Nanomaterials are defined as any material with at least one external dimension less than 100 nm. Recently, nanomaterials have become more common in medicine, technology, and engineering. One reason for their increased interest is due to nanomaterials having unique properties that allow them to interact effectively with biological systems. In terms of drug delivery, the lungs are a highly desirable site to administer therapeutic nanoparticles. Indeed, inflammatory diseases such as asthma and emphysema could potentially benefit from nanoparticle-mediated delivery. However, the lungs are also in constant contact with airborne particulate matter. Thus, harmful nanoparticles can enter the lungs and cause or even exacerbate inflammatory diseases. Our work focused on characterization of both therapeutic and potentially harmful nanoparticles in the lungs. We found that fluorescently-labeled nanoparticles were phagocytosed by macrophages and did not induce apoptosis or inflammation in the lungs, making them potentially useful as a therapeutic for inflammatory diseases. We also characterized a rare form of titanium-based particles called Magnéli phases, which have been shown to be produced via coal burning. We found that while these particles are non-inflammatory in the lungs of mice, they lead to apoptosis of macrophages as well as a change in gene expression associated with increased fibrosis. Ultimately, this was shown to lead to a decrease in lung function parameters and airway hyperresponsiveness, indicating increased lung stiffness after long-term nanoparticle exposure. Our data adds significant contributions to the field by assessing two nanoparticles with vastly different compositions in the lungs. Overall, we found that the unique properties of both particle types allows for interactions with cells and tissues. These interactions can have important outcomes on health, both in terms of disease treatment and exacerbation. / Ph. D. / Over the years, nanoparticles have become more common in medicine, technology, and engineering due to their unique properties. Many of these properties allow for increased interactions with biological materials. Organs such as the lungs are at increased risk of exposure because they naturally encounter microorganisms and airborne particles on a daily basis. However, the lungs are also a highly desirable site for drug delivery using nanoparticles, due to ease of access. Inflammatory diseases such as asthma and emphysema could potentially benefit from nanoparticle-mediated delivery. Additionally, harmful nanoparticles can enter the lungs and cause or even exacerbate these diseases. Unfortunately, there is a lack of knowledge pertaining to this subject. Our work focused on assessing the interactions of nanoparticles in the lungs. First, we looked at nanoparticles that could be used for drug delivery. We found that fluorescentlylabeled nanoparticles were taken up by phagocytic white blood cells called macrophages. Furthermore, these particles did not induce cell death or inflammation in the lungs. Therefore, we found that these particles could be useful for drug delivery in the lungs. Secondly, we investigated potentially harmful nanoparticles and their effects on the lungs. The titanium-based particles called Magnéli phases, have been shown to be produced through coal burning. We found that while these particles are non-inflammatory in the lungs, they do lead to programmed death of macrophages as well as the increase in genes associated with fibrosis. Ultimately these particles led to a decrease in lung function after long-term exposure.

