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Physiopathologie et épidémiologie des maladies respiratoires

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Université Paris Diderot

UFR de rattachement >

UFR Médecine

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UMRS

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INSERM

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-01455776] Severe Pulmonary Fibrosis as the First Manifestation of Interferonopathy (TMEM173 Mutation)

Date: 3 Feb 2017 - 18:20

Desc: We report three cases of pulmonary disease suggesting fibrosis in two familial and one sporadic case. Pulmonary symptoms were associated with various clinical features of systemic inflammation and vasculitis involving the skin, and appeared at different ages. A strong interferon signature was found in all three cases. Disease was not responsive to corticosteroids, and lung transplantation was considered for all three subjects at an early age. One of them underwent double-lung transplantation, but she immediately experienced a primary graft dysfunction and died soon after. Recognized causes of familial interstitial lung disease were all excluded. All three subjects had a mutation in the previously described autoinflammatory disease called SAVI (stimulator of interferon genes [STING]-associated vasculopathy with onset in infancy). These cases emphasize the need to consider this possibility in children and young adults with lung fibrosis after common causes have been ruled out.

[hal-02458897] NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Høyeraal-Hreidarsson syndrome

Date: 29 Ene 2020 - 08:51

Desc: Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR, and several cofactors including the H/ACA box ribonucleoproteins (RNP) Dyskerin, NOP10, GAR1, NAF1, and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure (BMF), and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal-Hreidarsson syndrome (HH), the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Lastly, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.

[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-02120788] Study protocol: exploring the efficacy of cyclophosphamide added to corticosteroids for treating acute exacerbation of idiopathic pulmonary fibrosis; a randomized double-blind, placebo-controlled, multi-center phase III trial (EXAFIP)

Date: 6 Mayo 2019 - 12:06

Desc: BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, with a median survival of 2-3 years and variable natural history, characterized by gradual and progressive deterioration. Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication, associated with poor survival and a mortality > 50%. To date, no treatment has proven effective in AE-IPF, with cyclophosphamide (CYC) the only therapy suggested to be effective on survival, primarily based on retrospective series. Considering the high fatality rates of AE-IPF, evaluating the efficacy of immunosuppressive agents in a randomized controlled trial proves crucial, as the results could significantly impact treatment and prognosis of AE-IPF. METHODS: The EXAFIP study is a French national multicenter double-blind placebo-controlled randomized trial. Its primary objective is to evaluate the efficacy of CYC compared to placebo on early survival in patients treated with corticosteroids. We hypothesize that adding CYC to high-dose corticosteroids would reduce 3-month mortality in AE-IPF patients. The primary outcome is all-cause mortality rate at Month 3; secondary objectives are to evaluate the efficacy of CYC compared to placebo on overall survival at Months 6 and 12, respiratory disease-specific mortality, respiratory morbidity, and chest high-resolution computed tomography features, and to determine prognostic factors in AE-IPF and compare the safety of the two treatment arms during 6 months' follow-up. DISCUSSION: There is an urgent unmet clinical need for effective AE-IPF treatment. The EXAFIP study is the first large Phase III placebo-controlled randomized trial evaluating the efficacy and safety of CYC added to corticosteroids in treating AE-IPF. The results of this study could significantly impact treatment strategy and prognosis of AE-IPF.

[hal-02191891] MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

Date: 23 Jul 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.).