Bakgrund: Kronisk obstruktiv lungsjukdom (KOL) är en av de tre främsta dödsorsakerna i världen. Samtidigt har den psykiska ohälsan i världen ökat drastiskt och psykologiska besvär som ångest och depression orsakar en tydlig börda av dödlighet och sjuklighet hos patienter med KOL. Andfåddheten som är ett av symtomen vid KOL beskrivs som en orsak till ångest och depression, vilket i sin tur förvärrar sjukdomstillståndet för patienterna. Syfte: Syftet var att belysa patienters upplevelser av ångest och depression vid kronisk obstruktiv sjukdom. Metod: Studiens design avser en allmän litteraturöversikt med kvalitativ ansats där syftet är att få en bredare bild på kunskapsområdet som studeras. Resultat: I studien presenteras följande huvudteman, det akuta behovet av luft, samt känsla av ensamhet som lidande, oförmågan att hantera aktiviteter i dagliga livet eller komplikationer, upplevelser av dödsångest. Vidare följt av följande subteman:  upplevelser av att andfåddheten utvecklar ångest, upplevelser av att sjukdomen stryper och kväver en, upplevelser av en ond cirkel, upplevelser av sjukdomens påverkan på det sociala livet, upplevelser av ofrivillig ensamhet och depression, upplevelser av att vara ovärdig och inte värdig, upplevelser av att vara beroende av andra, samt upplevelser av att behöva uppsöka akut vård kontinuerligt. Slutsatser: Patienter med KOL upplever ångest och depression till följd av sin sjukdom. Symtomen orsakar både psykiska och fysiska påfrestningar, vilket begränsar det vardagliga livet. Känslan av ångest och depression blir allt mer påtaglig i takt av sjukdomens förlopp. / Background: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world. Mental illness in the world has increased drastically and psychological problems such as anxiety and depression cause a clear burden of mortality and morbidity in patients with COPD. The shortness of breath that is one of the symptoms of COPD is described as a cause of anxiety and depression. Purpose: The purpose was to shed light on patients' experiences of anxiety and depression in chronic obstructive disease. Method: The design refers to a systematic literature review where the aim is to get a broader picture of the area of knowledge studied. This has been done as a result of previous empirical studies. Results: Four main themes were identified, the urgent need for air, the feeling of loneliness as suffering, the inability to manage activities of daily living or complications, and experiences of death anxiety.   Following of nine subthemes, experiences of shortness of breath developing anxiety, experiences of the disease strangling and suffocating, experiences of a vicious circle, experiences of the disease's impact on social life, experiences of involuntary loneliness and depression, experiences of being unworthy and not worthy, experiences of being dependent on others, and experiences of having to seek emergency care continuously. Conclusions: Patients with COPD experience anxiety and depression as a result of their disease. The symptoms cause both mental and physical stress, which limits everyday life. The feeling of anxiety and depression becomes more and more noticeable as the disease progresses.

Thesis (PhD (Sport Science))--Stellenbosch University, 2008. / The benefits of exercise training for patients with chronic obstructive pulmonary disease (COPD) are well-documented. In South Africa, exercise programmes for COPD patients are limited and often expensive and inaccessible to the broader community. The purpose of this study was to assess the responses of COPD patients to an exercise programme and to determine if the same results can be obtained through a less costly programme. In the primary programme of the study, 22 subjects were subjected to 12 weeks of exercise training. Each subject underwent comprehensive pre- and post-intervention assessments, which included the measurement of overall health status by a physician, level of dyspnoea, forced expiratory lung function, exercise capacity, body mass index and health-related quality of life. Exercise sessions included aerobic and strength training exercises and involved three, hour-long exercise sessions a week. In the modified programme, 18 subjects were randomly divided into an experimental and control group. Eleven subjects were included in the experimental group and seven subjects in the control group. Subjects had to complete 32, hour-long exercise sessions in a 10-week period. The experimental group’s exercise programme was adapted so that no specialised equipment was used, while the control group exercised in a well-equipped exercise- and rehabilitation centre.

