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
[inserm-02078851] Pseudomonas aeruginosa LasB Subverts Alveolar Macrophage Activity by Interfering With Bacterial Killing Through Downregulation of Innate Immune Defense, Reactive Oxygen Species Generation, and Complement Activation
Date: 25 Mar 2019 - 16:28
Desc: Pseudomonas aeruginosa (P.a) is a pathogen causing significant morbidity and mortality, in particular, in hospital patients undergoing ventilation and in patients with cystic fibrosis. Among the virulence factors secreted or injected into host cells, the physiopathological relevance of type II secretions system (T2SS) is less studied. Although there is extensive literature on the destructive role of LasB in vitro on secreted innate immune components and on some stromal cell receptors, studies on its direct action on myeloid cells are scant. Using a variety of methods, including the use of bacterial mutants, gene-targeted mice, and proteomics technology, we show here, using non-opsonic conditions (thus mimicking resting and naïve conditions in the alveolar space), that LasB, an important component of the P.a T2SS is highly virulent in vivo, and can subvert alveolar macrophage (AM) activity and bacterial killing, in vitro and in vivo by downregulating important secreted innate immune molecules (complement factors, cytokines, etc.) and receptors (IFNAR, Csf1r, etc.). In particular, we show that LasB downregulates the production of C3 and factor B complement molecules, as well as the activation of reactive oxygen species production by AM. In addition, we showed that purified LasB impaired significantly the ability of AM to clear an unrelated bacterium, namely Streptococcus pneumoniae. These data provide a new mechanism of action for LasB, potentially partly explaining the early onset of P.a, alone, or with other bacteria, within the alveolar lumen in susceptible individuals, such as ventilated, chronic obstructive pulmonary disease and cystic fibrosis patients.
[hal-01459399] Updated guidelines (2015) for management and monitoring of adult and adolescent asthmatic patients (from 12 years and older) of the Société de Pneumologie de Langue Francaise (SPLF)
Date: 7 Feb 2017 - 12:11
Desc: [...]
[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 Feb 2020 - 13:44
Desc: [...]
[hal-01791591] Rituximab for auto-immune alveolar proteinosis, a real life cohort study
Date: 28 May 2018 - 17:14
Desc: Background: Whole lung lavage is the current standard therapy for pulmonary alveolar proteinosis (PAP) that is characterized by the alveolar accumulation of surfactant. Rituximab showed promising results in auto-immune PAP (aPAP) related to anti-GM-CSF antibody.Methods: We aimed to assess efficacy of rituximab in aPAP in real life and all patients with aPAP in France that received rituximab were retrospectively analyzed.Results: Thirteen patients were included. No patients showed improvement 6 months after treatment, but, 4 patients (30%) presented a significant decrease of alveolar-arterial difference in oxygen after 1 year. One patient received lung transplantation and one patient was lost of follow-up within one year. Although a spontaneous improvement cannot be excluded in these 4 patients, improvement was more frequent in patients naive to prior specific therapy and with higher level of anti-GM-CSF antibodies evaluated by ELISA. No serious adverse event was evidenced. Conclusions: These data do not support rituximab as a second line therapy for patients with refractory aPAP.
[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