Medicine and Health Sciences Commons^™

Inflammation In The Neovaginal Microenvironment Of Transfeminine Individuals, Hannah M.J. Wilcox

Electronic Thesis and Dissertation Repository

Transfeminine individuals are assigned male at birth but do not identify as male. Some transfeminine individuals may choose to undergo the gender affirming surgery vaginoplasty to create a neovagina. There is a paucity of data on the neovaginal microenvironment to inform best gynecological practices. Vaginal and penile inflammation is modulated by local microbiota, but drivers of inflammation in the neovagina are poorly understood. The compositions of the neovaginal microbiota and immune milieu were elucidated from neovaginal swabs, using 16s rRNA gene sequencing and multiplex immunoassay, respectively. Immune data reduction and clustering was performed, and six unique immune profile types (IPTs) …

Assessing Inflammation In The Pathology Of Knee Osteoarthritis, Zachary J. Koudys

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) is a joint disease that causes pain, stiffness, and loss of function. Inflammation of the synovium plays a role in the pathology of OA. Macrophages are the dominant immune cells in synovial tissue. Activated macrophages over-express the translocator protein (TSPO). [¹⁸F]FEPPA is a 2^nd generation positron emission tomography (PET) tracer that can target TSPO with high specificity. Hybrid [¹⁸F]FEPPA PET/MRI may enable accurate quantification of macrophage activity in vivo. In this work, [¹⁸F]FEPPA tracer uptake in knee synovial tissue was measured ex vivo using autoradiography and was validated to correlate to …

The Effect Of Oral And Topical Antibiotics On Foreskin Inflammation And Hiv Target Cells In Ugandan Men., Zhongtian (Eric) Shao

Electronic Thesis and Dissertation Repository

Penile circumcision reduces HIV susceptibility by up to 60% in men; however, many men prefer to remain uncircumcised for personal or cultural reasons. Penile circumcision protects against HIV by reducing anaerobic bacteria on the penis. Penile anaerobes cause local inflammation and the recruitment of HIV-susceptible CD4+CCR5+ cells, increasing the likelihood that exposure to HIV during intercourse results in infection. To determine if a non-surgical intervention can reduce penile anaerobes and HIV target cells, we randomized men to antimicrobial treatment prior to circumcision. To be able to quantify the effect of antimicrobials, we developed a novel deep-learning algorithm to quantify HIV …

Development Of An In Vitro Model Of Ischemia Reperfusion Injury In Kidney Transplantation, Ashley Jackson

Electronic Thesis and Dissertation Repository

Kidney transplantation remains the optimal treatment option for patients with end-stage renal disease. We aim to improve organ preservation during transplantation by reducing damage from ischemia reperfusion injury (IRI) using existing clinically approved drugs. In this study, we developed and characterized an in vitro model that mimics the conditions of IRI in kidney transplant as a tool to screen and study the therapeutic effect of drugs in the context of IRI. We recapitulated several key outcomes in IRI in our model, including the induction of hypoxia, cell death, increased expression of damage markers (NGAL, HMBG-1) and pro-inflammatory cytokines in a …

Effects Of Annexin A5 On Endothelial Inflammation Induced By Lipopolysaccharide-Activated Platelets And Extracellular Vesicles, Brent Jeffrey Tschirhart

Electronic Thesis and Dissertation Repository

Sepsis is a dysregulated immune response to infection and the leading cause of mortality globally, accounting for 11 million deaths in 2017. To date, no therapeutics are available to treat the underlying septic response. Previous research from our laboratory has shown that annexin A5 (Anx5) treatment increased survival by 40% in mice with endotoxemia, a model of sepsis. During sepsis, activated platelets release membrane fragments called extracellular vesicles (EVs) with externalization of phosphatidylserine to which annexin A5 binds with a high affinity. We hypothesized that annexin A5 will block the pro-inflammatory response induced by activated platelets and EVs in vascular …

Measuring Inflammation In The Entire Myocardium In A Canine Model Of Myocardial Infarction With Hybrid Pet/Mri, Benjamin Wilk

