Les cellules musculaires lisses de l'artère pulmonaire (PA-PSM) peuvent contribuer à la pathogenèse de l'hypertension pulmonaire (PH) en produisant des facteurs sécrétés.Objectif: explorer le rôle de PH de protéines de la matrice extracellulaire libéré par Les cellules musculaires lisses de l'artère pulmonaire sénescentes (PA-PSM)Méthodes et résultats:L'analyse Microarray de l'ADN de PA-CML humaine subir à la sénescence réplicative révélé une régulation positive de l'ostéopontine, qui médie l'effet stimulateur ,du médium et de la matrice de l'AP-SMC de sénescentes, sur la croissance et de la migration des cellules musculaires lisses de l'artère pulmonaire. Osteopontin était régulé à la hausse dans les poumons de patients atteints de BPCO et de patients hypertension artérielle pulmonaire idiopathique (HAPi). Prominent ostéopontine immunocoloration a été noté dans le PA-SMC qui a également colorée pour p16 dans les sites de l'hypertrophie vasculaireet les niveaux de l'ostéopontine pulmonaire étalaient étroitement corrélée avec l'âge. Comparativement aux jeunes souris avec des souris ont 1 an affiche des niveaux plus élevés d'ostéopontine du poumon, et la pression systolique ventriculaire droite (de RVSP), et la muscularisation vasculaires pulmonaires, et le nombre de PA-CML colorée pour p16 ou p21 et aussi pour l'ostéopontine.Aucun de ces changements avec l'âge étaient observée dans les souris ostéopontine - / -, qui a développé atténués PH pendant l'hypoxie.Comparé de culture PA-CML, les PA-CML de souris ont 1 ans qui proliféraient plus rapide que PA-CML de jeunes souris. Avec un taux de croissance rapide a été observée avec PA-CML de jeunes souris stimulées par matrice ou médium issu de les PA-CML de souris âgées. Différences entre les anciens jeune souris / PA-SMC taux de croissance étaient supprimée par des anticorps anti-ostéopontine.culture de la PA-CML de souris ostéopontine - / - a augmenté de plus lente que fait chez PA-SMC de souris sauvage et ces cellules ont été stimulés par le medium et la matrice de PA-CML de type sauvage et cet effet était plus fort avec PA-CML de souris âgés par apport de souris jeunes.Conclusion: Osteopontin est un médiateur clé libéré par PA-SMC sénescente et contribuer à la progression de la HTAP. / Rationale: Senescent pulmonary artery smooth muscle cells (PA-SMCs) may contribute tothe pathogenesis of pulmonary hypertension (PH) by producing secreted factors.Objective: To explore the role in PH of extracellular matrix proteins released by senescentPA-SMCsMethods and results: Microarray analysis of human PA-SMCs undergoing replicativesenescence revealed osteopontin upregulation, which mediated the stimulatory effect ofsenescent PA-SMC media and matrix on PA-SMC growth and migration. Osteopontin wasupregulated in lungs from patients with COPD or idiopathic pulmonary arterial hypertension(PAH). Prominent osteopontin immunostaining was noted in PA-SMCs that also stained forp16 at sites of vascular hypertrophy, and lung osteopontin levels correlated closely with age.Compared to younger mice, 1-year-old mice displayed higher lung osteopontin levels, rightventricular systolic pressure (RVSP), pulmonary vessel muscularization, and numbers ofPA-SMCs stained for p16 or p21 and also for osteopontin. No such changes with age wereobserved in osteopontin-/- mice, which developed attenuated PH during hypoxia. Comparedto cultured PA-SMCs from young mice, PA-SMCs from 1-year-old mice grew faster; asimilar fast growth rate was seen with PA-SMCs from young mice stimulated by matrix ormedia from old mice. Differences between old/young mouse PA-SMC growth rates weresuppressed by anti-osteopontin antibodies. PA-SMCs from osteopontin-/- mice grew moreslowly than did wild-type PA-SMCs; they were stimulated by wild-type PA-SMCs mediaand matrix, and this effect was stronger with PA-SMCs from older vs. younger mice.Conclusion: Osteopontin is a key mediator released by senescent PA-SMCs andcontributing to PH progression.

