comparison of pulmonary perfusion before and after lung resection may provide a better understanding of compensation phenomena and, more importantly, additional clinical information for the inclusion of patients in these surgeries. To evaluate the pulmonary perfusion mechanisms in patients with lung diseases (COPD, nodule…), we used a novel approach using Dual energy CT scan (DECT). The aim is to produce a perfusion profile in surviving lobes, before and after surgery, allowing to quantize and localize potential changes in blood perfusion.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The CLIPPCAIR prospective study enrolls patients undergoing pulmonary resection due to non-small cell lung cancer, with the majority having pulmonary comorbidities such as COPD. 30 patients from this study were examinated. CLIPPCAIR focuses on patients scheduled for resection, excluding those with COPD stages 3 or 4. Patients performed a FEV1 (Forced Expiratory Volume in 1 second), and a FVC (Forced Vital Capacity) to assess their respiratory performances. The recording of these measurements provides elements to determine the COPD GOLD. For each patient, a DECT with an iodine injection (350&lt;!--&gt; &lt;!--&gt;mg/mL, Iomeron, Bracco Imaging) is achieved and reconstructed by GE Revolution (KvP switch between 80 and 140.200&lt;!--&gt; &lt;!--&gt;mA). Iodine concentration and lung parenchyma density maps were then generated. Iodine concentration is used as a biomarker for blood concentration. Lung blood vessels are segmented using Machine Learning. Then, the blood concentration is measured in voxels located in alveolar and small vessel areas, &lt;em&gt;i.e.&lt;/em&gt; non large vessels areas. The “large” vessels are those segmented by the ML algorithm, meaning a diameter larger than the voxel resolution, giving a cross-sectional area of 2.6 mm&lt;sup&gt;2&lt;/sup&gt;. This perfusion metric is plotted against the distance to the nearest blood vessel of cross-sectional area greater than 5 mm&lt;sup&gt;2&lt;/sup&gt; (BV5) (figure 1). This is done before and after surgery in all remaining lobes. It is then possible to compare the perfusion profile of the lobes before and after the resection.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Patients from the CLIPPCAIR cohort lost on average 21 % (standard deviation: 5.2) of their volume, while only showing a slight decrease of their DLCO and FEV1 performances, respectively 7.2 (6.7)% and 5.9 (5.5)%. While these metrics are not a complete picture of respiratory performances, their moderate decrease highlights the existence of compensation mechanisms in the remaining lobes. Indeed, we observe a statistically significant increase of 5.1 (1.6)% in iodine concentration -a proxy for blood perfusion- in the remaining lobes post surgery (p-value&lt;!--&gt; &lt;!--&gt;&lt;&lt;!--&gt; &lt;!--&gt;0.05).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Patients undergoing lung resection show much better DLCO and FEV1 than expected. We show that there is an increase in blood perfusion in the remaining lung parenchym","PeriodicalId":21548,"journal":{"name":"Revue des maladies respiratoires","volume":"42 4","pages":"Page 193"},"PeriodicalIF":0.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791501","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}