A doença pulmonar obstrutiva crônica (DPOC) é caracterizada por inflamação crônica e alterações estruturais que levam a obstrução das pequenas vias aéreas e destruição do parênquima alveolar. A composição da matriz extracelular (MEC) nos pulmões tem um importante papel em prover e sustentar a arquitetura pulmonar. No entanto, não há uma descrição abrangente da composição da matriz extracelular no trato respiratório de indivíduos portadores de DPOC. No presente estudo investigou-se a composição da MEC das vias aéreas grandes (VAG), pequenas (VAP) e do parênquima pulmonar de pacientes com DPOC. Utilizando imunohistoquímica e análise de imagem analisou-se a área fracionada de fibras elásticas, colágenos I, III e IV, versicam, decorina, biglicano, lumicam, fibronectina e tenascina nas VAG, VAP e no parênquima peribrônquico e distal de 26 indivíduos com DPOC e comparou-se à área fracionada nos pulmões de 26 fumantes sem DPOC e 16 indivíduos não fumantes. A área fracionada de fibras elásticas foi significante maior no grupo de fumantes não obstruídos em comparação com os demais grupos, em todos os compartimentos analisados. Houve menor expressão de colágeno I na camada interna das VAG e nas camadas interna, muscular e externa das VAP dos indivíduos com DPOC e na camada externa das VAP dos fumantes não obstruídos quando comparados ao grupo controle. A área fracionada de versicam mostrou-se menor apenas no parênquima distal do grupo DPOC comparado ao grupo controle. O estudo da matriz de glicoproteínas mostrou maior área fracionada de fibronectina nas camadas interna, muscular e externa das VAP dos indivíduos com DPOC comparados aos demais grupos, assim como maior área fracionada de tenascina foi observado na membrana basal das VAG e na camada interna das VAP do grupo DPOC comparados aos controles. Além disso, a composição da MEC correlacionou-se com valores funcionais, como o VEF1 (% predito). A partir desses resultados, concluímos que a DPOC é caracterizada por complexas alterações nas principais proteínas estruturais nas pequenas e grandes vias aéreas. Tais alterações podem contribuir para a lesão tecidual persistente e com a obstrução ao fluxo aéreo observado na DPOC / COPD is characterized by chronic inflammation and structural alterations leading to small airway obstruction and to destruction of the lung parenchyma. The extracellular matrix (ECM) composition of the lungs has an important role in determining airway structure. However, there are no comprehensive descriptions of the ECM composition along the respiratory tract in COPD patients. We postulated that the ECM composition in large and small airways and in lung parenchyma of COPD patients differs from that observed in smoking and non-smoking controls. Using immunohistochemistry and image analysis, fractional areas of elastic fibers, type-I, -III and IV collagen, the proteoglycans versican, decorin, biglycan and lumican; fibronectin and tenascin were quantified in the large (LA) and small airways (SA), in peribronchiolar (PP) and distal parenchyma (DP) of 26 COPD patients and compared to 26 smokers without COPD and 16 non-smoking controls. The fractional area of elastic fibers was higher in non-obstructed smokers than in COPD and non-smoking controls subjects, in all lung compartments. Type-I collagen fractional area was lower in the inner layer of LA and in the inner, muscle and outer layer (OL) of SA of COPD patients and in the OL of SA of non-obstructed smokers when compared to non-smoking controls. The versican fractional area was lower in DP of COPD patients than non-smokers. Fibronectin fractional área was higher in the inner, muscle and outer layer of SA of COPD patients compared to non-smokers. Tenascin fractional area was higher in the subepithelial area of LA and inner layer of SA of COPD when compared to non-smoking controls. Furthermore, ECM composition correlated with FEV1% predicted. Architectural alterations due to an altered ECM composition in COPD are likely to contribute to the persistent tissue injury and to the airflow obstruction characteristic of this disease

<p>Hronična opstruktivna bolest pluća (HOBP) jedna je od vodećih uzroka morbiditeta i mortaliteta &scaron;irom sveta. Uprkos stalnom napretku u medicini, uvođenju novih prognostičkih biomarkera, otkrivanju novih bronhodilatatornih, antiniflamatornih i antiinfektivnih lekova, ova bolest i danas beleži stalan porast broja obolelih i umrlih. Prema savremenom tumačenju HOBP je heterogena bolest koja je udružena sa brojnim komorbiditetima i sistemskim manifestacijama. Zajednički faktori rizika su osnova za javljanje udruženih hroničnih bolesti. Komorbiditeti i akutne egzacerbacije doprinose ukupnoj težini bolesti. S obzirom da se HOBP manifestuje i izvan pluća kod svakog pacijenta je neophodno proceniti postojanje sistemskih manifestacija i tragati za komorbiditetima. U reviziji &bdquo;Globalne strategije za dijagnozu, lečenje i prevenciju hronične opstruktivne bolesti pluća GOLD‖ iz 2011. godine navedene sledeće pridružene bolesti za kojima je potrebno aktivno tragati: kardiovaskularne bolesti, disfunkcija skeletnih mi&scaron;ića, metabolički sindrom, osteoporoza, depresija i karcinom pluća, bronhiektazije. Lečenje HOBP delimo u dve velike grupe: farmakolo&scaron;ko i nefarmakolo&scaron;ko. Farmakolo&scaron;ko lečenje prema GOLD-u, danas se zasniva na stepenastom pristupu. Treba ga sprovodi kod svakog pacijenta sa simptomima. Poslednjih godina na značaju veoma dobija nefarmakolo&scaron;ko lečenje pacijenata sa HOBP, zbog sve vi&scaron;e dokaza o pozitivnom efektu na smanjenje simptoma bolesti, popravljanja tolerancije na napor, smanjenje egzacerbacija. U nefarmakolo&scaron;ko lečenje ubrajamo: aktivno izbegavanje faktora rizika, prestanak pu&scaron;enja, oksigenoterapiju, vakcinaciju protiv gripa, psihosocijalnu podr&scaron;ku, respiratornu rehabilitaciju (RR) i hirur&scaron;ko lečenje. Danas se zna da RR ostvaruje brojne benefite kod pacijenata sa HOBP, kao i da je većina tih benefita zasnovana na dokazima (GOLD 2013): pobolj&scaron;ava kapacitet za vežbanje, smanjene osećaja nedostatka vazduha, pobolj&scaron;ava kvalitet života, smanjuje broj hospitalizacija i dužinu hospitalizacije, smanjuje anksioznost i depresiju povezane sa HOBP, efekti traju i nakon zavr&scaron;enog programa rehabilitacije, pobolj&scaron;ava preživljavanje ovih pacijenata. Primarni ciljevi na&scaron;eg istraţivanja bili su da se utvrdi procenat