Background: Physiological studies have shown that many preterm infants and infants with chronic lung disease may suffer chronic hypoxaemia, which possibly leads to poor growth and development. Anecdotal reports indicate that there is a drive to increase the oxygen saturation target range to a higher level in these infants due primarily to perceived benefits derived from clinical experience and from uncontrolled observational studies of babies discharged on home oxygen. Objective The BOOST (Benefits Of Oxygen Saturation Targeting) trial is the first randomised trial to assess the long-term benefits and harms of two different oxygen saturation target ranges. Methods: BOOST was a multicentre, double blinded, randomised controlled trial that enrolled 358 infants born at less than 30 weeks� gestation who remained oxygen-dependent at 32 weeks postmenstrual age. They were randomly assigned to target either a functional oxygen saturation range of 91-94% (standard or control group) or 95-98% (higher or treatment group). The primary outcomes were growth and neurodevelopmental measures at 12 months corrected age. Secondary outcomes included length of hospital stay, retinopathy of prematurity, health service utilisation, parental stress, and infant temperament. Results: Prognostic baseline characteristics did not differ between the two groups. Mean birth weight and gestational age of enrolled infants was 917g and 26.5 weeks respectively. The rate of antenatal corticosteroid use was 83%.

Background: Physiological studies have shown that many preterm infants and infants with chronic lung disease may suffer chronic hypoxaemia, which possibly leads to poor growth and development. Anecdotal reports indicate that there is a drive to increase the oxygen saturation target range to a higher level in these infants due primarily to perceived benefits derived from clinical experience and from uncontrolled observational studies of babies discharged on home oxygen. Objective The BOOST (Benefits Of Oxygen Saturation Targeting) trial is the first randomised trial to assess the long-term benefits and harms of two different oxygen saturation target ranges. Methods: BOOST was a multicentre, double blinded, randomised controlled trial that enrolled 358 infants born at less than 30 weeks� gestation who remained oxygen-dependent at 32 weeks postmenstrual age. They were randomly assigned to target either a functional oxygen saturation range of 91-94% (standard or control group) or 95-98% (higher or treatment group). The primary outcomes were growth and neurodevelopmental measures at 12 months corrected age. Secondary outcomes included length of hospital stay, retinopathy of prematurity, health service utilisation, parental stress, and infant temperament. Results: Prognostic baseline characteristics did not differ between the two groups. Mean birth weight and gestational age of enrolled infants was 917g and 26.5 weeks respectively. The rate of antenatal corticosteroid use was 83%.

Chronic obstructive lung disease is among the leading causes of adult hospital admissions and readmissions in the United States. Preventing acute exacerbations is the primary approach in therapy. Combinations of smoking cessation, pulmonary rehabilitation, vaccinations and inhaled and oral medications may all reduce the overall risk of acute exacerbations. When prevention is unsuccessful, treatment of exacerbations often does not require hospitalization but can be safely executed in the outpatient setting. In the patient who does not require mechanical ventilation or who manifests respiratory acidosis, oxygen supplementation, frequent short-acting inhaled bronchodilators, oral corticosteroids and often antibiotics can abort the decompensation and sometimes return the patient to his or her pre-attack baseline lung function. Several models exist for delivering this care in the ambulatory setting. Follow-up care after an exacerbation has resolved is important, though there are few hard data suggesting which approach is best in this setting.

No description available.

