Chronic obstructive pulmonary disease (COPD) patients are generally more sedentary and less physically active than healthy adults; putting them at increased risk of hospitalisation and death. For patients with mild-moderate COPD, physical activity appears to be reduced compared with apparently healthy adults but differences in time spent sedentary are less well established. Additionally, there is a need for a greater understanding of the correlates of behaviour in mild-moderate patients with much of the existing literature focusing on more severe or mixed stage patient samples and with many studies lacking objective behavioural monitoring, not adjusting for confounders and a paucity of data on correlates of sedentary time. Despite having mild-moderate airflow obstruction, these patients also report a range of symptom burdens with some individuals reporting severe symptoms. Subsequently, these patients represent a sub-set of individuals who may require lifestyle interventions. Therefore, factors associated with patients reporting more severe symptoms need to be identified to help understand how this phenomenon may manifest and be intervened upon. For patients with more advanced COPD who are admitted to hospital for an acute exacerbation behavioural intervention focussing on less intense movement may be a more suitable approach for reducing the risk of readmissions than more intense physical activity or exercise. To date no studies have specifically targeted reductions in sedentary behaviour in COPD. In addition, wearable self-monitoring technology may facilitate the provision of such interventions, removing important participation barriers such as travel and cost, but this has not been sufficiently examined in COPD. This thesis investigated: (i) objectively measured physical activity and sedentary time and the correlates of these behaviours for mild-moderate COPD patients and apparently healthy adults (Study One); (ii) factors associated with self-reported symptom severity and exacerbation history in mild-moderate COPD patients (Study Two) and (iii) the feasibility and acceptability of a home-based sedentary behaviour intervention using wearable self-monitoring technology for COPD patients following an acute exacerbation (Study Three). Methods: Study One: COPD patients were recruited from general practitioners and apparently healthy adults from community advertisements. Objectively measured moderate-to-vigorous physical activity (MVPA), light activity and sedentary time for 109 mild-moderate COPD patients and 135 apparently healthy adults were obtained by wrist-worn accelerometry. Patients with at least four valid days (≥10 waking hours) out of a possible seven were included in analysis. A range of demographic, social, symptom-based, general health and physical factors were examined in relation to physical activity and sedentary time using correlations and linear regressions controlling for confounders (age, gender, smoking status, employment status and accelerometer waking wear time). Study Two: In 107 patients recruited from general practitioners, symptoms were assessed using the COPD Assessment Test (CAT) and Modified Medical Research Council (mMRC) questionnaires. Twelve-month exacerbation history was self-reported. Exercise capacity was assessed via incremental shuttle walk test (ISWT) and self-reported usual walking speed. Physical activity and sedentary time were obtained from a wrist-worn accelerometer. Study Three: Patients were randomised in-hospital into a usual care (Control), Education or Education + Feedback group with the intervention lasting 14 days following discharge. The intervention groups received information about reducing prolonged sitting. The Education + Feedback group also received real-time feedback on their sitting time, number of stand-ups and step count at home through an inclinometer linked to a smart device app. The inclinometer also provided vibration prompts to encourage movement when the wearer had been sedentary for too long. Feasibility of recruitment (e.g. uptake and retention) and intervention delivery (e.g. fidelity) were assessed. Acceptability of the intervention technology (e.g. wear compliance, app usage and response to vibration prompts) was also examined. Results: Study One: COPD patients were more sedentary (592±90 versus 514±93 minutes per day, p < 0.05) and accrued less MVPA (12±18 versus 33±32 minutes per day, p < 0.05) than apparently healthy adults. For COPD patients, self-reported dyspnea and percentage body fat were independent correlates of sedentary time and light activity with exercise capacity (incremental shuttle walk test) an independent correlate of MVPA. For apparently healthy adults, percentage body fat and exercise capacity were independent correlates of sedentary time and light activity. Percentage body fat was an independent correlate of MVPA. Study Two: ISWT (B=-0.016±0.005, partial R2=0.117, p=0.004) and years living with COPD (B=0.319±0.122, R2=0.071, p=0.011) were independently associated with CAT