INTRODUCTION: Despite the use of modern minimally invasive surgical techniques, post-operative complications following lung cancer resection remain common and challenging to predict. Pulmonary ventilation imaging modalities offer detailed regional assessment of airflow obstruction and are highly sensitive to subclinical airway and/or parenchymal disease. Nevertheless, ventilation imaging is seldom integrated into pre-operative lung function assessment and risk stratification procedures. Therefore, the objective of this thesis was to quantify the burden of ventilation defects observed by Technegas SPECT and 129Xe MRI before lung cancer resection and establish their association with the occurrence and clinical impact of post-operative complications. METHODS: Patients undergoing lung cancer resection at St. Joseph’s Healthcare Hamilton were recruited into a prospective, proof-of-concept, six-week observational study. Participants were evaluated prior to resection surgery to document baseline demographics and clinical characteristics, performed standard pulmonary function tests and sputum induction, and underwent Technegas SPECT and 129Xe MRI to assess ventilation. Abnormal ventilation was quantified as the ventilation defect percent (VDP) and was considered abnormal if VDP was ≥mean+2 standard deviations of a healthy population. Following surgery, participants were followed for 4 weeks to document the incidence of post-operative complications, as specified by the Ottawa TM&M categorization system, and the length of hospital stay. RESULTS: One hundred and twenty-three participants were enrolled, of whom 103 were evaluated pre-operatively and followed for post-operative outcomes. Of the 103 participants (69±8 years, 58% female), 89% (92/103) underwent minimally invasive surgery, and 74% (76/103) underwent lobectomy. Abnormal ventilation was observed pre-operatively by Technegas SPECT and 129Xe MRI for 59% (58/99) and 84% (82/98) of participants, respectively. In a subset of 69 participants in whom sputum was collected, 51% (35/69) had intraluminal inflammation. A total of 64 post-operative complications occurred; 16 (25%) were pulmonary, and 48 (75%) were pleural complications. A post-operative complication occurred in 42% (41/103) of participants. Pre-operative Technegas SPECT and 129Xe MRI VDP were higher for participants with post-operative complications compared to those without (Technegas SPECT: 26±17% vs 19±7%, p=0.02; 129Xe MRI: 13±12% vs 7±6% p=0.003) and were positively correlated with post-operative length of hospital stay (Technegas SPECT: r=0.43, p<0.0001; 129Xe MRI: r=0.49, p<0.0001). Multivariable regression models revealed that preoperative Technegas SPECT and 129Xe MRI VDP were predictors of post-operative complications (Technegas SPECT: Odds ratio=1.08, p=0.005; 129Xe MRI: Odds ratio=1.16, p=0.002) and post-operative length of hospital stay (Technegas SPECT: unstandardized β=0.13, p<0.001; 129Xe MRI: unstandardized β=0.24, p<0.001). CONCLUSIONS: Abnormal ventilation, quantified by Technegas SPECT and 129Xe MRI VDP, is prevalent prior to lung cancer resection and a predictor of post-operative complications and length of hospital stay. / Thesis / Master of Science (MSc) / Post-operative complications are frequent adverse events following lung cancer resection, resulting in substantial patient morbidity and mortality that have a significant clinical and economic impact. Despite this, post-operative complications remain inadequately predicted, and limited research has been dedicated to reducing the risk of pulmonary complications after lung cancer resection. Standard clinical screening tools, such as pulmonary function tests, are used for patient selection in lung cancer resection surgery; however, they provide a global estimate of a complex multicompartment organ and may lack the sensitivity to detect subclinical lung pathology that influences post-operative outcomes. Thus, using high-resolution medical imaging modalities such as single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), we investigated the prevalence and clinical relevance of abnormal ventilation, a functional consequence of airway and/or parenchymal disease. One hundred and three participants were enrolled in a six-week prospective, proof-of-concept observational study. Participants performed pre-operative imaging and were followed for four weeks post-operatively to document post-operative complications and relevant clinical outcomes. Pre-operative SPECT and MRI revealed a high prevalence of abnormal ventilation. The pre-operative ventilation defect burden was greater in participants who developed one or more complications during the four-week post-operative period and was an independent predictor of both the incidence of post-operative complications and the length of hospital stay. These observations provide proof-of-concept evidence that abnormal ventilation, assessed by two ventilation imaging modalities, is prevalent and clinically relevant prior to lung cancer resection. Taken together, this thesis establishes that ventilation imaging may have implications for risk stratification and risk modification in patients scheduled to undergo lung cancer resection.

