Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
Antisynthetase syndrome is an inflammatory myopathy frequently associated with pulmonary manifestations, especially interstitial lung diseases, and uncommonly pulmonary hypertension. In the context of a suggestive clinical and radiological picture, positive anti-RNA synthetase antibodies confirm the diagnosis. Anti-Jo1, anti-PL7, and anti-PL12 antibodies are the more commonly encountered. The presence of a number of extra-thoracic manifestations in association with pulmonary disease may suggest the diagnosis. These include: myalgia or muscular deficit, Raynaud's phenomenon, polyarthritis, fever, mechanics hands. Serum creatine kinase levels are usually increased. Electromyogram, muscular magnetic resonance imaging or muscle pathology are not mandatory to make the diagnosis. There is a high variability in symptoms and severity, between patients but also during the course of the disease in the same patient. The presence of an interstitial lung disease is a major prognostic factor and an indication for more intensive treatment, principally with systemic corticosteroids with or without immunosuppressive drugs. Improving respiratory physicians’ knowledge of this disease, which is often revealed by its pulmonary manifestations, should help diagnosis, therapeutic management, and possibly prognosis.
Le syndrome des antisynthétases correspond à une myopathie inflammatoire fréquemment associée à une atteinte pulmonaire, surtout parenchymateuse (pneumopathie infiltrante diffuse) et plus rarement vasculaire (hypertension pulmonaire). Devant un tableau clinique et radiologique évocateur, la présence d’anticorps anti-ARNt synthétases signe le diagnostic. Les plus fréquents de ces auto-anticorps sont les anti-Jo1, les anti-PL7 et les anti-PL12. De nombreuses manifestations cliniques extrathoraciques associées à l’atteinte pulmonaire peuvent orienter le diagnostic : myalgies ou déficit musculaire, phénomène de Raynaud, polyarthrite, fièvre et « mains de mécaniciens ». Une augmentation des créatine-phospho-kinases est quasi constante. Le recours à l’électromyogramme, à l’imagerie musculaire par résonance magnétique ou à l’histologie n’est pas systématique. Néanmoins, il existe une grande variabilité des symptômes et de leur sévérité d’un patient à l’autre ou au long de l’évolution de la maladie. L’atteinte pulmonaire est un facteur pronostic majeur et incite à traiter de manière intensive les patients, principalement par corticothérapie systémique, voire d’emblée par association corticoïdes et immunosuppresseurs. Mieux connaître cette pathologie qui est souvent de révélation pneumologique permettrait d’améliorer le diagnostic et la prise en charge thérapeutique, voire même le pronostic.
ISSN: 0761-8425

hal-01085369
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01085369
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01085369/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01085369/file/Manifestations%20pulmonaires%20du%20syndrome%20des%20antisynth%C3%A9tases_accepted.pdf
DOI : 10.1016/j.rmr.2014.07.013

Éditeur(s) : HAL CCSD Thieme Publishing
Résumé : International audience
To determine the effect of triathlete performance level on the cardiorespiratory responses elicited by the cycle-run succession, eight regionally and nationally-ranked (Competitive) and five internationally-ranked (Elite) male triathletes underwent four successive laboratory trials: 1) an incremental treadmill test, 2) an incremental cycle test, 3) 30 min of cycling followed by 20 min of running (C-R), and 4) a 20-min control run (R) at the same speed as the run in C-R. Before and 10 min after the third and fourth trials the triathletes underwent lung function testing: spirometry and diffusing capacity testing for carbon monoxide (DL(CO)). During the C-R trial blood samples were drawn to measure venous lactate concentration. During all trials ventilatory data were collected every minute using an automated breath-by-breath system. The results showed that 1) the oxygen uptake (VO2) of post-cycling running versus running alone was similar for both groups; 2) the ventilatory responses (VE, VE/VO2, VE/VC02 and f) of C-R running versus R were significantly higher (P < 0.005) for the Competitive group; and 3) a significant decrease (P< 0.05) in DL(CO) was also noted after the C-R trial in the Competitive group but not in the Elite group. We concluded that 1) the ventilatory responses during a run subsequent to cycling may be related to the triathlete performance level, and 2) the C-R trial induced specific alterations in pulmonary function that may be associated with respiratory muscle alteration and exercise-induced hypoxemia in the Competitive triathletes.
ISSN: 0172-4622

