A doença pulmonar obstrutiva crônica (DPOC) promove limitações mecânicas e encurtamento muscular que determinam a elevação do tórax, o aumento do volume residual e da capacidade residual funcional dos pulmões. Alterações do padrão torácico e na complacência pulmonar se correlacionar com as funções estomatognáticas por meio do osso hióide e da mandíbula. O objetivo deste estudo foi analisar a influência das desordens respiratórias decorrentes da DPOC no sistema estomatognático por meio de análise eletromiográfica. Participaram do estudo 40 indivíduos de ambos os gêneros com idade entre 40 e 80 anos, divididos em dois grupos: GD, grupo DPOC (n=20), média de idade de 65,65±8,11 anos e IMC de 24,92±2,97, estádio GOLD II a IV; e GC, grupo controle (n=20), idade média de 65,80±8,18 anos e IMC de 26,19±2,38, composto por indivíduos sem a doença. Os indivíduos foram submetidos as avaliações de eletromiografia de superfície para análise dos músculos do sistema respiratório e estomatognático; e força muscular respiratória por meio da manovacuometria. Os valores obtidos foram normalizados, tabulados e submetidos à análise estatística (SPSS versão 22.0) por meio do test t-student de amostras independentes (p<0,05). Em relação aos resultados, o sistema respiratório apresentou diferenças significativas (p<0,05) entre o GD e GC, em especial para o músculo diafragma nas condições clínicas de repouso, ciclo respiratório e inspiração máxima com menor atividade das fibras musculares, expiração máxima com maior atividade e redução da força muscular respiratória. O sistema estomatognático apresentou maior atividade (p<0,05) das fibras dos músculos masseteres nas condições clínicas de repouso e protrusão, e na lateralidade esquerda para os músculos temporal e esternocleidomastoideo direito, quando comparados os grupos GD e GC. Sugere-se, que as alterações encontradas na atividade do músculo diafragma decorrentes da restrição da mobilidade torácica, parecem estar relacionadas com alterações nas condições posturais da mandíbula, ocasionando aumento na atividade das fibras musculares relacionadas ao sistema estomatognático de indivíduos com DPOC. / Chronic obstructive pulmonary disease (COPD) promotes mechanical limitations and muscle shortening that determine chest elevation, leading to increased residual volume and functional residual capacity of the lungs. Changes in the thoracic pattern and pulmonary complacency are related to the stomatognathic functions through the hyoid bone and the mandible. We aimed to analyze the influence of respiratory disorders due to chronic obstructive pulmonary disease in the stomatognathic system. We divided 40 participants of both genders, ranging from 40 to 80 years old, into two groups: DG, COPD group (n = 20), average age 65.65 ± 8.11 years and body mass index (BMI) 24.92 ± 2.97, GOLD II to IV; and CG, control group (n=20), average age 65.80 ± 8.18 years and BMI 26.19 ± 2.38, composed of individuals without the disease. The participants underwent respiratory and stomatognathic surface electromyography evaluations, and respiratory muscle strength tests through manovacuometry. The values were subjected to t-student test of independent samples (p<0.05). The respiratory system showed significant alterations (p<0.05) between the DG and CG groups, especially for the diaphragm muscles in the clinical conditions of rest, respiratory cycle, and maximal inspiration with a lower recruitment of muscle fibers, greater muscle activity during maximal expiration, and reduction of respiratory muscle strength. The stomatognathic system indicated greater activity (p<0.05) in the recruitment of the fibers of the masseter in the clinical conditions of rest and protrusion, and in the left laterality to the temporal and right sternocleidomastoid muscles, when comparing the DG and CG groups. It was concluded that alterations in diaphragm muscle activity influence the postural conditions of the mandible due to the restriction of thoracic mobility, causing an increase in the recruitment of muscle fibers related to the stomatognathic system in individuals with COPD.

