Die COPD ist eine Erkrankung mit hoher Prävalenz, die in den nächsten Jahren weiter zunehmen wird. Aufgrund der ausgeprägten klinischen Symptomatik, der hohen Mortalitätsrate und des stetig steigenden Alters in der Bevölkerung wird die COPD aus gesundheits- und sozio-ökonomischen Gründen in den nächsten Jahren immer mehr an Bedeutung gewinnen. Daher ist eine Risikostratifizierung der Erkrankung COPD nicht nur für die Betroffenen von starker Bedeutung. In der Robert-Koch-Klinik, dem Thoraxzentrum des Klinikums St. Georg Leipzig und Lehrkrankenhaus der Universität Leipzig wurden vom 01.01.2002 bis zum 01.03.2009 insgesamt 366 Patienten mit COPD in die Studie aufgenommen, nach international anerkannten Leitlinien in Schweregrade eingeteilt und retrospektiv hinsichtlich ihrer Begleiterkrankungen analysiert. Ziel der Arbeit war eine Evaluation von bedeutsamen Begleiterkrankungen der COPD. Dabei wurden die Häufigkeiten und Arten der Begleiterkrankungen in Zusammenhang mit den Schweregraden der COPD und deren Auswirkungen auf die Hospitalisationsrate untersucht und die Frage beantwortet, ob und wenn ja welche Risikofaktoren für das Erwerben der Begleiterkrankungen eine Rolle spielen. Das vorliegende Kollektiv war im Mittel 62,7±9,6 Jahre alt, bestand zu 64% aus Männern und hatte einen BMI von im Mittel 26,1±5,9. Die Patienten waren überwiegend Raucher oder Ex-Raucher. Als Begleiterkrankungen wurden die KHK mit 20,5%, die arterielle Hypertonie mit 58,5%, die Hyperlipoproteinämie mit 11,7%, der Diabetes Mellitus mit 21,4%, embolische Ereignisse mit 10,7% und die Osteoporose mit 15,3% nachgewiesen. Innerhalb des Beobachtungszeitraumes wurden 75,4% ein weiteres Mal in das Krankenhaus stationär aufgenommen. Nur bei der Begleiterkrankung Hyperlipoproteinämie ließ sich eine statistisch signifikante Assoziation mit den COPD-Schweregraden nachweisen. Bei der Anzahl der Wiederaufnahmen ergab sich ein statistisch signifikanter Zusammenhang mit dem Schweregrad der COPD-Erkrankung. Eine inverse Assoziation konnte zwischen dem BMI und dem ansteigenden COPD-Schweregrad berechnet werden. Das Geschlecht, das CRP und das Raucherverhalten konnten dagegen statistisch nicht mit dem steigenden Schweregrad der Erkrankung assoziiert werden. Im Einklang mit der aktuellen Literatur ließ sich in unseren Daten eine hohe Prävalenz bei Erkrankten mit COPD hinsichtlich der Begleiterkrankungen KHK, arterielle Hypertonie, Diabetes mellitus und Osteoporose nachweisen. Es ließ sich kein erhöhtes Auftreten der Anzahl von embolischen Ereignissen bei COPD-Erkrankten feststellen. Nur bei der Osteoporose konnte eine ansteigende Prävalenzhäufigkeit in den COPD-Stadien erkannt werden, die allerdings nicht statistisch signifikant war. Die Anzahl der stationären Wiederaufnahmen stiegen dagegen statistisch signifikant analog zum Schweregrad der COPD-Erkrankung an, während sich der Schweregrad der COPD invers zum BMI verhielt. In einer zusammenfassenden Bewertung konnte diese Arbeit den Zusammenhang zwischen der COPD und der Häufigkeit der aufgeführten Begleiterkrankungen zeigen. Es wurde dokumentiert, dass Patienten mit COPD für die untersuchten Begleiterkrankungen eine starke Prädisposition haben. Die Osteoporose, der BMI und die Hospitalisationsrate scheinen mit dem Schweregrad der COPD zusammenzuhängen, so dass insbesondere hinsichtlich dieser genannten Faktoren ein systematisches Screening erfolgen sollte. Die Erkenntnis der engen Beziehung der Begleiterkrankungen, insbesondere die mit dem Schweregrad zunehmende Prävalenz der Osteoporose, spielt in der Prävention COPD-Erkrankter und für deren Prognose eine große Rolle, da durch frühe Therapie Sekundärschäden verhindert werden könnten. Dies Arbeit zeigt, dass die COPD, unter Berücksichtigung der steigenden Morbidität der Grunderkrankung und der mit ihr verbundenen Begleiterkrankungen sowie der steigenden sozioökonomischen Kosten durch vermehrte Krankenhausaufenthalte, in Zukunft ein zentrales Thema in der Medizin werden wird und verdeutlicht die Forderung nach weiterer Forschung auf diesem Gebiet.