La protéine CCSP (« Club Cell Secretory Protein »), produite par les cellules Club au niveau de l’épithélium respiratoire, se retrouve déficiente chez les patients atteints de Bronchopneumopathie Chronique Obstructive (BPCO). Le but de ce travail était de comprendre la régulation et les différents rôles de la protéine CCSP afin d’en évaluer son potentiel intérêt thérapeutique. Nous avons dans un premier temps observé les effets du polymorphisme connu de CCSP au niveau de sa région promotrice, la mutation G38A, sur la transcription même du gène. Nous avons constaté in vivo dans une étude clinique prospective sur 1 an comprenant 66 patients souffrant de BPCO, et confirmé in vitro dans un modèle de cellules BEAS-2B transfectées, que la fumée de cigarette était un répresseur de la transcription de CCSP et que ce phénomène était amplifié par la présence de la mutation G38A. De plus, in vitro, certains facteurs de transcription tels que p53 et Nkx2.1, ainsi que les lipopolysaccharides, affectaient l'efficacité du promoteur de CCSP.Ensuite, nous avons caractérisé les cellules qui sécrètent cette protéine dans un modèle ex vivo de culture en interface air-liquide de cellules primaires épithéliales bronchiques. Nous avons observé par microscopie électronique à balayage des cellules en dôme, forme caractéristique des cellules Club, et par microscopie électronique à transmission des cellules contenant des granules de sécrétion contenant la protéine CCSP. Nous avons constaté par immunofluorescence que les cellules marquées CCSP+ étaient également MUC5AC+ (marqueur de cellules à mucus), P63+ (marqueur de cellules basales) ou encore KI-67+ (marqueur de prolifération). Nous suggérons donc que les cellules Club sont des cellules progénitrices, permettant ainsi la régénération de l’épithélium bronchique. Par ailleurs, nous avons évalué l’implication de la protéine CCSP dans le recrutement des neutrophiles, cellules inflammatoires prépondérantes dans la BPCO. Une étude pharmacologique a d’abord permis d’évaluer les effets de CCSP sur des neutrophiles de sujets témoins. Le déplacement des neutrophiles, stimulé par l’IL8 ou le fMLP (tous deux puissants agents chemoattractants), était inhibé par CCSP. Puis, par une étude in vitro, nous avons déterminé la modulation du sécrétome de l’épithélium bronchique par CCSP. Lorsque les sécrétions d’épithélia reconstitués ex vivo à partir de biopsies de fumeur et de BPCO étaient mis en présence de neutrophiles, un chimiotactisme exagéré des neutrophiles étaient constaté. Lorsque les épithélia étaient traités avec la protéine CCSP, à l’état de base ou stimulés par de la fumée de cigarette, ce chimiotactisme exagéré était alors diminué.Enfin, dans une dernière partie, nous nous sommes intéressés à la régulation de la protéine, dans un modèle de culture cellulaire NCI-H292, lignée de cellules bronchiques cultivées en monocouche. Nous avons supplémenté ces cellules en CCSP exogène afin d’analyser les variations du profil protéomique des secrétions engendrées (méthode LC-MS/MS). De façon générale, il s’avérait que la supplémentation en CCSP permettrait une restauration de la « machinerie » du protéasome avec une augmentation des protéines de la famille des tubulines.Ce travail de thèse a démontré que la protéine CCSP était un acteur potentiel de la physiopathologie de la BPCO. L’étude de sa régulation a montré que la synthèse de CCSP était effectivement diminuée dans la BPCO. Ainsi, une supplémentation en CCSP pourrait être une piste thérapeutique. / A defective in Club Cell Secretory Protein (CCSP) produced by nonciliated Club cells was observed in COPD (Chronic Obstructive Pulmonary Disease) airways. Our aim was to understand CCSP biological mechanisms of action and its dysregulation in COPD and whether it might be a therapeutic axis in COPD.First, the influence of the CCSP G38A polymorphism on CCSP transcription levels and its regulatory mechanisms were analyzed. Our in vivo study conducted in a 1 year prospective cohort consisting of 66 COPD patients confirmed that circulating CCSP levels were associated with smoking. Moreover, the CCSP G38A polymorphism and the smoking status significantly repressed CCSP serum levels. Our in vitro study conducted in BEAS-2B transfected cells supported those findings as CSE repressed the CCSP transcription of the A carrying transfected cells more intensely than the wild type cells. Noteworthy, LPS, Nkx2.1 and p53 transcription factors also modulated the CCSP promoter efficiency in vitro. Furthermore, CCSP producing cells were characterized in an air-liquid interface (ALI) culture model of bronchial epithelial cells. Transmission electron microscopy, scanning electron microscopy and confocal microscopy confirmed