Ever increasing applications of nanomaterials (materials with one or more dimension less than 100 nm) has raised awareness of their potential genotoxicity. They have unique physico-chemical properties and so could have unpredictable effects. Zinc oxide (ZnO) and titanium dioxide (TiO2) are widely used in a number of commercial products. There are published studies indicating that some forms of these compounds may be photo-clastogenic in mammalian cells. What has not been investigated before is the effect of nanoparticles from these compounds in human germ cells. Thus the present study has examined their effects in the presence and absence of UV light in human sperm and compared responses to those obtained with human lymphocytes using the Comet assay to measure DNA damage. The effect of nanoparticles (40-70nm range) was studied in human sperm and lymphocytes in the dark, after pre-irradiation with UV and simultaneous irradiation with UV. The studies do provide some evidence that there are photo-genotoxic events in sperm and lymphocytes in the absence of overt toxicity. The cytotoxic and genotoxic potentials of ZnO and TiO2 as well as their effect on phosphotyrosine expression, were examined in the human epithelial cervical carcinoma cells (Hela cells). This was done to try and determine the underlying molecular events resulting from their exposure to ZnO and TiO2 nanoparticles occurring at the same time as DNA is damaged. Concentration- and time-dependent cytotoxicity, and an increase in DNA and cytogenetic damage with increasing nanoparticle concentrations were reported in this study. Mainly for zinc oxide, genotoxicity was clearly associated with an increase in tyrosine phosphorylation. Nanotechnology has raced ahead of nanotoxicology and little is known of the effects of nanoparticles in human systems, let alone in diseased individuals. Therefore, the effects of TiO2 nanoparticles in peripheral blood lymphocytes from patients with respiratory diseases (lung cancer, chronic obstructive pulmonary disease (COPD) and asthma) were compared with those in healthy individuals using genotoxic endpoints to determine whether there are any differences in sensitivity to nano-chemical insult between the patient and control groups. The results have shown concentration dependent genotoxic effects of TiO2 in both respiratory patient and control groups in the Comet assay and an increasing pattern of cytogenetic damage measured in the micronucleus assay without being statistically significant except when compared with the untreated controls of healthy individuals. Furthermore, modulation of ras p21 expression was investigated. Regardless of TiO2 treatment, only lung cancer and COPD patients expressed measurable ras p21 levels that showed modulation as the result of nanoparticle treatment. Results have suggested that both ZnO and TiO2 nanoparticles can be genotoxic over a range of concentrations without either photoa-ctivation or being cytotoxic.

From a BPS perspective, COPD and other chronic diseases may have a significant negative impact on those living with them and may be associated with higher rates of depression and anxiety and lower levels of health-related quality of life (HRQOL). Certain factors, such as spirituality, may influence the negative impact of chronic disease on the relationship between mood and functional independence and HRQOL. Also, gender may influence the relationship between mood, spirituality, and HRQOL for men and women living with chronic diseases. The current study included 136 patients undergoing physical rehabilitation at an IRF. Anxiety, depression, spirituality, HRQOL, and functional independence were evaluated for all. Mediation models were tested to determine the impact of spirituality on the relationships between mood and HRQOL and functional independence, and moderation models were tested to evaluate the impact of gender on the relationships between mood, spirituality, functional independence, and HRQOL. The current study yielded some inconclusive results but did evidence that COPD patients in acute inpatient physical rehabilitation facilities (IRF) have higher levels of anxiety than patients without COPD and also revealed that men with COPD have better HRQOL than do women with COPD. Spirituality was found to partially mediate the relationship between depression and HRQOL in IRF patients with COPD, but gender did not appear to moderate the relationships between mood, spirituality, functional independence, or HRQOL in IRF patients. As few studies on IRF patients with chronic diseases exist, continuing to evaluate patients in IRFs is important to enhance our BPS understanding of chronic disease.