hal-00720719
https://hal.univ-antilles.fr/hal-00720719

Éditeur(s) : HAL CCSD
Résumé : International audience
INTRODUCTION: Alpha-1 antitrypsin, secreted by the liver, inhibits neutrophil elastase. Its deficiency favours the development of emphysema. Restoring a "protective" serum level in deficient patients should make it possible to inhibit the development of emphysema. STATE OF THE ART: Human plasma-derived alpha-1 antitrypsin is a blood-derived drug sold in France under the name Alfalastin(®). The recommended posology is an I.V. administration of 60mg/kg once a week. Human plasma-derived alpha-1 antitrypsin restores anti-elastase protection in the lower lung and prevents experimental emphysema induced by the elastasis of human neutrophils in hamster. The low number of patients with alpha-1 antitrypsin deficiency is one of the difficulties to perform sufficiently powerful randomised studies. However, randomised studies have reported the efficacy of human plasma-derived alpha-1 antitrypsin perfusions on mortality, FEV1 decline and the frequency of exacerbations. Randomised control trials have demonstrated the efficacy of human plasma-derived alpha-1 antitrypsin perfusions on the loss of lung density assessed by CT scan. CONCLUSION: Augmentation therapy is simple in its conception and implementation, but it is expensive. However, there are currently no other solutions.
Revue Des Maladies Respiratoires

hal-01146841
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146841
DOI : 10.1016/j.rmr.2014.10.001
PUBMED : 25908241

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: The aryl hydrocarbon receptor (AhR) has gradually emerged as a regulator of inflammation in the lung and other tissues. AhR may interact with the p65-subunit of the nuclear factor (NF)-κB transcription factors, but reported outcomes of AhR/NF-κB-interactions are conflicting. Some studies suggest that AhR possess pro-inflammatory activities while others suggest that AhR may be anti-inflammatory. The present study explored the impact of AhR and its binding partner AhR nuclear translocator (Arnt) on p65-activation and two differentially regulated chemokines, CXCL8 (IL-8) and CCL5 (RANTES), in human bronchial epithelial cells (BEAS-2B). RESULTS: Cells were exposed to CXCL8- and CCL5-inducing chemicals, 1-nitropyrene (1-NP) and 1-aminopyrene (1-AP) respectively, or the synthetic double-stranded RNA analogue, polyinosinic-polycytidylic acid (Poly I:C) which induced both chemokines. Only CXCL8, and not CCL5, appeared to be p65-dependent. Yet, constitutively active unligated AhR suppressed both CXCL8 and CCL5, as shown by siRNA knock-down and the AhR antagonist α-naphthoflavone. Moreover, AhR suppressed activation of p65 by TNF-α and Poly I:C as assessed by luciferase-assay and p65-phosphorylation at serine 536, without affecting basal p65-activity. In contrast, Arnt suppressed only CXCL8, but did not prevent the p65-activation directly. However, Arnt suppressed expression of the NF-κB-subunit RelB which is under transcriptional regulation by p65. Furthermore, AhR-ligands alone at high concentrations induced a moderate CXCL8-response, without affecting CCL5, but suppressed both CXCL8 and CCL5-responses by Poly I:C. CONCLUSION: AhR and Arnt may differentially and independently regulate chemokine-responses induced by both inhaled pollutants and pulmonary infections. Constitutively active, unligated AhR suppressed the activation of p65, while Arnt may possibly interfere with the action of activated p65. Moreover, ligand-activated AhR suppressed CXCL8 and CCL5 responses by other agents, but AhR ligands alone induced CXCL8 responses when given at sufficiently high concentrations, thus underscoring the duality of AhR in regulation of inflammation. We propose that AhR-signaling may be a weak activator of p65-signaling that suppresses p65-activity induced by strong activators of NF-κB, but that its anti-inflammatory properties also are due to interference with additional pathways.
ISSN: 1478-811X

inserm-01085082
http://www.hal.inserm.fr/inserm-01085082
http://www.hal.inserm.fr/inserm-01085082/document
http://www.hal.inserm.fr/inserm-01085082/file/s12964-014-0048-8.pdf
PUBMED : 25201625

