Physiopathologie et épidémiologie des maladies respiratoires
Présentation
Les maladies respiratoires (asthme, broncho-pneumopathies chroniques obstructives -BPCO-, emphysème et fibrose pulmonaire), sont une cause majeure de morbidité et de mortalité en France et dans le monde. Ces maladies évoluent toutes, dans leurs formes sévères, vers l'insuffisance respiratoire, et l'arsenal thérapeutique actuellement disponible est largement insatisfaisant. L'insuffisance respiratoire liée à ces maladies résulterait d'un processus de remodelage tissulaire centré sur la bronche et/ou l'alvéole, dont les déterminants cellulaires et moléculaires seraient peu ou pas sensibles aux thérapeutiques conventionnelles. Ce remodelage est la conséquence d'une réparation tissulaire incomplète, ou anarchique en réponse à des agressions aigues ou chroniques. Le projet de l'Unité 700 est centré sur la recherche des facteurs environnementaux, personnels et biologiques responsables du remodelage bronchique et/ou alvéolaire conduisant à une insuffisance respiratoire sévère et irréversible dans les maladies bronchiques (asthme et BPCO), et alvéolaires (emphysème et fibroses pulmonaires). Les objectifs sont :
- d'identifier les facteurs de susceptibilité personnels et environnementaux impliqués dans la constitution d'une insuffisance respiratoire ;
- de définir les mécanismes qui contrôlent son initiation et sa progression ;
- de rechercher des marqueurs cellulaires et moléculaires caractérisant plus précisément ce remodelage et sa relation avec les anomalies de la fonction respiratoire ;
- de tester des nouvelles stratégies thérapeutiques préventives ou curatives visant à inhiber le remodelage pulmonaire et les anomalies fonctionnelles respiratoires qui l'accompagnent.
Equipes de recherche
Equipe 1 : Epidemiologie des allergies respiratoires et des bpco : etiologie, histoire naturelle et prise en charge
Equipe 2 : Mecanismes cellulaires et moleculaires du remodelage bronchique dans l'asthme severe et la bpco
Equipe 3 : Inflammation et fibrogenese pulmonaires.
Equipe 4 : Immunité Innée et défenses pulmonaires anti-infectieuses - voir aussi l'UFR Sciences du Vivant
[hal-02125198] Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis
Date: 10 mai 2019 - 12:19
Desc: Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Morbidity is mainly due to early airway infection. We hypothesized that S. aureus clearance during the first hours of infection was impaired in CF human Airway Surface Liquid (ASL) because of a lowered pH. The ASL pH of human bronchial epithelial cell lines and primary respiratory cells from healthy controls (WT) and patients with CF was measured with a pH microelectrode. The antimicrobial capacity of airway cells was studied after S. aureus apical infection by counting surviving bacteria. ASL was significantly more acidic in CF than in WT respiratory cells. This was consistent with a defect in bicarbonate secretion involving CFTR and SLC26A4 (pendrin) and a persistent proton secretion by ATP12A. ASL demonstrated a defect in S. aureus clearance which was improved by pH normalization. Pendrin inhibition in WT airways recapitulated the CF airway defect and increased S. aureus proliferation. ATP12A inhibition by ouabain decreased bacterial proliferation. Antimicrobial peptides LL-37 and hBD1 demonstrated a pH-dependent activity. Normalizing ASL pH might improve innate airway defense in newborns with CF during onset of S. aureus infection. Pendrin activation and ATP12A inhibition could represent novel therapeutic strategies to normalize pH in CF airways.
[hal-02191891] MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease
Date: 23 juil 2019 - 17:57
Desc: BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7x10(-17)). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7x10(-35)) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3x10(-49)). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4x10(-5)), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5x10(-6)). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Societe Francaise de Rhumatologie and others.).
[hal-02466291] Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)
Date: 4 fév 2020 - 13:44
Desc: [...]
[hal-02063146] The Minasarc study: A case-control study measuring mineral exposome in sarcoidosis
Date: 10 Mar 2019 - 21:23
Desc: </br>Introduction: it has been suggested that sarcoidosis could be associated with exposure to inorganic particles (Newman LS Curr Opin All Clin Immunol 2012; 12:145-50, Vincent M et al Am J Ind Med 2015; 58:S31-8).</br></br> Objectives: in order to test this hypothesis the Minasarc study was designed to evaluate the mineral exposome by a specific questionnaire (SQ) and a mineralogical analysis performed on BALs by optical and electron microscopy in patients and healthy volunteers (HV). We present here the results obtained by the SQ which can be considered as a tool for global assessment of the “whole life” exposure to inorganic particles in occupational and environmental contexts.</br></br> Methods: The study was performed on 20 patients with sarcoidosis and 20 HV. Every HV was matched to a patient by sex, age and smoking habit. The SQ was calibrated with a representative sample of the French population (n=825) in the ELIPSSilice survey (ANR-10-Eqpx-19-01) and the result was expressed as a “dust score”. Scores were compared by a Wilcoxon signed-rank test.</br></br> Results: The “dust score” was found significantly higher in patients with sarcoidosis than in HV (p=0,036; Wilcoxon signed-rank test). Moreover we found a significant overrepresentation of people exposed to building activities among the cases. However this remains to be assessed on a larger series.</br></br> Conclusion: The SQ demonstrated a significantly higher level of exposure to inorganic dusts in patients with sarcoidosis compared to HV. Such preliminary results encourage 1) to study the association between sarcoidosis and inorganic dust exposure and 2) to submit routinely this exposure questionnaire to every patient with a granulomatous disease.
[hal-02438688] Contribution of mutations in genes of the surfactant system to idiopathic interstitial pneumonia (IIP)
Date: 14 jan 2020 - 12:21
Desc: <strong>Background:</strong> Children and adult IIP are heterogeneous and severe disorders. Whereas telomerase gene mutations are preferentially found in adult IIP, surfactant gene mutations are mainly reported in children. The study aimed to assess the contribution of surfactant gene mutations in a large pediatric and adult IIP cohort. <strong>Methods:</strong> Patients with IIP were prospectively included in the French network of rare lung diseases centres. All SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3, NKX2-1 exons and flanking intronic sequences were analyzed. The identified variations were assessed in silico. Only pathogenic or likely pathogenic mutations were taken into account. <strong>Results:</strong> 477 patients were included in 4 years (190 children; 287 adults). The mean age at diagnosis was 40 years (0-100) and the sex ratio was 1.47 M/F. The IIP was familial in 22% of cases. A personal or family history of lung cancer was found in 44 (15%) adults. A mutation was identified in a surfactant gene in 45 (9.4%) patients, including 22 (11.6%) children and 23 (8%) adults. Mutations were identified in all the studied genes in children and in adults, except for a SFTPB mutation identified in an adult. A mutation was found in 25% of the 44 adults with a history of IIP and lung cancer (SFTPA = 10, SFTPC = 1). <strong>Discussion and conclusion:</strong> Surfactant gene mutations encounter for an important part of IIP, thereby strongly suggesting that these molecular analyses should be part of the diagnosis process of IIP, regardless of the patient’s age, especially in case of family history of IIP and/or lung cancer. Such systematic approach should help guiding the most relevant genetic tests to be performed according to the disease phenotype. This is an ERS International Congress abstract. No full-text version is available.
Autres contacts
Université Paris Diderot - Paris 7
U.F.R. de Médecine Paris Diderot - Paris 7 (site Xavier Bichat)
16, rue Henri Huchard - B.P. 416
75870 PARIS CEDEX 18