<p>The focus of this thesis was the role of fibrocytes in chronic lung disease. These bone marrow derived cells have been identified in the lung and the circulation in patient samples and animal models of lung injury. However, the precise mechanistic role of the fibrocyte is still to be elucidated.</p> <p>Live assessment of lung changes in animal models of chronic lung disease allows for real time observation of changes, and gives a readout which can be translated to humans who undergo similar tests. In this thesis, we adapted an existing model of lung injury, and delivered a discrete treatment to a single lung lobe while monitoring its successful delivery.</p> <p>I also developed a robust system to examine the relationship between fibrocyte response, and cytokine expression previously identified in chronic lung disease. We found a connection between cytokine expression and fibrocyte mobilisation. Our model showed that fibrocyte mobilisation in the presence of existing lung injury does not improve and rather can worsen existing lung injury. This was a significant finding as it confirms the role of the fibrocyte as a participator or conductor in fibrogenesis and it suggests that this cell may play a role in the development of chronic lung diseases.</p> <p>Finally, we contributed to the ongoing characterisation of the fibrocyte as a prospective biomarker. We confirmed the cell’s identity by characterising it by its known markers and biological characteristics. We also identified the presence of this cell in chronic lung disease and linked its presence to disease progression.</p> / Doctor of Philosophy (Medical Science)

Cigarette smoke contributes to 90% of lung cancer cases and 80% of COPD cases. These concerns loom large as lung cancer represents 13% of all cancer deaths and estimates report by 2020 COPD will be the third leading cause of death in the world. The master regulator of the ER stress response, IRE-1, in the context of cigarette smoke exposure lacks study. Interestingly, its downstream pathways are activated. In fact, the 2014 Surgeon General’s report on the health consequences of smoking highlighted the endoplasmic reticulum (ER) stress response as a potential mechanism leading to the development of lung cancer and Chronic Obstructive Pulmonary Disorder (COPD). Following acute cigarette smoke exposure, mouse lung homogenates exhibited increased levels of XBP-1 along with downstream mediators of IRE-1 activation— GRP-78 and CHOP. Specifically observing macrophages, an important immune cell and source of acute inflammation, cigarette smoke induced activation of IRE-1/XBP-1 pathway through splicing of XBP-1 mRNA. However, upon assaying for pro-inflammatory cytokines we were unable to determine that cigarette smoke directly caused inflammation in vitro. Furthermore, cigarette smoke inhibited the activation of M2 macrophages, an anti-inflammatory and tissue healing subset seen through CCL18 inhibition. A majority of M2 and M1 macrophage markers were decreased from IRE-1/XBP-1 inhibition. This suggests a different phenotype than classical M1 or M2 polarization being induced by cigarette smoke. In addition, it suggests the IRE-1/XBP-1 pathway having a robust role in controlling gene expression and balance of cellular proteomics. / Thesis / Master of Science (MSc) / Cigarette smoke exposure damages the lungs and over time places the user at risk for increased infections, progressive decreases in lung function and cancer. A specific cell of the immune system and found in the lungs, macrophages or “Big Eater” cells, responds first by picking up debris and responding to harmful foreign substances by releasing proteins signaling the immune system to become activated. Within all animal cells, an organelle called the Endoplasmic Reticulum (ER) manufactures a third of proteins produced allowing the cell to adapt to foreign substances, including cigarette smoke. Cigarette smoke could cause the ER, a plastic organelle, to change in size and function at a heightened level due to activation of a sensing protein integrated in the ER, Inositol Requiring Enzyme-1 (IRE-1). Both activation of the ER and cigarette smoke causes macrophages to behave as “tissue-healing” or M2 subsets that release factors promoting reconstruction of the lungs; alternatively, M1 macrophages fight diseases and promote further inflammation. Using genetic analysis of macrophages exposed to cigarette smoke in culture dishes and analyzing the proteins secreted, we determined cigarette smoke inhibits M1 macrophages and the “tissue-healing” subset, while increasing adhesion molecule expression. Overall, cigarette smoke affected the polarization of M1 and M2 phenotype, analyzed through proteins and genes expression. We observed an increase in sXBP-1, indicative of IRE-1/XBP-1 pathway activation, from cigarette smoke extract exposure in macrophages. However, the use of IRE-1 inhibitors increased ER stress markers while affecting M1 and M2 markers. This suggests ER compensation from the use of inhibiting one arm of the ER stress response.