ispitanika kod kojih je ostvaren pozitivan ishod respiratorne rehabilitacije, da se odredi povezanost sledećih faktora sa ishodom respiratorne rehabilitacije: pol, godine života, &bdquo;pack/years―, dužina trajanja bolesti, broj egzacerbacija u prethodnoj godini, pridružena oboljenja: ishemijska bolest srca, srčana insuficijencija, hipertenzija, osteoporoza, depresija, dijabetes, bronhiektazije, karcinom pluća, tuberkuloza pluća. Takođe smo želeli da utvrdimo i uticaj sledećih parametara na ishod rr:FEV1, BMI, satO2, 6-minutni test hoda, &bdquo;CAT― upitnik, &bdquo;mMRC― upitnik, BODE indeks. Urađena je retrospektivno-prospektivna studija, koja je uključila 500 pacijenata sa HOBP, svih stadijuma I-IV , u stabilnoj fazi bolesti, koji su u toku dvogodi&scaron;njeg perioda odradili kompletan program ambulantne respiratorne rehabilitacije. Program je sprovođen u Poliklinici za plućne bolesti, Instituta za plućne bolesti Vojvodine. Dobijeni rezultati pokazali su da je 452 pacijenta (90,4%) ostvarilo pozitivan ishod RR: najvi&scaron;e ispitanika 142 (28,4%) bilo je u kategoriji vrlo dobar, potom slede kategorije dobar sa 129 ispitanika (25,8%), zadovoljavajući sa 102 ispitanika (20,4%), i na kraju kategorija odličan sa ukupno 79 (15,8%) ispitanika. Nakon programa RR do&scaron;lo je do statistički značajnih pobolj&scaron;anja u vrednostima FEV1, 6MTH, satO2, CAT, mMRC, BODE indeksa. Pol, starost, pu&scaron;ački status, dužina trajanja bolesti i &ge;2 egzacerbacije u prethodnoj godini nemaju uticaja na uspe&scaron;an ishod RR. Utvrđeno je postojanje statistički značajne negativne korelacije između srčane slabosti i pozitivnog ishoda respiratorne rehabilitacije, dok nije nađena statistički značajna povezanost ostalih ispitivanih komorbiditeta sa pozitivnim ishodom respiratorne rehabilitacije. Kao statistički značajni univarijantni prediktori pozitivnog ishoda respiratorne rehabilitacije jesu: manji broj pridruženih bolesti, odsustvo srčane slabosti, niža saturacija hemoglobin kiseonikom, veći BMI, mMRC &ge; 2, CAT &ge; 10, B i D stadijumi bolesti, dok je multivarijantnom logističkom regresionom analizom pokazano da su nezavisni prediktori pozitivnog ishoda respiratorne rehabilitacije: manji broj pridruženih bolesti, odsustvo srčane slabosti, veći BMI, CAT &ge; 10.</p> / <p>Chronic obstructive pulmonary disease (COPD) is one of the leading morbidity and mortality causes all over the world. Despite the steady advance in scientific research, introduction of novel prognostic biomarkers, new and potent bronchodilation, anti-inflammatory and anti-infectious drugs, a constant increase in the number of the affected and deceased from chronic obstructive pulmonary diseas has still been permanently evidenced in the 21st century. In a modern concept, the chronic obstructive pulmonary disease (COPD) is understood as a heterogenous disorder associated with numerous comorbidities and systemic manifestations. Common risk factors represent the basis for concomitant chronic diseases to develop. Comorbidities and acute exacerbations contribute to the overall disease severity. As a COPD may develop extrapulmonary manifestations as well, each patient should be evaluated for systemic manifestations and comorbidities. The 2011 update of the &bdquo;Global Strategy for Chronic Obstructive Lung Disease Diagnosis, Management, and Prevention &ndash;GOLD‖ lists the following comorbidities to be actively searched for: cardiovascular diseases, skeletal muscle dysfunction, metabolic syndrome, osteoporosis, depression, lung cancer and bronchiectases. The treatment of COPD can be devided in two groups: pharmacological and non-pharmacological. Pharmacological treatment is today, according to GOLD, based on incremental approach. It should be carry out in every patient with simptoms. In last few years, non-pharmacological treatment of COPD is very popular, due to the evidence of positive effects on decreasing the simptoms, increasing the tolerance to exertion and decreasing the exacerbations. Non-pharmacological treatment consider: active avoiding the risk factors, smoking cessation, oxigenotherapy, vaccination against the flu, psicho-social support, respiratory rehabilitation and surgery. It is well known today that respiratory rehabilitation achieve numerous benefits in COPD patients and most of that benefits are evidence based (GOLD 2013): increasing the exercise capacity, decreasing the shortness of breath, increasing the quality of life, reduces the number and length of hospital stay, decreasing the anxiety and depression conected to COPD, the effects lasts and after the rehabilitation program, improves the survival of this patients. The primary goals of this investigation were to establish the percentage of patients with positive outcome after the respiratory rehabilitation, to determine the conection of the following factors with the outcome of respiratory rehabilitation: gender, age, &bdquo;pack/years―, duration of the disease, the number of exacerbations in previous year, comorbidities: ischemic heart disease, heart failure, arterial hypertension, osteoporosis, depression, diabetes mellitus, bronchiectasis, lung cancer, tuberculosis. The other goals were to establish the influence of some parametars on the outcome of respiratory rehabilitation: FEV1, BMI, SaO2 ,6 minute walk test, &bdquo;CAT― questionnaire, &bdquo;mMRC― questionnaire, BODE index. This was retrospective-prospective study the included 500 patients with COPD, from I to IV stadium, in stable disease, who have done the two years complete program of ambulatory respiratory rehabilitation. The program have been done in polyclinic for respiratory diseases, Institute for pulmonary disesases of Vojvodina, Sremska Kamenica. The results showed that 452 patients (90,4%) achieved positive outcome of respiratory rehabilitation. The majority of patients 142 (28,4%) were in ―very good‖ caterogy, the 129 patients (25,8%) in category ―good‖, ―satisfied‖ 102 patients (20,4%) and ―excellent‖ 79 patients (15.8%). After completion of the respiratory rehabilitation program, statistically significant improvements of the following parameters have been achieved: FEV1, 6MTH, SaO2, mMRC, BODE index. Gender, age, smoking, duration of the disease and &ge;2 exacerbations in previous year did not have influence on the successful respiratory rehabilitation outcome. The statistically significant negative correlation between the heart failure and positive respiratory rehabilitation outcome has been achieved, while there were no statistically significant correlations among other comorbidities and the successful respiratory rehabilitation outcome. The statistically significant univariant predictors of positive outcome of respiratory rehabilitation are: less comorbidities, absence of heart failure, lower oxygen saturation, higher BMI, , mMRC &ge; 2, CAT &ge; 10, B i D stadium of disease, while multivariant logistic regression analysis showed that the independent predictors of positive outcome of respiratory rehabilitation are: less comorbidities, absence of heart failure, higher BMI, CAT &ge; 10.</p>