Éditeur(s) : HAL CCSD
Résumé : International audience
BACKGROUND: The aryl hydrocarbon receptor (AhR) has gradually emerged as a regulator of inflammation in the lung and other tissues. AhR may interact with the p65-subunit of the nuclear factor (NF)-κB transcription factors, but reported outcomes of AhR/NF-κB-interactions are conflicting. Some studies suggest that AhR possess pro-inflammatory activities while others suggest that AhR may be anti-inflammatory. The present study explored the impact of AhR and its binding partner AhR nuclear translocator (Arnt) on p65-activation and two differentially regulated chemokines, CXCL8 (IL-8) and CCL5 (RANTES), in human bronchial epithelial cells (BEAS-2B). RESULTS: Cells were exposed to CXCL8- and CCL5-inducing chemicals, 1-nitropyrene (1-NP) and 1-aminopyrene (1-AP) respectively, or the synthetic double-stranded RNA analogue, polyinosinic-polycytidylic acid (Poly I:C) which induced both chemokines. Only CXCL8, and not CCL5, appeared to be p65-dependent. Yet, constitutively active unligated AhR suppressed both CXCL8 and CCL5, as shown by siRNA knock-down and the AhR antagonist α-naphthoflavone. Moreover, AhR suppressed activation of p65 by TNF-α and Poly I:C as assessed by luciferase-assay and p65-phosphorylation at serine 536, without affecting basal p65-activity. In contrast, Arnt suppressed only CXCL8, but did not prevent the p65-activation directly. However, Arnt suppressed expression of the NF-κB-subunit RelB which is under transcriptional regulation by p65. Furthermore, AhR-ligands alone at high concentrations induced a moderate CXCL8-response, without affecting CCL5, but suppressed both CXCL8 and CCL5-responses by Poly I:C. CONCLUSION: AhR and Arnt may differentially and independently regulate chemokine-responses induced by both inhaled pollutants and pulmonary infections. Constitutively active, unligated AhR suppressed the activation of p65, while Arnt may possibly interfere with the action of activated p65. Moreover, ligand-activated AhR suppressed CXCL8 and CCL5 responses by other agents, but AhR ligands alone induced CXCL8 responses when given at sufficiently high concentrations, thus underscoring the duality of AhR in regulation of inflammation. We propose that AhR-signaling may be a weak activator of p65-signaling that suppresses p65-activity induced by strong activators of NF-κB, but that its anti-inflammatory properties also are due to interference with additional pathways.
Cell communication and signaling: CCS

hal-01063555
https://hal.archives-ouvertes.fr/hal-01063555
DOI : 10.1186/s12964-014-0048-8

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The use of recombinant antigens has been shown to improve both the sensitivity and the standardization of the serological diagnosis of Farmer's lung disease (FLD). The aim of this study was to complete the panel of recombinant antigens available for FLD serodiagnosis with antigens of Lichtheimia corymbifera, known to be involved in FLD. L. corymbifera proteins were thus separated by 2D electrophoresis and subjected to western blotting with sera from 7 patients with FLD and 9 healthy exposed controls (HEC). FLD-associated immunoreactive proteins were identified by mass spectrometry based on a protein database specifically created for this study and subsequently produced as recombinant antigens. The ability of recombinant antigens to discriminate patients with FLD from controls was assessed by ELISA performed with sera from FLD patients (n = 41) and controls (n = 43) recruited from five university hospital pneumology departments of France and Switzerland. Forty-one FLD-associated immunoreactive proteins from L. corymbifera were identified. Six of them were produced as recombinant antigens. With a sensitivity and specificity of 81.4 and 77.3% respectively, dihydrolipoyl dehydrogenase was the most effective antigen for discriminating FLD patients from HEC. ELISA performed with the putative proteasome subunit alpha type as an antigen was especially specific (88.6%) and could thus be used for FLD confirmation. The production of recombinant antigens from L. corymbifera represents an additional step towards the development of a standardized ELISA kit for FLD diagnosis. © 2016 Rognon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ISSN: 1932-6203

hal-01367148
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01367148
DOI : 10.1371/journal.pone.0160888