COPD wird zunehmend als eine von den Atemwegen und der Lunge ausgehende systemische Erkrankung verbunden mit einer systemischen Entzündungsreaktion verstanden. Monozyten wird eine Schlüsselrolle in der Inflammation zugeschrieben, so dass sich die Suche nach einer verträglichen, antientzündlich wirkenden Substanz als therapeutische Konsequenz ergibt. Ätherische Öle wurden in letzter Zeit verstärkt bezüglich ihrer antientzündlichen Wirkung evaluiert. Methodik: Die Untersuchung wurde als offene, single- center Studie durchgeführt. Primärer Endpunkt war die Reduktion der aus in vitro von COPD- Patienten (n=26) kultivierten Monozyten sezernierten Zytokine TNF-α, IL-1β und IL-6. Die Zellen wurden mit LPS mit Myrtol N, Eukalyptus-, oder Orangenöl über 20 Stunden coinkubiert und die Zytokinkonzentrationen im Zellüberstand mittels ELISA quantifiziert. Ergebnisse: Die Zellvitalität nach Inkubation betrug jeweils >80%. Orangenöl: Eine Konzentration von 1,5*10-4% nicht aber 1,5*10-3% reduzierte das extrazellulär sezernierte IL-6 um 7,5%. Extrazelluläres IL-1β wurde bei 1,5*10-4% um 17,1% reduziert. Bei Konzentrationen von 1,5*10-3%, 1,5*10-4% und 1,5*10-6% blieb TNF-α nahezu konstant. 1,5*10-5% führte dagegen zu einer TNF-α- Steigerung um 17,24%. Myrtol N: IL-6 sank bei Konzentrationen von 1,5*10-3% -1,5*10-5% um 4,76%, 2,81% und 7,02%. IL-1β blieb bei Konzentrationen von 1,5*10-3% - 1,5*10-5% nahezu konstant (Reduktion:-3,66%, -2,91%, +6,73%). 1,5*10-5% senkte TNF-α um 27,5% (p=0,341), während Konzentrationen von 1,5*10-3% und 1,5*10-4% TNF-α nicht beeinflussten. Eukalyptusöl: Bei Konzentrationen von 1,5*10-3% und 1,5*10-4% kam es zu einem leichten Anstieg von IL-6 um 7,89% und 2,42%. 1,5*10-5% führte zu einer leichten IL-6- Reduktion (-3,11%). IL-1β wurde von Eukalyptusöl (1,5*10-3% und 1,5*10-4%) tendenziell um 4,38% und 6,76% reduziert. TNF-α wurde durch Eukalyptusöl (1,5*10-3%-1,5*10-5%) dagegen um 18-22% gesteigert. Schlussfolgerung: Ein eindeutiger antiinflammatorischer Effekt der Öle konnte in dem hier auf Monozyten basierenden Zellmodel durch die Arbeit nicht verifiziert werden.:1 Einleitung 1 1.1 Die chronisch- obstruktive Lungenerkrankung (COPD) 1 1.1.1 Definition und Epidemiologie 1 1.1.2 Ätiologie und Risikofaktoren 3 1.1.3 Pathogenese und Pathophysiologie 5 1.1.4 Klinik, Diagnostik und Einteilung 13 1.2 COPD- eine systemische Erkrankung 16 1.2.1 Die systemische Entzündung im Rahmen der COPD 16 1.2.2 Die systemische Entzündung als Prognosefaktor 23 1.2.3 Extrapulmonale Manifestationen der COPD 25 1.3 Die therapeutische Beeinflussbarkeit der Entzündung im Rahmen der COPD 33 1.3.1 Allgemeine Therapieprinzipien der COPD 33 1.3.2 Kortikosteroide 36 1.3.3 N- Acetylcystein 38 1.3.4 Ambroxol 40 1.4 Ätherische Öle 42 1.4.1 Allgemeine Wirkung und Eigenschaften 42 1.4.2 Eukalyptusöl und sein Hauptinhaltsstoff 1,8- Cineol 43 1.4.3 Orangenöl 45 1.4.4 Myrtol N 46 2 Aufgabenstellung 48 3 Material und Methoden 49 3.1 Studiendesign und Patientenauswahl 49 3.2 Isolierung humaner Monozyten aus peripherem Blut 50 3.3 Zellzählung