Introduction. L’Enquête Littoral Souffle Air Biologie Environnement (ELISABET) a pour objectif général l’étude de la santé respiratoire et cardiovasculaire dans les communautés urbaines de Lille (CUDL) et Dunkerque (CUD). Les objectifs spécifiques de cette thèse sont d’étudier : (i) la prévalence et le sous-diagnostic des troubles ventilatoires obstructifs (TVO), (ii) l’évolution de la prévalence des principaux facteurs de risque cardiovasculaire (FDRCV) dans la CUDL entre 1986 et 2013, (iii) les interactions entre deux biomarqueurs de l’asthme (fraction exhalée du monoxyde d’azote (FENO) et taux d’éosinophiles sanguin (S-eos)) et le statut tabagique, (iv) le rôle de médiateur de l’inflammation chronique de bas-grade dans la relation entre diabète et baisse de la fonction pulmonaire, et (v) l’impact à court terme de la pollution atmosphérique sur la fonction respiratoire.Méthodes. Les 3276 participants (âgés de 40 à 65 ans) à l’enquête transversale en ELISABET ont été sélectionnés à partir de listes électorales par échantillonnage aléatoire et inclus entre janvier 2011 et novembre 2013. Un questionnaire détaillé, des explorations fonctionnelles respiratoires et un prélèvement sanguin ont été effectués. (i) Les TVO ont été définis par un rapport du volume expiratoire maximal à la première seconde (VEMS) sur la capacité vitale forcée (CVF) inférieur à 0.70 ou à la limite inférieure de la normale calculée à partir des dernières équations de référence disponibles. (ii) La prévalence des principaux FDRCV a été estimée à partir d’échantillons représentatifs de la population de la CUDL issus des enquêtes MONICA1986-88, MONICA1995-96, MONALISA2005-07 et ELISABET2011-13. (iii) L’asthme allergique a été défini comme un asthme (auto-déclaration, et sifflements dans la poitrine dans les 12 derniers mois ou prise de traitement) avec terrain atopique. (iv) Le diabète était défini par la prise d’un traitement antidiabétique ou une glycémie à jeun ≥ 1.26 g/L ou des valeurs d’hémoglobine A1c ≥ 6.5%. L’inflammation chronique a été mesurée par la Protéine C réactive ultra-sensible (CRPus). Une analyse de médiation a été conduite sur un échantillon de sujets sans pathologie respiratoire ou athérosclérotique. (v) Les valeurs des particules inférieures à 10 µm (PM10) et du dioxyde d'azote (NO2) ont été fournies par les stations de mesures ATMO des CUDL et CUD.Principaux résultats. (i) La prévalence des TVO s’étendait de 9.5% à 16% (dépendant du centre et de la définition utilisée) ; le taux de sous-diagnostic était élevé (environ 75 %). (ii) La prévalence des principaux FDRCV diminuait régulièrement sur une période de 25 ans, à l'exception de l'usage du tabac chez les femmes, du diabète chez les hommes (tous deux stables) et de la surcharge pondérale chez les hommes (augmentée). (iii) Une interaction positive entre le statut tabagique et l'asthme allergique a été observée dans les modèles expliquant le FENO (p = 0,003) et les S-eos (p = 0,001). Ainsi, les participants souffrant d'asthme allergique avaient (comparés à ceux n’en souffrant pas) des valeurs plus élevées de FENO (+ 63,4 %, IC95% = [39; 92]) et de S-eos (+ 63,2 % [38,2; 92,7]) chez les non-fumeurs, mais pas chez les fumeurs actuels. (iv) Le diabète était associé à une diminution des pourcentages prédits du VEMS (-3.5% [-5.8; -1.3]) et de la CVF (-3.6% [-5.9; -1.3]). La force de ces associations diminuait (-3.1% [-5.4; -0.9] pour les deux) après ajustement sur la CRPus. Ainsi, la part médiée de la CRPus valait 12% [2.4; 37] et 13% [3.7; 39.4] pour le VEMS et la CVF, respectivement. (v) Les mesures de PM10 et NO2 semblaient associées à une diminution du débit expiratoire maximal à 25 % de la CVF (résultat préliminaire).Conclusion. Les données de l’enquête ELISABET ont permis l’étude de la prévalence des TVO et des principaux FDRCV au sein de notre population d’étude. Elles ont également permis d’obtenir des résultats originaux à partir d’études cliniques et physiopathologiques. / Introduction. The general goal of the ELISABET (Enquête Littoral Souffle Air Biologie Environnement) survey is to study the respiratory and cardiovascular health in two urban areas in northern France (Lille and Dunkirk). The specific objectives of this thesis are to study: (i) the prevalence and underdiagnosis of airway obstruction (AO), (ii) long-term time trends in the prevalence of cardiovascular risk factors between 1986 and 2013 in the Lille urban area, (iii) the relationships between both the fractional exhaled nitric oxide (FENO) and the blood eosinophil count (B-eos) on one hand and asthma and atopy on the other, according to smoking status, (iv) whether low-grade systemic inflammation (as measured by the level of high sensitivity-C-reactive protein, hs-CRP) mediated the relationship between