<p><strong>Abstract:</strong><strong> </strong></p> <p><em>Introduction:</em></p> <p>Because the relationship between pulmonary function and exercise tolerance is highly variable in COPD, other contributing factors were investigated. Physiological factors that contribute to exercise tolerance must contribute to the symptoms limiting exercise, thus the symptoms limiting exercise in COPD and their contributing factors were explored, including an investigation of novel mechanisms to explore the reported tiotropium bromide-mediated improvement in exercise tolerance in COPD.</p> <p><em>Methods:</em></p> <p>We conducted a retrospective, cross-sectional analysis of 4,424 COPD patients and 4,221 healthy subjects; referred to McMaster University Medical Center for exercise testing. Multiple linear regression, ridge regression, and MANOVA were utilized to determine the factors contributing to exercise tolerance, important symptoms limiting exercise, and factors contributing to dyspnea.</p> <p>A randomized, double-blind, placebo-controlled, crossover study of 20 COPD subjects was performed. Repeated measures ANOVA was utilized to determine effects of 3 weeks tiotropium bromide vs. 3 weeks placebo on cardiac output and efficiency of gas exchange during exercise.</p> <p><em> </em></p> <p><em>Results:</em></p> <p>MBC, DL_CO, and quadriceps strength were the three major, independent, contributors to exercise capacity (MPO = -206.3 + 5.1*Quadriceps Strength + 1.8*MBC + 10.0*DL_CO, r² = 0.677). MANOVA further illustrated this.</p> <p>Dyspnea, alone or in equal combination with leg effort, was the most important symptom limiting exercise in COPD. V_E and MBC were the two major, independent, contributors to dyspnea (Dyspnea = 0.95 + 0.08*V_E + -0.01*MBC, r² = 0.457). The increase in dyspnea with V_E was much greater than the decrease with MBC.</p> <p>Tiotropium bromide did not significantly (p = 0.72) improve the efficiency of gas exchange for oxygen, significantly worsened (p = 0.005) the efficiency of gas exchange for carbon dioxide, and did not improve cardiac output.</p> <p><em>Conclusion:</em></p> <p>We concluded the reported tiotropium bromide-mediated improvement in exercise tolerance in COPD is not mediated through improvements in gas exchange efficiency and/or cardiac output.</p> <p><strong><br /></strong></p> / Doctor of Philosophy (Medical Science)

<p>Cancer patients undergoing chemotherapy have an elevated risk for thrombosis. Although thrombosis is a common complication in cancer patients, the mechanisms of chemotherapy-induced thrombosis remain unclear. We investigated the procoagulant effects of lung cancer chemotherapy agents (carboplatin, paclitaxel, cisplatin, and gemcitabine) on endothelial cells, A549 cells, and monocytes. We also investigated the <em>in </em>vivo procoagulant effects of the aforementioned chemotherapeutic agents as well as the anti-angiogenic agent bevacizumab. Tissue factor (TF) activity, TF antigen and phosphatidylserine (PS) levels were measured on chemotherapy-treated human umbilical vein endothelial cells (HUVEC), A549 cells, and monocytes. Treatment of HUVECs, A549 cells, and monocytes with lung cancer single agent and combination chemotherapy resulted in significant increases in TF activity. However, only cisplatin- and gemcitabine- treated monocytes were found to have increased TF antigen levels. PS exposure was increased only on HUVEC and monocytes treated with cisplatin/gemcitabine combination therapy. Interestingly, addition of paclitaxel to carboplatin resulted in reduced levels of PS exposure on monocytes. This study is the first to explore the procoagulant effects of lung cancer chemotherapy agents on monocyte and A549 cell TF activity levels, as well as to investigate the mechanisms by which lung cancer agents may promote TF decryption on these cell lines<strong>.</strong> Our <em>in vivo</em> results demonstrated that treatment of healthy mice with bevacizumab, paclitaxel and carboplatin moderately increased plasma TAT levels in healthy mice. These studies reveal potential mechanisms by which lung cancer chemotherapy may increase the risk of thrombosis. These studies reveal potential mechanisms by which lung cancer chemotherapy agents induce a hypercoagulable state.</p> / Master of Science (MSc)

<p>Pre-clinical imaging has provided pulmonary researchers with a number of valuable tools for studying both the lung and lung disease. A greater understanding of the structure/function relationships within the rodent lung would help to bridge the gap between functional images of the lung and its underlying anatomy.</p> <p>The objectives of this work were to visualize and measure the components of rodent lung anatomy. Contrast-enhanced microCT images were used to visualize the airways and major blood vessels from both the Sprague-Dawley rat and the BALB/c mouse. These observations and measurements were used in the development of a pulmonary lung model containing both the conducting airways and blood vessels. The model can be applied to unenhanced images of the rodent lung to facilitate the regionalization of functional imaging data (SPECT/PET). The model has been used to simulate bronchoconstriction and deposition patterns of inhaled particles. Extensive validation revealed that the model was unable to fully reproduce the rodent lung and that further refinement is necessary.</p> <p>The finer structure of the rodent lung, which could not be resolved using our microCT system, was measured using histological sections of the rodent lung. Software was developed and validated to automatically quantify the increases in airspace size that are associated with several respiratory conditions.</p> <p>Together, this work sheds light on the underlying anatomy of the rodent lung that is present in both anatomical and functional images. The knowledge will help researchers to understand some of the structural changes that are occurring with the development of lung disease.</p> / Doctor of Philosophy (PhD)