<p>Hronična opstruktivna bolest pluća je jedna od najče&scaron;ćih hroničnih bolesti pluća i važan uzrok morbiditeta i mortaliteta u svetu. Egzacerbacije predstavljaju značajan događaj u toku bolesti, jer imaju negativan uticaj na mortalitet, kvalitet života, opadanje plućne funkcije i povećanje tro&scaron;kova lečenja. Cilj rada je utvrditi nezavisne faktore rizika za egzacerbaciju i smrtni ishod tokom jednogodi&scaron;njeg praćenja obolelih od hronične opstruktivne bolesti pluća i kreiranje prediktivnog modela za neželjeni događaj. U ispitivanje je uključeno 200 pacijenata sa potvrđenom dijagnozom hronične opstruktivne bolesti pluća, koji su lečeni prema preporukama smernice Globalne inicijative za hroničnu opstruktivnu bolest pluća. Pacijenti su praćeni godinu dana, evaluirani na kontrolnim pregledima i beležen je broj egzacerbacija na osnovu vanrednih poseta i eventualni smrtni ishod. Statističkom obradom podataka utvrđeni su nezavisni prediktori egzacerbacije (starost &gt; 65 godina, test procene hronične opstruktivne bolesti pluća &gt; 9, modifikovana skala dispneje &gt; 2, saturacija hemoglobina kiseonikom &le; 93%) i smrtnog ishoda (starost &gt;65 godina, potreba za primenom antiagregacione terapije, brzina maksimalnog ekspiratornog protoka na 25% vitalnog kapaciteta &le; 1,16 l, modifikovana skala dispneje &gt;2, puls &gt; 89). Od navedenih nezavisnih faktora su kreirani modeli za predikciju neželjenih događaja. Unutra&scaron;njom validacijom modela dokazana je dobra prediktivna vrednost oba matematička modela, bez statistički značajne razlike opserviranog i očekivanog procenta pojave egzacerbacije i smrtnog ishoda tokom praćenja pacijenata obolelih od HOBP.</p> / <p>Chronic obstructive pulmonary disease is one of the most common chronic lung diseases and is an important cause of morbidity and mortality in the world. Exacerbations are an important event in the course of the disease, as they have a negative impact on mortality, quality of life, lung function decline and increased costs of treatment. The aim of study is to identify risk factors for exacerbation or death during the one-year follow-up of patients with chronic obstructive pulmonary disease, and creation of predictive models for exacerbation and mortality during the follow-up period. The study included 200 patients with a confirmed diagnosis of chronic obstructive pulmonary disease who have had the therapy according to the Global initiative for chronic obstructive airway diseases guidelines. Patients were followed for one year, evaluated the number of exacerbations on the basis of emergency visits and eventual death. With statistical data processing there were identified independent predictors of exacerbations (age &gt; 65 years, COPD Assessment Test &gt; 9, modified Medical Research Council scale &gt;2, oxygen saturation &le; 93%) and death (age &gt; 65 years, the need for application of antiplatelet therapy, the rate of maximum expiratory flow at 25% of vital capacity &le; 1,16 l, modified Medical Research Council scale &gt;2, heart rate &gt; 89th). Of these independent factors was created a models for the prediction of adverse events during the one-year mark of COPD patients. Internal validation showed good predictive value of both models. No difference between the observed and the expected percentage of occurrence of exacerbations or death during the the follow-up period.</p>

A doença pulmonar obstrutiva crônica (DPOC) é caracterizada por inflamação crônica e alterações estruturais que levam a obstrução das pequenas vias aéreas e destruição do parênquima alveolar. A composição da matriz extracelular (MEC) nos pulmões tem um importante papel em prover e sustentar a arquitetura pulmonar. No entanto, não há uma descrição abrangente da composição da matriz extracelular no trato respiratório de indivíduos portadores de DPOC. No presente estudo investigou-se a composição da MEC das vias aéreas grandes (VAG), pequenas (VAP) e do parênquima pulmonar de pacientes com DPOC. Utilizando imunohistoquímica e análise de imagem analisou-se a área fracionada de fibras elásticas, colágenos I, III e IV, versicam, decorina, biglicano, lumicam, fibronectina e tenascina nas VAG, VAP e no parênquima peribrônquico e distal de 26 indivíduos com DPOC e comparou-se à área fracionada nos pulmões de 26 fumantes sem DPOC e 16 indivíduos não fumantes. A área fracionada de fibras elásticas foi significante maior no grupo de fumantes não obstruídos em comparação com os demais grupos, em todos os compartimentos analisados. Houve menor expressão de colágeno I na camada interna das VAG e nas camadas interna, muscular e externa das VAP dos indivíduos com DPOC e na camada externa das VAP dos fumantes não obstruídos quando comparados ao grupo controle. A área fracionada de versicam mostrou-se menor apenas no parênquima distal do grupo DPOC comparado ao grupo controle. O estudo da matriz de glicoproteínas mostrou maior área fracionada de fibronectina nas camadas interna, muscular e externa das VAP dos indivíduos com DPOC comparados aos demais grupos, assim como maior área fracionada de tenascina foi observado na membrana basal das VAG e na camada interna das VAP do grupo DPOC comparados aos controles. Além disso, a composição da MEC correlacionou-se com valores funcionais, como o VEF1 (% predito). A partir desses resultados, concluímos que a DPOC é caracterizada por complexas alterações nas principais proteínas estruturais nas pequenas e grandes vias aéreas. Tais alterações podem contribuir para a lesão tecidual persistente e com a obstrução ao fluxo aéreo observado na DPOC / COPD is characterized by chronic inflammation and structural alterations leading to small airway obstruction and to destruction of the lung parenchyma. The extracellular matrix (ECM) composition