the pseudostratified organization of the reconstituted epithelium. Evidences of full differentiation were identified and labeled with MUC5AC (goblet cells), tubulinIV (ciliated cells), P63 (basal cells) and CCSP (club cells). Moreover, the ex vivo reconstituted COPD epithelium released higher levels of IL8 and MUC5AC. Ki-67 and collocating antibodies with CCSP argued for an accessory stem cell and a transitory differentiating roles for CCSP+ cells.Then, we aimed to investigate whether exaggerated airway neutrophilia was driven by the CCSP-defective COPD airway epithelium. CCSP action on healthy neutrophil chemotaxis was evaluated in a pharmacological study demonstrating that CCSP directly inhibited neutrophil chemotaxis induced by fMLP and IL8. Then, in an in vitro study, ALI-reconstituted COPD airway epithelium in a clean environment promoted an exaggerated neutrophilic chemotaxis compared to smokers and controls at steady state. Treating the airway epithelium with exogenous CCSP prevented baseline and CSE-induced neutrophil chemotaxis.Finally, CCSP regulation was studied in NCI-H292 cells, a human pulmonary cell line. The cells were supplemented with CCSP. Proteomic profile (LC-MS/MS method) of the bronchial epithelium in response to CCSP treatment demonstrated that the proteasome machinery and the tubulin family members were upregulated.This work supported the potential implication of CCSP in the pathophysiology of COPD. CCSP was confirmatively defective in COPD patients, therefore, restoring physiological concentrations of CCSP by exogenous supplementation may be a therapeutic perspective.

La bronchopneumopathie chronique obstructive (BPCO) est une maladie caractérisée par une réaction inflammatoire intense avec une destruction du parenchyme pulmonaire et une perte d’élasticité du poumon conduisant à une obstruction quasi-irréversible des voies aériennes. L’utilisation du tabac est le principal facteur de risque de cette maladie. La fumée de cigarette active les cellules épithéliales et les macrophages résidents en libérant des protéases et des chimiokines. Ces phénomènes sont responsables de l’infiltration de cellules inflammatoires dans le poumon, telles que les neutrophiles, les macrophages et les lymphocytes. Ces cellules libèrent des enzymes protéolytiques capables de dégrader les composants de la matrice extracellulaire. Parmi ces protéases, l’élastase du neutrophile (NE) semble stimuler la sécrétion de cytokines, participant ainsi à une inflammation chronique. De fortes évidences montrent que des infections bactériennes récurrentes contribuent à ce processus inflammatoire et par conséquent à l’aggravation de la BPCO. A partir de ces observations, nous nous sommes intéressés aux événements précoces du développement de la BPCO associés à une infection bactérienne récurrente. Dans un premier temps, nous avons montré que l’association d’un extrait de fumée de cigarette à de faibles doses de LPS est capable d’augmenter de façon synergique la libération des chimiokines par les cellules épithéliales alvéolaires. Ce phénomène implique l’activation des voies de signalisation MAP kinase ERK1/2 et JAK/STAT. Nous avons mis en évidence que l’inhibiteur de la phosphodiestérase 4, le roflumilast N-oxide, empêche la sécrétion de ces cytokines inactivant ainsi les voies JAK/STAT et ERK1/2. Dans un deuxième temps, nous avons démontré que la NE peut conduire à la libération de chimiokines par des cellules épithéliales alvéolaires en activant la voie de signalisation p38 et que le roflumilast N-oxide diminue le taux de ces chimiokines. Une approche in vitro sur un modèle de cellules épithéliales alvéolaires a permis de démontrer l’effet synergique du CSE associé au LPS sur la libération de cytokines et sur l’activation des voies de signalisation. Cet effet pourrait être responsable de la progression et de l’exacerbation de la BPCO. Notre étude montre aussi les effets du roflumilast sur la libération de cytokines induites par la NE ou par le CSE/LPS. Ces résultats mettent en lumière d’autres mécanismes par lesquels le roflumilast N-oxide exerce son effet anti-inflammatoire dans la BPCO. / Chronic obstructive pulmonary disease (COPD) is a pathology characterized by an abnormal inflammatory response and associated with a destruction of lung parenchyma and loss of lung elasticity, leading to an airway limitation not fully reversible. Tobacco smoking continues to be a major cause of COPD. Cigarette smoke activates epithelial cells and resident macrophages by releasing proteases and chemokines. This phenomenon is responsible of the migration of inflammatory cells in the lung tissue such as neutrophils, macrophages and lymphocytes. These cells are able to release proteolytic