Éditeur(s) : HAL CCSD National Institute of Environmental Health Sciences
Résumé : International audience
BACKGROUND: Women of reproductive age can be exposed to endocrine-disrupting chemicals (EDCs) at work, and exposure to EDCs in pregnancy may affect fetal growth. OBJECTIVES: We assessed whether maternal occupational exposure to EDCs during pregnancy as classified by application of a job exposure matrix was associated with birth weight, term low birth weight (LBW), length of gestation, and preterm delivery. METHODS: Using individual participant data from 133,957 mother-child pairs in 13 European cohorts spanning births from 1994 through 2011, we linked maternal job titles with exposure to 10 EDC groups as assessed through a job exposure matrix. For each group, we combined the two levels of exposure categories (possible and probable) and compared birth outcomes with the unexposed group (exposure unlikely). We performed meta-analyses of cohort-specific estimates. RESULTS: Eleven percent of pregnant women were classified as exposed to EDCs at work during pregnancy, based on job title. Classification of exposure to one or more EDC group was associated with an increased risk of term LBW [odds ratio (OR) = 1.25; 95% CI: 1.04, 1.49], as were most specific EDC groups; this association was consistent across cohorts. Further, the risk increased with increasing number of EDC groups (OR = 2.11; 95% CI: 1.10, 4.06 for exposure to four or more EDC groups). There were few associations (p < 0.05) with the other outcomes; women holding job titles classified as exposed to bisphenol A or brominated flame retardants were at higher risk for longer length of gestation. CONCLUSION: Results from our large population-based birth cohort design indicate that employment during pregnancy in occupations classified as possibly or probably exposed to EDCs was associated with an increased risk of term LBW.
ISSN: 0091-6765

hal-01405823
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01405823
DOI : 10.1289/EHP208
PUBMED : 27152464

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
PURPOSE: Dairy farming is a risk factor for the development of chronic obstructive pulmonary disease (COPD). We assessed the prevalence of farming-induced COPD (FI-COPD) using a new screening device, and we analyzed symptoms and occupational risk factors. METHODS: We performed on-site screening study of bronchial obstruction using an electronic mini-spirometer (EMS) on an entire population of dairy farmers (n = 147) from two villages in Brittany, France. Suspected bronchial obstruction (FEV1/FEV6 <0.8) was confirmed with standardized lung function tests (FEV1/FVC ≤0.7). We assessed past medical histories, respiratory symptoms, and occupational tasks of subjects with bronchial obstruction; asthmatics were defined as atopic and/or reversible; smoking-induced COPD patients were defined as non-reversible, non-atopic with smoking histories (≥5 PY); and FI-COPD patients were defined as non-reversible, non-atopic, and non-smokers. RESULTS: Using the EMS, 30.6% (n = 45) of dairy farmers were suspected of bronchial obstruction and underwent standardized spirometry. The FEV1/FEV6 ratio and FEV1/FVC ratio were in good agreement (r² = 0.66, P < 0.0001). The prevalence of confirmed bronchial obstruction was 9.5% (n = 14), which included 4 asthmatics, 3 smoking-induced COPD subjects, and 7 FI-COPD subjects. All the COPD patients were GOLD Stage II, and none were aware of their respiratory disease. Foddering duration was significantly higher in FI-COPD subjects compared with non-obstructive subjects, with 44 versus 17 min/day, respectively. CONCLUSIONS: The EMS was a convenient mean of screening for bronchial obstruction, especially in on-site settings, and allowed us to diagnose FI-COPD in a non-spontaneously complaining dairy farmer population. Foddering was considered a significant risk factor.
ISSN: 0340-0131

hal-00872929
https://hal.archives-ouvertes.fr/hal-00872929
DOI : 10.1007/s00420-011-0708-6
PUBMED : 21986906

Éditeur(s) : HAL CCSD
Résumé : International audience
INTRODUCTION: Auto-immune pulmonary alveolar proteinosis is a rare disorder characterized by the accumulation of surfactant proteins in the alveoli. CASE REPORT: We report a case of a 41-year-old smoker, presenting initially with acute respiratory failure. Whole lung lavages were effective initially but only for a few weeks. GM-CSF subcutaneous injections were not effective, and then plasmapheresis were tried. CONCLUSION: This is the fifth report of the use of this treatment in auto-immune pulmonary alveolar proteinosis. Plasmapheresis was not effective in our patient.
Revue Des Maladies Respiratoires

hal-01526427
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526427
DOI : 10.1016/j.rmr.2016.06.002
PUBMED : 27743827