of the lungs has an important role in determining airway structure. However, there are no comprehensive descriptions of the ECM composition along the respiratory tract in COPD patients. We postulated that the ECM composition in large and small airways and in lung parenchyma of COPD patients differs from that observed in smoking and non-smoking controls. Using immunohistochemistry and image analysis, fractional areas of elastic fibers, type-I, -III and IV collagen, the proteoglycans versican, decorin, biglycan and lumican; fibronectin and tenascin were quantified in the large (LA) and small airways (SA), in peribronchiolar (PP) and distal parenchyma (DP) of 26 COPD patients and compared to 26 smokers without COPD and 16 non-smoking controls. The fractional area of elastic fibers was higher in non-obstructed smokers than in COPD and non-smoking controls subjects, in all lung compartments. Type-I collagen fractional area was lower in the inner layer of LA and in the inner, muscle and outer layer (OL) of SA of COPD patients and in the OL of SA of non-obstructed smokers when compared to non-smoking controls. The versican fractional area was lower in DP of COPD patients than non-smokers. Fibronectin fractional área was higher in the inner, muscle and outer layer of SA of COPD patients compared to non-smokers. Tenascin fractional area was higher in the subepithelial area of LA and inner layer of SA of COPD when compared to non-smoking controls. Furthermore, ECM composition correlated with FEV1% predicted. Architectural alterations due to an altered ECM composition in COPD are likely to contribute to the persistent tissue injury and to the airflow obstruction characteristic of this disease

Les maladies chroniques impliquant le système respiratoire nécessitent un suivi sur la durée. L’activité physique et les paramètres cardiovasculaires sont essentiels pour ces pathologies. Nous nous sommes intéressés en particulier à la BPCO et à l’apnée obstructive du sommeil. La BPCO est caractérisée par un cercle vicieux d’inactivité : une gêne respiratoire entraîne une diminution de l’activité, qui elle-même augmente la gêne respiratoire par désentraînement. Le monitoring de l’activité, en lien avec la SpO2 est donc essentiel pour cette pathologie. Les désaturations nocturnes sont un paramètre cardinal de l’apnée du sommeil. Un actimètre permet d’évaluer la qualité du sommeil, complétant ainsi le suivi de cette pathologie. De plus, l’activité diurne est un indicateur de l’asthénie provoquée par le syndrome. Le but de ce travail a donc été la mise au point d’un actimètre communicant, capable de mesurer l’activité diurne, d’évaluer le temps de sommeil et de s’interfacer avec un oxymètre de pouls pour synchroniser la collecte de données. À partir des données récoltées durant 26 jours d’enRégistrements, nous avons mis au point et évalué un algorithme permettant de mesurer le temps passé assis, debout et allongé. Cet algorithme a été conçu pour être embarqué dans un microcontrôleur, ayant des ressources de calcul limitées. Nous avons également proposé un algorithme de détection des pas, dont le fonctionnement a été validé sur plus de 5 heures de marche, sur 22 patients différents, contre un comptage manuel. Nous avons enfin proposé une méthode de détection des transitions assis-debout pour l’instrumentation du test de levers de chaise de 3 minutes. Lors de l’analyse nocturne, nous avons mis au point un algorithme de détection du temps de sommeil, testé sur 25 nuits. Nous avons également proposé une méthode d’analyse de l’onde de pouls permettant d’extraire le rapport LF/HF de la variabilité cardiaque, permettant de détecter le sommeil paradoxal. Nous avons montré le résultat de l’agrégation des différentes données acquises par le système formé de l’actimètre et de l’oxymètre lors d’une nuit d’examen, comme outils à disposition du praticien. L’actimètre mis au point dans le cadre de ces travaux et les méthodes d’analyse du signal associées sont adaptés au suivi non invasif de pathologies respiratoires. Ils peuvent également être intégrés à un système de télémédecine via une passerelle informatique pour un suivi de long terme. / Chronic diseases affecting the respiratory system require a long-term monitoring. Physical activity and cardiovascular parameters are essential in those pathologies. We focused on two of those diseases : COPD and obstructive sleep apnea. COPD is characterized by a downward cycle of inactivity : a respiratory impairment leads to a reduction of activity, whose in turn worsen the respiratory impairment by a conditioning loss. As a consequence, activity monitoring and SpO2 are essential for the monitoring of this pathology. Nocturnal oxygen desaturation are a main feature of sleep apnea. An actimeter allows for sleep quality evaluation, and is a logical choice for a complementary measure of this disease. Moreover, diurnal activity is an indicator of the degree of physical weakness that can occur as a consequence of sleep apnea. The main goal of the work has been the developement of a connected actimeter, able to monitor diurnal activity, estimate the duration of sleep and collect data from a pulse oximeter to synchronise the data. From 26 days of accelerometric measures, we designed and validated an algorithm that compute the time spend sitting, standing and lying. This algorithm has been designed to be embedded in a microcontroler with limited computing power. We also proposed a step detection algorithm validated on 5 hours of walking, on 22 different patients, against a visual count. Finally, we designed a method to detect the sitting-standing change of posture to monitor the 3-minutes chair stand test. On the nocturnal aspect, we designed an algorithm used to estimate the sleep duration during a night. It as been tested on 25 nights. We also proposed a pulse wave analysis method to extract the LF/HF ratio of cardiac variability, to detect REM sleep. We showed the result of the aggregation of the different parameters collected by the system composed of the actimeter and the oximeter during a monitored night, as a tool to the healthcare professional. The actimeter design in the context of this work and the associated signal processing methods are appropriate to the monitoring of respiratory pathologies with a light equipment. They also can be integrated into a telemedecine system through a gateway computer, allowing for a long-term monitoring.