Introduction: NKT cells are categorised as borderline between NK and T cells, sharing phenotypic and functional characteristics of both cells, demonstrating their capacity to contritube to both pro- or anti-inflammatory processes. However, the role of these cells among lung transplant recipients remains largely unknown. The aim of this study was to determine the role of NKT cells following lung transplantation. Methods: NKT cells were quantified and characterised according to markers of: activation (CD107a, CD161, NKG2D) and immunomodulation (CD200 and CD200R) in peripheral blood and BALs. NKT cell numbers and phenotypes were correlated to clinical variables: immunosuppression, acute rejection, acute infections (viral, bacterial and fungal), bronchiolitis obliterans syndrome (BOS grade), lung function, and demographic variables. Interactions between NKT cells and the transplanted lung were linked by determining the relative expression of immunomodulatory ligand CD200 in lung biopsies. In vitro models were employed to determine the role of NKT cells to acute lung injury, either alone or in combination with cells of the mononuclear phagocyte system (MPS). Results: Higher numbers of immunomodulatory NKT cells (CD200+ and CD200R+) were found as lung function decreased. Data from peripheral blood indicates that recipients whose donors or themselves had been exposed to CMV infection demonstrated increased numbers of NKT cells. Patients with active EBV infections demonstrated higher NKT cell numbers expressing CD200 and CD200R. Data from BALs, indicates that patients with active fungal infections present higher immunomodulatory (CD200R) NKT cells and lower cytotoxicity marker (CD107a). In peripheral blood, lung recipients demonstrated higher NKT cell numbers compared to healthy volunteers. However, the lower relative mean expression of functional markers in the lung transplant group suggests that cells are less active. In vitro cultures with immunosuppressants demonstrated that cell cycle inhibitors (MMF and AZA) and corticosteroids (Prednisolone) are likely to inhibit NKT cell proliferation, while calcineurin inhibitors (Cyclosporine A and Tacrolimus) decrease the relative mean expression of activation markers. Clinical observations indicate that higher doses of Azathioprine may correlate with increased NKT cell numbers and the relative expression of CD200 and CD200R. However, under these conditions the relative expression of activation marker NKG2D decreases. In vitro data from the acute injury model indicates that NKT cells are capable to migrate into the injured lung and become activated following transmigration which is facilitated by the presence of monocytes. We also observed the interaction of NKT cells with endothelial cells, monocytes and macrophages. Also, the relative mean expression of CD200 and CD200R increased at the capillary layer, regardless of injury while upregulation of activation markers (CD107a, CD161 and NKG2D) was found at the capillary layer, following injury. In contrast, the alveolar layer demonstrated a decrease in both activation and immunomodulatory markers, following acute injury. Conclusions: Despite immunosuppression, NKT cells remain present in peripheral blood and BAL following lung transplantation. NKT cell proliferation is likely to be reduced by effect of cell cycle inhibitors, while calcineurin inhibitors exert an immunomodulatory effect. Our data indicates that NKT cells can participate in inflammatory and immunomodulatory events at the alveolar bilayer. Their capacity to infiltrate the lungs was assisted by cells of the mononuclear phagocyte system (MPS), which play an important role in antigen presentation and modulation of acute injury. Further research is needed to elucidate the signals and mechanisms occurring between NKT and MPS interactions and the outcomes these populations drive in acute lung injury.

