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The use of exercise is a valuable tool in the healthcare management of young patients with chronic chest diseases (CCD). Indeed, exercise testing yields important prognostic data which are a strong predictor of survival. Such information can indicate to the clinician to increase drug therapy treatment, and functional capacity of the patient can be monitored over time with repeated testing. Exercise training has been shown to improve both aerobic and anaerobic fitness and quality of life in patients with lung disease. The use of exercise testing and training in the healthcare of patients with lung disease in the UK, however, has not been investigated. In order for recommendations for exercise testing and training based on scientific evidence to be implemented, they should relate to current standards and resources. Therefore, the first study of the present thesis sought to characterise the use of both exercise testing and training in UK Cystic fibrosis (CF) clinics through a nationwide audit. Data from the audit showed that exercise testing and training are underused despite recognition of the importance of each in the healthcare of the patient by clinicians and other healthcare providers. Indeed, resources for exercise testing in UK CF clinics are limited. A patient over the age of 8 y will only have a 41.1 % chance of receiving an exercise test of any type over a 12 month period, and the exercise test will be quite crude. Exercise training is frequently discussed with the patient; however, there is a strong likelihood (72.9 %) that the advice given will only be general encouragement. The prognostic value of exercise testing is becoming increasingly recognised. Indeed, peak oxygen uptake (VO2peak) derived through maximal cardiopulmonary exercise testing (CPET) has been reported to be equal or superior to that of resting spirometric lung function tests in the prognostic evaluation of patients with CCD. Furthermore, a high correlation between VO2peak and long term survival in both adults and children with CF has been reported. Other physiological data from CPET, such as oxygen uptake (VO2) recovery following CPET, has not been investigated in young patients with CCD and may provide an additional physiological marker of patient health. The aim of study two, therefore, was to investigate recovery following CPET in young patients with CCD, and determine if any significant relationships exist between VO2 recovery and measures of disease severity in these patients. Data from study two showed that young patients with CCD compared to healthy controls had significantly reduced aerobic fitness (t52 = - 2.64, P = 0.011), and the fast component of the VO2 recovery following CPET, analysed by a mono-exponential model, is significantly prolonged (t52 = 2.63, P = 0.011). Furthermore, the fast component of the VO2 recovery is significantly related to disease severity, as assessed by the Shwachman score (SS), in the CF subgroup (r = - 0.75, P < 0.001), and as assessed by forced expiratory volume in 1 s (FEV1), in the young patients with CCD (r = - 0.49, P = 0.009). Thus, indicating that greater disease severity is associated with a longer VO2 recovery following CPET. A significant relationship between VO2peak and VO2 recovery was shown in the young patients with CCD (r = - 0.45, P = 0.018). Although the relationship is significant, however, it is still quite weak, and, therefore, indicates that the VO2 recovery is not closely related to the VO2peak in these patients. Quality of life and likelihood of survival are greater in patients with CCD with higher levels of aerobic fitness, and regular exercise has been shown to improve both lung function and exercise capacity in these patients. Indeed, exercise training programmes tailored to the individual patient are recommended in the standards of patient healthcare in the UK. Whilst the chronic effects of regular exercise have been investigated, the acute physiological responses to exercise training have not been studied in young patients with CCD. In study three young patients with CCD and healthy controls performed intermittent exercise (IE) designed to replicate the typical activity and exercise patterns of young people. Following IE, in the healthy controls the VO2 required to sustain moderate steady-state exercise fell significantly from 3 min to 1 h and 1 h to 24 h, however, in the young patients with CCD VO2 during moderate steady-state exercise increased significantly from 3 min to 1 h and then decreased significantly from 1 h to 24 h (main effect for time: F1.5,79.2 = 22.82, P < 0.001). A significant time × group interaction between young patients with CCD and controls in VO2 during moderate steady-state exercise 3 min, 1 h and 24 h following IE (interaction: F1.5,79.4 = 30.01, P < 0.001) may suggest that metabolic stress is still evident over this time period, which may be indicative of fatigue. Data from the present thesis shows that exercise is underused in UK CF clinics, with the availability of equipment and personnel both being limiting factors. Furthermore, a lack of standardisation in the provision of exercise between clinics is evident. In studies two and three, data shows different physiological responses following CPET and IE, respectively, between children with CCD and controls. The present thesis has advanced our understanding of the provision of exercise in the healthcare of CF in the UK, and furthered knowledge in how young patients with CCD respond physiologically to exercise.