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory disease, characterized by progressive and largely irreversible airflow limitation due to alveolar destruction (emphysema), small airway narrowing, and chronic bronchitis. It is one of the leading causes of morbidity and mortality worldwide and in the UK, it may affect approximately 1.5 per cent of the population; and up to one in eight emergency admissions may be due to COPD,corresponding to over one million bed days, with some 24160 people in the UK dying as a result of COPD in 2005 (Burden of Lung Disease 2nd Edition,British Thoracic Society 2006). Most cases of COPD are triggered by chronic inhalation of cigarette smoke.However, some people do not suffer from COPD even if they smoke for many years. COPD cannot be cured, and patients usually live with poor life quality. Treatments include giving up smoking, medication and oxygen therapy. Genetic factors contribute to the development of COPD. In Northern Europe,Z-AT homozygotes (342Glu Lys) develop emphysema in their third or forth decade. One explanation is AT deficiency because they form inactive polymers. However, this cannot explain why bronchoalveolar lavage fluid (BALF) from Z-AT homozygotes with emphysema contains more neutrophils than BALF from individuals with emphysema and normal AT (M-AT). Inhaling pollutants which include smoking (cigarettes, pipes, cigars, etc.) and other fumes such as those found in many industrial work environments probably also plays a role in an individual’s development of COPD. Previously, it has been shown that the polymeric conformer of AT is present in BALF from Z-AT homozygotes and that it is a chemoattractant for neutrophils in vitro (Parmar JS, 2002). These findings have been confirmed by others (Mulgrew AT, 2004). However, it is unknown where the polymers form and if 4 they are chemotactic in vivo. My colleague Dr Carl Atkison† showed that polymers of Z 1-AT are present in the alveolar wall of Z-AT homozygotes with emphysema, which accounts for 20% of the total AT from lung homogenates.These Z-AT individuals also have an excess of neutrophils in the alveolar wall compared with M-AT homozygotes. Furthermore, neutrophils and polymeric AT co-localize in the alveolar wall (Mahadeva R, 2005). To investigate whether there was a direct relationship between polymers of Z-AT and the excess neutrophils, polymers of AT were instilled into the lungs of wild-type mice (Mahadeva R, 2005). This produced a significant increase in neutrophil influx into the lungs compared with instillation of the native protein.Examination of the time course demonstrated that the influx of neutrophils was closely linked to the presence of polymeric AT. The mechanism of neutrophil recruitment in this mouse model was subsequently shown to be a direct chemotactic effect rather than stimulation of IL-8 homologues or other CXC chemokines. Oxidized AT (Ox-AT) promotes release of human monocyte chemoattractant protein-1 (MCP-1) and IL-8 from human lung type epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells. Native, cleaved, polymeric AT and secretory leukoproteinase inhibitor (SLPI) and oxidized conformations of cleaved, polymeric AT and SLPI did not have any significant effect on MCP-1 and IL-8 secretion. These findings were supported by the fact that instillation of Ox-AT into murine lungs resulted in an increase in JE (mouse MCP-1) and increased macrophage numbers in the bronchoalveolar lavage fluid. The effect of Ox-AT was dependent on NF- B and activator protein-1 (AP-1)/JNK. These findings have important implications. They demonstrate that the oxidation of methionines in AT by oxidants released by cigarette smoke or inflammatory cells not only reduces the anti-elastase lung protection, but also converts AT into a proinflammatory stimulus. Ox-AT generated in the airway † My colleagues’ contributions are acknowledged in future text where appropriate by the following superscripts: (a) Dr Sam Alam, (b) Dr Jichun Wang, (c) Dr Carl Atkinson, (d) Dr Sabina Janciauskiene. 5 interacts directly with epithelial cells to release chemokines IL-8 and MCP-1,which in turn attracts macrophages and neutrophils into the airways. The release of oxidants by these inflammatory cells oxidizes AT, perpetuating the cycle, potentially contributing to the pathogenesis of COPD. Furthermore, this demonstrates that molecules such as oxidants, anti-proteinases, and chemokines, rather than acting independently, collectively interact to cause emphysema (Li Z, 2009). To investigate the molecular basis for the interaction between Z-AT and Ox-AT associated with cigarette smoking, female mice transgenic for normal (MAT)or Z-AT on CBA background were exposed to cigarette smoke (CS). Transgenic mice for Z-AT developed a significant increase in pulmonary polymers following acute CS exposure. Increased levels of neutrophils in CSZ lungs were tightly correlated with polymer concentrations. Oxidation of human plasma Z-AT by CS or -chlorosuccinimide greatly accelerated polymerization, which could be abrogated by antioxidants. The results showed that cigarette smoke accelerated polymerization of Z-AT by oxidative modification, which in so doing further reduced pulmonary defense and increased neutrophil influx into the lungs. These novel findings provided a molecular explanation for the striking observation of premature emphysema in ZZ homozygote smokers, and raised the prospect of anti-oxidant therapy in ZAT related COPD (Alam S, 2011).