Éditeur(s) : HAL CCSD Wiley-VCH Verlag
Résumé : International audience
Saccharopolyspora rectivirgula is the principal cause of farmer's lung disease (FLD). Serodiagnosis is based on immunoprecipitation techniques or enzyme immunoassays with homemade crude antigens and is not standardized. We aimed to produce specific recombinant antigens for the development of a standardized ELISA. We recruited 41 patients and 43 healthy exposed controls from five university hospital pneumology departments in France and Switzerland. S. rectivirgula proteins were extracted, separated by 2D electrophoresis, and subjected to Western blotting, with sera from FLD patients or controls. FLD-specific proteins were identified by MS and were produced as recombinant antigens. The diagnostic performance of ELISA tests using the recombinant antigens was assessed with all the sera from FLD patients and controls. We identified 25 FLD-specific proteins, some of which play important roles in transport, nutrition, or virulence. We produced 17 of these proteins as recombinant antigens and assessed their suitability for inclusion in the ELISA test. A combination of three of these proteins (SR1FA, SR17, and SR22) proved remarkably effective at discriminating between patients and controls, with a sensitivity of 83% and a specificity of 77%. The recombinant antigens produced in this study constitute a major step toward the improvement of diagnostic performance and the standardization of FLD serodiagnosis.
ISSN: 1862-8346

hal-01115880
https://hal.archives-ouvertes.fr/hal-01115880
DOI : 10.1002/prca.201400024
PUBMED : 25264606

Éditeur(s) : HAL CCSD
Résumé : National audience
Nocardiosis is an infectious disease with wide range of clinical features, which can eventually lead to death. The agent responsible belongs to the genus Nocardia that includes about fifty different species. Nocardiosis occurs mainly in immunocompromised hosts. We report here three cases of disseminated nocardiosis misdiagnosed initially as cerebral metastatic lung cancer. These patients, including two immunocompetent hosts, presented with both pulmonary and cerebral lesions. In all three patients, the diagnosis was based on magnetic resonance imaging with diffusion sequence, apparent diffusion coefficient reconstruction and neurosurgical cerebral biopsies. Treatment with an appropriate antibiotic regimen was prolonged for several months. Progress was favorable with full resolution of the neurological symptoms and the radiological abnormalities. These three cases emphasize the diagnostic challenge of nocardiosis, especially in disseminated disease.
Revue Des Maladies Respiratoires

hal-01659440
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01659440
DOI : 10.1016/j.rmr.2017.08.002
PUBMED : 28918971

Éditeur(s) : HAL CCSD American College of Sports Medicine (ACSM)
Résumé : International audience
PURPOSE AND METHODS: To determine the effects of cycling on a subsequent triathlon run, nine male triathletes underwent four successive laboratory trials: 1) an incremental treadmill test, 2) an incremental cycle test, 3) 30 min of cycling followed by 5 km of running (C-R), and 4) 30 min of running followed by 5 km of running (R-R). Before and 10 min after the third and fourth trials, the triathletes underwent pulmonary function testing including spirometry and diffusing capacity testing for carbon monoxide (DL(CO)). During the C-R and R-R trials, arterialized blood samples were obtained to measure arterial oxygen pressure (PaO2). During all trials, ventilatory data were collected every minute using an automated breath-by-breath system. RESULTS: The results showed that 1) the oxygen uptake (VO2) observed during subsequent running was similar for the C-R and R-R trials; 2) the ventilatory response (VE) during the first 8 min of subsequent running was significantly greater in the C-R than in R-R trial (P < 0.05); 3) only the C-R trial induced a significant increase (P < 0.05) in residual volume (RV), functional residual capacity (FRC), and the ratio of residual volume to total lung capacity (RV/TLC); and 4) although a significant decrease (P < 0.05) in DL(CO) was noted after C-R, no difference between the two exercise trials was found for the maximal drop in PaO2. CONCLUSIONS: We concluded that 1) the C-R trial induced specific alterations in pulmonary function that may be associated with respiratory muscle fatigue and/or exercise-induced hypoxemia, and 2) the greater VE observed during the first minute of running after cycling was due to the specificity of cycling. This reinforces the necessity for triathletes to practice multi-trial training to stimulate the physiological responses experienced during the swim-cycle and the cycle-run transitions.
ISSN: 0195-9131

hal-00720412
https://hal.univ-antilles.fr/hal-00720412
https://hal.univ-antilles.fr/hal-00720412/document
https://hal.univ-antilles.fr/hal-00720412/file/Article.pdf