enzymes leading to the degradation of components of the extracellular matrix. Among these proteases, neutrophil elastase (NE) seems to stimulate the secretion of cytokines involved in chronic inflammation. Strong evidence shows that recurrent bacterial infections contribute to the inflammatory process and consequently to the worsening of COPD. Based on these observations, we studied the early events in the development of COPD associated with recurrent bacterial infection. Initially we showed that the combination of a cigarette smoke extract associated with low doses of LPS is able to synergistically increase the release of chemokines, by alveolar epithelial cells through the activation of MAP kinase signaling pathways ERK1/2 and JAK/STAT. We also demonstrated that the phosphodiesterase 4 inhibitor, roflumilast N-oxide (RNO) inhibits the secretion of these cytokines, thereby inactivating pathways JAK/STAT and ERK1/2. Moreover, we have demonstrated that neutrophil elastase (NE) can lead to the release of chemokines by alveolar epithelial cells by activating the p38 signaling pathway. Moreover the treatment of the cells with roflumilast N-oxide significantly reduces the production of these chemokines. This in vitro model demonstrates the synergistic effect of CSE associated with LPS on the release of cytokines and activation of signaling pathways. This effect could be responsible for the progression and exacerbation of COPD. Our study also shows the effect of RNO on the release of cytokines induced by NE or by the combination CSE/LPS. These results highlight other mechanisms by which Roflumilast N-oxide exerts its anti-inflammatory effect in COPD

L’inflammation et le remodelage des voies aériennes sont des processus pathologiques de signification pronostique différente qui caractérisent la plupart des maladies obstructives bronchiques, asthme et bronchopneumopathie chronique obstructive (BPCO) notamment. L’examen histologique de l’inflammation et du remodelage requiert un geste biopsique invasif qui est rarement réalisé en routine. Le développement de méthodes d’évaluation non invasives autoriserait un phénotypage plus précis des patients et le développement de thérapeutiques ciblées. Les progrès de la tomodensitométrie (TDM) ont favorisé l’essor d’une imagerie quantitative permettant des mesures morphométriques des lumières et parois bronchiques. Ces paramètres morphométriques sont corrélés aux indices fonctionnels d’obstruction mais leur manque de standardisation limite leur utilisation en routine. Nous avons étudié chez l’homme et le petit animal des paramètres TDM basés non pas sur la morphométrie mais sur la densitométrie de la paroi bronchique. Nos résultats dans l’asthme et la BPCO indiquent que l’atténuation pariétale bronchique possède une valeur diagnostique au moins équivalente à celle des paramètres morphométriques, est mieux corrélée aux indices d’obstruction fonctionnelle, et pourrait être un marqueur du remodelage dans l’asthme. Chez la souris asthmatique, les paramètres d’atténuation péribronchique extraits d’image de micro-TDM sont aussi corrélés au remodelage histologique. Le concept d’atténuation pariétale bronchique est donc prometteur pour l’étude non invasive du remodelage même si des étapes supplémentaires de validation sont nécessaires pour s’assurer de la reproductibilité des méthodes. / Asthma and chronic obstructive pulmonary disease (COPD) are frequent conditions characterized by two main pathological changes: bronchial inflammation and remodelling. Pathological examination requires invasive biopsy, which is rarely performed in routine. Therefore there is a great interest in developing non-invasive methods that would lead to more precise phenotyping of patients and the development of new targeted treatments. Computed tomography (CT) can provide a quantitative morphometry-based analysis of the airways. These morphometric parameters have been shown to correlate with functional obstruction but are poorly used in routine practice due to their lack of standardisation. The aim of our studies was to investigate the value of CT attenuation-based parameters in humans and animals. In asthma and COPD, we have shown that the wall attenuation value had diagnostic performances comparable to those of morphometric parameters, correlated better with functional obstructive indexes, and could be a marker of remodelling in asthma. In asthmatic mice, peribronchial attenuation values extracted from respiratory-gated micro-CT images correlate with remodeling. Therefore, the concept of bronchial wall attenuation seems to be promising for assessing non-invasively airways remodeling. Further studies are required to ensure the full reproducibility of these methods.