Doctor of Philosophy(PhD) / Over the last 20 years both asthma and obesity have increased in prevalence. What is the link? There are data to suggest that increasing obesity is a risk for the increase in prevalence of asthma. A number of mechanisms have been postulated including the effects of reduced lung volume on bronchial reactivity and mechanical changes with lower lung volumes. Other possibilities include other obesity-induced co-morbidities including gastro-oesophageal reflux. The aim of this thesis was to evaluate the link between asthma and obesity in both adult and childhood populations and to undertake experimental studies to examine the effects of changes in lung volume on bronchial reactivity. In chapter 1, the literature is reviewed. The current literature suggests that there is a link between diagnosis of asthma, new onset of asthma, symptoms of shortness of breath and wheeze. In chapter 2, data on 1997 adults in 3 population studies were analysed and the association between body mass index (BMI) and symptoms of shortness of breath and wheeze, diagnosis of asthma, medication usage for asthma, lung function and bronchial responsiveness were studied. This study showed that obesity was a risk for recent asthma (OR 2.04; 95%CI 1.02-3.76, p=0.048), symptoms of shortness of breath and wheeze (OR 2.6; 95%CI 1.46- 4.70, p=0.001), and medication usage for asthma (OR 2.53; 95%CI 1.36-4.70, p=0.003). There was a reduction in lung volume as measured by forced vital capacity (FVC), but there was no increase in bronchial hyperresponsiveness (BHR) (OR 0.87; 95% CI 0.35-2.21, p=0.78). Thus although the symptoms of asthma are increased there were no increases in BHR, despite significantly reduced lung volumes. The increase the medication usage is unlikely to have normalised the BHR, as there were ongoing symptoms suggestive of asthma. In chapter 3, data on 5993 children in 7 population studies were analysed and the association between BMI percentile and symptoms of cough, wheeze, ix diagnosis of asthma, medication usage for asthma, atopy, lung function and bronchial responsiveness was studied. After adjusting for atopy, sex, age, smoking and family history, BMI was a significant risk factor for wheeze ever (OR=1.06; 95%CI 1.01-1.10, p=0.008) and cough (OR=1.09; 95%CI 1.05-1.14, p=0.001) but not for recent asthma (OR=1.02; 95%CI 0.98-1.07 p=0.43), or bronchial hyperresponsiveness (OR=0.97; 95%CI 0.95-1.04 p=0.77). In girls, a higher BMI was significantly associated with higher prevalence of atopy (x2 trend 7.9, p=0.005), wheeze ever (x2 trend 10.4, p=0.001), and cough (x2 trend 12.3, p<0.001). These were not significant in boys. With increasing BMI in children, there was no reduction in lung volume, no increase in airway obstruction and no increase in bronchial responsiveness. In chapter 4, the hypothesis that obesity per se is associated with bronchial responsiveness was tested. Six obese women without asthma were compared to 6 non-obese women without asthma with high dose methacholine challenges to assess the bronchial responsiveness. There was no increase in bronchial responsiveness, and no difference in the position or shape of the high dose methacholine curve despite the fact that these women had reduced lung volumes associated with their obesity. In chapter 5, the hypothesis whether reduced lung volume per se would cause a change in greater mechanical effect, ie more marked airway narrowing in both non-asthmatic and asthmatic subjects was tested. Lung volumes and methacholine challenges were undertaken in the supine and erect position on different days. As expected in normal subjects there was a small reduction in lung volume on lying down, this was associated with an increase in the measure of bronchial reactivity DRR. In contrast, in asthmatics, there was no acute fall in lung volume and there were variable changes in the index of reactivity suggesting non-homogeneity in the lung function abnormality. This suggests changes in bronchial reactivity can occur without any relationship to lung volume change. These negative results suggest that lung volume changes that may occur in obesity are unlikely contributors to the apparent increase in asthma symptoms. In chapter 6, the hypothesis that the supposed increase in asthma symptoms in the obese were due to the effects of gastro-oesophageal reflux were assessed in 147 obese subjects graded for gastro-oesophageal reflux severity using manometry and gastroscopy. This study showed that subjects with increased gastro-oesophageal reflux did not have subjective increases in asthma prevalence, obstructive sleep apnoea, or snoring however they had a clear worsening of gas transfer as measured by carbon monoxide transfer suggesting a greater level of parenchymal disease. The overall results are that there is an increase of diagnosis of asthma, increase in symptoms of asthma and medication usage for the treatment of asthma in the obese. Objectively despite reductions in lung volume, there is no increase in bronchial responsiveness in this group suggesting that these symptoms are not related to true asthma, but to alternative co-morbidities associated with obesity such as gastro-oesophageal reflux. Notably gastrooesophageal reflux was not associated with increased asthma prevalence or airway obstruction. However it was associated with reduced gas transfer suggesting parenchymal disease. This suggests that the increase in symptoms of wheeze and shortness of breath in the obese should not be attributed to asthma in the absence of variable airflow limitation that is reversible spontaneously or with treatment, or with an increase in the existing bronchial hyperresponsiveness (BHR) to a variety of stimuli.