score. ISWT (B=-0.002±0.001, R2=0.123, p < 0.001) and vector magnitude counts per minute (VMCPM) (B=0.0001±0.0000, R2=0.050, p=0.011) were independently associated with mMRC grade. MVPA was independently associated with previous exacerbations (B=-0.034±0.012, R2=0.081, p=0.005). Patients reporting a CAT score of > 20 or an mMRC score of ≥2 had lower VMCPM, were more sedentary and took part in less light activity than patients reporting a CAT score of 0-10 or mMRC of 0, respectively. Patients reporting ≥2 exacerbations took part in less MVPA than patients reporting zero exacerbations. Study Three: Study uptake was 31.5% providing a final sample of 33 COPD patients. Retention of patients at two-week follow-up was 51.5% (n=17). Reasons for drop-out were mostly related to being unable to cope with their COPD. Patients wore the inclinometer for 11.8±2.3 days (and charged it 8.4±3.9 times) with at least one vibration prompt occurring on 9.0±3.4 days over the 14 day study period. Overall, 325 vibration prompts occurred with patients responding 106 times (32.6%). 40.6% of responses occurred within 5 minutes of the prompt with patients spending 1.4±0.8 minutes standing and 0.4±0.3 minutes walking, taking 21.2±11.0 steps. Discussion: Study One: COPD patients were less active and more sedentary than apparently healthy adults; however, factors predicting behaviour were similar between groups. Correlates differed between sedentary time, light activity and MVPA for both groups. Interventions to boost physical activity levels and reduce sedentary time should be offered to patients with mild-moderate COPD, particularly those reporting more severe breathlessness. Study Two: Worse exercise capacity, low levels of physical activity and more time spent sedentary are some of the factors associated with patients of the same severity of airflow limitation reporting differing symptom severities. These patients may benefit from both lifestyle and exercise interventions. Study Three: Recruitment and retention rates suggest a trial targeting sedentary behaviour in hospitalised COPD patients is feasible. A revised intervention, building on the successful components of the present feasibility study is justified. Conclusion: The findings from this thesis have contributed a greater understanding of physical activity and sedentary behaviour in COPD and can inform the development of tailored physical activity and sedentary behaviour interventions for patients across the grades of COPD severity.

Introduction: Chronic obstructive pulmonary disease (COPD) is characterized by increasedresistance in the airways which in turn leads to dyspnea, especially during physical activity. Dyspneamay subsequently cause anxiety. Music has, according to previous studies, been seen to reduce theperception of dyspnea and anxiety during physical activity amongst patients suffering from COPD.The results are promising but however inconclusive. Aim: The primary aim was to evaluate the impact of music therapy (MT) on physical endurance, andon respiratory and psychological symptoms during physical activity in patients clinically diagnosedwith COPD. Secondly, to explore the meaning of music on life quality for these individuals. Methods: This study is a randomized cross-over pilot study of 10 patients with clinically diagnosedCOPD. Mixed methods, which is a combination of qualitative and quantitative design methods, wereutilized during data collection. Patient’s physical endurance was measured by a 6- minute walkingtest. Patients were randomly selected to listen to music throughout one of 2 walking tests. Basicphysiological parameters such as heart rate and oxygen saturation was measured before and after eachwalking test. In addition, questionnaires were used to measure perceived exertion, dyspnea andanxiety. Quantitative data was analyzed using paired Student´s T-test. Qualitative data was gainedthrough semi-structured interviews with patients concerning the influence of music. Results: 10 patients were recruited for the study. Preliminary results suggest that MT waseffective in reducing perceived anxiety and dyspnea during physical exercise amongst 70 % and40 % of the patients respectively. MT has however not demonstrated an effect on physicalendurance where results proved statistically insignificant. A common factor among the studyparticipants was that music is very important in improving their life quality. Conclusion: The study has indicated positive trends in MT being effective in reducing perceivedanxiety and dyspnea during physical exercise amongst some patients with COPD. Our findingsdo not support that music affects the tolerance for physical exercise. An important finding of thisstudy is that music plays an important role in the lives of the participants, and thus improve their lifequality. If future research confirms the effectiveness of music, the aspiration is for musicrehabilitation to be implemented in the COPD treatment program to further improve the life qualityof these patients, which is of great importance.