Le remodelage bronchique regroupe des entités physiopaphologiques commel’hypertrophie musculaire lisse dans l’asthme ou l’augmentation d’épaisseur bronchique surl’infiltration de cellules inflammatoires et l’accumulation de fibrose dans la BPCO. Cesremodelages sont corrélés à l’obstruction fonctionnelle et donc à la sévèrité de ces maladies.L’analyse de biopsies bronchique ou pulmonaire permet d’étudier ce phénoméne qui, aprèsune meilleure compréhension, est une cible thérapeutique intérressante. Le premier articleest une revue d’indications de bronchoscopie chez les patients de réanimation. La deuxièmeétude a montré une augmentation des fibrocytes sanguins au cours d’exacerbation sévèrede patient BPCO et une corrélation entre leur taux et le risque de décès du patient. La voiede signalisation du CXCR4 semble impliquée dans ce recrutement. La troisième étudecherche à explorer la localisation et les caractéristiques intra-pulmonaires des fibrocyteschez le patient BPCO à l’état stable. La quatrième étude a montré, in vivo, que le gallopamil,un inhibiteur calcique, pouvait diminuer la taille de muscle lisse bronchique de patientasthmatique sévère en ciblant la biogenèse mitochondriale. Ceci pourrait en faire une armethérapeutique interressante et totalement novatrice. La dernière étude a permis d’isoler unphénotype de patient asthmatique non sévère à « muscle lisse bronchique augmenté » quiprésente un risque accru d’exacerbation et de contrôle non optimal de leur asthme. Lesmitochondries semblent jouer un rôle clé comme dans l’asthme sévère. / Airway remodeling groups pathophysiological entities such as smooth musclehypertrophy in asthma or increase bronchial thickness due to infiltration of inflammatory cellsand fibrosis in COPD. These remodeling is correlated with the functional obstruction andtherefore with the severity of these diseases. The bronchial or lung biopsies analysis allowsto study this phenomenon which, after understanding, is an interesting therapeutic target.The first article is a review of indications of bronchoscopy in critically ill patients. The secondstudy showed an increase in blood fibrocytes during severe exacerbation of COPD patientand a correlation between their rate and the risk of patient death. CXCR4 signaling pathwayseems to be involved in the fibrocyte recruitment. The third study seeks to explore thelocation and characteristics of intra-pulmonary fibrocytes in stable COPD patients. The fourthstudy has shown, in vivo, that gallopamil, a calcium channel blocker, could reduce airwaysmooth muscle size in severe asthmatic patient by targeting mitochondrial biogenesis. Thiscould make it an interesting therapeutic weapon and totally innovative. The last study hasisolated a non-severe asthma phenotype with "increased bronchial smooth muscle," whichpresents an increased risk of exacerbation and a suboptimal control of their asthma. Themitochondria appear to play a key role as in severe asthma.

Abstract Reactive oxygen species (ROS) can cause severe damage to cells and organs but they are also important mediators of inflammatory responses and cellular signalling. Due to the significant role of ROS, the cells have evolved a broad antioxidative system to regulate the concentration of these species. Peroxiredoxins (Prxs) are enzymes that participate in the regulation of the cellular redox-homeostasis by detoxifying hydrogen peroxide. Prxs are not classified as conventional antioxidant enzymes and their physiological role, whether protective or regulatory, is still unclear. The aim of this project was to study the localization and regulation of Prxs in normal human lung and also their role in selected lung disorders (pulmonary sarcoidosis, pleural mesothelioma, lung carcinomas and chronic obstructive disorder, COPD). Additionally the expression of thioredoxin (Trx) and thioredoxin reductase (TrxR) was analysed in the lung of smokers and COPD patients. These enzymes are important reductants in cell and Prxs are one of their targets. Lung is an important organ in the field of ROS and antioxidant research since it is especially vulnerable to exogenous oxidative stress caused by pollutants, cigarette smoke and also by high oxygen pressure. The results showed that all six human Prxs were expressed in healthy human lung but in a cell-specific manner. The most prominent expression was detected in the epithelium and in macrophages, the cells most prone to oxidative stress. There were also differences in subcellular locations of Prxs. The expression of Prxs in non-malignant lung diseases (pulmonary sarcoidosis and COPD) and in smoker's lung was very similar with that in normal lung. Higher expression of Prx V and VI was detected in a subpopulation of macrophages sampled from COPD patients' lung. In contrast, Trx expression was induced in the bronchial epithelium of smoker's lung. Differences in the expression compared to normal lung were seen in lung malignancies (pleural mesothelioma and lung carcinomas). Interestingly, different Prxs were highly expressed in different types of carcinomas. In pleural mesothelioma, all Prxs except Prx IV were highly expressed when compared to normal pleura, in adenocarcinoma Prxs I, II, VI and especially IV, and in squamous cell carcinoma Prxs I, II and IV were upregulated. Tests performed on cultured cells in vitro revealed only a minor increase in the Prx expression after severe oxidant stress in malignant lung cell line originating from alveolar type II pneumocytes (A549) or non-malignant cell line derived from bronchial epithelium. None of the tested growth factors or cytokines affected Prx expression or oxidation state, but severe oxidant stress influenced remarkably the oxidation state of the Prxs.