Chronic obstructive pulmonary disease (COPD) is characterized by a non-fully reversible airflow limitation and a chronic inflammatory response accompanied by the development of emphysema. The β2-adrenoceptor agonists and anticholinergic agents are widely used in patients with COPD due to their bronchodilator properties. Today, many studies in vitro and in vivo in experimental animal models have shown that these bronchodilators also exert anti-inflammatory effects, but their protective roles against lung inflammation and the development of emphysema in patients with COPD remain to be determined. The imbalance between the activity of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) is considered to play a key role in the pathogenesis of COPD, especially in the development of pulmonary emphysema. The modulation of inflammatory responses and emphysema via the inhibition of the MMPs activity induced by the use of synthetic inhibitors of MMPs suggests that MMPs may be therapeutic targets for COPD patients. However, very few studies have demonstrated the regulation exerted by β2-adrenoceptor agonists and anticholinergic agents on the activity of MMPs. The combination of β2-adrenoceptor agonists with anticholinergic agents has been found to exert an additive and even synergistic bronchodilator effect, but nothing is known about their combination on the inflammatory pathogenesis and the development of emphysema. Thus, a better knowledge of the activities of β2-adrenoceptor agonists and anticholinergic agents on controlling pulmonary inflammation and emphysema in COPD could provide a new therapeutic approach in this area. The first goal of the present work was to investigate the effects of formoterol, a β2-adrenoceptor agonist and/or ipratropium bromide, an anticholinergic agent, on acute pulmonary inflammation induced by cadmium inhalation in rats. In addition, we examined whether the expected anti-inflammatory effects of formoterol and/or of ipratropium bromide were associated with a modulation of the gelatinase A (MMP-2), gelatinase B (MMP-9) and macrophage metalloelastase (MMP-12) activity. Compared with the data observed in rats exposed to a single dose of cadmium, the pre-administration of formoterol or ipratropium bromide inhibited the cadmium-induced increase in airway resistance. Formoterol significantly reduced the total cell, neutrophil and macrophage counts in bronchoalveolar lavage fluid (BALF), whereas, ipratropium bromide only reduced the neutrophil number. Both bronchodilators administrated alone attenuated significantly the lung lesions associated with parenchyma inflammatory cell influx and congestion observed in cadmium-group. The increased MMP-9 activity was significantly attenuated. A reduction of pulmonary edema was also detected by measuring the lung wet-to-dry weight ratio. However, no additive or synergistic effect was obtained when formoterol was administrated in combination with ipratropium bromide. In conclusion, formoterol and ipratropium bromide partially protect the lungs against inflammation by reducing the neutrophilic infiltration. This protective effect may be related to the reduction of MMP-9 activity which plays an important role in the acute inflammation. Up to now, the impact of a long-term administration of bronchodilators aiming to control the chronic inflammation and the development of emphysema in experimental animal models and in patients with COPD has been poorly investigated. In this context, it was rational to investigate whether the protective role of formoterol and ipratropium bromide identified in acute conditions persists in a rat model of subacute neutrophilic pulmonary inflammation with an enlargement of airspaces. In the second part of this study, we also intended to determine whether these anti-inflammatory effects are related to the modulation of imbalance between MMPs and TIMPs. Though ipratropium induced no effect on the subacute pulmonary inflammation and the airspace enlargement induced by repeated cadmium inhalations during 5 weeks in rats, formoterol elicited marked anti-inflammatory effects on the increase of total cell and neutrophil counts as well as the activity of MMP-9 mainly expressed in alveolar macrophages and epithelial cells. This drug also prevented the inflammatory infiltration in alveoli and in interstitial tissue and significantly inhibited the airspace enlargement as demonstrated by the significant decrease in the mean linear intercept (Lm). The combination of both bronchodilators at inefficient concentrations induced synergistic inhibitory effects on the total cell and neutrophil counts and on the cadmium-induced increased Lm associated with a reduction of MMP-9 activity in BALF. These data suggest that formoterol alone or combined with ipratropium could protect lungs against subacute pulmonary inflammation and the airspace enlargement by inhibiting neutrophilic infiltration via the reduction of MMP-9 activity. To the best of our knowledge, this is the first report which reveals the anti-inflammatory effects of β2-adrenoceptor agonists and anticholinergic agents in an animal model which mimics the main features of COPD. The data obtained in this work contribute to identify new therapeutic targets in COPD for drugs currently used in clinical practice./ La broncho-pneumopathie chronique obstructive (BPCO) est caractérisée essentiellement par une limitation du débit aérien qui n'est pas entièrement réversible et une inflammation chronique pulmonaire accompagnée dun développement demphysème. Les agonistes β2-adrénergiques et les anticholinergiques sont largement utilisés chez les patients atteints de BPCO en raison de leurs propriétés bronchodilatatrices. Aujourdhui, de nombreuses études expérimentales in vitro et in vivo, utilisant des modèles animaux, ont montré que ces bronchodilatateurs exerçaient également des effets anti-inflammatoires. Leur rôle protecteur contre linflammation pulmonaire et le développement d'emphysème chez des patients souffrant de BPCO reste à déterminer. Le déséquilibre entre les métalloprotéinases de la matrice (MMPs) et leurs inhibiteurs tissulaires (TIMPs) est considéré comme un mécanisme clé dans lévolution de la maladie et surtout dans le développement d'emphysème pulmonaire. La modulation des réactions inflammatoires et de lemphysème obtenue grâce à la réduction de lactivité des MMPs induite par des inhibiteurs synthétiques suggère que les MMPs pourraient être des cibles thérapeutiques importantes dans le traitement de la BPCO. Mais jusquà ce jour, très peu détudes ont été consacrées à la régulation de lactivité des MMPs par les agonistes β2-adrénergiques et les anticholinergiques. Lassociation dun agoniste β2-adrénergique avec un anticholinergique donne lieu à une amplification des effets bronchodilatateurs, mais il nest pas certain que leur combinaison débouche sur des effets additifs ou synergiques sur le plan dun meilleur contrôle de la réaction inflammatoire. Ainsi, une meilleure connaissance des activités des agonistes β2-adrénergiques et des anticholinergiques visant au contrôle de l'inflammation pulmonaire et de l'emphysème dans la BPCO pourrait fournir une