<p><strong>Purpose: </strong>Habitual aerobic exercise improves vascular function; however, the acute vascular response to exercise is poorly understood. The present investigation compared the time course of acute changes in vascular function following two different types of aerobic exercise. <strong>Methods: </strong>Ten untrained males (23 ± 2 yrs) completed one bout of sustained moderate-intensity cycling (END) (30 mins at 55% peak power) or high-intensity interval (HIT) cycling (10 one-minute intervals at 80% peak power) on different days. Endothelium-dependent dilation was assessed by brachial artery flow-mediated dilation (baFMD) at baseline, immediately post-exercise, 1 hour post-exercise and 24 hours post-exercise. Endothelium-independent dilation was assessed via nitroglycerin (NTG) at all time points, except 1 hour post-exercise. <strong>Results:</strong> baFMD values were not significantly different between END and HIT at any time point. Immediately post-exercise baFMD values were unchanged from baseline. 1 Hour post-exercise, relative (p £ 0.001) and absolute (p £ 0.05) baFMD values were attenuated compared to all other time points for both HIT (%FMD baseline: 5.9 ± 2.3%; 1 hour post-exercise: 2.5 ± 1.5%) and END (%FMD baseline: 6.8 ± 2.4%; 1 hour post-exercise: 2.6 ± 1.9%). Relative (p £ 0.05) and absolute (p £ 0.05) NTG responses were attenuated immediately post-exercise compared to baseline for both HIT (%NTG baseline: 18.8 ± 4.4%; immediately post-exercise: 12.3 ± 3.1%) and END (%NTG baseline: 18.3 ± 3.1%; immediately post-exercise: 10.9 ± 4.9%). <strong>Conclusions: </strong>Immediately post-exercise, endothelium-dependent dilation is maintained; but reduced 1 hour following exercise cessation. Similar acute vascular responses are found following HIT and END.</p> / Master of Science in Kinesiology

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In this paper, old as well as new technological findings to decrease premature infant mortality are reviewed. This paper discusses fetal development throughout pregnancy from conception to full-term status as well as fetal lung development specifically from conception until full-term status. Several ideas to rapidly develop and mature fetal lungs are discussed such as mothers ingesting artificial surfactant supplements, either independently or coupled with antenatal corticosteroids, as well as intra-amniotic instillation prior to 28 weeks gestational. Drawbacks regarding these two are mentioned as well such as the fetus’s lungs not being mature enough to use the artificial surfactant leading into the idea of researching ways to rapidly develop fetal lungs, either week-by-week or stage-by-stage. Lastly, if the baby is born pre-maturely and is severely underdeveloped, research is currently being done on an artificial womb that the baby can be placed in to simulate a uterus where the fetus can develop on a normal timeline as he or she would in the mother’s womb.

Functional hyperemia and arteriolar vasodilation are impaired with chronic ischemia. We sought to examine the impact of chronic ischemia on collateral artery function. For this we used two hindlimb ischemia models to dissect the impact of different repair processes on collateral function. Ligation of the femoral artery increases shear stress in the muscular branch and results in outward remodeling and arteriogenesis. In contrast, resection of the femoral artery proximal to the muscular branch induces blood flow divergence and neutral remodeling along with expectedly greater hypoxia and inflammation. On day 14 after each surgery the diameter of the muscular branch was measured using sidestream dark field (SDF) imaging before and after gracilis muscle stimulation. A slight, but not statistically significant, impairment in functional vasodilation was observed in ligated mice (69±10% average diameter increase compared to 74±7% average diameter increase). Resected mice exhibited slightly (not statistically significant) enhanced collateral artery functional vasodilation (104±16% average diameter increase) but were also refractory to the restoration of resting vascular tone following the cessation of stimulation. Outward remodeling did not significantly impair vascular function, whereas neutral remodeling and tissue hypoxia induced impaired vascular tone.

Uromodulin (UMOD) is a protein made exclusively in the thick ascending limb. Clinical studies have demonstrated that rare missense mutations in UMOD result in autosomal dominant tubulointerstitial kidney diseases manifest by tubulointerstitial fibrosis (TIF), tubular cysts and a rapid progression to renal failure. In addition, several genome wide association studies reported that common single nucleotide polymorphisms in the UMOD gene are associated with an increased risk of chronic kidney disease (CKD) and hypertension. Interestingly, Dahl salt-sensitive (SS) rats exhibit many of the same pathologies observed in these clinical populations with alterations in UMOD. The goal of this study was to assess the qualitative and quantitative aspects of UMOD via western blotting, and the extent of SS hypertension and proteinuria in Dahl SS vs. a consomic rat strain in which chromosome 1 of the salt-resistant Brown-Norway (BN) rat, harboring the UMOD gene, has been introgressed into the Dahl SS background (SS.BN1). We hypothesized that differences in UMOD would be apparent in SS vs. SS.BN1 rats maintained on a low salt-diet and that the extent of SS hypertension and proteinuria would be attenuated in SS.BN1 vs SS rats. Western blot of urinary UMOD was performed in 16 week old SS (n=5), SS.BN1 (n=7) and BN (n=6) rats maintained on a low salt (LS) diet. BP (radiotelemetry) and proteinuria were assessed during LS feeding and during three weeks of high salt (HS) feeding in a different group of 8-10 week old SS (n=9) and SS.BN1 (n=8) rats. For western blotting, urine was normalized based on the protein concentration, and the density of the 85 kDa UMOD band in SS and SS.BN1 samples were normalized to the average density observed in BN rats. The UMOD band was 4.5 fold higher (p In summary, these data demonstrate striking qualitative and quantitative differences in UMOD between SS and SS.BN1 rats. The pattern of UMOD expression in SS rats is consistent with that observed in some patient populations of UMOD associated kidney disease. Finally, the evidence that SS.BN1 rats, harboring the UMOD gene from BN rats, exhibit significant protection against SS hypertension and proteinuria is consistent with the notion that an alteration in UMOD function may, in part, be responsible for such pathologies in SS rats.