Vivre avec une maladie pulmonaire obstructive chronique (MPOC), c’est vivre avec une maladie chronique, dégénérative et irréversible. La dyspnée qui l’accompagne demande une adaptation continuelle à de multiples incapacités. La qualité de vie des personnes vivant avec la MPOC s’en trouve compromise. Au Québec, le taux de mortalité de la MPOC a doublé depuis 20 ans. Si plusieurs études se sont intéressées à la symptomatologie vécue dans la dernière année de vie, aucune n’a abordé spécifiquement les perceptions de personnes vivant avec une MPOC sévère au regard de leur fin de vie. La présente étude avait justement pour but de décrire ces perceptions dans la perspective de la théorie de l’humain en devenir. Cette étude qualitative descriptive fut réalisée auprès de six personnes dans un centre hospitalier universitaire de la région de Montréal. L’analyse des entrevues a été réalisée selon la méthode de Miles et Huberman (2003) à partir de la transcription intégrale des entrevues. Cette analyse a permis de dégager quatre thèmes qui reflètent les perceptions des participants au regard de leur fin de vie, soit: 1) vivre et se voir décliner, 2) vivre et se préparer à mourir, 3) mourir d’une MPOC c’est étouffer et 4) mourir entouré à l’hôpital. Cette étude a mis en évidence que les personnes vivant avec une MPOC sévère souhaitent mourir à l’hôpital entouré de leurs proches. Cette étude contribue à une connaissance plus globale de l’expérience de fin de vie. De plus, elle propose des recommandations pour la recherche, la pratique, la formation et la gestion infirmière. / Living with chronic obstructive pulmonary disease (COPD) means living with a chronic, degenerative and irreversible disease. The associated disabilitated dyspnoea justified an adaptation to the multiples limitations. The quality of life is compromised. The mortality rate of COPD has a steadily increasing incidence. In Québec, it has doubled in the last 20 years. If many studies have been interested by the symptomatology during the last year of life, none have addressed specific interest to the perceptions concerning end of quality life. The aim of this study was to describe the perceptions of people living with severe COPD concerning end of life in the perspective of human living with is health. This descriptive qualitative study has been realised with six persons in a university hospital of the metropolitan area of Montreal. This analysis has been realised based on the integral transcripts of interviews as per the Miles and Huberman (2003) method. This study has permitted to identify four themes reflecting the perceptions concerning end of life. The themes were: 1) living and seeing decline, 2) living and preparing to die, 3) dying of COPD means dying of suffocation and 4) dying in the hospital surrounding by lovers. This study has permitted to the participants to express themselves concerning their perceptions of elements contributing to their end of life. So it has been show that people living with COPD wish to die in the hospital surrounding by lovers. In describing their perceptions of living with COPD, this study contributes to a more complete knowledge of the experience of the experience of a end of life when the death is coming. Furthermore, the study proposes some recommendations for the nursing research, practice, formation and management.