Abstract Reactive nitrogen species (RNS) and reactive oxygen species (ROS) have been linked with the pathogenesis of lung malignancies and chronic obstructive pulmonary disease (COPD). In vitro studies indicated that mesothelioma and lung carcinoma cell lines synthesize nitric oxide synthases (NOS) mRNA. The Comet-assay indicated that asbestos fibers caused DNA single -strand breaks in mesothelial cells, and this effect was enhanced by glutathione depletion. The use of FPG in the Comet assay indicated that the asbestos induced DNA strand breaks were oxidant mediated. In vivo non-neoplastic pleura was mostly negative for inducible NOS (iNOS), while inflamed pleura was positive. The immunohistochemical expression of iNOS was detected in 74% and 96% of malignant mesotheliomas and metastatic pleural adenocarcinomas, respectively. Epithelial and mixed mesotheliomas expressed more often intense iNOS immunoreactivity compared to the sarcomatoid subtype. Normal mesothelial cells showed occasional positivity for endothelial NOS (eNOS), but reactive mesothelial cells were strongly stained. eNOS was found in 89% of mesotheliomas. Vascular endothelial growth factor (VEGF) was identified in 47%, a VEGF receptor FLK1 in 69% and the VEGF receptor, FLT1, in 71% of mesotheliomas. FLK1 or FLT1 immunoreactivities were more often seen in epithelioid and biphasic mesotheliomas than in sarcomatoid mesotheliomas. In lung samples of non-smokers, smokers and COPD patients, the levels of nitrotyrosine were higher in alveolar macrophages of smokers and COPD patients than in the non-smokers and in the alveolar epithelium of smokers and COPD patients than in the non-smokers. The iNOS expression was weak in the bronchial and alveolar epithelium in all groups but eNOS was most prominently expressed in alveolar macrophages while neuronal NOS (nNOS) was negative in all of the major cell types of the lung. Bronchial metaplasia-dysplasia-sequence was clearly positive for iNOS, nNOS and nitrotyrosine. Thus, smoking can cause protein nitration also in normal lung. Prominent iNOS and nNOS immunoreactivity in metaplasia-dysplasia-lesions suggests a divergent role of NOSs in carcinogenesis and destruction of alveolar epithelium in emphysematous lung. In lung cancer samples, iNOS was detected in 40% cases, while 89% and 81% cases were positive for eNOS and nNOS, respectively. Intense eNOS staining was seen more often in adenocarcinomas than in squamous cells carcinomas, and iNOS immunoreactivity was seen more often in grade I-II tumors than in grade III tumors. The patients with tumors showing high expression of iNOS, eNOS and nNOS, exhibited better survival, but this was not an independent prognostic factor.