nouvelle approche thérapeutique dans ce domaine. Lobjectif de la première partie de ce travail était donc d'étudier les effets du formotérol, un agoniste β2-adrénergique et / ou du bromure d'ipratropium, un anticholinergique, sur l'inflammation pulmonaire aiguë provoquée par linhalation de cadmium chez le rat. En outre, nous voulions aussi vérifier si ces effets anti-inflammatoires étaient associés à une modulation de lactivité de la gélatinase A (MMP-2), de la gélatinase B (MMP-9) et de la métallo-élastase du macrophage (MMP-12). Par rapport aux effets observés chez des rats exposés à une dose de cadmium, ladministration préventive de formotérol ou de bromure dipratropium a atténué laugmentation de la résistance des voies aériennes. Le formotérol a induit une diminution significative du nombre de cellules totales, des neutrophiles et des macrophages dans le liquide de lavage broncho-alvéolaire (BALF). Par contre, le bromure dipratropium na entraîné quune diminution du nombre de neutrophiles. Les lésions pulmonaires caractérisées par de la congestion et une réaction inflammatoire du parenchyme ont été significativement inhibées par ces deux bronchodilatateurs administrés séparément. Lélévation remarquable de lactivité de MMP-9 dans le BALF a été significativement atténuée par le prétraitement au formotérol ou au bromure dipratropium. Il en est de même pour ldème pulmonaire évalué par le biais du rapport entre le poids humide et le poids sec du parenchyme. Lorsque les deux principes actifs ont été combinés et administrés préventivement à laction du cadmium, aucun effet synergique ou additif na été constaté. En conclusion, le formotérol et le bromure dipratropium préviennent partiellement linflammation pulmonaire aiguë en réduisant linfiltration neutrophilique du parenchyme pulmonaire faisant suite à une exposition aiguë au cadmium. Cet effet protecteur pourrait être lié à une réduction de lactivité de MMP-9 qui joue un rôle pro-inflammatoire important dans linflammation aiguë. Jusquici, les effets potentiels des bronchodilatateurs contre linflammation chronique et lévolution de lemphysème pulmonaire chez des animaux et chez les patients atteints de BPCO restent mal connus. Il nous restait donc à vérifier si les effets protecteurs du formotérol et du bromure dipratropium révélés par nos premières études au cours desquelles les rats ont été exposés de manière aiguë au cadmium persistent dans un modèle dinflammation pulmonaire subaiguë accompagnée dun élargissement des espaces aériens. Nous voulions également déterminer si ces effets étaient liés à la modulation du déséquilibre entre les MMP-2/9/12 et les TIMP-1/2. Bien que le bromure dipratropium nait aucun effet sur linflammation subaiguë pulmonaire et lélargissement des espaces aériens induits par des inhalations répétées de cadmium chez le rat, le prétraitement par du formotérol a, quant à lui, inhibé significativement laugmentation du nombre de cellules totales et des neutrophiles ainsi que de lactivité de MMP-9 exprimée principalement dans les macrophages et les cellules épithéliales alvéolaires. En outre, une atténuation importante des lésions pulmonaires caractérisées par un élargissement des espaces aériens les plus distaux et une infiltration de cellules inflammatoires dans les alvéoles et le tissu ont été observées. La combinaison des deux bronchodilatateurs, à des concentrations pourtant inefficaces, a provoqué un effet synergique sur la plupart des paramètres étudiés, en particulier sur linfiltration par les neutrophiles et lactivité de MMP-9 dans le BALF. Ce travail suggère que le formotérol, seul ou combiné avec le bromure dipratropium, pourrait protéger partiellement les poumons contre linflammation pulmonaire et lélargissement des espaces aériens en réduisant l'infiltration neutrophilique éventuellement via l'inhibition de lactivité de MMP-9. A notre connaissance, il sagit du premier rapport montrant les effets anti-inflammatoires des agonistes β2-adrénergiques et des anticholinergiques dans un modèle animal mimant les principales caractéristiques physiopathologiques de la BPCO. Les données obtenues dans ce travail pourraient contribuer à identifier de nouvelles cibles thérapeutiques pour cette maladie.

ABSTRACTThe general aim of this thesis was to investigate behavioral change communication at nurse-led chronic obstructive pulmonary disease (COPD) clinics in primary health care, focusing on communication in self-management and smoking cessation for patients with COPD.Designs: Observational, prospective observational and experimental designs were used.Methods: To explore and describe the structure and content of self-management education and smoking cessation communication, consultations between patients (n=30) and nurses (n=7) were videotaped and analyzed with three instruments: Consulting Map (CM), the Motivational Interviewing Treatment Integrity (MITI) scale and the Client Language Assessment in Motivational Interviewing (CLAMI). To examine the effects of structured self-management education, patients with COPD (n=52) were randomized in an intervention and a control group. Patients&#8217; quality of life (QoL), knowledge about COPD and smoking cessation were examined with a questionnaire on knowledge about COPD and smoking habits and with St. George&#8217;s Respiratory Questionnaire, addressing QoL. Results: The findings from the videotaped consultations showed that communication about the reasons for consultation mainly concerned medical and physical problems and (to a certain extent) patients&#180; perceptions. Two consultations ended with shared understanding, but none of the patients received an individual treatment-plan. In the smoking cessation communication the nurses did only to a small extent evoke patients&#8217; reasons for change, fostered collaboration and supported patients&#8217; autonomy. The nurses provided a lot of information (42%), asked closed (21%) rather than open questions (3%), made simpler (14%) rather than complex (2%) reflections and used MI non-adherent (16%) rather than MI-adherent (5%) behavior. Most of the patients&#8217; utterances in the communication were neutral either toward or away from smoking cessation (59%), utterances about reason (desire, ability and need) were 40%, taking steps 1% and commitment to stop smoking 0%. The number of patients who stopped smoking, and patients&#8217; knowledge about the disease and their QoL, was increased by structured self-management education and smoking cessation in collaboration between the patient, nurse and physician and, when necessary, a physiotherapist, a dietician, an occupational therapist and/or a medical social worker.Conclusion The communication at nurse-led COPD clinics rarely involved the patients in shared understanding and responsibility and concerned patients&#8217; fears, worries and problems only to a limited extent. The results also showed that nurses had difficulties in attaining proficiency in behavioral change communication. Structured self-management education showed positive effects on patients&#8217; perceived QoL, on the number of patients who quit smoking and on patients&#8217; knowledge about COPD.