Electronic Thesis and Dissertation Repository

Background: After myocardial infarction (MI), fibrosis and an ongoing dysregulated inflammatory response are associated with adverse cardiac remodeling. Fluorodeoxyglucose (FDG) positron emission tomography (PET) is sensitive to inflammation provided suppression protocols are implemented to restrict the uptake of glucose in myocytes. Magnetic resonance imaging can be used to determine extracellular volume, a surrogate measure of fibrosis. In some cases, patients present with markedly reduced flow in the setting of a large infarct, i.e. microvascular obstruction, restricting the delivery of FDG and contrast agents. To overcome this problem, a constant infusion was explored as an alternative to the clinical standard bolus …

Implications Of Long Non-Coding Rnas In The Pathogenesis Of Diabetic Retinopathy: A Novel Epigenetic Paradigm., Saumik Biswas

Electronic Thesis and Dissertation Repository

With the rising incidence of diabetic retinopathy (DR), there is an urgent need for novel therapies. Presently, several altered metabolic pathways have been implicated in the pathogenesis of DR. Recent advances in genomic technologies have identified considerable epigenetic alterations that also contribute to DR progression. Long non-coding RNAs (lncRNAs; >200 nucleotides), critical regulators of gene expression, are aberrantly expressed in DR and have not been comprehensively characterized. Our microarray analyses using human retinal endothelial cells (HRECs) revealed thousands of differentially expressed lncRNAs following high glucose (HG) exposure, with profound increases in the lncRNAs MALAT1 and HOTAIR. Using multiple techniques, …

The Role Of Synovium And Synovial Macrophages In Experimental Post-Traumatic Knee Osteoarthritis, Yue Lai-Zhao

Electronic Thesis and Dissertation Repository

In osteoarthritis (OA), synovitis is associated with symptom severity. As synovium secretes both catabolic and anabolic factors into the joint, the impact of synovitis in OA remains unclear. We developed a novel co-culture system using tissues from an established rat model of post-traumatic knee OA (PTOA) to study signaling between synovium and chondrocytes. We found that synovium from early stage but not later stage PTOA joints caused an overall protective effect in chondrocytes. We then selectively treated synovial macrophages with liposomal drugs causing depletion, STAT1 inhibition, or STAT6 inhibition in early PTOA joints. We found cartilage damage in vivo was …

Comorbid Metabolic Syndrome And Prodromal Alzheimer's Disease In A Rat Model, Nadezda Ivanova

Electronic Thesis and Dissertation Repository

Metabolic syndrome (MetS), the development of which is associated with high-caloric Western diet intake, represents a risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and appears to contribute to AD progression when MetS and AD are comorbid. The interaction between AD and MetS might be through white matter inflammation, since white matter abnormalities and inflammation are important early events in the etiopathogenesis of both diseases. In these investigations, the effect of a high-caloric diet (HCD), to induce metabolic disturbances, on white matter neuroinflammation and cognitive function was investigated in a transgenic (TG) rat model of prodromal AD …

Modulation Of Inflammation Driven Wound Healing After Glaucoma Surgery, James J. Armstrong

Electronic Thesis and Dissertation Repository

Dysregulated wound healing contributes to most currently unanswered ophthalmological morbidity. Opacification and structure altering contractures compromise the delicate ocular anatomy upon which ocular function and healthy vision are reliant. Glaucoma filtration surgery, corneal stromal injury, proliferative vitreoretinopathy and age-related macular degeneration are major contributors to ocular morbidity – all with myofibroblast transdifferentiation and pathognomonic scarring activity at their core.