Little is known about the recovery of patients after pneumonectomy and the impact of the surgery on the lifestyle of young, employed, ex-smokers and their families. This study was conducted to address this knowledge deficit, and gather information that would help health professionals to be able to assist people facing pneumonectomy. A qualitative study using van Manens methodological approach to interpretive phenomenology was chosen, in order to capture a full and rich understanding and meaning of the phenomenon that patients live. The names, age, operation, histological cell type, stage of disease, and disease free status of potential participants were obtained from a Lung Cancer Surgical Database after obtaining ethical approval for the study. Nine participants (three females and six males) met the inclusion criteria and gave informed consent for the study. Data collection comprised of open-ended interviews that were audiotaped, then transcribed verbatim into hard data. Data interpretation was based on the selective reading approach of van Manen from which six thematic statements arose. These are living the discomforts of treatment and recovery, discovering new limitations on myself; functional and emotional, my reliance on support, my financial security is threatened, my survival is at threat, and I wish I had known more. The study found that each participant had a unique experience of recovery and consequently the degree of recovery attained varied between participants. They all had a very strong desire to survive lung cancer and considered the risks of major surgery and loosing a lung to be insignificant compared to the certainty of loosing their life if they did not undergo surgery. This study provided a glimpse of what it was like for a group of patients to live the experience of life after a pneumonectomy and it provides a basis from which nurses can explore further the experiences of patients who are subjected to lung cancer surgery.

Thesis (M.P.A.)--Kutztown State College, 1982. / Source: Masters Abstracts International, Volume: 45-06, page: 2942. Typescript. Abstract precedes thesis as preliminary leaves 1-3. Includes bibliographical references (leaves 74-79).

Sox2 is the most frequently amplified oncogene in lung squamous cell carcinoma (SCC). Lung SCC arises in the proximal to central airways and is thought to originate from the p63-positive basal progenitor cells. Since Sox2 amplification occurs early in SCC pathogenesis, we investigated the oncogenic role of Sox2 using normal primary human lung basal progenitor cells. Although Sox2 is highly expressed in normal basal progenitors in a quiescent tracheal epithelium in vivo, we found that Sox2 expression decreases substantially during in vitro proliferation. When Sox2 expression is elevated in the proliferating basal cells in vitro to a level clinically observed in lung SCCs, Sox2 causes hyperplasia and promotes both squamous and Mucin16-positive glandular lineages at the expense of ciliated cell differentiation. Furthermore, our data suggest that the squamous and glandular-differentiating activity of Sox2 is differentially modulated by Receptor tyrosine kinase (RTK) and/or PI3-kinase signaling to promote squamous metaplasia of basal progenitor cells during SCC development.

Sox2 is the most frequently amplified oncogene in lung squamous cell carcinoma (SCC). Lung SCC arises in the proximal to central airways and is thought to originate from the p63-positive basal progenitor cells. Since Sox2 amplification occurs early in SCC pathogenesis, we investigated the oncogenic role of Sox2 using normal primary human lung basal progenitor cells. Although Sox2 is highly expressed in normal basal progenitors in a quiescent tracheal epithelium in vivo, we found that Sox2 expression decreases substantially during in vitro proliferation. When Sox2 expression is elevated in the proliferating basal cells in vitro to a level clinically observed in lung SCCs, Sox2 causes hyperplasia and promotes both squamous and Mucin16-positive glandular lineages at the expense of ciliated cell differentiation. Furthermore, our data suggest that the squamous and glandular-differentiating activity of Sox2 is differentially modulated by Receptor tyrosine kinase (RTK) and/or PI3-kinase signaling to promote squamous metaplasia of basal progenitor cells during SCC development.

Thesis (Ph. D.)--University of Florida, 2002. / Typescript. Vita. Includes bibliographical references (leaves 98-110).

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