Sammanfattning Bakgrund: KOL är en obstruktiv lungsjukdom med luftflödesbegränsningar pga.  kronisk bronkit och emfysem. De patofysiologiska mekanismer är en progressiv inflammatorisk process som påverkar hela kroppen. De viktigaste behandlingsstrategierna är rökstopp, farmakologisk behandling samt fysisk träning.  Personer med KOL har ofta en nedsatt fysisk funktionsnivå, som inte behöver vara kopplad till sjukdomens svårighetsgrad.  De viktigaste fysioterapeutiska interventionerna för KOL är mätning av fysisk kapacitet, aerob- och muskelstärkande träning, tekniker för sekretmobilisering via motståndsandning samt undervisning i energibesparande arbetssätt. Interventionerna leder till förbättrad funktionsnivå, bromsar upp sjukdomen, minskar risken för samsjuklighet med andra icke smittsamma sjukdomar (NCD), minskar risken för execerbationer, förbättrad livskvalitet, samt minskar risken att dö för tidigt (6MWT >350 m).     God bålkontroll är central för en effektiv biomekanisk funktion i syfte att maximera kraft och minimera skaderisker. En bra bålkontroll har hos friska personer visats ha en positiv effekt på diafragmas funktion, samt att bålkontrollen påverkas av andningen vilket blir extra tydligt vid fysiskt ansträngande arbete.     Sambandet mellan bålkontroll, syrgasmättnad, fysisk funktion och självskattade symtom hos personer med KOL har enligt författarens kännedom inte studerats tidigare. Syfte: Studien syftar till att undersöka om fysisk aktivitet, med fokus på förbättrad bålstabilitet och sluten läppandning, kan förbättra syrgasmättnad, fysisk kapacitet, benmuskelstyrka, balans och självskattade symtom hos personer med KOL, stadium 2. Metod: Single subject experimental design (SSED) med AB design (baslinje undersökning – intervention) användes. Primärt utfallsmått var saturation och gångsträcka mätt med 6MWT. Sekundära utfallsmått var enbensstående balans, CS-30 samt CAT. Data på kvotskalenivå analyserades visuellt med stöd av 2-SD-bands analys och celerationslinje analys. Förändringar i CAT före och efter interventionen redovisas i procent. Resultat: Fyra personer inkluderades i studien. Resultatet visar en möjlig interventionseffekt avseende gångsträcka vid 6MWT och enbensstående balans för två av deltagarna, som vid studiestart låg under eller tangerade förväntade normalvärden i samtliga parametrar. En av dessa stabiliserades avseende lägsta värde på saturation vid 6MWT. Det fanns en effekt/möjlig effekt på förbättrad benstyrka (CS-30) för de deltagare som vid studiestart låg över förväntade normalvärden i samtliga parametrar. Självskattade lungsymtom (CAT) förbättrades hos tre av deltagarna (31–55 procent) och försämrades hon en av deltagarna (-17 procent). Konklusion: Studien visar en möjlig positiv effekt av bålstabiliserande träning på gångsträcka (6MWT), enbensstående balans, antalet uppresningar vid CS-30 samt självupplevda lungsymptom (CAT) för personer med KOL, stadium 2. Fler studier behövs för att stärka validiteten av dessa fynd. / Abstract Background: COPD is an obstructive pulmonary disease with air flow constraints due to chronic bronchitis and emphysema. The pathophysiological mechanisms are a progressive inflammatory process that affects the entire body. The main treatment strategies are smoking cessation, pharmacological treatment and physical exercise. People with COPD often have a reduced physical function level, which not need to be linked to the severity of the disease. The most important physiotherapeutic interventions for COPD are measurement of physical capacity, aerobic and muscle strength training, techniques for mobilization of sputum through resistance breathing techniques and teaching in energy-saving work methods. The interventions lead to improved functional levels, slow down the disease, reduce the risk of comorbidity with other non-communicable diseases (NCD), reduce the risk of exacerbation, improve quality of life, and reduce the risk to die prematurely (6MWT> 350m).     A well-functioning core stability is considered central to an effective biomechanical function to maximize strength and minimize risks of injury and has been shown by healthy individuals to have a positive effect on diaphragm function. It has also been shown that the ability to core-control is affected by deep breathing and especially during hard physical work.    A correlation between oxygen saturation, physical function, self-estimated symptoms and core stability in people with COPD, has to the knowledge of the author not been studied earlier.     Aim: The aim of the study was to investigate whether there are a correlation exercise together with improved core stability and pursed lip breathing, can improve oxygen saturation, physical capacity, leg muscle strength, balance and self-estimated symptoms in people with COPD in stage 2.Methodology: A single subject experimental design (SSED) with AB design (baseline survey - intervention) was used. As primary outcome saturation and walking distance measured at 6MWT were used. Secondary outcomes were CS-30, single balance and CAT. Data at nominal level were analyzed by using Two Standard Deviation Band Analysis and Celeration Line Analysis, Changes in CAT, pre- and post-intervention, was analyzed by percentage. Result: Four participants were included in the study. The result indicates a possible intervention effect regarding walking distance at 6MWT and single leg balance for two of the participants, who at study start were below or dropped below expected normal values in all parameters. One of these participants was stabilized for the lowest value of saturation at 6MWT. There was an effect/possible effect in the CS-30 for participants who at study start exceeded expected normal values in all parameters. Self-estimated symptoms (CAT) were improved in three participants (31–55 percent) and got worse in one participant (17 percent).Conclusion: The study indicates that core stability training focusing on improved motor control for stabilizing core muscles may have a positive effect on walking distance (6MWD) single leg balance, number of up rises in CS-30 and self-estimated lungsymptoms for people with COPD, stage 2. More studies are needed to validate these preliminary findings.