This thesis aims to revaluate the means by which dysregulated ocular wound healing is combated with evidence describing a novel strategy to mitigate its effects. A translational approach was used. An initial retrospective analysis of over ten thousand glaucoma surgeries found …

White Matter Inflammation And Executive Dysfunction: Implications For Alzheimer Disease And Vascular Cognitive Impairment, Alexander Levit

Electronic Thesis and Dissertation Repository

White matter integrity is crucial to healthy executive function, the cognitive domain that enables functional independence. However, in the ageing brain, white matter is highly vulnerable. White matter inflammation increases with age and Alzheimer disease (AD), which disrupts the normal function of white matter. This may contribute to executive dysfunction, but the relationship between white matter inflammation and executive function has not been directly evaluated in ageing nor AD. White matter is also particularly vulnerable to cerebrovascular disease, corresponding with the common presentation of executive dysfunction in vascular cognitive impairment (VCI). Thus, white matter may be an important substrate by …

Hepcidin-Mediated Iron Regulation In P19 Cells Is Detectable By Mri, Kobra Alizadeh Pourbouyeh

Electronic Thesis and Dissertation Repository

Magnetic resonance imaging (MRI) can be used to track cellular activities in the body using iron-based contrast agents. However, intrinsic cellular iron handling mechanisms may also influence the detection of magnetic resonance (MR) contrast. For instance, inflammation involves downregulation of iron export in macrophages by the hormone hepcidin, due to degradation of the iron export protein, ferroportin (Fpn). We examined the effect of hepcidin on iron regulation and MR transverse relaxation rates in multi-potent P19 cells, which display high iron export activity, similar to macrophages. In response to varying conditions of iron supplementation, our results showed similar Fpn expression in …

Effect Of Carbon Monoxide-Releasing Molecule-3 On The Severity Of Endothelial Dysfunction Due To Elevation Of Hydrostatic Pressure In An In Vitro Model Of Compartment Syndrome, Michel A. Taylor

Electronic Thesis and Dissertation Repository

Compartment syndrome (CS) is a surgical emergency caused by elevated pressure within a closed osseofascial compartment. It leads to microvascular dysfunction, limiting oxygen and nutrient delivery, gas exchange, resulting in cellular anoxia, muscle necrosis and cell death.

Currently, the only effective treatment is surgical fasciotomy. Recently, carbon monoxide (CO) delivered via carbon monoxide releasing molecule-3 (CORM-3) has been shown to improve microvascular perfusion and convey anti-inflammatory benefits in animal models of CS.

The contribution of elevated hydrostatic pressure (EHP) to the pathophysiology of CS was examined in an in vitro model of CS. We found that EHP led to increased …

Evaluating Evolving Leukocyte Populations In Peripheral Blood Circulation Post-Concussion In A Human Longitudinal Analysis Of Female Athletes, Kevin A. Blackney

Electronic Thesis and Dissertation Repository

Concussions are generating increasing concern due to potential long-term neurological consequences. Currently there is no universally recognized diagnostic approach for concussion. I hypothesize that a signature temporal response of biomarkers of inflammation in systemic circulation will provide an objective diagnosis of concussion and could also be used to track patient recovery. The Western University women’s rugby team underwent blood draws at pre-season and post-season as a baseline evaluation, and players determined to have sustained a concussion underwent repeat blood analysis post-concussion. Blood samples were analyzed by flow cytometry to profile immune cell populations alongside accepted concussion assessments, and complete blood …

Therapeutic Application Of Carbon Monoxide In Acute Limb Compartment Syndrome, Aurelia Bihari

Electronic Thesis and Dissertation Repository

Acute limb compartment syndrome (CS), a devastating complication of musculoskeletal trauma, develops in response to elevation of the pressure within a closed osseofascial compartment, producing muscle- and limb-threatening ischemia. Full decompression of all involved compartments by fasciotomy is the current gold-standard therapy, but it must be performed within a surgical window of 6-8 hours, before tissue damage becomes permanent.