Class of 2016 Abstract / Objectives: To assess the relationship between adherence to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for the management of chronic obstructive pulmonary disease (COPD) exacerbations and the corresponding 30-day, all-cause readmissions rate in a community hospital. Methods: A retrospective chart review was conducted on patients admitted with the primary diagnosis of a COPD exacerbation. Medications administration records relevant to the GOLD guidelines were examined as separate independent variables in relation to a readmission within 30 days of discharge. Additional factors examined included: demographic data, resident of a long-term care facility, pre-index hospitalization, pulmonary consult, vaccines, length of stay (LOS), discharge medications, and follow-up appointments. Results: Electronic health records of 120 patients were reviewed and divided into non-readmitted patients (n = 65, mean age 73.4 ± 10.1 years), all-cause readmissions (n = 55, mean age 70.15 ± 9.69 years), and COPD-related readmissions (n = 21, mean age 70.7 ± 11.1 years). Patients with heart failure (p = 0.024), a LOS >5 days (p = 0.045), a pre-index hospitalization (p = 0.001), or who were long-term care residents (p = 0.024) experienced more all-cause readmissions. Females experienced less all-cause readmissions (p = 0.035). Significantly more patients with a pre-index hospitalization had a COPD-related readmission (p = 0.027). Lastly, adherence to the GOLD treatment parameters was not significantly different across all groups. Conclusions: COPD is a complex disease and adherence to the GOLD guidelines during an exacerbation is unlikely to significantly impact 30-day readmission rates.

Research on sex and gender in chronic obstructive pulmonary disease (COPD) has primarily focused on differences in pulmonary function. Detailed gender- and sex-based analyses of other aspects of COPD, including epidemiology, risk factors other than cigarette smoke, pathophysiology, and measurement tools are warranted. In Chapter Two we analyzed administrative health services data to compare the prevalence, mortality and use of drugs and spirometry in men and women with COPD. Contrary to recent predictions, we did not detect a dramatic increase in the prevalence or mortality of COPD over time in women compared to men. We discuss how different coding practices in medical billing can impact the results. In Chapter Three we examined sex differences in COPD phenotypes. We hypothesized that male smokers would have more emphysema whereas female smokers would have more airway wall remodeling using data from high resolution computed tomography (HRCT) scans. We did detect more emphysema in male smokers but there was no evidence of increased airway remodeling in women. We discuss the limits of HRCT to detect airway differences in women and men. In Chapter Four we examined the use of HRCT in assessing emphysema. We hypothesized that the computer-derived estimates of emphysema (the fractal value and the % low attenuation area (%LAA)) would differentiate COPD from non-COPD as accurately as the radiologist’s emphysema scores, and would provide similar predictions in both men and women. Instead, we found that the subjective rating of emphysema best differentiated COPD, and the fractal value (a measure of emphysematous lesion size) better differentiated COPD compared with an established objective measurement, the %LAA. These results were generally the same in men and women. In Chapter Five we examined characteristics of COPD in women exposed to biomass smoke. We hypothesized that biomass smoke would induce an airway disease-predominant phenotype. We found that women with biomass smoke-exposed COPD had greater airway remodeling and less emphysema than women with tobacco smoke-exposed COPD. In summary, these findings suggest that sex and gender differences are present in COPD epidemiology and pathophysiology. However, current research measurement tools may limit the ability to accurately measure these differences. / Graduate and Postdoctoral Studies / Graduate