Objetivo: Traduzir e adaptar para o português falado no Brasil a escala Dyspnoea-12. Fornecer dados de validação da escala para pacientes com DPOC e hipertensão pulmonar (HP). Métodos: A versão em inglês da escala Dyspnoea-12 sofreu processo clássico de tradução, até obtenção de versão definitiva em português denominada Dispneia-12-Pt. A escala Dispneia-12-Pt foi aplicada a 51 pacientes com DPOC (33 homens; idade: 66,4±8,1 anos; VEF1: 48,7±17,2%) e 15 com HP de diferentes etiologias (12 mulheres; idade: 45,8±12,7 anos; pressão sistólica da artéria pulmonar: 88±33,2 mmHg). Os voluntários responderam a escala de dispneia do Medical Research Council(MRC), o índice de dispneia basal (IDB), a escala hospitalar de ansiedade e depressão, questionário respiratório de Saint George (QRSG), avaliação funcional respiratória e teste da caminhada dos seis minutos (TC6min). Sessenta voluntários responderam a escala uma segunda vez, duas semanas após a primeira avaliação. Resultados: No grupo DPOC a escala Dispneia-12-Pt apresentou correlações significantes com as escalas MRC (r=0,4641; p=0,0006), IDB (r=0,515; p <0,0001), QRSG (r=0,8113; p<0,0001), ansiedade (r=0,4714; p=0,0005), depressão (0,4139; p=0,0025) e distância percorrida no TC6min (r=0,3293; p=0,0255). No grupo com HP a escala mostrou correlações significantes com as escalas MRC (r=0,5774; p=0,0242), QRSG (r=0,6907; p=0,0044), distância percorrida no TC6min (r=0,7193; p=0,0025) e difusão do monóxido de carbono (r=0,564; p=0,0447). O alfa de Cronbach para os voluntários analisados em um único grupo foi 0,927 e o coeficiente de correlação intraclasse 0,8456. Conclusões: A escala Dispneia-12-Pt apresenta propriedades biométricas aceitáveis e pode ser empregada em pacientes brasileiros com dispneia de diferentes etiologias. / Objective: To translate and to adapt for the Portuguese spoken in Brazil the scale Dyspnoea-12. To obtain validation data, regarding the use of this scale in patients with COPD and pulmonary hypertension (PH). Methods: The English version of the scale Dyspnoea-12 received a formal translation process and the final version was called Dispneia-12-Pt. The latter was applied to 51 COPD patients (33 men; age: 66.4±8.1 years; FEV1: 48.7±17.2 % pred) and 15 subjects with PH from different etiologies (12 women; age: 45.8±12.7 years; systolic pulmonary arterial pressure: 88±33.2 mmHg). The volunteers also answered the Medical Research Council dyspnea scale (MRC), the basal dyspnea index (DBI), the hospital scale of anxiety and depression, the Saint George Respiratory Questionnaire (SGRQ), respiratory functional evaluation and the six minute walk test (6 MWT). Sixty volunteers also answered the Dispneia-12-Pt scale about two weeks after the first evaluation. Results: In the COPD group the Dispneia-12-Br showed significant correlations with the scales MRC (r=0.4641; p=0.0006), BDI (0.515; p<0.0001), SGRQ (r=0.8113; p<0.0001), anxiety (r=0.4714; p=0.0005), depression (0.4139; p=0.0025) and walked distance in the 6 MWT (r=0.3293; p= 0.0255). In the HP group the scale showed significant correlations with the scales MRC (r=0.5774; p=0.0005), SGRQ (r=0.6907; p=0.0044), walked distance in the 6 MWT (0.7193; p=0.0025) and carbon dioxide diffusion capacity (r=0.564; p=0.0447). Cronbach´s alpha calculated for all volunteers evaluated as a whole was 0.927 while the intraclass correlation coefficient was 0.8456. Conclusions: The Dispneia-12-Pt exhibits acceptable biometric properties and may be used as a tool in Brazilian patients with dyspnea of different etiologies.