La Broncho-Pneumopathie Chronique Obstructive (BPCO) est une pathologie inflammatoire chronique caractérisée par une détérioration irréversible des voies aériennes et des espaces alvéolaires. L'emphysème est la composante principale de la BPCO et l'exposition à la fumée de cigarette en est le principal facteur étiologique. La réponse inflammatoire au cours de la BPCO est caractérisée par une infiltration massive du tissu respiratoire par les cellules inflammatoires qui sécrètent de nombreuses protéases. Ces protéases participent à la dégradation des composants de la matrice extracellulaire et en particulier à la dégradation de l'élastine. Cette dégradation conduit à la genèse de peptides solubles d'élastine (PE) retrouvés dans les différents liquides biologiques de patients BPCO. Si les lymphocytes T CD4+ et les PE sont décrits dans la littérature comme impliqués dans la physiopathologie de la BPCO, en revanche, l'impact de leur interaction sur la polarisation Th reste à élucider. Le travail réalisé au cours de cette thèse a permis de mettre en évidence une polarisation de la réponse lymphocytaire T vers un profil de type Th1 et Th17 au cours de l'emphysème murin induit par le peptide d'élastine VGVAPG. Cette polarisation est dépendante de l'interaction du VGVAPG avec son récepteur spécifique à la surface des lymphocytes T, et est inhibée en présence d'analogues antagonistes du récepteur à l'élastine. Ces résultats permettent d'envisager l'utilisation de tels antagonistes comme des agents pharmacologiques régulant les effets délétères pro-inflammatoires de la réponse T helper au cours de la BPCO. / Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory disease characterized by irreversible damage to airways and alveolar spaces. Emphysema is the main component of COPD and exposure to tobacco smoke is the main etiological factor. The inflammatory response in COPD is characterized by a massive infiltration of respiratory tissue by inflammatory cells that secrete many proteases. These proteases participate in the degradation of extracellular matrix components and particularly in elastin degradation. This elastin breakdown leads to the genesis of soluble elastin peptides (EP) found in various biological fluids of COPD patients. If CD4+ T cells and EP are described in the literature as being involved in the pathophysiology of COPD, consequence of their interaction on the T helper polarization remains to elucidate. The work done during this thesis allowed highlighting the polarization of T cell response towards a Th1 and Th-17 profile during VGVAPG-induced murine emphysema. This polarization, which is dependent of the VGVAPG interaction with its specific receptor expressed on T cells, is inhibited using analogous antagonist elastin receptor peptides. These results allowed us to envisage such antagonist peptides as pharmacological agents that regulate the deleterious pro-inflammatory effects of the T helper cell response during COPD.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2016-05-25T18:51:15Z No. of bitstreams: 1 Wellignton dos Santos Alves.pdf: 1612582 bytes, checksum: 2e50043705c6562fcff36b21898a815f (MD5) / Made available in DSpace on 2016-05-25T18:51:15Z (GMT). No. of bitstreams: 1 Wellignton dos Santos Alves.pdf: 1612582 bytes, checksum: 2e50043705c6562fcff36b21898a815f (MD5) Previous issue date: 2015-02-26 / Introduction: One of the most common diseases in the present century, COPD (Chronic Obstructive Pulmonary Disease) has its mark on pulmonary inflammation, characterized by a number of cells such as macrophages, lymphocytes and neutrophils mainly degrading elastic fibers and release a series of inflammatory mediators that recruit other cells that act in defense in the lung. Objective: To develop a COPD model with passive inhalation of cigarette smoke in a 45 day period and promote the treatment of the disease with low-power laser. Methodology: the animals were organized into groups, control (breathing room air without cigarette smoke), the COPD group (45 days of passive inhalation of cigarette smoke) and Laser (45 days of passive inhalation + 15 days of application low power laser) .Results: Total and differential cell counts as well as histological and biochemical analysis shows the presence of COPD. Data from low-power laser-treated group shows that there was a reduction in the number of inflammatory cells and the concentration of the inflammatory mediators present in animal tissue in COPD. Conclusion: The passive inhalation of cigarette smoke for 45 days resulted in COPD, and the low-power laser was effective in the treatment because it took the reduction of inflammatory mediators and cells present in