und Einstellung der Zellkonzentration 52 3.4 Präparatherstellung zur Reinheitsbestimmung 53 3.5 Stimulation und Kultivierung der Monozyten 54 3.6 Gewinnung der Überstände und Vitalitätsprüfung mittels Trypanblau 56 3.7 Zytokinbestimmung 57 3.7.1 Allgemeines 57 3.7.2 TNF-α, Interleukin-6 und Interleukin- 1β 58 3.8 Statistik 59 4 Ergebnisse 60 4.1 Patientencharakteristika 60 4.2 Medikamentenanamnese der Patienten 60 4.3 Lungenfunktion der Patieten 62 4.4 Serumchemie der Patienten 63 4.5 Zytotoxizität von Orangenöl, Eukalyptusöl und Myrtol N 64 4.6 Antiinflammatorische Wirkung von Orangenöl 64 4.6.1 Interleukin-6 64 4.6.2 Interleukin-1β 66 4.6.3 Tumornekrosefaktor α 68 4.7 Antiinflammatorische Wirkung von Myrtol N 69 4.7.1 Interleukin-6 69 4.7.2 Interleukin -1β 70 4.7.3 Tumornekrosefaktor-α 71 4.8 Antiinflammatorische Wirkung von Eukalyptusöl 73 4.8.1 Interleukin-6 73 4.8.2 Interleukin-1β 74 4.8.3 Tumornekrosefaktor-α 75 4.9 Antiinflammatorische Wirkung von Orangenöl, Myrtol N und Eukalyptusöl im Vergleich 76 5 Diskussion 79 6 Zusammenfassung 87 7 Abbildungsverzeichnis 90 8 Tabellenverzeichnis 91 9 Literatur 92 10 Erklärung 103 11 Danksagung 104 12 Lebenslauf 105

Over 1.1 billion people smoke worldwide despite the association of smoking with numerous diseases including chronic obstructive pulmonary disease (COPD). The decline in lung function observed in COPD patients is thought to be related to smoke-induced inflammation. COPD patients are also at increased risk of acquiring lung bacterial infections that are associated with exacerbations, characterized by worsened disease symptoms and inflammation. The focus of this thesis is on how cigarette smoke impacts bacterial-host interactions and bacterial community interactions to promote infection and disease. In chapter 3.1, we sought to understand how cigarette smoke primed the lungs towards an amplified inflammatory response to bacterial infection reflective of COPD exacerbations that accelerate disease progression. We present a novel finding that exacerbated neutrophilia elicited by nontypeable Haemophilus influenzae (NTHi) lung challenge in smoke-exposed mice occurred dependent on IL-1α. Smokers and patients with COPD are additionally at increased risk of acquiring bacterial infection that may be related to impaired containment of nasally colonizing pathogens. In chapter 3.2, we found that cigarette smoke predisposed mice to invasive pneumococcal disease (IPD) following nasal pneumococcal colonization associated with attenuated nasal inflammatory responses. To our knowledge, this is the first study to describe the progression from asymptomatic nasal pneumococcal colonization to the development of IPD in the context of cigarette smoking. It has been suggested that smokers have higher rates of pathogen colonization as a consequence of cigarette smoke-induced nasal microbiome dysbiosis. The last study in chapter 3.3 advanced knowledge in the field by testing this hypothesis. We observed that cigarette smoke alone did not alter the mouse nasal microbiome and