Background: Acute lung injury (ALI) and nosocomial pneumonia are major causes of morbidity and mortality. There are 200,000 cases per year of ALI in the US with a mortality of 40%. On the intensive care unit (ICU), ALI accounts for over 40% of all ventilated patients at any one time. Despite this huge burden on healthcare and the relatively high prevalence, no therapies currently exist in clinical practice that attenuate the condition. The pathophysiology and aetiology of ALI is multifactorial but neutrophilic influx and consequent damage to the endothelial-epithelial interface are regarded as central features. Alongside neutrophils, peripheral blood monocytes (PBMs) are recruited to the acutely inflamed lung. The role played by PBMs in perpetuating the pathogenic neutrophilic influx remains poorly characterised. Nosocomial pneumonia is also a major problem with drug resistant organisms. With the increasing prevalence of antibiotic resistance and the paucity of novel antimicrobials being generated by pharmaceutical companies, there is real concern that the end of the ‘antibiotic era’ may be approaching. AIMS 1) To develop murine models of lung inflammation and infection 2) To establish the role of the PBM in perpetuating the neutrophilic response in ALI 3) To develop non-invasive methodologies to study the trafficking of cells and molecular events within the inflamed lung 4) To apply a novel antimicrobial to prevent and treat nosocomial pneumonia Methods: A murine model of ALI was utilised using direct intratracheal instillation of lipopolysaccharide. To this model 3 different PBM depletion strategies were applied to study the effect on neutrophil recruitment and consequent lung injury. Non invasive optical imaging was utilised to study the effect of PBM depletion on proteolytic events within the murine lung. To understand cellular trafficking, cell labeling strategies were compared for primary murine macrophages with whole body optical imaging in mice. Murine models of Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cepacia were established and a novel antimicrobial agent called the nonalysine like peptoid (NLLP) tested in vitro and in vivo for efficacy. Results: PBM depletion significantly attenuated neutrophil recruitment in an established model of ALI. Near infrared (NIR) optical imaging permitted the non invasive tracking of primary murine cells. A non toxic peptidomimetic agent (NLLP) possessed antimicrobial activity against gram positive and gram negative pathogens with therapeutic and prophylactic efficacy in vivo. Conclusions: PBM depletion is a potential therapeutic strategy for treating ALI. Further studies are required to determine the exact mechanism by which PBMs orchestrate neutrophil recruitment. Optical imaging is a versatile platform for molecular imaging. A novel antimicrobial agent termed NLLP has been discovered with therapeutic and prophylactic efficacy against multi-drug resistant pathogens.

The aim of this thesis was to develop and evaluate a complex intervention for major depression in patients with lung cancer. Major depression is a leading cause of disease burden worldwide and is particularly important in patients with lung cancer, not only because it is common in this poor prognosis cancer group but also because it substantially reduces the quality of the often short period of time that patients have left to live. The thesis describes a systematic review of the relevant research literature, the development of a complex intervention and a multi-centre randomised controlled trial. I found no trials, in my systematic review, that had evaluated the effectiveness of treatments for depression in patients with lung cancer. I did, however, find six trials of interventions intended to improve symptoms or quality of life in this patient group, the findings of which suggested that enhanced care approaches were more effective in reducing depressive symptoms than standard medical care. I developed the complex intervention ‘Depression Care for People with Lung Cancer’ (DCPLC) with 12 patients who had major depression and lung cancer. DCPLC was delivered by a team of cancer nurses and psychiatrists in collaboration with the patient’s GP. It included education about depression, antidepressant medication, psychological treatments (behavioural activation and problem solving therapy) and systematic progress monitoring. The trial comparing DCPLC with usual care included 142 patients. Patients who received DCPLC reported significantly lower average depression severity during their time in the trial, and better self-rated depression improvement, anxiety, quality of life, role functioning and perceived quality of depression care. The methodological limitations, relevant literature and implications of these findings for future research and for clinical practice are discussed.

Dajun DaiRadon is a colorless, odorless, naturally occurring gas. It is currently the second leading cause of lung cancer and the number one cause of lung cancer to non-smokers in the United States. DeKalb County offers free screening for radon for residents. However, screening rates vary across the county. This pilot study focused on 14 selected tracts within DeKalb County with relatively low levels of radon screening. Over 200 households were recruited and homes were tested for indoor radon concentrations on the lowest livable floor over an 8-week period from March – May 2016. Tract-level characteristics were examined to understand the varitations of race, income, education, and poverty status between the 14 selected tracts and all of DeKalb County. The 14 selected tracts were comparable to all of DeKalb County in most factors besides race. Radon was detected in 73% of the homes sample and 4% had levels above the EPA guideline of 4 pCi/L. Multi-variate linear regression was used to compare all housing construction characteristics with radon concentrations and suggested that having a basement was the strongest predictive factor for detectable and/or hazardous levels of radon. Radon screening can identify problems and spur home owners to remediate but low screening rates may impact the potential health impact of free screening programs. More research should be done to identify why screening rates vary in order to identify ways to enhance screening and reduce radon exposure in DeKalb County.

Angiogenesis, the formation of new blood vessels from a pre-existing vasculature, is crucial during development and for many diseases including cancer. Despite tremendous progress in the understanding of the angiogenic process, many aspects are still not fully elucidated. Several attempts have been made to identify novel genes involved in endothelial cell biology and angiogenesis. Here we focused on Pald1, a recently identified, vascular-enriched gene encoding paladin. Our in vitro studies indicate that paladin is a lipid phosphatase catalyzing dephosphorylation of phosphatidylinositol phosphates, a process essential for endocytosis and intracellular vesicle trafficking. We confirmed paladin’s vascular expression pattern and revealed a shift from a broad endothelial cell expression during development to an arterial mural cell-restricted expression in several vascular beds in adult mice. Paladin expression in the lung, however, was not restricted to the vasculature, but was also observed in pneumocytes and myofibroblasts. Lungs of female, but not male, Pald1 null mice displayed an obstructive lung phenotype with increased alveolar air sacs that were already apparent early in the alveolarization process. Only endothelial cells, but not other main lung cell types, were affected by loss of paladin. Endothelial cell number was reduced in 4-week old mice, possibly due to increased endothelial turnover in Pald1 deficient lungs. Vascular defects were also found in the retina. Loss of paladin led to reduced retinal vascular outgrowth accompanied by a hyperdense and hypersprouting vascular front. Downstream signaling of the major angiogenic driver, vascular endothelial growth factor receptor 2 (VEGFR2) was sustained in Pald1 null mice, and VEGFR2 degradation was impaired. Furthermore, paladin inhibited endothelial cell junction stability and loss of paladin led to reduced vascular permeability. Whether the differences in VEGFR2 signaling and adherens junction stability are connected remains to be fully explored. The newly identified lipid phosphatase activity of paladin and its specific effects on VEGFR2 signaling and adherens junction stability indicate that paladin may be controlling the endocytic pathway.

published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy

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