Les m?canismes de l?emphys?me pulmonaire, caract?ris? par la destruction des alv?oles pulmonaire, sont incompl?tement connus. L?hypoth?se d?fendue par cette th?se est qu?une alt?ration des syst?mes d?alv?olog?n?se et de r?paration alv?olaire port?s par les fibroblastes pulmonaires contribue au d?veloppement des l?sions au cours de cette maladie. Les travaux pr?sent?s ici ont permis d??tablir que les fibroblastes pulmonaires cultiv?s in vitro ? partir de poumon emphys?mateux pr?sentaient un ph?notype alt?r? dans le sens d?une perte de leur capacit? ? participer ? la r?g?n?ration et ? la r?paration des alv?oles : Ces cellules s?cr?taient ? un niveau faible ou non stimulable le Hepatocyte Growth Factor et le Keratinocyte Growth Factor (KGF), qui ciblent les cellules ?pith?liales et endoth?liales de l?alv?ole. De plus, l?expression par ces cellules de l??lastine, le composant majeur de la matrice extracellulaire pulmonaire, n??tait pas induite par l?acide tout-trans r?tino?que, stimulus central de l?alv?olog?n?se, du fait d?une faible expression de Cellular Retinoic Acid Binding Protein 2 (CRABP2). Le r?le du KGF dans l?hom?ostasie de l?alv?ole a ?t? d?montr? dans le mod?le d?emphys?me induit par l??lastase in vivo : Les souris trait?es par le KGF avant l?instillation d??lastase ?taient prot?g?es de l?emphys?me. Les souris dont le g?ne de CRABP2 ?tait inactiv? de fa?on globale n??taient pas sensibilis?es vis-?-vis de l?emphys?me dans ce mod?le. Les donn?es physiopathologiques pr?sent?es dans ce m?moire pourraient contribuer ? l?identification de nouvelles cibles th?rapeutiques pour l?emphys?me. / The mechanisms of pulmonary emphysema, characterized by the destruction of alveolar walls, remain incompletely understood. Our hypothesis is that a deficiency in fibroblast-borne alveolar repair systems accounts partly for the constitution of lesions in this disease. In our experiments, we show that fibroblasts isolated in vitro from human emphysematous lung express the Hepatocyte Growth Factor and the Keratinocyte Growth Factor (KGF), which target alveolar epithelial and endothelial cells, at low or unstimulable levels. Additionally, emphysema fibroblasts did not increase their expression of elastin, the main component of the pulmonary extracellular matrix, in response to retinoic acid, due to a low expression of Cellular Retinoic Acid Binding Protein 2 (CRABP2). The role of KGF In alveolar homeostasis was demonstrated in vivo in the elastase-induced emphysema model: Mice treated with KGF before elastase instillation were protected against emphysema. CRABP2- knockout mice were not protected against emphysema in this model. Our pathophysiological data may help in the identification of novel therapeutic targets for emphysema.