concluded that microbiome dysbiosis observed in smokers likely occur as a consequence of nasal pathogen colonization. Overall, work presented in this thesis advanced our understanding of how cigarette smoking alters bacterial-host interactions to promote infection and disease. / Thesis / Doctor of Philosophy (PhD) / Over 1.1 billion people smoke worldwide and can develop chronic obstructive pulmonary disease (COPD), a serious inflammatory disease compromising lung function. Additionally, smokers and COPD patients have higher rates of bacterial infection. The goal of this thesis is to understand how smoking impacts our ability to combat infection. Lung infection in COPD patients causes exacerbation, with worsened disease symptoms. Using mouse models, we learned how smoking causes increased lung inflammation following bacterial infection, contributing to damage reflective of COPD exacerbations, and identified a potential intervention. We elucidated smokers may have increased infections due to impaired immune responses in the nose, a major pathogen entry point. It is thought smoking reduced beneficial bacteria that counter pathogen acquisition in the nose. We confirmed smoking did not impact these bacteria, directing research focus towards other ways smokers acquire pathogens. Overall, this thesis advanced knowledge and will help efforts to control disease in smokers.

In this thesis nanoparticles consisting of a calcium phosphate core encapsulated by poly(lactic-co-glycolic) acid and polyethylenimine were developed for the delivery of siRNA in vivo. The nanoparticles were efficiently endocytosed by different cell types in vitro without exhibiting cytotoxic characteristics. Without possessing endogenous immune response activating properties, the nanoparticles had a highly preferable composition for the delivery of siRNA and subsequent gene knockdown. The delivery of siRNA with nanoparticles was tested in two different murine disease models: DSS-induced colitis as model for human IBD and a TH1-induced lung inflammation as model for COPD. In IBD and COPD chemokines and cytokines are predominant players in the progression of the inflammatory response. The local interference of cytokine signalling mediated by siRNA-loaded nanoparticles might therefore be a promising new therapeutic approach. In both murine models, the aim was to deliver siRNA directed against inflammation related cytokines by nanoparticles for the local treatment of mucosal inflammation. The local administration of nanoparticles loaded with siRNA to mice suffering from intestinal or lung inflammation led to significantly decreased target gene expression on mRNA as well as protein level in biopsies from the target tissues. Furthermore, reduced cytokine levels were accompanied by diminished inflammatory pathologies and augmented clinical signs of sickness. The results of this thesis indicate that a specific and local modulation of inflammatory responses by nanoparticle-based siRNA delivery is feasible and demonstrates a major therapeutic potential.