Chronic obstructive pulmonary disease (COPD) is in up to 90 % of all cases caused by smoking. COPD often has negative effects on circulation, effects that first and foremost can be observed as respiratory insufficiency. Reduced function of the right ventricle of the heart is common in patients suffering from chronic obstructive pulmonary disease, especially if they also have hypoxemi; insufficient levels of oxygen in blood or tissue. The incidence of this cardiac complication reduces the survival time. It is possible in chronic obstructive pulmonary disease that the pressure in the pulmonary circulation gradually increases resulting in pulmonary hypertension followed by a slow adaptation of the right ventricle by hypertrophy of the myocardium. To investigate a correlation between COPD and pulmonary hypertension COPD patients were subjected to spirometry and ultrasound on heart. Of 14 examined patients 5 had developed pulmonary hypertension. A correlation between obstruction in the COPD- patients and an increase in left ventricular diameter was found. DLCO (diffusion capacity) of the lungs is directly connected to PA (pulmonary arterial pressure). The lower DLCO, the higher risk to develop pulmonary hypertension. However, we could not find a significant correlation between COPD and pulmonary hypertension in this study even if most patients had a decreased DLCO.

Purpose: The aim of the systematic review was to explore the role that anxiety plays in hospital admissions for those with Chronic Obstructive Pulmonary Disease (COPD). The empirical study aimed to examine whether the frequency of COPD related admissions is related to psychological factors (anxiety, depression, catastrophising, and mindfulness), disease severity, perceived disability and demographic factors. It also sought to examine whether cognitive factors (mindfulness and catastrophising) may explain unique variance in predicting anxiety and COPD-related admissions when other relevant factors are controlled for. Methods: The literature was systematically searched for research related to the predictive power of anxiety in relation to COPD related hospital admissions. A postal cross-sectional survey of 54 people with COPD examined the psychological profile of those who are admitted to hospital for COPD, and if mindfulness and catastrophising can predict anxiety and COPD hospital admissions. Correlations and multiple regressions were utilised to explore these hypotheses. Results: Fourteen studies met inclusion criteria for the systematic review, demonstrating mixed results regarding whether anxiety plays a role in COPD related hospital admissions. Findings from the empirical study suggest that a significant relationship exists between disease severity and number of COPD hospital admissions and catastrophising and overall mindfulness predicted 16.3% of variance in COPD hospital admissions (non-significant). Anxiety scores were significantly correlated with breathlessness, depression, catastrophising and mindfulness with catastrophising and mindfulness predicting 22.3% of variance in anxiety (significant). Conclusions: Further research with robust measures of anxiety and hospital utilization are needed to aid our understanding of the role of anxiety in COPD related admissions. Further research is necessary to determine if mindfulness and catastrophising are useful constructs in predicting anxiety levels and hospital admissions in those with COPD. This will help to inform future psychological interventions with this population.

La bronchopneumopathie chronique obstructive (BPCO) est une maladie essentiellement liée au tabagisme, caractérisée par une limitation du débit aérien secondaire à deux processus histologiques : l’emphysème pulmonaire (destruction du tissu alvéolaire) et l’atteinte des voies aériennes (remodelage pariétal et rétrécissement luminal). C’est une maladie hétérogène dans laquelle deux patients avec une même limitation du débit aérien peuvent avoir des proportions différentes d’emphysème pulmonaire et d’atteinte des voies aériennes. Le phénotypage par tomodensitométrie (TDM) de ces deux processus est cliniquement important car il permet de sélectionner et suivre certains traitements, et d’identifier des patients à risques accrus de morbidité et de mortalité. Cependant, alors que les mesures TDM d’emphysème pulmonaire sont bien établies, de nombreuses questions restent en suspens concernant les mesures TDM de l’atteinte des voies aériennes, constituant un frein à l’intégration de la TDM dans le traitement de la BPCO. Notre travail a consisté en quatre études originales investiguant quatre mesures TDM de voies aériennes de 3ème et 4éme générations, corrélées aux mesures histologiques des voies aériennes distales et aux mesures spirométriques. Une première étude a testé l’effet des exacerbations de BPCO sur ces mesures. Une deuxième étude a testé l’effet de la bronchodilatation sur ces mesures et a permis de calculer le nombre de voies aériennes à mesurer. Une troisième étude a comparé des variabilités de ces mesures avec celles des mesures spirométriques. Enfin, une quatrième étude a testé les effets de la capacité pulmonaire totale, du genre et de la taille sur ces mesures. Au terme de ces investigations, nous avons proposés deux mesures TDM appropriées pour mesurer les voies aériennes chez le patient BPCO: l’épaisseur pariétale des voies aériennes de 3ème génération et la racine carrée de la surface pariétale à un périmètre interne de 10 mm. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