this lung disease. / Introdução: Uma das doenças mais comuns no século atual , a DPOC (Doença Pulmonar Obstrutiva Crônica) tem a sua marca na inflamação pulmonar, caracterizada por uma série de células como os macrófagos, linfócitos e principalmente os neutrófilos que degradam as fibras elásticas e liberam uma série de mediadores inflamatórios que recrutam outras células que atuam na defesa a nível pulmonar. Objetivo: desenvolver um modelo de DPOC com inalação passiva de fumaça de cigarro num período de 45 dias e promover o tratamento da doença com o laser de baixa potência. Metodologia: os animais foram organizados em grupos, o controle (respira o ar ambiente sem fumaça de cigarro), o grupo DPOC (45 dias de inalação passiva de fumaça de cigarro) e Laser (45 dias de inalação passiva + 15 dias de aplicação do laser de baixa potência). Resultados: A contagem total e diferencial das células, bem como as análises histológicas e bioquímicas mostra a presença da DPOC. Os dados do grupo tratado com laser de baixa potência mostra que houve redução do número de células inflamatórias e da concentração dos mediadores inflamatórios presentes na DPOC nos tecidos animais. Conclusão: A inalação passiva de fumaça de cigarro por 45 dias ocasionou a DPOC, e o laser de baixa potência foi eficaz no seu tratamento pois levou a redução dos mediadores inflamatórios e células presentes nesta doença pulmonar.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2018-06-21T18:36:20Z No. of bitstreams: 1 Fernanda Dultra Dias.pdf: 1137972 bytes, checksum: 8be1c4f185164e0cb296225d70598e1b (MD5) / Made available in DSpace on 2018-06-21T18:36:20Z (GMT). No. of bitstreams: 1 Fernanda Dultra Dias.pdf: 1137972 bytes, checksum: 8be1c4f185164e0cb296225d70598e1b (MD5) Previous issue date: 2016-12-18 / Introduction: The VMNI has been showing an adjuvant treatment resource for patients with stable COPD or exacerbation. However little is known about the action that the NIV promotes in thoracic and abdominal and mobility if it is able to promote improvement of asynchrony. Objectives: to evaluate the effects of the NIV in thoracic and abdominal mobility, comparing variables in spontaneous breathing and during the use of NIV in patients with COPD by OEP. Methods: Two groups of individuals (GC with 14 healthy and COPD with 16 patients) were assessed in relation to the thoracic-abdominal asynchrony, respiratory and àcontrubuição variables of each thoracic compartment using a Plethysmograph SPOS System (BTS, Italy) in spontaneous breathing and with two VMNI modes. Results: Patients with COPD evaluated presented ATA in home, we also observed that the COPD asynchrony in all compartments in relation to healthy, which in turn has always maintained its AF next to zero and when it observes only the COPD group, using both methods of VMNI promote decrease of asynchrony in compartment CTS vs. ABD and the key changes found in the COPD group are related to the distribution of aid and action of each compartment toracico. Conclusion: There are ATA in patients with COPD, even at home, the degree of airway obstruction of these patients correlates with the presence of asynchronous Thoracoabdominal, the use of VMNI in the mode continuous positive airway pressure is able to improve thoracic abdominal synchrony in patients with COPD, as well as the use of some blood pressure to A6 led and that the VMNI is able to promote changes in compartmental contribution without promoting significant changes in respiratory variables in patients with COPD compared with age-matched healthy. / Introdução: A VMNI vem se mostrando um recurso adjuvante ao tratamento de pacientes com DPOC estável ou na exacerbação.No entanto pouco se sabe sobre a ação que a VNI promove na mobilidade tóraco abdominal e se é capaz de promover melhora da assincronia respiratória. Objetivos: Avaliar os efeitos da VNI na mobilidade e sincronia tóraco-abdominal, comparando as variáveis em respiração espontânea e durante o uso de VNI em pacientes com DPOC por meio da OEP. Método: Dois grupos de indivíduos (GC com 14 saudáveis e DPOC com 16 pacientes) foram avaliados em relação à assincronia toraco-abdominal, às variáveis respiratórias e àcontrubuição de cada compartimento torácico, utilizando-se um pletismógrafo OEP System (BTS, Italy) em respiração espontânea e com aplicação de dois modos de VMNI. Resultados: Os pacientes com DPOC avaliados apresentaram ATA em repouso, observou-se também que o DPOC apresentou assincronia em todos os compartimentos em relação ao Saudável, que por sua vez sempre manteve seu AF próximo a zero e quando se observa somente o grupo DPOC, o uso de ambas as modalidades de VMNI promovem diminuição da