<p><strong>Sammanfattning </strong>Syftet med studien var att få ökad kunskap och undersöka om det finns några konsekvenser i det dagliga livet för personer som får diagnosen kronisk obstruktiv lungsjukdom, KOL. Syftet var också att undersöka vilken betydelse individuell information och utbildning, nutrition och träning samt omvårdnad har för personer som får diagnosen KOL. För att få svar på frågeställningarna valde författarna att göra en deskriptiv litteraturstudie. Data samlades in via databaserna SweMed, PubMed/Medline och Cinahl. Författarna valde sökorden KOL, nutrition, omvårdnad, träning, information och livskvalitet på både engelska och svenska som kombinerades på olika sätt för att få bästa sökresultat. Resultatet baseras på 15 vetenskapliga artiklar där det framkom att det var mycket viktigt med individuell information och utbildning om sjukdomen KOL till en person som får diagnosen. I flera av studierna framkom det att nutritionen var av stor betydelse för sjukdomsförloppet. Övervikt samt malnutrition var vanligt förekommande och ska alltid ses som ett allvarligt problem. Flera av studierna som berörde ämnesområdet fysisk aktivitet sade emot varandra. Några studier visade positiv effekt av fysisk aktivitet medan andra studier inte visade någon förbättring av den fysiska funktionen dock inte heller någon försämring.  <strong><em>Nyckelord:</em></strong> KOL, nutrition, fysisk aktivitet, omvårdnad, information</p> / <p><strong>Abstract </strong></p><p>The aim of the study was to gain knowledge and to find out if there are any consequences in the daily life for a person diagnosed with chronic obstructive pulmonary disease, COPD. The aim was also to find out what influence individual information and education, nutrition, exercising and nursing have on a person diagnosed with COPD.  In order to receive this information the authors decided to make a descriptive study of literature. Data were collected from the data bases SweMed, PubMed/Medline and Cinahl by using key words <em>COPD, nutrition, nursing, exercising, information</em> and <em>quality of life</em>. These key words were used in English as well as in Swedish. They were also combined in various ways in order to receive the best results of the computer search. The result is based on 15 scientific articles which all establish that for a person diagnosed with COD it is very important to receive individual information and education about the disease. Several studies showed that nutrition has an impact on the progression of the disease. Obesity and malnutrition is a common issue among persons with COPD and this issue should always be considered as a serious problem. Several studies on the subject of physical activity showed contradictory results. Some studies showed that physical activity has a positive effect on the physical function while others showed that physical activity neither has a positive nor a negative effect on the physical function.  </p><p> </p><p><strong><em>Keywords:</em></strong> COPD, nutrition, physical activity, nursing, information</p>

Objective: The objective of this study is to develop a national assessment of the length of stay (LOS), total costs, and in-hospital mortality among patients with chronic obstructive pulmonary disease (COPD), using retrospective data derived from Nationwide Inpatient Sample (NIS) of the Healthcare Cost and Utilization Project (HCUP). / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Pharmacy Administration / MS; / Thesis;

Sammanfattning Syftet med studien var att få ökad kunskap och undersöka om det finns några konsekvenser i det dagliga livet för personer som får diagnosen kronisk obstruktiv lungsjukdom, KOL. Syftet var också att undersöka vilken betydelse individuell information och utbildning, nutrition och träning samt omvårdnad har för personer som får diagnosen KOL. För att få svar på frågeställningarna valde författarna att göra en deskriptiv litteraturstudie. Data samlades in via databaserna SweMed, PubMed/Medline och Cinahl. Författarna valde sökorden KOL, nutrition, omvårdnad, träning, information och livskvalitet på både engelska och svenska som kombinerades på olika sätt för att få bästa sökresultat. Resultatet baseras på 15 vetenskapliga artiklar där det framkom att det var mycket viktigt med individuell information och utbildning om sjukdomen KOL till en person som får diagnosen. I flera av studierna framkom det att nutritionen var av stor betydelse för sjukdomsförloppet. Övervikt samt malnutrition var vanligt förekommande och ska alltid ses som ett allvarligt problem. Flera av studierna som berörde ämnesområdet fysisk aktivitet sade emot varandra. Några studier visade positiv effekt av fysisk aktivitet medan andra studier inte visade någon förbättring av den fysiska funktionen dock inte heller någon försämring.  