Carbon monoxide (CO), a byproduct of heme metabolism, has been shown protective in ischemia. While inhalation of CO leads to elevation of carboxyhemoglobin (COHb), recent development of transitional metal carbonyls, CO-releasing molecules (CO-RMs), particularly the water-soluble CORM-3, delivers CO in a …

Systemic Cyotkines/Chemokines Contribute To Microvascular Dysfunction And Tissue Injury In Compartment Syndrome, Erin S. Donohoe

Electronic Thesis and Dissertation Repository

There are few more devastating complications of musculoskeletal trauma than compartment syndrome (CS). It occurs secondary to elevated pressure within a closed osseofascial compartment, leading to microvascular dysfunction, hypo- perfusion of the tissues, cellular anoxia and ultimately cell death. The aim of this thesis was to prove that CS leads to a systemic inflammatory response, and to examine the specific cytokines/chemokines associated with CS. Twenty-four cytokines/chemokines were measured in a rat model of CS. Additionally, microvascular dysfunction, tissue injury and inflammatory response following the neutralization of pro-inflammatory cytokine, TNF-α, at the time of fasciotomy were assessed using intravital video microscopy …

Potential Therapeutic Role Of Hydrogen Sulfide-Releasing Molecule Gyy4137 In A Rat Model Of Acute Compartment Syndrome., Moustafa Haddara

Electronic Thesis and Dissertation Repository

Acute limb compartment syndrome (ACS) causes a unique form of limb ischaemia, which induces intense inflammatory response resulting in microcirculatory dysfunction, neutrophil activation and cell injury. Increased intracompartmental pressure is the hallmark of ACS. Decompression by fasciotomy is the gold standard treatment. While fasciotomy saves the limb from ischaemic threat, paradoxically, it causes further damage to the muscle by reperfusion injury. In addition, it does not address the inflammatory element purported to increase the tissue injury in ACS.

Recent evidence suggests that hydrogen sulfide (H₂S) can mitigate the damage associated with ischaemia-reperfusion injury. The purpose of this thesis …

Timp3 Regulation Of Macrophage Activation And Apoptosis, Michael S. Brock

Electronic Thesis and Dissertation Repository

Acute respiratory distress syndrome (ARDS) is a lung disease involving profound inflammation. Origins of persistent inflammation in select cases of ARDS are poorly understood, and we propose persistent inflammatory macrophages may be one of its mechanisms. Macrophages polarize to either promote inflammation, or suppress inflammation. Tissue inhibitor of metalloproteinases 3 (TIMP3) reduces the pro-inflammatory polarization in macrophages. Additionally, studies have shown TIMP3 promotes apoptosis, and its absence delays recovery from bleomycin-induced lung injury.

We hypothesize that TIMP3 promotes apoptosis of murine macrophages through inhibition of metalloproteinase activity and stabilization of FAS on the cell surface. Pro-inflammatory Timp3^-/- bone marrow-derived …

Regulation Of Lipid Homeostasis, Inflammatory Signalling And Atherosclerosis By The Peroxisome Proliferator-Activated Receptor Delta, Lazar A. Bojic

Electronic Thesis and Dissertation Repository

The peroxisome proliferator-activated receptor (PPAR) δ is a ligand-dependent transcription factor that has been implicated in metabolic and inflammatory regulation. The molecular and physiological mechanisms by which PPARδ activation regulates lipid metabolism, inflammatory signaling and protection from atherosclerosis in states of metabolic disturbance such as insulin resistance and dyslipidemia, were investigated in a series of in vitro and in vivo studies. In vitro experiments demonstrated that PPARδ activation inhibits atherogenic lipoprotein-induced lipid accumulation and the associated proinflammatory responses. The primary mechanisms for these effects were increased fatty acid β-oxidation, decreased lipoprotein lipase (LPL) activity, reduced MAPK signaling and improved insulin …

In Vivo Cellular Mri In Experimental Traumatic Spinal Cord Injury, Laura E. Gonzalez-Lara

Electronic Thesis and Dissertation Repository

Spinal cord injury (SCI) remains one of the most devastating conditions in medicine; it is a complex medical condition with no cure currently available. Inflammation plays an important role in SCI as it can have both beneficial and detrimental effects. Cell therapy has emerged as a promising treatment for SCI due to the potential for stem cells, including multipotent mesenchymal stromal cells (MSC), for tissue regeneration and immunomodulation of the inflammatory cascade after the initial trauma. However, there are still important, unresolved questions regarding cell therapy that magnetic resonance imaging (MRI) can help to address by producing high-resolution images with …