Hintergrund: Die chronisch obstruktive Lungenerkrankung (COPD) ist eine der Haupttodesursachen weltweit. Eine gesteigerte Aktivität des sympathischen Nervensystems wird als wesentlicher pathophysiologischer Aspekt vermutet. Grundsätze: Die vorliegende Arbeit untersuchte die muskelsympathische Nervenaktivität (MSNA) und die Baroreflex-Sensitivität bei COPD-Patienten und gesunden Probanden in Ruhe sowie unter moderater körperlicher Belastung. Ergebnisse: COPD-Patienten zeigten in Ruhe eine signifikant gesteigerte MSNA sowie eine signifikant verminderte Baroreflex-Sensitivität. Diese Ergebnisse bestätigen die Resultate vorausgegangener Publikationen der Arbeitsgruppe. In der vorliegenden Arbeit konnte erstmals ein signifikanter Anstieg der MSNA unter moderater statischer Belastung bei COPD-Patienten nachgewiesen werden. Fazit: In der vorliegenden Arbeit konnte erstmals eine Korrelation zwischen sympatho-vagaler Imbalance und verminderter körperlicher Leistungsfähigkeit bei COPD-Patienten nachgewiesen werden. Eine Modifikation der neuro-humoralen Aktivität bei COPD-Patienten könnte in Zukunft eine Rolle in der Behandlung der COPD spielen und sollte in größeren, randomisierten Studien untersucht werden.

Einleitung: Bei PSV beendet der Respirator die Druckunterstützung, wenn der Inspirationsfluss auf einen prozentualen Anteil des Spitzenflusses, welcher als Umschaltkriterium be-zeichnet wird, absinkt. Bei obstruktiver Lungenerkrankung ist der Abfall des Inspirationsflusses verlangsamt, wodurch verspätetes Umschalten in die Exspiration begünstigt wird. Der verwendete Beatmungszugang, das etwaige Vorliegen von Leckage bei nicht-invasiver Beatmung, die Höhe der Druckunterstützung und die Atemfrequenz sind potentielle Faktoren, welche das Umschalten in die Exspiration beeinflussen können. Die synchrone Unterstützung der Patienteninspirationsbemühung ist entscheidend für den Erfolg der assistierten Beatmungstherapie. Methode: In einer Lungenmodellstudie wurde obstruktive Lungenmechanik simuliert und der Einfluss der Variation des Umschaltkriteriums auf die Patient-Respirator-Interaktion untersucht. Die Beatmungszugänge Endotrachealtubus, Nasen-Mund-Maske und Beatmungshelm wurden nacheinander in den Versuchsaufbau eingebracht. Bei nicht-invasiver Beatmung wurde mit und ohne Leckage gemessen. Bei Vorliegen von Leckage wurde zusätzlich in einem nicht-invasiven Beatmungsmodus beatmet. Die Höhe der Druckunterstützung (5 cmH2O, 15 cmH2O) und die Atemfrequenz (15/min, 30/min) wurden verändert. Die Patient-Respirator-Interaktion wurde bei Verwendung der Umschaltkriterien 10 %, 20 %, 30 %, 40 %, 50 %, 60 % und 70 % des Spitzenflusses analysiert. Aus aufgezeichneten Flusskurven wurden Parameter, welche die Synchronisation zwischen Patient und Respirator beschreiben (nicht-unterstützte Atemzüge, Doppeltrigger, inspiratorische und exspiratorische Triggerlatenz) sowie das Tidalvolumen bestimmt. Aus aufgezeichneten Druckkurven wurden der intrinsische PEEP und Druck-Zeit-Produkte bestimmt, welche in den verschiedenen Phasen des Atemzyklus die durch den Respirator geleistete Entlastung (PTPPEEP, PTPINSP) oder Belastung (PTPEXSP) der Atemmuskulatur beschreiben. Ergebnisse: Bei konventionell eingestelltem Umschaltkriterium (20 % - 30 %) wurde stets verspätetes Umschalten beobachtet. Die Erhöhung des Umschaltkriteriums resultierte in einer Reduktion der exspiratorischen Triggerlatenz, PTPEXSP und des intrinsischen PEEP. In der Folge wurden nicht-unterstützte Inspirationsbemühungen, die inspiratorischen Triggerlatenz sowie der zur Auslösung der Druckunterstützung erforderliche Kraftaufwand (PTPPEEP) reduziert. Bei übermäßiger Erhöhung des Umschaltkriteriums beendete der Respirator die Druckunterstützung vor dem Ende der simulierten Inspirationsbemühung. Vorzeitiges Umschalten ging mit einer Abnahme des Tidalvolumens und der effektive Druckunter-stützung (PTPINSP), sowie der Auslösung von Doppeltrigger, einher. Vorzeitiges Umschalten trat bei niedriger Atemfrequenz bei Verwendung der Umschaltkriterien 50 % bzw. 60 % bis 70 % auf. Bei Beatmung via Endotrachealtubus und Nasen-Mund-Maske wurden vergleichbare Ergebnisse beobachtet. Bei Beatmung via Beatmungshelm war die Interaktion zwischen Patient und Respirator wesentlich beeinträchtigt, wodurch vorzeitiges Umschalten begünstigt wurde. Bei Messungen mit Leckage war die exspiratorische Triggerlatenz verlängert. Bei Verwendung des NIV-Beatmungsmodus konnte die exspiratorische Triggerlatenz teilweise minimiert werden. Bei hoher Druckunterstützung war die exspiratorische Triggerlatenz, bei Beatmung via Endotrachealtubus und Nasen-Mund-Maske, verlängert. Konklusion: Die Variation des Umschaltkriteriums stellt eine effektive Möglichkeit dar, die Patient-Respirator-Interaktion zu optimieren. Bei obstruktiver Lungenerkrankung sollte das Umschaltkriterium, über das konventionell eingestellte Umschaltkriterium hinaus, erhöht werden. Das Umschaltkriterium ist maßvoll zu erhöhen, um eine vorzeitige Unterbrechung der Druckunterstützung zu verhindern. Das Risiko verfrühten Umschaltens ist bei Beatmung via Beatmungshelm, sowie bei niedriger Atemfrequenz, erhöht. Des Weiteren müssen das etwaige Vorliegen von Leckage, der bei nicht-invasiver Beatmung verwendete Beatmungsmodus, die Höhe der Druckunterstützung sowie die Atemfrequenz bei der Wahl des Umschaltkriteriums berücksichtigt werden.