Nyckelord: KOL, nutrition, fysisk aktivitet, omvårdnad, information / Abstract The aim of the study was to gain knowledge and to find out if there are any consequences in the daily life for a person diagnosed with chronic obstructive pulmonary disease, COPD. The aim was also to find out what influence individual information and education, nutrition, exercising and nursing have on a person diagnosed with COPD.  In order to receive this information the authors decided to make a descriptive study of literature. Data were collected from the data bases SweMed, PubMed/Medline and Cinahl by using key words COPD, nutrition, nursing, exercising, information and quality of life. These key words were used in English as well as in Swedish. They were also combined in various ways in order to receive the best results of the computer search. The result is based on 15 scientific articles which all establish that for a person diagnosed with COD it is very important to receive individual information and education about the disease. Several studies showed that nutrition has an impact on the progression of the disease. Obesity and malnutrition is a common issue among persons with COPD and this issue should always be considered as a serious problem. Several studies on the subject of physical activity showed contradictory results. Some studies showed that physical activity has a positive effect on the physical function while others showed that physical activity neither has a positive nor a negative effect on the physical function.     Keywords: COPD, nutrition, physical activity, nursing, information

Background: Excess plugging of small airways is associated with premature death in chronic obstructive pulmonary disease (COPD). Over-expression of beta-epithelial sodium channel (β-ENaC) in airway epithelia in mice resulted in plugging of small airways while cystic fibrosis transmembrane regulator (CFTR) negatively regulated ENaC activity in cell models. Purpose: To test the hypothesis that accumulation of mucus exudates observed with the progression of COPD is related to excess airway epithelial sodium re-absorption as a result of over-expression of β-ENaC and reduced expression of CFTR by small airway epithelia. Methods: Small airway epithelial samples from frozen lungs from patients at different levels of COPD severity were isolated by laser capture microdissection (LCM). β-ENaC, CFTR, and β-actin (control) gene expression was determined by qRT-PCR and compared to expression in entire airways and lung parenchyma surrounding these airways. β-ENaC protein as well as epithelial mucin expression and mucus plugging were localized and quantified after immunohistochemical and periodic acid Schiff staining, respectively. Results: β-ENaC mRNA expression had a strong positive correlation with that of CFTR (p<O.0001) in airway epithelia and surrounding lung parenchyma (p=O.Ol) but not whole airways. β-ENaC mRNA and protein expression were positively correlated (p=O.4O, p=O.O5) and protein expression significantly increased with GOLD stage of COPD severity. Epithelial mucin expression positively correlated with β-ENaC (p=O.38, p=O.O5) and CFTR (p=OAO, p=O.O4.) mRNA and with mucus plugging (p=O. 43 , ptO.OOO2). CFTR mRNA also correlated positively with mucus plugging (p=O. 48 , p=O.O2). Conclusions: Strong positive correlations between β-ENaC and CFTR mRNA expression that are limited to the lung parenchyma and epithelium suggest a novel mechanism of mRNA regulation. This differs from their functional relationship where an inverse relationship between CFTR expression and β-ENaC activity has been reported. Positive correlations of epithelial mucin or mucus plugging with CFTR mRNA but not β-ENaC protein expression in the small airway epithelium suggest that CFTR may regulate mucin at this site independently of β-ENaC protein. The relationship between β-ENaC mRNA andepithelial mucin expression could be due to strong correlations between β-ENaC and CFTR mRNA expression but β-ENaC’s relationship with COPD GOLD stage suggests it may nevertheless play a role in COPD.