La sénescence, perte irréversible des capacités réplicatives des cellules associée à la sécrétion de médiateurs inflammatoires, pourrait participer au développement de l'atteinte pulmonaire dans la bronchopneumopathie chronique obstructive (BPCO) en initiant, maintenant et propageant un état inflammatoire. L'objectif de ce travail était d'évaluer les mécanismes de la sénescence impliqués dans l'induction et le maintien de l'inflammation au cours de la BPCO. Ainsi, des fibroblastes pulmonaires de témoins et de patients atteints de BPCO ont été mis en culture à long terme. Un phénotype sénescent majoré associée à un sécrétome pro-inflammatoire était détectée dans les fibroblastes de patients avec BPCO par rapport aux témoins. Par ailleurs, ces fibroblastes présentaient une expression accrue des récepteurs à la PGE2 (EP2 /4)au stade non sénescent et une production accrue de PGE2, un médiateur lipidique pro-inflammatoire, au stade sénescent. Dans cette optique, une partie du travail a consisté à déterminer si la PGE2 pouvait induire la sénescence et l'inflammation des fibroblastes pulmonaires de sujets atteints ou non de BPCO. Nous avons pu démontrer que la PGE2 synthétisée par les fibroblastes sénescents induisait, maintenait (effet autocrine) et propageait (effet paracrine) la sénescence et l'inflammation associée via une voie EP2/4 / COX-2 / oxydants / p53. L'implication des oxydants dans l'induction de la sénescence nous a conduit à étudier les effets de l'hème oxygénase (HO)-1, un système anti-oxydant et anti-inflammatoire sur la prévention de la sénescence des fibroblastes pulmonaires. Ainsi, des fibroblastes pulmonaires ont été traités chroniquement avec des substances pharmacologiques modulant l'activité d'HO-1. Des résultats préliminaires nous ont permis d'observer que l'activation de HO-1 prévenait l'induction de la sénescence chez des fibroblastes pulmonaires de témoins et de BPCO. Au total, la modulation des voies de la PGE2 et de l'HO-1 pourrait contribuer à limiter la sénescence des fibroblastes pulmonaires dans la BPCO / Cellular senescence, a state of irreversible loss of replicative capacity associated with the secretion of inflammatory mediators, could participate in the development of chronic obstructive pulmonary disease (COPD) by initiating, maintaining and propagating an inflammatory state. The aim of this PhD project was to evaluate the mechanisms involved in senescence induction in COPD lung fibroblasts. COPD fibroblasts exhibited an increased senescent phenotype as compared to control cells. In addition, COPD fibroblasts showed an increased PGE2 receptors (EP2 /4) expression at non senescent stage and PGE2 production, apro-inflammatory lipid mediator at senescent stage. In this context, one part of the study was devoted to determine whether PGE2 could induce senescence of lung fibroblasts of subjects with and without COPD. We have shown that PGE2 synthesized by senescent fibroblasts induced, maintained (autocrine effect) and propagated (paracrine effect) senescence and associated inflammation via EP2 /4 / COX-2 / oxidants / p53 pathway. The essential role of oxidants production in the induction of senescence in COPD led us to study the effects of heme oxygenase (HO)-1, an antioxidant and anti-inflammatory system on the prevention of senescence in COPD fibroblasts. Pharmacological activation of HO-1 by hemin prevented the induction of senescence in lung fibroblasts from COPD patients probably in relation with an anti -oxidant effect. The modulation of PGE2 and HO-1 pathways may contribute to attenuate fibroblasts senescence in COPD