As a leading cause of disability that often leads to death, chronic obstructive pulmonary disease (COPD) can be characterized as both a chronic illness and a life-threatening one. As a result, the experience of individuals with COPD can include psychological concerns that are associated with both rehabilitation and palliative care. At the same time, the often-uncertain trajectory of COPD obscures a clear transition from rehabilitation to palliative care. It is not surprising, therefore, that treatments aimed at addressing patients’ rehabilitative and palliative needs largely proceed independently of each other. This dissertation contains two studies conducted with patients participating in a pulmonary rehabilitation program for COPD (N = 242). Separately, each study stems from a research tradition grounded in either the rehabilitative or palliative approach to treatment. Together, the studies highlight an opportunity for a model of more integrated care. Study 1 is derived from the rehabilitation literature and focuses on the issue of “catastrophizing” about breathlessness. Catastrophizing is characterized by a magnification of a symptom’s threat value, rumination about its perceived negative impact, and a sense of helplessness in addressing it. In some medical conditions with a primary symptom, such as chronic pain, catastrophizing demonstrates a strong relationship with the development of disability. Study 1 examines whether this relationship is found in the context of breathlessness. The study also reports the initial validation of the Breathlessness Catastrophizing Scale (BCS) as a means of assessing this phenomenon. Study 2 has its conceptual basis in the palliative care literature and highlights patients’ existential concerns around loss of dignity. Loss of dignity is a central construct in recent health care debates, because it is a primary reason underlying the requests of terminally ill individuals to seek medically hastened deaths (i.e., euthanasia or assisted suicide). Until now, however, loss of dignity has only been examined among patients with cancer. Study 2 examines whether loss of dignity is as prevalent among those with advanced COPD, and whether it improves with treatment. In Study 1 the BCS was found to be a reliable measure of breathlessness catastrophizing, with good convergent validity and sensitivity to change. Interestingly, it appears that breathlessness catastrophizing need not be a barrier to functional improvement in COPD. In Study 2, a “fractured” sense of dignity was found among 13% of patients with advanced COPD, suggesting that it is at least as prevalent as among those receiving palliative cancer care. It was also evident that loss of dignity is amenable to change with appropriate rehabilitation. This finding is important for societal debates regarding the provision of medically hastened deaths, which are often described as offering “death with dignity”. Together these studies demonstrate that in an interdisciplinary environment, such as the pulmonary rehabilitation program, not only is collaboration possible, but the distinct rehabilitative and palliative needs of patients can be met.

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

This paper examines the influence of air pollution on humans. Suggesting the possible consequences of each action of air pollutants on human health but also the possible economic impacts of air pollution. It primarily exploers the effects of concentration of suspended particulate matter (PM10) on the incidence of chronic obstructive pulmonary disease. The response variable in the regression model serves to determine the effect of PM10 on the incidence of chronic obstructive pulmonary disease was a percentage share of patients with chronic obstructive pulmonary disease among the clients of the General Health Insurance Company in individual regions of the Czech Republic. Explanatory variables were the mean annual concentration of PM10 and gross added value per capita. The model suggests that there is a statistically significant positive correlation between the incidence of chronic obstructive pulmonary disease in the Czech Republic and PM10 concentrations.

Introduktion: Kroniskt obstruktiv lungsjukdom (KOL) är en sjukdom som kännetecknas av ihållande luftvägssymtom och begränsningar i luftflöde. Personer med KOL är betydligt mindre aktiva än friska individer. Sänkt fysisk aktivitet är en stark prediktor för mortalitet för personer med KOL.   Syfte: Syftet med denna studie var att undersöka om motiverande samtal om fysisk aktivitet kan användas som intervention för personer med KOL för att påverka self-efficacy (ESES) för fysisk aktivitet samt nivå av ångest och depression. Syftet är även att undersöka om det finns ett samband mellan förändring i self-efficacy samt förändring av fysisk förmåga.   Metod: Studien inkluderar data från 83 deltagare. Under en 6 månader lång interventionsfas har testdeltagarna fått motiverande samtal om fysisk aktivitet. Vår statistiska analys inkluderar hypotesprövning av skillnader på utvalda enkäter. Hypotesprövning av samband har gjorts med Pearsons r.    Resultat: Motiverande samtal ledde till en signifikant ökad self-efficacy gällande fysisk aktivitet efter intervention (m=23.8; sd=7.43) jämfört med före intervention (m=22.3; sd=7.04) med motiverande samtal (p=0.025). Ingen effekt påvisades beträffande ångest och depression. Det finns ett statistiskt signifikant samband (p = &lt;0.001) mellan självskattad self-efficacy gällande fysisk aktivitet och fysisk förmåga mätt med 6-minuters gångtest efter 6 månader. Sambandet var svagt positivt (Pearsons r = 0.410).   Konklusion: Motiverande samtal har visats förbättra self-efficacy, det vill säga tilltro till egen förmåga att utföra fysisk aktivitet. Det finns ett samband mellan tilltro till egen förmåga samt fysisk kapacitet, vilket kan betyda att motiverande samtal är en bra intervention för svårt sjuka personer med KOL.