Éditeur(s) : HAL CCSD
Résumé : International audience
Background. In a French large population-based case-control study we investigated the dose-response relationship between lung cancer and occupational exposure to diesel motor exhaust (DME), taking into account asbestos exposure. Methods. Exposure to DME was assessed by questionnaire. Asbestos was taken into account through a global indicator of exposure to occupational carcinogens or by a specific JEM. Results. We found a crude dose response relationship with most of the indicators of DME exposure, including with the cumulative exposure index. All results were affected by adjustment for asbestos exposure. The dose response relationships between DME and lung cancer were observed among subjects never exposed to asbestos. Conclusions. Exposure to DME and to asbestos is frequently found among the same subjects, which may explain why dose-response relationships in previous studies that adjusted for asbestos exposure were inconsistent.
Journal of Cancer Epidemiology

hal-01205352
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01205352
DOI : 10.1155/2015/879302
PUBMED : 26425123

Éditeur(s) : HAL CCSD Lippincott, Williams & Wilkins
Résumé : International audience
Objectives: Lung cancer risk associated with occupational cleaning activities has been investigated in the population-based case-control study ICARE. Methods: Occupational history was collected by standardized interviews. Jobs were first defined according to the International Standard Classification of Occupations (ISCO) codes and then categorized according to activity sectors. Adjusted odds ratios (ORs) were estimated by unconditional logistic regression, separately for women (619 cases and 760 controls) and men (2265 and 2780). Results: Thirty percent of women and 2.3% of men controls ever held a cleaner or care job. Women who worked as housemaids longer than 7 years showed an OR of 1.76 [95% confidence interval (95% CI) 1.09 to 2.87] with respect to controls. Women employed in domestic service sector for a long time had an OR of 2.06 (95% CI 1.15 to 3.66). Conclusion: We confirmed and redefined the association of lung cancer with occupational cleaning, which concerns a considerable proportion of women workers.
ISSN: 1076-2752

hal-01359564
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359564
DOI : 10.1097/JOM.0000000000000722
PUBMED : 27206119

Éditeur(s) : HAL CCSD
Résumé : Macrophages (MΦ), well-known to play a key role in immune response, also respond to environmental toxic chemicals such as diesel exhaust particles (DEP), an air pollutant recently classified as carcinogenic to humans. MΦ are heterogeneous and plastic cells which activate according to their microenvironment into either an M1 subtype (so called classically activated or pro-inflammatory) under IFNγ and LPS stimulation or an M2 subtype (so called alternatively activated or anti-inflammatory) under IL-4 and/or IL-13 stimulation. However, potential effects of DEPs on M1/M2 MΦ polarization remain poorly documented. First, we characterized the expression marker of in vitro M-CSF-differentiated MΦ from human monocytes and activated into the M1 or M2 subtypes. Our main results show that M-CSF-generated MΦ considered as anti-inflammatory are actually able to switch to an M1 phenotype after IFNγ/LPS stimulation. Furthermore, the markers identified in this study were used to assess the impact of organic extracts of DEP (DEPe) on MΦ polarization and more generally on their physiology. DEPe alter some M1 and M2 markers expressed by polarized MΦ, without causing the overall inhibition of the M1 and M2 polarization process or the switch to a different phenotype. This phenotype alteration is associated with a decrease in the LPS-dependent inflammatory response in M1 MΦ and the chemotactic capacities in M2 MΦ. DEPe decrease the secretion of some cytokines and chemokines such as IL-6, IL-12p40 and CCL18 via AhR and/or Nrf2 activation. At the same time, we show that M1 and M2 MΦ in response to DEPe are able to secrete a sufficient level of a pro-fibrotic growth factor, the platelet derived growth factor B (PDGF-B) via AhR activation, leading to stimulation of lung fibroblast proliferation. Finally, these works show that DEPe have immunotoxic properties with regards to the physiology of human in vitro polarized MΦ. This immunotoxicity may then contribute to the deleterious effects of these urban environmental contaminants on human health.
Les macrophages (MΦ), des cellules clefs de la réponse immunitaire peuvent répondre à des contaminants environnementaux comme les particules diesel (DEP), des polluants atmosphériques récemment classés cancérigènes pour l'Homme. Les MΦ sont des cellules hétérogènes et plastiques qui s'activent en fonction de leur microenvironnement soit en MΦ M1 (dits classiquement activés ou pro-inflammatoires) sous l'effet de l'INFγ et du LPS soit en MΦ M2 (dits alternativement activés ou réparateurs) sous l'effet de l'IL-4 et/ou de l'IL-13. Les effets des DEP sur la polarisation M1/M2 des MΦ restent peu documentés. Nous avons dans un premier temps caractérisé l'expression des marqueurs des MΦ différenciés in vitro en présence de M-CSF à partir de monocytes humains et polarisés en sous-type M1 ou M2. Nos principaux résultats montrent que les MΦ différenciés au M-CSF considérés comme des MΦ anti-inflammatoires, sont en réalité capables de s'activer vers un phénotype M1 après une stimulation au LPS/IFNγ. De plus, les marqueurs mis en évidence au cours de ce travail ont permis d'évaluer l'impact d'extraits organiques de DEP (DEPe) sur la polarisation des MΦ et plus généralement sur leur physiologie. Les DEPe altèrent l'expression de certains marqueurs M1 et M2 des MΦ, sans toutefois provoquer d'inhibition globale des processus de polarisation M1 et M2 ou de transition d'un phénotype vers un autre. Cette altération du phénotype est associée à une diminution de la réponse inflammatoire LPS-dépendante dans les MΦ M1 et des capacités chimiotactiques des MΦ M2. Les DEPe diminuent la sécrétion de certaines cytokines et chimiokines comme l'IL-6, l'IL-12p40 et le CCL18 via l'activation d'AhR et/ou de Nrf2. Parallèlement, nous montrons que les MΦ M1 et M2 exposés aux DEPe sécrètent le platelet deried growth factor B (PDGF-B), un facteur de croissance profibrosant, via l'activation d'AhR en quantité suffisante pour stimuler la prolifération de fibroblastes pulmonaires. Au total, ces travaux démontrent que les DEP possèdent des propriétés immunotoxiques vis-à-vis de la physiologie des macrophages humains polarisés in vitro. Cette immunotoxicité pourrait participer aux effets délétères de ces contaminants environnementaux urbains sur la santé humaine.
https://tel.archives-ouvertes.fr/tel-01188679