Background: Excess plugging of small airways is associated with premature death in chronic obstructive pulmonary disease (COPD). Over-expression of beta-epithelial sodium channel (β-ENaC) in airway epithelia in mice resulted in plugging of small airways while cystic fibrosis transmembrane regulator (CFTR) negatively regulated ENaC activity in cell models. Purpose: To test the hypothesis that accumulation of mucus exudates observed with the progression of COPD is related to excess airway epithelial sodium re-absorption as a result of over-expression of β-ENaC and reduced expression of CFTR by small airway epithelia. Methods: Small airway epithelial samples from frozen lungs from patients at different levels of COPD severity were isolated by laser capture microdissection (LCM). β-ENaC, CFTR, and β-actin (control) gene expression was determined by qRT-PCR and compared to expression in entire airways and lung parenchyma surrounding these airways. β-ENaC protein as well as epithelial mucin expression and mucus plugging were localized and quantified after immunohistochemical and periodic acid Schiff staining, respectively. Results: β-ENaC mRNA expression had a strong positive correlation with that of CFTR (p<O.0001) in airway epithelia and surrounding lung parenchyma (p=O.Ol) but not whole airways. β-ENaC mRNA and protein expression were positively correlated (p=O.4O, p=O.O5) and protein expression significantly increased with GOLD stage of COPD severity. Epithelial mucin expression positively correlated with β-ENaC (p=O.38, p=O.O5) and CFTR (p=OAO, p=O.O4.) mRNA and with mucus plugging (p=O. 43 , ptO.OOO2). CFTR mRNA also correlated positively with mucus plugging (p=O. 48 , p=O.O2). Conclusions: Strong positive correlations between β-ENaC and CFTR mRNA expression that are limited to the lung parenchyma and epithelium suggest a novel mechanism of mRNA regulation. This differs from their functional relationship where an inverse relationship between CFTR expression and β-ENaC activity has been reported. Positive correlations of epithelial mucin or mucus plugging with CFTR mRNA but not β-ENaC protein expression in the small airway epithelium suggest that CFTR may regulate mucin at this site independently of β-ENaC protein. The relationship between β-ENaC mRNA andepithelial mucin expression could be due to strong correlations between β-ENaC and CFTR mRNA expression but β-ENaC’s relationship with COPD GOLD stage suggests it may nevertheless play a role in COPD.

Background: Excess plugging of small airways is associated with premature death in chronic obstructive pulmonary disease (COPD). Over-expression of beta-epithelial sodium channel (β-ENaC) in airway epithelia in mice resulted in plugging of small airways while cystic fibrosis transmembrane regulator (CFTR) negatively regulated ENaC activity in cell models. Purpose: To test the hypothesis that accumulation of mucus exudates observed with the progression of COPD is related to excess airway epithelial sodium re-absorption as a result of over-expression of β-ENaC and reduced expression of CFTR by small airway epithelia. Methods: Small airway epithelial samples from frozen lungs from patients at different levels of COPD severity were isolated by laser capture microdissection (LCM). β-ENaC, CFTR, and β-actin (control) gene expression was determined by qRT-PCR and compared to expression in entire airways and lung parenchyma surrounding these airways. β-ENaC protein as well as epithelial mucin expression and mucus plugging were localized and quantified after immunohistochemical and periodic acid Schiff staining, respectively. Results: β-ENaC mRNA expression had a strong positive correlation with that of CFTR (p<O.0001) in airway epithelia and surrounding lung parenchyma (p=O.Ol) but not whole airways. β-ENaC mRNA and protein expression were positively correlated (p=O.4O, p=O.O5) and protein expression significantly increased with GOLD stage of COPD severity. Epithelial mucin expression positively correlated with β-ENaC (p=O.38, p=O.O5) and CFTR (p=OAO, p=O.O4.) mRNA and with mucus plugging (p=O. 43 , ptO.OOO2). CFTR mRNA also correlated positively with mucus plugging (p=O. 48 , p=O.O2). Conclusions: Strong positive correlations between β-ENaC and CFTR mRNA expression that are limited to the lung parenchyma and epithelium suggest a novel mechanism of mRNA regulation. This differs from their functional relationship where an inverse relationship between CFTR expression and β-ENaC activity has been reported. Positive correlations of epithelial mucin or mucus plugging with CFTR mRNA but not β-ENaC protein expression in the small airway epithelium suggest that CFTR may regulate mucin at this site independently of β-ENaC protein. The relationship between β-ENaC mRNA andepithelial mucin expression could be due to strong correlations between β-ENaC and CFTR mRNA expression but β-ENaC’s relationship with COPD GOLD stage suggests it may nevertheless play a role in COPD. / Medicine, Faculty of / Medicine, Department of / Experimental Medicine, Division of / Graduate