assincronia no compartimento CTS vs ABD e as principais alterações encontradas no grupo DPOC estão relacionadas a distribuição da contribuição e ação de cada compartimento toracico. Conclusão: Há ATA em pacientes com DPOC, mesmo em situação de repouso, o grau de obstrução das vias aéreas desses pacientes não se correlaciona com a presença de assincronia toracoabdominal, o uso de VMNI no modo pressão positiva contínua nas vias aéreas é capaz de melhorar a sincronia tóraco-abdominal em pacientes com DPOC, assim como a utilização de alguns níveis pressóricos de Bilevel e que a VMNI é capaz de promover alterações na contribuição compartimental sem promover alterações significativas nas variáveis respiratórias nos pacientes com DPOC comparando com saudáveis pareados por idade.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2018-07-17T20:55:37Z No. of bitstreams: 1 Carla Lima Feitoza.pdf: 1039396 bytes, checksum: 54b4b08906cba375881a20315af80122 (MD5) / Made available in DSpace on 2018-07-17T20:55:37Z (GMT). No. of bitstreams: 1 Carla Lima Feitoza.pdf: 1039396 bytes, checksum: 54b4b08906cba375881a20315af80122 (MD5) Previous issue date: 2016-12-13 / Introduction: Chronic obstructive pulmonary disease (COPD) is characterized by persistent obstruction that is usually progressive and associated with an inflammatory response in the airways and lungs, by harmful particles or gases. The thoracoabdominal mobility of COPD patients alters as a result of this obstructive process that causes permanent pulmonary hyperinflation, altering respiratory mechanics. As a result, physical efforts can increase minute ventilation by reducing the time to expiration, increasing this hyperinflation. Positive airway expiratory pressure (PEP) is a physiotherapeutic resource that helps reduce air trapping during exacerbations of the COPD patient, but little is known about the effects of PEP on pulmonary hyperinflation. As a rule, PEP with high pressures has been contraindicated. Objective: Evaluate the effects of physical effort and PEP on pulmonary hyperinflation and Thoracoabdominal mobility through optoeletronic plethysmography (OEP) in patients with COPD and in healthy individuals. Materials and Methods: Thoracoabdominal mobility was evaluated by OEP in 30 subjects, in two groups, 15 of them with GOLD (GDPOC) and 15 healthy subjects (GC), with a mean age of 58.1 ± 11 years, before and after a daily life simulation activity, up and down the step and before and after performing a series of exercise with PEP. Results: Both the age and the anthropometric data of the studied population as weight and height showed no difference. The spirometric variables showed a significant difference, in favor of the CG, as expected. There were no significant differences in the contribution of the thoracoabdominal compartments at rest between groups, except for Ti / Tot in the GDPOC, with median of 0.77 characterizing possible hyperinflation or respiratory muscle fatigue. After physical exertion, for 2 minutes, the GDPOC group showed an increase in the Abd contribution in thoracoabdominal movements, higher than CG (52.2 ± 12.6% vs. 41.1 ± 14.6%). After PEP, there was an increase of abdominal compartment in the subjects of the GDPOC (50.5 ± 19.1% x 36.9 ± 16.4%). After the PEP the patients of the GDPOC had a normalization of Ti / Ttot, with a median of 0.41. As the analysis of the compartments in the GDPOC there is a greater involvement of the abdominal compartment in three moments evaluated and after PEP this abdominal participation is also greater than in the CG. Conclusion: Physical effort and the use of PEP alter the participation of thoracic and abdominal compartments differently between groups and PEP in COPD seems to contribute to the reduction of hyperinflation. / Introdução: A doença pulmonar obstrutiva crônica (DPOC) é caracterizada por obstrução persistente que é geralmente progressiva e associada a uma resposta inflamatória nas vias aéreas e pulmões, por partículas ou gases nocivos. A mobilidade toracoabdominal de portadores de DPOC se altera em decorrência deste processo obstrutivo que causa hiperinsuflação pulmonar permanente, alterando a mecânica respiratória. Em decorrência disso, esforços físicos podem aumentar a ventilação minuto reduzindo o tempo hábil para a expiração, aumentando essa hiperinsuflação. A pressão expiratória positiva (PEP) é um recurso fisioterapêutico que auxilia na redução do aprisionamento de ar durante as exacerbações do paciente com DPOC, porém pouco se sabe sobre os efeitos do PEP em tal cirunstância de hiperinsuflação pulmonar, na qual, via de regra, a PEP com altas pressões tem sido contraindicada. Objetivo: Avaliar os efeitos