NNT : 2015REN1S011
tel-01188679
https://tel.archives-ouvertes.fr/tel-01188679
https://tel.archives-ouvertes.fr/tel-01188679/document
https://tel.archives-ouvertes.fr/tel-01188679/file/JAGUIN_Marie.pdf

Éditeur(s) : HAL CCSD
Résumé : International audience
Objective: To estimate the social cost of respiratory cancers attributable to occupational risk factors in France in 2010. Methods: We estimated the number of cases ofrespiratory cancers attributable to each identified occupational risk factor according to the attributable fractions method. We also estimated direct (costs of hospital stays, drugs, outpatient care) and indirect costs (production losses) related to morbidity (absenteeism and presenteeism) and mortality (years of lost production). Production losses for paid work and unpaid domestic activities were taken into account. Results: The social cost of respiratory cancers (lung, larynx, sinonasal, pleural mesothelioma) attributable to exposure to asbestos, chromium, diesel engine exhaust, polycyclic aromatic hydrocarbons, painting occupations (unidentified carcinogen), crystalline silica, wood and leather dust in France in 2010 was estimated to be between 960 and 1,866 million. The cost of lung cancer represents between 804 and 1,617 million. The three risk factors with the greatest impact are asbestos ((sic)530 to 890 million), diesel engine exhaust ((sic)227 to 394 million), and crystalline silica ( 116 to 268 million). Conclusion: These results provide a conservative estimate of the public health and economic burden of respiratory cancers attributable to occupational risk factors from a societal perspective.
ISSN: 0995-3914

hal-01659246
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01659246
DOI : 10.3917/spub.174.0509
PUBMED : 29034666

Éditeur(s) : HAL CCSD
Résumé : International audience
Over the past few years, genetics has significantly improved the understanding of interstitial lung diseases (ILD)...
European Respiratory Journal

hal-01534151
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01534151
DOI : 10.1183/13993003.00407-2017
PUBMED : 28495697

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : National audience
INTRODUCTION:The AIRBAg study screens for bronchial obstruction in dairy farmers. We present the preliminary results after one year.METHODS:A prospective screening study based on questionnaires and electronic mini-spirometry (Néo-6(®)) that includes a representative sample of dairy farmers from the departments of Morbihan and Île-et-Vilaine in Brittany. The dairy farmers had an occupational medicine appointment and, if they demonstrated at least one marker of possible bronchial obstruction (chronic cough, chronic bronchitis, dyspnoea, wheezing, FEV1/FEV6<0.8), they were referred to a pulmonologist. The data we present here were extracted from the occupational medicine appointments because the pulmonologists' appointments are still running.RESULTS:Among the 277 dairy farmers included, 125 (45%) demonstrated "possible bronchial obstruction". The total score of the CAT questionnaire was higher in these farmers (9.1±6.2 versus 5.8±4.0; P<0.0001). In multivariate analysis markers of "possible bronchial obstruction" were eczema, manual foddering and duration of mechanical straw litter spreading.CONCLUSION:Occupational medicine appointments identified markers of "possible bronchial obstruction". We will have the complete results from AIRBAg study in 2015.
ISSN: 0761-8425

hal-01117944
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01117944
DOI : 10.1016/j.rmr.2014.03.014
PUBMED : 25847201