Le syndrome d’apnées obstructives du sommeil (SAOS) est associé à de nombreuses co-morbidités métaboliques et cardiovasculaires. L’hypoxie intermittente chronique, une des composantes du SAOS, induit des mécanismes intermédiaires délétères tels que stress oxydatif, inflammation, insulino-résistance ou encore dyslipidémie, à l’origine de ces comorbidités. Ces mécanismes intermédiaires sont également communs à d’autres pathologies respiratoires chroniques telles que la bronchopneumopathie chronique obstructive (BPCO) et le syndrome d’obésité hypoventilation (SOH).L’hypoxie intermittente et les mécanismes intermédiaires associés sont aussi à l’origine de l’existence et de la progression de la stéatopathie métabolique (« non alcoholic fatty liver disease »). Ce lien entre pathologies respiratoires chroniques et atteinte hépatique est un mécanisme essentiel mais plus récemment étudié des co-morbidités dans le SAOS et la BPCO. Différents biomarqueurs cardiométaboliques ont donc été étudiés dans ces pathologies respiratoires chroniques à la fois pour caractériser les co-morbidités et l’atteinte systémique et pour apprécier l’impact de différentes thérapeutiques. La première partie de cette thèse sera consacrée à une revue systématique des différents biomarqueurs cardio-métaboliques liés à chacune de ces 3 pathologies respiratoires chroniques : SAOS, BPCO et SOH.Le traitement du SAOS par pression positive continue (PPC) a un effet bénéfique sur les symptômes fonctionnels liés à cette pathologie. Cependant, l’impact de la PPC sur d’autres conséquences cardio-métaboliques délétères du SAOS reste encore à démontrer par des essais randomisés contrôlés, notamment sur l’atteinte hépatique.Dans la seconde partie de cette thèse, nous détaillerons l’impact de la PPC sur les différents marqueurs cardiométaboliques du SAOS à l’aide d’une revue systématique puis d’une étude randomisée contrôlée sur l’impact de la PPC sur les marqueurs d’atteinte hépatique.Par ailleurs, les patients atteints de SAOS, BPCO ou SOH reçoivent du fait de leur polypathologie (multimorbidité) des traitements médicamenteux multiples qui visent à contrôler au mieux les co-morbidités. Il est donc primordial de considérer la prise en charge globale de ces patients du point de vue de leurs traitements instrumentaux (PPC et ventilation non invasive) mais aussi en considérant l’impact des traitements médicamenteux associés. En effet, les traitements médicamenteux peuvent interférer avec la sévérité de la pathologie elle-même et impacter les biomarqueurs liés aux comorbidités associées. La troisième partie de cette thèse sera consacrée à l’étude d’un antihypertenseur chez le patient SAOS et envisagera l’influence des médicaments sur la pertinence de l’usage des bicarbonates comme marqueurs diagnostiques du SOH.En conclusion, nous insisterons sur la nécessité d’une prise en charge intégrée multi systémique et d’une prise en charge personnalisée de ces patients. / Obstructive sleep apnea (OSA) is associated with related metabolic and cardiovascular comorbidities. Chronic intermittent hypoxia the hallmark of OSA induces deleterious intermediary mechanisms such as oxidative stress, systemic inflammation, insulin resistance and dyslipidemia. Cardiovascular and metabolic comorbidities are also key features of other chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and obesity hypoventilation syndrome (OHS). Chronic hypoxia and deleterious intermediary mechanisms also trigger occurrence and progression of non alcoholic fatty liver disease. This link between chronic respiratory diseases and liver injury is observed through modifications of specific liver biomarkers in OSA and COPD. A variety of cardiometabolic biomarkers have been studied for stratification of cardio-metabolic risk and assessing treatment impact in chronic respiratory diseases. The first part of this PhD thesis is a systematic review of cardio-metabolic biomarkers in 3 respiratory diseases: OSA, COPD and OHS.Continuous positive airway pressure (CPAP) the first line therapy for OSA improves symptoms and quality of life. However, CPAP effects on cardio-metabolic consequences remains still debated. In the second part of the PhD thesis, we will address CPAP impact on different cardiometabolic biomarkers and more specifically in markers of liver injury by reporting original results of a randomized controlled trial (RCT).Polypharmacy is usual in patients with OSA, COPD or OHS. Beyond CPAP or non invasive ventilation treatment, it is essential address the contribution of associated medications. Indeed, pharmacological treatments can interfere with the severity of the disease and control of associated comorbidities. The third part of the thesis will present a RCT evaluating Bosentan in hypertensive OSA patients and will present how medications for comorbidities decrease bicarbonate diagnosis value for OHS.We will conclude by underlining the crucial importance of personalized medicine and integrated care in chronic respiratory diseases.