<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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Serotonergic neurons modulate a wide range of behaviors and functions, from mood and aggression to vital autonomic processes like heart rate, respiratory dynamics, and body temperature. We hypothesize that this broad scope reflects the collective actions of many functionally and molecularly distinct subtypes of serotonergic neurons, each with specialized roles in different neural processes. Supporting this idea are examples of heterogeneity among serotonergic neurons with respect to developmental origin, biophysical properties, and molecular expression; yet deciphering the functional and behavioral relevance of these differences has been challenging. In order to better understand serotonergic system organization, we have developed and applied a set of mouse genetic tools to subdivide serotonergic neurons into groups based on molecular criteria, and then to query these subtypes for differences with respect to biophysical properties, hodology, gene expression, and whole animal function. We applied these tools in a stage-wise fashion, from neural system en masse, as reference, and then to specific serotonergic neuron subtypes. From this, we have established that serotonergic neurons play key roles in at least two life-sustaining reflexes - the respiratory chemoreflex (breathing modulation to keep tissue PCO2/pH within physiological limits) and body temperature regulation. We found that chemoreflex modulation, but not body temperature regulation, maps to a specific serotonergic neuron subtype - that subtype with a developmental history of Egr2 gene expression. Further, in brain slice preparations, we found that this subtype is chemosensitive, increasing firing rate in response to conditions of hypercapnic acidosis. Thus, in vivo, Egr2-serotonergic neurons likely transduce chemosensory information into action potential firing to increase respiratory drive and ultimately breathing. Further, we found that Egr2-serotonergic neurons project selectively to respiratory nuclei involved in PCO2/pH sensory signal transduction, but not primary respiratory motor nuclei. This indicates that the serotonergic system has distinct sensory and motor divisions - another unexpected finding. In summary, these results establish a previously unappreciated functional modularity and organization to the serotonergic system, and open up potential for tailored function-specific therapeutic strategies, for example here as relates to disorders of respiratory homeostasis or thermoregulation.

Diss. (sammanfattning) Linköping : Univ., 2004. / Härtill 4 uppsatser.

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.