Background: The clinical and pathological presentation of COPD is heterogeneous. ‘Chronic bronchitis’ is a phenotype of COPD, which is a clinical diagnosis of a productive cough of ≥ 3 months for ≥ 2 consecutive years. Chronic bronchitis is associated with worse lung function, frequent exacerbations, recurrent hospitalisations and premature death in patients with COPD. Chronic bronchitis sufferers can be further subphenotyped into those who produce sputum during exacerbation or during winter months only and those who are ‘persistent sputum producers,’ who experience mucous hypersecretion throughout the year. An improved understanding of persistent sputum producers is the object of this thesis. Aims: 1) To compare the clinical characteristics and airway inflammatory biomarker profile of COPD persistent sputum producers to that of COPD sputum non-producers 2) To investigate the short term repeatability of sputum parameters in COPD persistent sputum producers 3) To study the expression and relationship of mucins, hypoxia inducible factor (HIF-1α) and carbonic anhydrase IX (CAIX) in COPD persistent sputum producers. Methods: 1) Lung physiology, health status, sputum inflammatory biomarkers and sputum culture results were compared between COPD persistent sputum producers and sputum non-producers 2) Repeatability of spontaneous and induced sputum parameters at 8 weeks was assessed in COPD persistent sputum producers 3) Immunohistochemistry was performed on bronchial biopsies of COPD persistent sputum producers and control groups (COPD sputum non-producers, smokers with normal lung function and lifelong healthy non-smokers with normal lung function) to study the expression of MUC5AC, MUC5B, HIF-1α and CAIX 4) The association between HIF-1α and MUC5B expression was investigated in vitro. Results and Conclusions: The findings suggest that 1) COPD persistent sputum producers have clinically more severe disease, increased airway inflammation, increased impact on health status, increased rate of bacterial colonization and higher number of exacerbations compared to COPD sputum non-producers 2) Induced sputum is repeatable over short term in COPD persistent sputum producers 3) Expression of MUC5B, HIF-1α and CAIX is increased in COPD persistent sputum producers compared to COPD sputum non-producers, smokers with normal lung function and healthy non-smokers 4) HIF-1α can potentially cause increased MUC5B expression. This work reveals potential targets for the development of novel therapies to limit mucous hypersecretion in COPD.

Au cours de ma thèse je me suis intéressé à deux aspects de l’immunité dans les pathologies pulmonaires chroniques : l’immunité innée et l’inflammation dans le développement de l’hypertension artérielle pulmonaire (HTAP) ; l’immunité adaptative et la réponse vaccinale antigrippale chez des patients atteint de la broncho-pneumopathie chronique obstructive (BPCO).Ma première étude a porté sur l’implication de la voie de signalisation IL-1ß/IL-1R1/MyD88 dans le développement de l’HTAP, l’IL-1ß étant une cytokine majeure de l’immunité innée. Nos résultats montrent que le remodelage vasculaire pulmonaire et l'inflammation dans l’HTAP dépendent de la voie de signalisation IL-1R1/MyD88. L’IL-1R1 et MyD88 sont tout deux nettement surexprimés dans les vaisseaux pulmonaires de patients atteints d’HTAP idiopathique. Chez les souris exposées à une hypoxie chronique de 21 jours, l’augmentation de la production d'IL-1ß et de l'expression de IL-1R1 et MyD88 précèdent le développement de l’HTAP. Les souris IL-1R1-/- et MyD88-/- étant protégées similairement contre le développement de l’HTAP, nous avons pu identifier IL-1R1 comme un acteur majeur dans la pathogenèse de l’HTAP, affectant à la fois la prolifération des cellules musculaires lisses d’artères pulmonaires (CML-AP) et le recrutement des macrophages. La protection partielle contre la maladie des souris M.lys-Cre MyD88fl/fl indique que les effets de l’IL-1ß/IL-1R1 sur l’HTAP sont médiés en partie par l'activation des macrophages. De plus, l’anakinra (IL-1Ra) permet de reverser partiellement l’HTAP établie, chez les souris SM22-5HTT+ et chez les rats exposés à la monocrotaline.Ma seconde étude a porté sur l’efficacité de la réponse vaccinale antigrippale chez des patients atteints de BPCO. Sur une cohorte de 15 sujets atteints de BPCO et 15 sujets sains, nos résultats montrent une altération de la réponse humorale et de la réponse cellulaire au vaccin antigrippale où l’on observe une production d’anticorps anti-hémagglutinine affaiblie et une diminution de la production d’IFNγ par les lymphocytes T auxiliaires (CD4+). L’analyse des sous-populations lymphocytaires indique qu’il existe chez ces patients un défaut de différentiation des cellules B, où l’on observe un taux de cellules B naïves (CD21+CD27-) plus important et un taux de cellules B mémoires (CD21+CD27+) switchées moindre (CD27+IgD-) que chez les patients contrôles, pouvant expliquer l’altération de la réponse vaccinale. Enfin, nous avons observé que les sous-populations lymphocytaires, en particulier les cellules B naïves et mémoires, sont corrélées avec deux paramètres cliniques de la maladie, la DLCO et le score d’emphysème.Ces travaux de thèse montrent donc que les interventions pharmacologiques ciblant la voie IL-1ß/IL-1R1 peuvent être prometteuses