da pressão expiratória positiva na mobilidade toracoabdominal e na hiperinsuflação induzida pelo exercício físico, por meio da Pletismografia optoeletrônica (POE). Material e Método: A mobilidade toracoabdominal foi avaliada pela POE em 30 indivíduos, em dois grupos, sendo 15 com DPOC nível II pelo GOLD (GDPOC) e 15 indivíduos saudáveis (GC), com idade média de 58,1±11 anos, antes e após uma atividade de simulação de vida diária, subir e descer degrau e, antes e após realizarem uma série de exercício com PEP. Resultados: Tanto a idade quanto os dados antropométricos da população estudada como peso e altura não mostraram diferença. Já as variáveis espirométricas mostraram diferença significativa, à favor do GC, conforme o esperado; não houve diferenças significativas na contribuição dos compartimentos toracoabdominal, em repouso, entre os grupos, com exceção do Ti/Tot no GDPOC, com mediana de 0,77 caracterizando possível hiperinsuflação ou fadiga muscular respiratória. Após o esforço físico, por 2 minutos, houve alteração na mobilidade toracoabdominal no grupo GDPOC, apresentou aumento da contribuição do compartimento abdominal, maior que o CG (52,2±12,6% x 41,1±14,6%). O mesmo aumento houve após a PEP, no GDPOC (50,5±19,1% x 36,9±16,4%). Após a PEP os pacientes do GDPOC tiveram uma normalização de Ti/Ttot, com mediana de 0,41. Quanto a análise dos compartimentos no GDPOC há uma participação maior do compartimento abdominal nos três momentos avaliados sendo que após PEP essa participação abdominal também é maior do que no GC. Conclusão: O esforço físico e o uso de PEP alteram a participação de compartimentos torácicos e abdominais, de forma diferente entre os grupos e, a PEP na DPOC parece contribuir para a redução da hiperinsuflação.

Accurate, cross-scanner assessment of in-vivo air density used to quantitatively assess amount and distribution of emphysema in COPD subjects has remained elusive. Hounsfield units (HU) within tracheal air can be considerably more positive than -1000 HU. With the advent of new dual-source scanners which employ dedicated scatter correction techniques, it is of interest to evaluate how the quantitative measures of lung density compare between dual-source and single-source scan modes. This study has sought to characterize in-vivo and phantom-based air metrics using dual-energy computed tomography technology where the nature of the technology has required adjustments to scatter correction. Anesthetized ovine (N=6), swine (N=13: more human-like rib cage shape), lung phantom and a thoracic phantom were studied using a dual-source MDCT scanner (Siemens Definition Flash. Multiple dual-source dual-energy (DSDE) and single-source (SS) scans taken at different energy levels and scan settings were acquired for direct quantitative comparison. Density histograms were evaluated for the lung, tracheal, water and blood segments. Image data were obtained at 80, 100, 120, and 140 kVp in the SS mode (B35f kernel) and at 80, 100, 140, and 140-Sn (tin filtered) kVp in the DSDE mode (B35f and D30f kernels), in addition to variations in dose, rotation time, and pitch. To minimize the effect of cross-scatter, the phantom scans in the DSDE mode was obtained by reducing the tube current of one of the tubes to its minimum (near zero) value. When using image data obtained in the DSDE mode, the median HU values in the tracheal regions of all animals and the phantom were consistently closer to -1000 HU regardless of reconstruction kernel (chapters 3 and 4). Similarly, HU values of water and blood were consistently closer to their nominal values of 0 HU and 55 HU respectively. When using image data obtained in the SS mode the air CT numbers demonstrated a consistent positive shift of up to 35 HU with respect to the nominal -1000 HU value. In vivo data demonstrated considerable variability in tracheal, influenced by local anatomy with SS mode scanning while tracheal air was more consistent with DSDE imaging. Scatter effects in the lung parenchyma differed from adjacent tracheal measures. In summary, data suggest that enhanced scatter correction serves to provide more accurate CT lung density measures sought to quantitatively assess the presence and distribution of emphysema in COPD subjects. Data further suggest that CT images, acquired without adequate scatter correction, cannot be corrected by linear algorithms given the variability in tracheal air HU values and the independent scatter effects on lung parenchyma.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22728号 / 医博第4646号 / 新制||医||1045(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 萩原 正敏, 教授 松田 道行 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM