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’ 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’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´ 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’ reasons for change, fostered collaboration and supported patients’ 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’ 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’ 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’ 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’ perceived QoL, on the number of patients who quit smoking and on patients’ 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.

Diss. (sammanfattning) Umeå : Umeå universitet, 2010.

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.

?rea de concentra??o: Ci?ncias Fisiol?gicas. / Submitted by Jos? Henrique Henrique (jose.neves@ufvjm.edu.br) on 2017-10-26T18:38:02Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) vanessa_kelly_silva_lage.pdf: 1557890 bytes, checksum: f19cfa3f49dfb4300750d35b50ea527f (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2017-11-08T14:15:37Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) vanessa_kelly_silva_lage.pdf: 1557890 bytes, checksum: f19cfa3f49dfb4300750d35b50ea527f (MD5) / Made available in DSpace on 2017-11-08T14:15:37Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) vanessa_kelly_silva_lage.pdf: 1557890 bytes, checksum: f19cfa3f49dfb4300750d35b50ea527f (MD5) Previous issue date: 2017 / A Doen?a Pulmonar Obstrutiva Cr?nica (DPOC) ? caracterizada por uma obstru??o cr?nica persistente ao fluxo a?reo. Estudos que avaliaram o uso da vibra??o de corpo inteiro (VCI) em pacientes com DPOC demonstraram melhora em par?metros cl?nico-funcionais, contudo, o conhecimento a respeito do efeito agudo da VCI na DPOC ainda ? escasso O estudo teve como objetivo, caracterizar a intensidade do exerc?cio em diferentes frequ?ncias de VCI e dos tipos de agachamento (est?tico ou din?mico) durante uma sess?o de exerc?cio, bem como, avaliar o efeito agudo do exerc?cio sobre as respostas cardiorrespirat?rias e inflamat?rias na DPOC.Os volunt?rios da pesquisa foram pareados quanto ao sexo, idade, IMC e foram divididos em 2 grupos, sendo eles: grupo controle (GC, n=13), composto por sujeitos sem DPOC e grupo DPOC (DPOC, n=13). A familiariza??o e aplica??o do Teste de Caminhada de 6 minutos foram realizadas em 1 dia, ap?s 1 semana, a caracteriza??o com o exerc?cio de VCI foi realizada em 4 dias com um intervalo de 48 horas entre as sess?es. O agachamento est?tico foi realizado nas frequ?ncias 30, 35 e 40 Hz e o agachamento din?mico na frequ?ncia 35 Hz. Os dois grupos passaram pelas mesmas condi??es experimentais. Foram mensurados os par?metros cardiorrespirat?rios durante todos os dias de exerc?cio e os par?metros inflamat?rios foram avaliados durante o exerc?cio est?tico na frequ?ncia de 35 Hz atrav?s da concentra??o plasm?tica da adiponectina, resistina, IL-6, IL-8, IL-10, BDNF e receptores sol?veis de TNF (STNFR-1 e STNFR-2). Os resultados demonstraram que o agachamento est?tico promoveu maior varia??o (39,2%) na FC quando comparado ao din?mico. A an?lise nas 3 frequ?ncias de VCI demonstraram comportamento semelhante entre os grupos com aumentos significativos do VO2 (GC: 27,4 a 40% e DPOC: 21,5 a 28,5%) e da FC (GC: 10,2 a 12,5% e DPOC: 4,3 a 12,7%). Foram encontradas altas concentra??es basais das adipocinas e IL-8 e baixos valores de IL-10 no grupo DPOC. Ap?s a VCI foi observado aumento das concentra??es de IL-10 (40,6%) no grupo DPOC alcan?ando valores semelhante a concentra??o basal do GC. Em conclus?o, o presente estudo traz subs?dios para a elabora??o de protocolos de treinamento com a VCI, uma vez que o exerc?cio foi caracterizado como de baixa intensidade (<2 METs) nas frequ?ncias avaliadas, sendo aplic?vel e seguro na DPOC. Adicionalmente, a VCI parece modular as concentra??es de IL-10 na popula??o de DPOC avaliada. / Disserta??o (Mestrado) ? Programa Multic?ntrico de P?s-gradua??o em Ci?ncias Fisiol?gicas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2017. / Chronic Obstructive Pulmonary Disease (COPD) is characterized by chronic persistent airflow obstruction. Studies evaluating the use of whole body vibration (WBV) in patients with COPD have shown improvement in clinical-functional parameters, however, knowledge about the acute effect of WBV in COPD is still scarce. The objective of this study was to characterize the intensity (static or dynamic) during an exercise session, as well as to evaluate the acute effect of exercise on cardiorespiratory and inflammatory responses in COPD. The study volunteers were matched for gender, age, BMI and were divided into 2 groups: control group (GC, n = 13), composed of subjects without COPD and COPD group (COPD, n = 13). Familiarization with WBV exercise and the application of the 6-minute Walk Test were performed in one day, after 1 week, the characterization of the WBV exercise was performed in 4 days with a 48-hour interval between sessions. Static squatting was performed at frequencies 30, 35 and 40 Hz and dynamic squatting at 35 Hz frequency. Both groups underwent the same experimental conditions. Cardiorespiratory parameters were measured during all exercise days and inflammatory parameters were evaluated during static exercise at the 35 Hz frequency through the plasma concentration of adiponectin, resistin, IL-6, IL-8, IL-10, BDNF and soluble TNF receptors (STNFR-1 and STNFR-2). The results showed that static squatting promoted greater variation (39.2%) in HR when compared to dynamic. The analysis of 3 frequencies of WBV showed similar results between the groups with significant increases in VO2 (GC: 27.4 to 40% and COPD: 21.5 to 28.5%) and HR (CG: 10.2 a 12.5% e COPD: 4.3 a 12.7%). Baseline concentrations of adipokines and IL-8 showed higher values, in the other hand low IL-10 values were found in the COPD group. After WBV, an increase in IL-10 concentrations (40.6%) was observed in the COPD group reaching values similar to basal GC concentration. In conclusion, the present study provides subsidies for the elaboration of training protocols with WBV, since exercise was characterized as low intensity (<2 METs) in the frequencies evaluated, being applicable and safe in COPD. In addition, VCI appears to modulate IL-10 concentrations in the COPD population evaluated.

La BPCO se traduit rapidement par l'apparition d'une susceptibilité aux infections liées aux atteintes des mécanismes de défense du poumon. Les travaux antérieurs de l’équipe montrent qu'une altération de la réponse IL-17/IL-22 et de la fonction des cellules dendritiques (DC) participe au développement de l’exacerbation de la BPCO par les bactéries. Les mécanismes responsables de ce défaut de réponse ne sont pas élucidés. Au cours de cette thèse, nous nous sommes intéressés aux points suivants :1-Mécanismes cellulaires responsables du défaut de production d'IL-17 et d'IL-22 au cours de l'infection.Les cellules présentatrices d'antigène (APC) et en particulier, les DC jouent un rôle essentiel dans la réponse antimicrobienne, par leur fonction de phagocytes et par l’activation et la polarisation de cellules immunitaires innées et adaptatives. Sur des modèles murins d’exacerbation de la BPCO par Streptococcus pneumoniae ou Haemophilus influenzae non typable (NTHi), nous avons réalisé des tris de macrophages, DC et monocytes inflammatoires du poumon par cytométrie en flux. Ces analyses montrent que les cellules APC pulmonaires présentent des altérations fonctionnelles aboutissant à une limitation de leur capacité à polariser la réponse Th17 de Lymphocytes T CD4+. Une analyse transcriptomique est également effectuée sur les ARN des APC triées afin de préciser les altérations fonctionnelles de ces cellules par rapport aux souris contrôles.2-Rôle des cytokines IL-20 dans la susceptibilité à l'infection et l'exacerbation de la BPCO Myles et al ont montré en 2013 que les cytokines IL-20 (IL-19, IL-20 et IL-24) jouent un rôle délétère dans la réponse immunitaire cutanée contre Staphylococcus aureus par un mécanisme impliquant une inhibition indirecte d’IL-17 produite par les cellules T. La fonction des DC peut être affecté par l'environnement cytokinique. Comme les cytokines IL-20 sont surexprimées chez les souris BPCO, notre objectif a été de définir leur rôle au cours de l'exacerbation de la BPCO et l'impact de ces cytokines sur les DC dans ce contexte.Dans notre modèle d’exacerbation de la BPCO, nous avons bloqué cette voie en neutralisant l'IL-20RB qui est commune aux 2 récepteurs de ces cytokines afin d’étudier leur impact sur l'exacerbation et sur la réponse immune associée, notamment la réponse IL-17/IL-22. En parallèle, nous avons analysé la modulation de la fonction des DC humaines par ces cytokines dans un contexte d'infection bactérienne. Nos résultats montrent que le traitement avec l'anticorps bloquant anti-IL-20RB permet de bloquer le développement de l'exacerbation de la BPCO en diminuant la charge bactérienne et l'inflammation associée. Cet effet est associé à une diminution importante de la mobilisation des DC dans le poumon mais sans affecter sur la réponse IL-17/IL-22. In vitro, les cytokines IL-20 sont produites par les DC dans un contexte infectieux. De plus, ces cytokines sont capables de diminuer l'activation des ces cellules par les bactéries et de réduire leur capacité à activer les Lymphocytes T dans ce contexte.3-Capacité d'un immunostimulant à restaurer la réponse IL-17/IL-22, et à limiter le développement de l'exacerbation.L’utilisation d’immunostimulant dont la flagelline (agoniste du TLR-5, principale composante du flagelle bactérien) est souvent proposé comment pouvant promouvoir la réponse immunitaire des muqueuses et en particulier la réponse IL-17/IL-22. Nous avons analysé la capacité de cet agoniste du TLR-5 à améliorer la réponse à S. pneumoniae et NTHi dans notre modèle d’exacerbation de la BPCO.Le traitement par la flagelline permet de limiter les conséquences de l'infection bactérienne chez les souris BPCO en diminuant l'inflammation et les lésions pulmonaires associées. L'effet de ce ligand de TLR est au moins en partie dépendant de la production d'IL-22._A terme, ces données permettent d'envisager de nouvelles options thérapeutiques pour le traitement des exacerbations de la BPCO. / Patients with COPD often presented a susceptibility to respiratory infections. Previous works in our lab have showed that a defect of IL-17/IL-22 response and an altered dendritic cell (DC) function is involved in COPD exacerbation with bacteria. However, the mechanism responsible for this defect is not elucidated yet. In order to better define these mechanisms and to develop new therapeutic approaches against COPD exacerbation, we focused on the following points during this PhD project:1-Cellular mechanisms responsible of the defect of IL-17 and IL-22 production during infection in COPD.Antigen presenting cells (APC) particularly, DC are essential in antimicrobial immune response since they are professional phagocytes able to engulf and kill bacteria, but also by their essential role in the polarization of innate and adaptive immune responses. We worked on COPD exacerbation mice model infected with Streptococcus pneumoniae or Nontypeable Haemophilus influenzae (NTHi). APC including macrophages, DC and inflammatory monocytes were sorted by flow cytometry for phenotype and functional analysis. We found an altered function of these lung APC showing limited capacity of Th17 polarization. Transcriptional analysis on total RNA from sorted APC is performed to decipher the mechanisms involved in this functional alteration regarding to control mice.2-The role of IL-20 cytokines in the susceptibility to infection during COPD exacerbation.Myles et al showed in 2013 that IL-20 cytokines (IL-19, IL-20 and IL-24) are deleterious in skin immune response against Staphylococcus aureus. Indeed, these IL-20 cytokines indirectly inhibited IL-17 produced by T cells. The function of DC is also controlled by the presence of cytokines in the microenvironment. Because IL-20 cytokines are overexpressed in COPD, we aimed to determine their role during COPD exacerbation and the impact on DC.We used IL-20RB (common subunits of the 2 receptors) neutralizing antibodies to blocked IL-20 cytokines in COPD exacerbation mice model. We analyzed the impact of this treatment on the immune response, more particularly IL-17/IL-22 response. In addition, we analyzed the modulation of human monocyte derived DC (MDDC) function by IL-20 cytokines in the context of bacterial infection.Our results shows that treatment with IL-20 RB neutralizing antibodies limited COPD exacerbation by reducing the bacterial burden and the associated inflammatory response. This process was associated to reduced number of DC in the lung without impacting IL-17 and IL-22 production. In vitro, MDDC produced IL-20 cytokines upon bacterial infection. Additionally, these cytokines impaired MDDC activation following bacterial infection, which was associated to a reduced capacity of MDDC to activate T lymphocytes.3-The possibility to restore IL-17 and IL-22 response with immuno-stimulants in order to limit the development of COPD exacerbation.Flagellin (a TLR-5 agonist, the main component of bacterial flagellum) is an immuno-stimulant often used to promote mucosal immune response. This activity is related to its ability to promote IL-17 and IL-22 production. In this PhD work, we analyzed the capacity of this TLR-5 agonist to improve the immune response during S. pneumoniae and NTHi infection in COPD exacerbation mice model.Flagellin treatment reduced the bacterial burden and limited the consequences of bacterial infection in COPD mice, by lowering the inflammation and the associated lung remodeling. We also found that the immunomodulatory effect of flagellin was at least partially IL-22 dependent.Finally, these data allow to identify new therapeutic tools potentially useful for the treatment of COPD exacerbations.

Introdução: A DPOC caracteriza-se pela limitação ao fluxo aéreo associada à resposta inflamatória anormal dos pulmões a partículas ou gases nocivos. As alterações mecânicas decorrentes da DPOC estão relacionadas com a disfunção mecânica das fibras do diafragma, já observadas nas fases iniciais da doença. Alguns estudos têm demonstrado o elevado potencial da Técnica de Oscilações Forçadas (FOT) na detecção das alterações mecânicas da DPOC. Contudo, tais aplicações da FOT não permitiam a análise em tempo real das alterações do sistema respiratório, bem como da mobilidade toracoabdominal destes indivíduos. Desta forma, os objetivos desta pesquisa foram analisar, em tempo real, as alterações de impedância do sistema respiratório nas distintas fases do ciclo em portadores de DPOC, assim como avaliar a movimentação toracoabdominal destes indivíduos. Metodologia: Trata-se de um estudo observacional controlado, prospectivo onde foram analisados 48 indivíduos, 23 indivíduos controles e 25 portadores de DPOC com grau de obstrução acentuado. Os indivíduos realizaram exames de FOT para análise da impedância do sistema respiratório e mobilidade toracoabdominal, simultaneamente. Posteriormente aos exames da FOT os indivíduos foram submetidos à Espirometria. Resultados: Os resultados demonstraram aumento da impedância do sistema respiratório nos indivíduos com DPOC em comparação ao grupo controle, em nos parâmetros estudados (Zt, Zi, Ze, Zii, Zie, Zrs e Zpp) (p<0,0001). Em relação às distintas fases do ciclo, os indivíduos deste estudo apresentaram impedâncias maiores na fase inspiratória quando comparadas à fase expiratória (p<0,004). Somente 10% dos portadores de DPOC apresentaram assincronia toracoabdominal (&#966; &#8805; 45), sendo que os valores médios não apresentaram diferença estatística quando comparados ao grupo controle. Discussão: A impedância total do sistema respiratório (Zt) aumentada nos portadores de DPOC confirma o aumento da carga mecânica do sistema respiratório destes indivíduos. Essas alterações são coerentes com o processo fisiopatológico, evidenciado pela obstrução ao fluxo aéreo e destruição do parênquima pulmonar. O aumento da impedância na fase inspiratória quando comparada à fase expiratória, sugere um aumento no trabalho resistivo e elástico. Não foram evidenciados sinais de assincronia na mobilidade toracoabdominal na maior parte dos indivíduos, sugerindo que alguns mecanismos adaptativos atuam na tentativa de evitar a fadiga do músculo respiratório. Conclusões: A DPOC resulta no aumento da carga mecânica do sistema respiratório, alterações identificadas pelo aumento da impedância do sistema respiratório, medida pela FOT em tempo real. Este aumento foi mais evidente durante a fase inspiratória. A mobilidade toracoabdominal não se mostrou alterada na maior parte dos indivíduos com DPOC. Estes resultados são consistentes com publicações prévias e fundamentos fisiopatológicos, confirmando o potencial da FOT monofreqüência na avaliação das modificações relacionadas à DPOC. / Introduction: COPD is carachterized by airflow limitation associated abnormal inflammatory response of the lung to noxious particles or gases. The mechanical alterations associated with COPD have been related with dysfunction of the diaphragm, observed since the initial phases of the disease. Several studies have confirmed the high potential of FOT in the assessment of the mechanics modifications related to COPD. However, such studies did not allow a real-time analysis of the changes in the respiratory system, and the thoracoabdominal mobility of these individuals. Thus, the goals of the present study were to analyze, in real-time, the impedance alterations of the respiratory system in different phases of the respiratory cycle of COPD patients. Methodology: This research consists of a controlled observational study where 48 individuals were analyzed, 23 controls and 25 individuals with COPD and severe airway obstruction. Firstly, they performed simultaneous analysis of impedance of the respiratory system and thoracoabdominal motion. In subsequent examinations, these subjects were submitted to spirometry. Results: The results demonstrated an increase of the respiratory system impedance in individuals with COPD compared with the control group in all of the studied parameters (Zt, Zi, Ze, Zii, Zie, &#916;Zrs e Zpp) (p<0.0001). Considering the different phases of the respiratory cycle, higher impedances were observed in the inspiratory phase (p<0.004). Only 10% of individuals with COPD showed thoracoabdominal asynchrony (&#966;&#8805; 45), and the mean values showed no statistical difference when compared to the control group. Discussions: The total impedance of the respiratory system increased in individuals with COPD, which describes the increase of the mechanic load of the respiratory system in these individuals. These alterations are coherent with the physiopathology of COPD, associated with airflow obstruction and lung parenchyma destruction. The increase of the impedance in the inspiratory phase suggests an increase of the resistive and elastic work. There were not signals of thoracoabdominal asynchrony in the major part of the studied individuals, suggesting that some adaptation mechanisms act to compensate respiratory muscle fatigue. Conclusion: The COPD results in the increase of the mechanic load of the respiratory system. These alterations were identified by the increase of the respiratory system impedance, which was more evidence in the inspiratory phase. The thoracoabdominal asynchrony was not usual in individuals with COPD. Those results are consistent with previously published data and physiopathological fundamentals, confirming the potential of monofrequency FOT in the assessment of the modifications related to COPD.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A doença pulmonar obstrução crônica (DPOC) é caracterizada pela limitação de fluxo parcialmente reversível, classificada por níveis de obstrução pós-broncodilatador. Há várias evidências de que o FEV1 sozinho não é capaz de mostrar a broncodilatação de pacientes com DPOC, mesmo naqueles que apresentam melhora clínica. A técnica de oscilações forçadas (TOF) tem mostrado alta sensibilidade na detecção precoce de alterações mecânicas na DPOC, contudo o efeito broncodilatador na impedância respiratória de pacientes com DPOC ainda não está esclarecido. Objetiva avaliar a utilidade da TOF nos diferentes estágios de obstrução das vias aéreas; (2) avaliar a resposta da impedância respiratória ao salbutamol em indivíduos saudáveis ao exame espirométrico e pacientes com DPOC em diferentes graus de gravidade. Foram avaliados 25 indivíduos saudáveis sem história de tabagismo, 24 tabagistas e 151 pacientes com DPOC classificados em graus I, II, III e IV. Todos os sujeitos foram avaliados pela TOF seguida da espirometria, antes e após o uso do salbutamol spray. As curvas de resistência e reatância demonstraram alteração em todos os estágios de obstrução das vias aéreas após o uso do salbutamol. O grupo de risco apresentou alterações mecânicas semelhantes ao grupo leve (p=ns). Os parâmetros R0, Rm, Csr,din e Z4Hz apresentam desempenho diagnóstico adequado (AUC > 0,85) em todos os estágios de gravidade da doença. Todos os parâmetros de TOF e espirometria apresentaram diminuição após uso do salbutamol. Os indivíduos saudáveis apresentaram uma pequena diminuição comparada aos subgrupos de DPOC. A variação em termos absolutos da &#916;Z4Hz e das derivadas da resistência, &#916;R0, &#916;Rm, &#916;S, apresentaram variação significativa (p<0,0001, p<0,003; p<0,04; p<0,0002, respectivamente) com o aumento da obstrução brônquica. Nas derivadas da reatância o &#916;Xm aumentou com a gravidade da doença (p<0,0002). Por outro lado, a &#916;Crs,dyn não demonstrou diferença significativa com a gravidade da DPOC. Em termos percentuais os parâmetros da TOF apresentaram variação expressiva em &#916;Rm% (p<0,02), &#916;S% (p<0,02) e &#916;Xm% (p<0,004) com o aumento da obstrução nas vias aéreas. Por outro lado, &#916;R0%, &#916;Crs,dyn% e &#916;Z4Hz% não variaram entre os estágios da DPOC. A associação entre a broncodilatação nas vias aéreas e a impedância pulmonar foi fraca entre &#916;Xm vs &#916;FVC (r=0,32, p<0,0001) e &#916;Z4Hz% vs &#916;FEV1% vs &#916;FVC% (r=0.28, p<0,0005; r=0,29, p<0,0003, respectivamente). A TOF é útil na avaliação das alterações mecânicas nos diferentes níveis de obstrução das vias aéreas na DPOC. Demonstramos o benefício da medicação broncodilatadora, quantificando a melhora da ventilação através da TOF. A impedância respiratória diminui em todos os estágios da DPOC, o estágio leve melhorou tanto quanto o estágio muito grave. Isto sugere que a medida da impedância pulmonar não é dependente do volume como ocorre na espirometria e que a broncodilatação ocorre em todas as fases da progressão da DPOC. / Chronic obstructive pulmonary disease (COPD) is characterized by partially reversible flow limitation, classified by the post-bronchodilator level of airway obstruction. There is abundant evidence that FEV1 alone is not able to show bronchodilation in COPD patients, even in patients with clinical improvement. The forced oscillation technique (FOT) has shown high sensitivity for early detection of mechanical changes in COPD. However, the bronchodilator effect on respiratory impedance is still unclear. Objective to evaluate the utility of FOT in the diagnosis of different stages of airway obstruction, (2) to investigate the response to salbutamol in healthy, smoking and COPD patients in different degrees of severity. We evaluated 25 healthy subjects with no history of smoking, 24 smokers and 151 COPD patients classified into grades I, II, III and IV of severity. All subjects were assessed by the FOT followed by spirometry before and after the use of salbutamol spray. The resistance and reactance curves showed change at all stages of airway obstruction after the use of salbutamol. The smoking group showed similar mechanical changes to the mild group (p=ns). The parameters R0, Rm, Csr,din and Z4Hz presented adequate diagnostic accuracy (AUC>0.85) in all stages of disease severity. All FOT and spirometry parameters showed decreased after salbutamol use. Healthy individuals showed a small decrease compared with the subgroups of COPD. The variations of the impedance module (&#916;Z4Hz) and resistance parameters, (&#916;R0, &#916;Rm, &#916;s) were significant (p<0.0001, p<0.003, p<0.04 and p<0.0002, respectively) with increased bronchial obstruction. Mean reactance (&#916;Xm) increased with disease severity (p<0.0002). The &#916;Crs,dyn showed no significant change with the severity of COPD. In percentage terms, FOT parameters showed significant variation in &#916;Rm% (p<0.02), &#916;s (p<0.02) and &#916;Xm% (p<0.004) with increased airway obstruction. &#916;R0% &#916;Crs,dyn% and &#916;Z4Hz% did not vary between different stages of COPD. The association between bronchodilation in the airways and lung impedance was weak between &#916;Xm vs &#916;FVC (r=0.32, p<0.0001) and &#916;Z4Hz% vs &#916;FEV1% vs &#916;FVC% (r=0.28, p<0.0005, r=0.29, p<0.0003, respectively). The FOT is useful in the evaluation of the mechanical changes at different levels of airway obstruction in COPD. We demonstrate the benefit of a bronchodilator, quantifying the improvement of ventilation through the FOT. The respiratory impedance decreases in all stages of COPD. This suggests that the impedance changes are not dependent on lung volume as in spirometry and that bronchodilation occurs at all stages of the progression of COPD.

Made available in DSpace on 2016-06-02T20:19:05Z (GMT). No. of bitstreams: 1 DissKTM.pdf: 1102711 bytes, checksum: d76e056aa60fb57b915498ceaff325b0 (MD5) Previous issue date: 2007-02-23 / Universidade Federal de Sao Carlos / Objective: To compare the effects of different physiotherapeutic intervention during simulation of activities of daily living (ADL) in patients with chronic obstructive pulmonary disease (COPD) moderate to severe. Methods: Thirty one patients with COPD (30%&#8804;forced expiratory volume in first second (FEV1)<80% of predict), randomized in: Group PT (GPT, n=8): physical training (PT) in treadmill for 30 minutes; Group NIV (GNIV, n=9): PT associated to non-invasive ventilation (NIV) for 30 minutes; Group MT (GMT, n=8): PT of upper-limb and Control Group (CG, n=6), enduring six weeks, three times for week. In the test of ADL simulated: to erase blackboard, catch weight, elevate weight, sweep, to climb steps and walk in the treadmill, realizing five minutes each activity, except climb steps and walk with duration of six minutes. Results: Intragroup analysis: significative reduction of E/MVV in the post-treatment for PTG and NIVG in basal and walk. The MTG showed significative decrease erasing the blackboard and walk, being similar as for O2/ O2max. The dyspnea showed significative reduction for PTG to the walk, and increase in the CG post-treatment. The number of climbs on the steps redu / Objetivo: Comparar os efeitos das diferentes intervenções fisioterapêuticas na simulação das atividades da vida diária (AVD) realizadas por pacientes com DPOC apresentando obstrução moderada a grave. Métodos: Trinta e um indivíduos com DPOC (30%&#8804;volume expiratório forçado no primeiro segundo (VEF1)<80% do previsto) randomizados em Grupo TF (GTF, n=8): treinamento físico (TF) em esteira rolante; Grupo VNI (GVNI, n=9): TF em esteira rolante associado à ventilação nãoinvasiva (VNI); Grupo TM (GTM, n=8): TF dos membros superiores (MMSS) e Grupo Controle (GC, n=6), por seis semanas, três vezes por semana. No teste das AVD simulava-se: apagar lousa, pegar peso, elevar peso, varrer, subir degrau e caminhar na esteira, com cinco minutos cada atividade, exceto subir degrau e caminhar que duravam seis minutos. Resultados: Análise intragrupo: redução significante da E/VVM no póstratamento para GTF e GVNI no basal e ao caminhar e diminuição significante ao apagar lousa e caminhar para GTM, sendo semelhante quanto à O2/ O2max para este grupo. A dispnéia reduziu significantemente para GTF ao caminhar pós-tratamento e aumentou no GC. O número de subidas no degrau reduziu significantemente para GC e aumentou no pós-tratamento para GTF, GVNI e GTM, bem como distância percorrida no GTF. Análise intergrupos: diferença significante para dispnéia no pós-tratamento, sendo maior para GC ao caminhar. Conclusão: Diferentes protocolos de TF utilizados proporcionaram benefícios à tolerância ao exercício físico, destacando que GTM apresentou melhor desempenho na atividade envolvendo sustentação dos MMSS, sugerindo adaptações metabólicas e melhor coordenação dos músculos participantes da elevação dos MMSS.