pour le traitement de l'HTAP et que de nouvelles stratégies vaccinales antigrippales doivent être développées pour les patients atteints de BPCO afin d’augmenter l’efficacité du vaccin et de prévenir les exacerbations. / During my thesis, I was interested in two aspects of immunity in chronic lung diseases: innate immunity and inflammation in the development of pulmonary arterial hypertension (PAH); adaptive immunity and influenza vaccine response in patients with chronic obstructive pulmonary disease (COPD).My first study was focused on the involvement of the IL-1ß/IL-1R1/MyD88 signaling pathway in the development of PAH; IL-1ß is a major cytokine in innate immunity. Our results show that the pulmonary vascular remodeling and inflammation in PAH depend on IL-1R1/MyD88 signaling pathway. IL-1R1 and MyD88 are both significantly overexpressed in pulmonary vessels of patients with idiopathic PAH. In mice exposed to chronic hypoxia during 21 days, the increase in production of IL-1ß and expression of IL-1R1 and MyD88 are involved in the development of PAH. Mice deleted with IL-1R1 and MyD88 were similarly protected against the development of PAH. We identified IL-1R1 as a major player in the pathogenesis of PAH, affecting both pulmonary arteries smooth muscle (PA-SMC) proliferation and recruitment of macrophages. The partial protection against the disease in mice M.lys-Cre MyD88fl/fl indicates that the effects of IL-1ß/IL-1R1 on PAH are mediated partially by activation of macrophages. In addition, anakinra (IL-1Ra) partially reverse established PAH in SM22-5HTT + mice and rats exposed to monocrotaline.My second study was focused on the efficacy of influenza vaccine response in patients with COPD. In a cohort of 15 subject with COPD and 15 healthy subjects, our results show that both the humoral and the cellular responses to influenza vaccination are impaired in patients with COPD, with a blunted antibody response and decreased INFγ production by helper T lymphocytes (CD4+). Analysis of lymphocyte subpopulations indicates an impairment of B cell differentiation in these patients: naive (CD21+ CD27-) B cell counts were higher and switched memory B-cell (CD27+ IgD-) counts were lower in COPD patients, which could explain the impairment of vaccine response. Interestingly, these changes in B cell subsets correlated with DLCO and the CT emphysema score.This thesis work thus shows that pharmacological interventions targeted towards IL-1ß/IL-1R1 may be promising for the treatment of PAH and new influenza vaccine strategies should be developed for COPD patients to increase vaccine efficacy and prevent exacerbations.

Background: Chronic obstructive pulmonary disease (COPD) is a serious and common disease that is one of the most common causes of hospitalization. The most common cause of the disease is tobacco smoking and exposure to chemical substances. But, there is also a genetic factor behind i.e lack of protein (alpha 1 antitrypsin) deficiency and old age. To prevent the disease from worsening, it is important to stop smoking and persons who have been diagnosed with COPD should consider exercising, physical activity and take their prescribed medications to stop the progression of the disease. Objective: To describe the quality of life in COPD patients cared for at home. Furthermore, the aim is to describe the included articles data collection method. Method: Descriptive literature with 15 scientific articles from the database PubMed has been used. Articles results and methodology were analysed and summarized in four categories. These categories were: Physical and Mental health. Needs of Support &amp; Fears and Concerns, as well as the included articles Data Collection Method. Results: Self-care program for COPD patients has been shown to have positive effects on their physical and mental health and ultimately their quality of life. The patients who received pulmonary rehabilitation program reported that they experienced a high quality of life that was linked to increased physical health. Support from family members and from health care was considered important. The patients who were near death associated with the disease often experienced anxiety and fear of dying, which meant that their quality of life was low. Patients receiving oxygen therapy in the home experienced an improvement in breathing which raised their quality of life. Conclusion: Patient education proved to have good effect on COPD patients' self-care. Patients who have undergone training in pulmonary rehabilitation appeared to experience a high quality of life. COPD patients experiencing isolation when the disease leads to a sedentary life and a sense of exclusion from social life. The studies showed that it is important to support and provide information to COPD patients for them to cope with their illness.