La BPCO est une affection de l’appareil respiratoire associée à une réponse inflammatoire chronique. La BPCO associe une bronchite chronique, avec obstruction des voies aériennes, et un emphysème caractérisé par la destruction du parenchyme pulmonaire. Si l’exposition au tabac est le facteur de risque principal de la BPCO, plusieurs observations cliniques sont en faveur du rôle du vieillissement dans la pathogénèse de la maladie. La dégradation des fibres élastiques du poumon en peptides solubles d’élastine (PE) est une caractéristique constante de la BPCO, et le vieillissement physiologique du poumon est associé à une augmentation de son activité élastinolytique. Nous avons montré dans un travail précédent que l’instillation de PE à des souris induit un emphysème aigu. La relation existant entre l’élastolyse et le vieillissement conforte l’hypothèse que le vieillissement pourrait représenter un risque majeur de la BPCO par le biais de production de PE. Le travail de thèse présenté dans ce manuscrit a porté sur l’étude comparative des paramètres histologiques, inflammatoires et immunitaires liés à l’emphysème induit par les PE dans des souris jeunes et des souris âgées. Les résultats obtenus montrent que l’emphysème est d’apparition plus précoce chez les souris âgées et que cette précocité s’accompagne d’une augmentation de la production de PE et de clones T CD28- mémoires spécifiques des PE et du processus d’immunosénescence. / Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible inflammatory state of the lung. COPD includes chronic bronchitis, with obstruction of small airways, and emphysema, characterized by the destruction of lung parenchyma. Although cigarette smoke exposure is the best known risk factor for COPD development, several clinical observations support the hypothesis that aging also play a key role in the pathogenesis of COPD. Degradation of lung elastin fibers, generating soluble elastin peptides (EP), is a feature of COPD development, and normal physiological aging of the lung is associated with increased elastolysis. We previously demonstrated in mice that endotracheal instillation of EP resulted in an acute emphysema establishment. The positive association between lung elastin breakdown and aging is consistent with the hypothesis that aging is a major risk factor of COPD through EP production. The work done during this thesis focused on the comparative study of histological, inflammatory and immune parameters related to PE-induced emphysema in young and elderly mice. The results we obtained show that emphysema development is earlier in the elderly mice and that this earliness is associated with an increase of EP-specific CD28- senescent memory T cell clones.

Introduction: les follicules lymphoïdes (FL) sont absents du poumon normal mais ont été décrits dans les poumons de patients atteints de mucoviscidose ou de dilatations de bronches non mucoviscidosiques, suggérant un rôle pour l’infection bronchique dans la néogenèse lymphoïde (NL). Nous avons étudié la dynamique de la néogenèse lymphoïde dans l’infection bactérienne. Méthodes: les souris C57BL/6 ont reçu une instillation intratrachéale de billes d’agarose contenant du PAO1 ou du S. aureus (106 CFU/animal) permettant une infection prolongée et ont été comparées à des souris contrôles (billes stériles ou absence de billes). Les souris ont été sacrifiées à J1, J4, J7 et J14. Résultats: l’instillation unique de billes d’agarose contenant du PAO1 ou du S. aureus induit en 14 jours des FL fonctionnels situés sous l’épithélium en regard des zones d’infection. Le marquage pour CXCL12 et CXCL13 est faible chez contrôles, mais présent dans l’épithélium (CXCL13) dès J1 et présent également dans les FL (CXCL12 et CXCL13) à J14 chez les souris infectées. Le traitement des souris par un anticorps anti CXCL12 ou anti CXCL13 n’inhibe pas la formation des FL induite par l’infection à PAO1. Conclusion: nos données suggèrent un rôle pour l’infection bactérienne prolongée et l’épithélium respiratoire dans la NL des bronchopathies chroniques. Notre modèle permet d’évaluer les mécanismes de la formation et de persistance des FL dans le poumon. / Introduction: lymphoid follicles (LF) are absent in normal lungs, but are described in lungs of subjects with cystic fibrosis (CF) or non-CF bronchiectasis, suggesting a role for bacterial infection in lymphoid neogenesis. We aimed to study the dynamic of pulmonary lymphoid neogenesis (LN) during bacterial infection. Methods: C57BL/6 mice were instilled intratracheally with PAO1- or S. aureus-coated (1.106 CFU/mouse) agarose beads (which produced prolonged airway infection) and compared to controls (sterile beads or no instillation). Mice were sacrificed on day (d)1, d4, d7, and d14 after instillation. Results: chronic pulmonary infection with PAO1 or S. aureus induced organised LF in 14 days after a single challenge with PAO1- or S. aureus-coated beads. Bacteria- induced LF were exclusively localized in the subepithelium of infected airways. Staining for CXCL12 and CXCL13 was weak in airway epithelium of controls, but was positive in airway epithelium (CXCL13) at 1 day and in LF (both) of infected mice at 14 days. Treatment with anti CXCL12 or anti CXCL13 Ab did not reduce LN induced by PAO1 infection. Conclusions: chronic bacterial infection and respiratory epithelium could contribute to LN in chronic airway diseases. Our unique model allows to study mechanisms for the formation and maintenance of lung LF.