diabetes and lung function, and (v) the short-term impact of atmospheric pollution on lung function.Methods. The 3276 participants (aged from 40 to 64) in the 2011-2013 ELISABET cross-sectional survey were selected from electoral rolls by random sampling, and recruited between January 2011 and November 2013. A detailed questionnaire, lung function tests, and a blood sample collection were performed. (i) AO was defined by a forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC) ratio below 0.70 or below the lower limit of normal calculated by the most recent reference equations of the Global Lung Initiative. (ii) The prevalence of the main cardiovascular risk factors was estimated from representative samples inhabitants of Lille urban area from MONICA1986-88, MONICA1995-96, MONALISA2005-07 and ELISABET2011-13 surveys. (iii) Allergic asthma was defined as asthma (a self-report of physician-diagnosed asthma, and wheezing in the previous 12 months or the use of asthma medications) with atopy. (iv) Diabetes mellitus was defined as ongoing diabetes treatment or a fasting blood glucose level ≥1.26 g/L or a hemoglobin A1c value ≥6.5%. A mediation analysis was performed to assess and quantify the hs-CRP level as a mediator of the relationship between diabetes and lung function from a sample of participants without self-reported pulmonary and atherosclerotic disease. (v) Measurements of particles less than 10 mm in diameter (PM10) and nitrogen dioxide (NO2) were provided by measuring stations ATMO in the two urban areas.Main results. (i) The prevalence of AO in northern France ranged from 9.5 to 16.0%, depending on the centre and definition used; the underdiagnosis rate was high (around 75%). (ii) A steady decline in the prevalence of cardiovascular risk factors over a 25-year period was observed, with the exception of tobacco use in women, prevalence of diabetes in men (both of which remained stable) and prevalence of overweight in men (which increased). (iii) A positive interaction between smoking status and allergic asthma was observed in multivariate models explaining FENO (p=0.003) and B-eos (p=0.001). Thus, compared to those without allergic asthma, participants with allergic asthma had higher FENO values (+63.4%, 95%CI=[39; 92]) and higher B-eos (+63.2% [38.2; 92.7]) in never and former smokers, but not in current smokers. (iv) Diabetes was associated with FEV1 (-3.5% [-5.8; -1.3]) and FVC (-3.6% [-5.9; -1.3]). Strength of both latter associations fell to -3.1% [-5.4; -0.9] after adjustment for hs-CRP. Hence, the proportion of the effect that is mediated by hs-CRP was 12% [2.4; 37] and 13% [3.7; 39.4] for FEV1 and FVC, respectively. (v) Measurements of PM10 and NO2 seemed to be associated with lower values of the expiratory flow at 25% of the FVC (preliminary result).Conclusion. Data from the ELISABET survey have allowed the study of the prevalence of AO and the main cardiovascular risk factors in our population. They also allowed obtaining original results from clinical and pathophysiological studies.

No description available.

Une croissance intra-utérine insuffisante représente, avec la prématurité et les malfor-mations congénitales, une des principales causes de morbidité et de mortalité néonatales. Ces pathologies sont liées entre elles, les nouveau-nés prématurés étant souvent atteints de RCIU (RCIU). Les études épidémiologiques récentes ont montré que le RCIU était associé à une augmentation de la morbidité respiratoire dès la période néonatale, avec, en particulier, une augmentation du risque de dysplasie broncho-pulmonaire (DBP), principale séquelle respira-toire de la prématurité. La DBP est caractérisée par des anomalies du développement alvéo-laire et vasculaire, considérées comme les conséquences d’agressions multiples sur un poumon immature. La physiopathologie exacte reste encore largement méconnue. Nous nous sommes intéressés dans ce travail au lien entre RCIU et DBP avec un abord expérimental et clinique. Alors que les études épidémiologiques sont relativement concordantes sur le lien entre RCIU et DBP, les études expérimentales, montrent des résultats divers tant sur le développement pulmonaire qu’au niveau moléculaire. Nous avons donc voulu identifier, dans un premier temps, un modèle de RCIU reproduisant les anomalies du développement alvéolaire observées chez l’Homme en utilisant trois modèles précédemment validés chez le rat : un modèle de res-triction protidique per-gestationnelle , un modèle de ligature unilatérale de l’artère utérine, un modèle d’injection d’un inhibiteur chimique de la NO synthase, le L NAME. Seule la restric-tion protidique anténatale permet de reproduire à long terme des lésions de l’alvéolisation proches de celles observées dans la DBP. En revanche, dans ce modèle, les modifications des principaux gènes identifiés précédemment dans les anomalies le développement alvéolaire ne sont pas observées, que ce soit avant, pendant ou après l’alvéolisation. Ce résultat nous a ame-né à entreprendre une étude multigénique qui a permis d’identifier plusieurs voies modifiées pendant l’alvéolisation dans ce modèle. Parmi celles-ci, les gènes impliqués dans la contractili-té et l’adhésion cellulaire, l’immunité ou la voie des « Peroxisome Proliferator-Activated Re-ceptor ». Dans la partie clinique de cette étude, nous avons évalué le risque de DBP chez les extrêmes prématurés atteints de RCIU dont les mères présentaient des signes de pathologie vasculaire de la grossesse (prééclampsie). Cette étude rétrospective unicentrique sur 184 en-fants a permis de comparer des enfants atteints de RCIU à des enfants eutrophes pris en charge de manière homogène. Le RCIU d’origine vasculaire multiplie le risque de DBP par 6. Un marqueur précoce de l’évolution vers une DBP est un taux de plaquettes bas à la naissance, évoquant le rôle d’un taux élevé de facteurs anti-angiogéniques circulants. Une étude est en cours pour corréler les facteurs anti-angiogéniques circulants présents chez les mères pré-éclamptiques au devenir respiratoire, en particulier à l’évolution vers une DBP, de leurs nou-veau-nés d’âge gestationnel inférieur à 30 semaines d’aménorrhée. En conclusion, nous avons montré expérimentalement que seule la restriction protidique anténatale chez le rat reproduisait les troubles de l’alvéolisation comparables à ceux observés dans la DBP. De nouvelles voies moléculaires potentiellement impliquées dans les anomalies de l’alvéolisation ont été mises en évidence. Par ailleurs, le rôle de facteurs anti-angiogéniques d’origine maternelle comme fac-teurs de développement d’une DBP est en cours d’évaluation. / Insufficient intrauterine growth is with prematurity and congenital malformations, a major cause of neonatal morbidity and mortality. These conditions are interrelated, the preterm infants often suffered of intrauterine growth restriction (IUGR). Recent epidemiological stud-ies showed that IUGR was associated with increased respiratory morbidity as soon as the ne-onatal period, with an increased risk of bronchopulmonary dysplasia (BPD), the main respira-tory sequelae of prematurity. BPD is characterized by impaired alveolar and vascular devel-opment and is the consequence of multiple insults on an immature lung. The exact pathophysi-ology is still largely unknown. We study in this work the relationship between IUGR and DBP with an experimental and clinical approach. While epidemiological studies are relatively concordant on the relationship between IUGR and BPD, experimental studies showed various results in lung development and molecular process. We wanted to identify, at first, a model of IUGR reproducing impaired alveolar development observed in humans using three previously validated models in rats: a model of per-gestational protein restriction, a model of unilateral ligation uterine artery, an injection pattern of a chemical inhibitor of NO synthase, L NAME. Only antenatal protein restriction can reproduce long-term impaired alveolarization as those observed in BPD. However, in this model, changes in key genes previously identified in pathological alveolar development are not observed before, during or after alveolarization. This result led us to perform a genome-wide analysis which identified several modified path-ways during alveolarization. Among these, the genes involved in the “cardiac contractility”, “cell adhesion molecules”, “immunity”, “molecular adhesion” or the "Peroxisome Proliferator-Activated Receptor" pathways. In the clinical part of this study, we evaluated the risk of BPD in extreme preterm infants with IUGR whose mothers had evidence of vascular disease of pregnancy (preeclampsia). This single-center retrospective study of 184 children was used to compare children with IUGR in adjusted for gestational age children. The vascular IUGR increases the risk of DBP by 6. An early marker of progression to BPD is a low platelet count at birth, referring to the role of high levels of circulating anti-angiogenic factors. A study is ongoing to correlate circulating anti-angiogenic factors present in preeclamptic mothers to res-piratory outcome and particularly BDP, in newborn younger than 30 weeks of gestational age at birth. In conclusion, we have shown experimentally that only prenatal protein restriction in rats reproduced impaired alveolarization comparable to those observed in the BPD. New mo-lecular pathways potentially involved in the impaired alveolarization were highlighted. More-over, the role of placental anti-angiogenic factors leading to development of BPD is evaluat-ed.