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The underlying cause of morbidity in cystic fibrosis (CF) is the decline in lung function, which results in part from chronic inflammation. Inflammation and infection occur early in infancy in CF and the role of innate immune defense in CF has been highlighted in the last years. Once thought simply to be consumers of bacteria, macrophages have emerged as highly sensitive immune cells that are located at the balance point between inflammation and resolution of this inflammation in CF pathophysiology. In order to assess the potential role of macrophage in CF, we review the evidence that: (1) CF macrophage has a dysregulated inflammatory phenotype; (2) CF macrophage presents altered phagocytosis capacity and bacterial killing; and (3) lipid disorders in CF macrophage affect its function. These alterations of macrophage weaken innate defense of CF patients and may be involved in CF disease progression and lung damage.
ISSN: 1569-1993

hal-01560280
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280/file/Chouly-The%20impact%20of%20impaired%20macrophage%20functions.pdf
DOI : 10.1016/j.jcf.2016.10.011

Éditeur(s) : HAL CCSD Paris, Masson et Cie
Résumé : National audience
Decreased frequency of pulmonary exacerbations, mainly related to immunomodulatory effects of macrolide antibiotics, has been demonstrated in bronchiectasis and chronic obstructive pulmonary diseases (COPD). Due to its tolerance, azithromycin is the antibiotic of choice for maintenance therapy at the dose of 250 mg per day or 500 mg × 3 per week (for body weight >55 kg). Maintenance therapy with macrolide could be proposed in selected patients with bronchiectasis or COPD with more than 3 acute exacerbations in the previous year or decreased lung function despite compliance with optimum treatment. The risk of sudden cardiac death with azithromycin is rare and controversial. It should be avoided in patients with a high baseline risk of cardiovascular disease, QT>450 msec, pulse rate>100 bpm and potential drug interactions, particularly those known to cause QT prolongation. It is recommended to search for hearing deficit (audiometry) and sputum culture positive for mycobacteria. Patients must also be aware that it can rapidly lead to macrolide resistance in commensal or pathogenic flora. Follow-up evaluation every 3 month can be proposed with medical history (hearing deficit) and electrocardiography. After one year, the treatment should be stopped in the absence of reduction in the frequency of exacerbations.
Points essentielsLes macrolides administrés au long cours permettent, grâce en partie à leurs propriétés anti-inflammatoires, de diminuer la fréquence des exacerbations dans la DDB et la BPCO.Du fait de sa tolérance, l’azithromycine est le macrolide de choix, pouvant être utilisé à la dose de 250 mg/j ou 500 mg 3 fois par semaine chez les patients de plus de 55 kg.Un traitement par macrolides au long cours pourrait être proposé à des patients atteints de DDB ou de BPCO ayant eu plus de 3 exacerbations l’année précédente ou ayant une dégradation de leur fonction respiratoire malgré un traitement de fond bien conduit.Du fait d’un risque rare et controversé de mort subite d’origine cardiaque, il ne doit pas être proposé en cas de pathologie cardiovasculaire évoluée, d’intervalle QT > 450 ms, de traitement pouvant allonger l’intervalle QT, de tachycardie > 100/min.Il est recommandé de s’assurer de l’absence de troubles auditifs (audiogramme) et de mycobactérie atypique dans les cultures des expectorations. Les patients doivent aussi être informés du risque d’apparition de résistance aux macrolides de la flore commensale et pathogène.Une surveillance clinique, avec en particulier la recherche de troubles auditifs et électrocardiographique, peut être proposée tous les 3 mois. L’absence de diminution de la fréquence des exacerbations, lors du bilan annuel, justifie l’arrêt du traitement.
ISSN: 0032-7867

hal-01073027
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01073027
DOI : 10.1016/j.lpm.2013.08.006
PUBMED : 24631048