There is considerable evidence that cigarette smoking is the primary etiology of chronic obstructive pulmonary disease (COPD), and that oxidative stress occurs in COPD with the family of tissue nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzymes playing a significant role in lung pathogenesis. The purpose of this study was to determine the effects of cigarette smoke extract (CSE) on Nox signaling to epithelial sodium channels (ENaCs). Pre-treatment with diphenyleneiodonium (DPI), a pan-Nox inhibitor, prevented stimulatory effects of CSE on ENaC activity; open probability (Po) changed from 0.36 +/- 0.09 to 0.11 +/- 0.02; n=10, p=0.01 following CSE and DPI exposure. Likewise, Fulvene-5 (which inhibits Nox2 and Nox4 isoforms) decreased the number of ENaC per patch (from 2.75 +/- 0.25 to 1 +/- 0.5, n=9, p=0.002) and open probability (0.18 +/- 0.08 to 0.02 +/- 0.08, p=0.04). Cycloheximide chase assays show that CSE exposure prevented alpha-ENaC subunit degradation, whereas concurrent CSE exposure in the presence of Nox inhibitor, Fulvene 5, resulted in normal proteolytic degradation of alpha-ENaC protein in primary isolated lung cells. In vivo, co-instillation of CSE and Nox inhibitor promoted alveolar flooding in C57Bl6 mice compared to accelerated rates of fluid clearance observed in CSE alone instilled lungs. Real-time PCR indicates that mRNA levels of Nox2 were unaffected by CSE treatment while Nox4 transcript levels significantly increased 3.5 fold in response to CSE. Data indicate that CSE is an agonist of Nox4 enzymatic activity, and that CSE-mediated Nox4 plays an important role in altering lung ENaC activity.

Class of 2012 Abstract / Specific Aims: The purpose of this study was to evaluate the effectiveness of various post-operative prophylaxis methods in lung transplant patients by comparing the incidence of venous thromboembolism (VTE) before and after the implementation of a standardized hospital order set at the University of Arizona Medical Center (UAMC) in April 2007. Methods: Paper and electronic medical charts were retrospectively reviewed if patients had a lung transplant date between October 31, 2003 – October 31, 2010. A computerized database was used to collect demographic data, length of stay (LOS), comorbid conditions, prophylaxis type (including dose/frequency), and date/type of thromboembolic events in the post-operative period prior to discharge and up to 1-year post- discharge. Main Results: Ninety-two patient charts were included in the study with 35 charts in the pre-order set (“Before”) group and 57 charts in the post- order set (“After”) group. All baseline characteristics were similar between groups except age (mean age difference 8.1 yrs, p=0.003), use of mycophenolate (Before n=24, After n=54; p=0.002), and use of medications that increase risk of VTE (Before n=6, After n=2; p=0.05). The April 2007 protocol significantly increased the number of patients receiving any method of prophylaxis (p<0.0001). However, receiving prophlyaxis did not significantly reduce event rates or readmissions due to VTE. Conclusions: Although implementation of the April 2007 protocol did not significantly reduce VTE event rates and readmissions, VTE prophylaxis should continue to remain a priority. Adherence to the implemented protocol may reduce the number of patients left without effective methods of prophylaxis.

Das Lungenkarzinom ist weltweit die häufigste Krebstodesursache. Ein möglicherweise erfolgsversprechender Angriffspunkt in der Therapie stellt die Tumorangiogenese dar, welche sich immunhistochemisch quantifizieren lässt. In der vorliegenden Arbeit wurde CD31, welcher als Marker für vorhandene Neoangiogenese fungiert, sowie PEDF als Antiangiogensesfaktor beschrieben und deren Einfluss auf die Gefäßbildung untersucht. Die Zielsetzung der Arbeit war es zu untersuchen, ob Unterschiede im Expressionsmuster bei einem Plattenepithel- und Adenokarzinom der Lunge zu sehen sind, ob eine Korrelation in der Expression von CD31 und PEDF zu erkennen ist und ob eine Aussage zur Prognose anhand der Expression möglich ist. Das Kollektiv umfasste klinisch anotierte Proben von 42 Patienten mit einem Plattenenpithelkarzinom der Lunge und 27 Patienten mit einem Adenokarzinom der Stadien Ia-IIIB. Sowohl die CD31 als auch die PEDF-Expression waren zwischen den Tumorentitäten nicht signifikant unterschiedlich. Im Expressionsvergleich von CD31 und PEDF zeigte sich beim Kollektiv der Plattenepithelkarzinome eine signifikante negative Korrelation bezogen auf CD31 und PEDF, gemessen anhand der Intensität. Beim Kollektiv der Adenokarzinompatienten zeigt sich eine positive Korrelation bezogen auf das CD31-Signal und der PEDF-Fläche. Für die Untersuchung zur Überlebensanalyse wurde das Kollektiv der Patienten, welche an einem Plattenepithelkarzinom erkrankt waren betrachtet. Die in der Literatur beschriebenen klassischen Einflussgrößen wie Tumorgröße, Lymphknotenstatus und Tumorstadieneinteilung auf die Überlebensraten konnten in dieser Arbeit bestätigt werden, allerdings erbrachte lediglich die Untersuchung der Tumorgröße eine statistisch signifikante Aussage. Hier konnte gezeigt werden, dass Patienten mit einem pT1-Tumor eine deutlich bessere Überlebensprognose haben als Patienten mit einem Tumor der Größe T2 oder größer (p=0.029). In der vorliegenden Studie ergab eine hohe CD31-Expression ein statistisch signifikant besseres Überleben der Patienten mit einem Plattenepithelkarzinom (p=0.038). Die 5JÜR der Patienten mit hoher CD31-Expression beträgt 67%, die mit niedriger 37%. Die Untersuchungen zur PEDF-Fläche als auch zur PEDF-Intensität ergaben keine Korrelation auf das Überleben und somit auf die Prognose.