Medicine and Health Sciences Commons^™

Exploration Into The Relationship Between Colitis And Depression: A Potential Role For The Aryl Hydrocarbon Receptor, Kasie Lynn Roark

Theses and Dissertations

Inflammatory Bowel Disease (IBD) is a group of chronic gastrointestinal disorders with unclear etiology comprised of two defined disorders – Crohn’s Disease (CD) and Ulcerative Colitis (UC). IBD leads to chronic pain, socially isolating symptoms, and an overall reduction in patient quality of life. There is currently no cure for IBD. Due to decreased mucous production and weakening of the colonic epithelial lining, gut-microbiota and their metabolites can invade the intestinal lamina propria and circulate systemically, a term known as “leaky gut”. Recent studies show a relationship exists between peripheral inflammation, such as IBD, and depression. The gut-brain axis (GBA) …

The Inflammatory Potential Of Diet And Its Relationship With Metabolic, Mental, And Cardiovascular Health Among Childhood Cancer Survivors: The St. Jude Lifetime Cohort Study (Sjlife), Christian Ricardo Alvarado

Theses and Dissertations

Background: Diet is now known to play an important role in the process of inflammation and subsequent chronic health events, such as cancer, metabolic syndrome (MetS), anxiety, depression, and cardiovascular disease (CVD). The Dietary Inflammatory Index (DII®) and energy-adjusted DII (E-DIITM) are tools that can estimate the inflammatory potential of diet of individuals. Previous research has focused predominantly on diet-associated inflammation and adverse health effects in populations that were not composed of cancer survivors. As of the time of this dissertation, none have focused on childhood cancer survivors. Childhood cancer survivors are at an elevated risk of suffering from an …

Cardiac Arrest And Global Ischemia Reperfusion Injury: Role Of Mitochondria And Cannabinoid Receptor 2 Signaling., Jennifer L. Bradley

Theses and Dissertations

We explored the effects of cardiac arrest on mitochondria populations and heart whole tissue lysate proteomics utilizing the Weil Institute’s in vivo rat model of cardiac arrest and cardiopulmonary resuscitation. We have discovered that brain mitochondria are more sensitive to global ischemia compared to heart mitochondria. Additionally, complex I is the most sensitive electron transport chain complex to ischemic injury and is a major control point of the rate of oxidative phosphorylation following cardiac arrest and cardiopulmonary resuscitation. Preservation of brain mitochondrial activity and function during cardiac arrest may enhance outcomes and recovery.

A recent article focusing on acute myocardial …

The Effects Of Interleukin-1Β On Cardiac Reserve And Exercise Capacity In The Mouse, Habeebah Z. Vohra

Theses and Dissertations

Heart failure (HF) is characterized by dyspnea, fatigue, and exercise intolerance. Clinical evidence points to increased interleukin-1β (IL-1β) activity in patients with HF, with an IL-1 blockade improving the exercise capacity in HF patients. In healthy mice, recombinant-mouse IL-1β (rmIL-1β) induces acute systolic dysfunction, peaking 4 hours after administration. However, the direct effects of rmIL-1β on exercise capacity are unknown. We hypothesized that rmIL-1β diminishes the exercise capacity in the mouse. Adult mice were trained to run on a treadmill and exercise capacity was assessed before, 4 hours, and 96 hours after intraperitoneal administration of rmIL-1β (3 μg/kg) or vehicle …

Gm-1111 Preserves Phagocytic Function Of Macrophages Exposed To Prolonged Hyperoxia Via Interruption Of Hmgb1-Mediated Signaling, Leanne Daley

Theses and Dissertations

Supraphysiological levels of oxygen (i.e. hyperoxia) are used to treat patients with respiratory distress. Prolonged exposure to hyperoxia can impair alveolar macrophage functions and increase susceptibility to ventilator-associated pneumonia (VAP). Hyperoxia-induced alveolar macrophage dysfunction is, in part, mediated by high airway levels of the pro-inflammatory mediator, high mobility group box-1 (HMGB1). An early generation glycosaminoglycan (GAG), 2-O, 3-O desulfated heparin (ODSH), attenuates hyperoxia-compromised innate immunity by preventing the binding of HMGB1 with receptors that activate pro-inflammatory pathways. In this study, we investigated whether the next generation GAG, GM-1111, can attenuate hyperoxia-compromised macrophage function. GM-1111 (100μM) prevented hyperoxia-induced (95% O2 for …

The Impact Of Aging And Mechanical Injury On Alveolar Epithelial And Macrophage Responses In Acute Lung Injury And Inflammation, Michael S. Valentine

Theses and Dissertations

Patients with severe lung pathologies, such as Acute Respiratory Distress Syndrome (ARDS), often require mechanical ventilation as a clinical intervention; however, this procedure frequently exacerbates the original pulmonary issue and produces an exaggerated inflammatory response that potentially leads to sepsis, multisystem organ failure, and mortality. This acute lung injury (ALI) condition has been termed Ventilator-Induced Lung Injury (VILI). Alveolar overdistension, cyclic atelectasis, and biotrauma are the primary injury mechanisms in VILI that lead to the loss of alveolar barrier integrity and pulmonary inflammation. Stress and strains during mechanical ventilation are believed to initiate alveolar epithelial mechanotransduction signaling mechanisms that contribute …

Anticholinergic Burden And Risk Of Cognitive Impairment In Older Adults, Syeda Hashimi

Theses and Dissertations

Studies reveal that 10-27% of older adults chronically use anticholinergic medications. Increased cumulative anticholinergic burden scores are associated with increased risks of dementia. The mechanisms by which anticholinergic drugs negatively impact cognition remain elusive. However, researchers speculate that the drug’s impairment of cholinergic neurons promotes neuroinflammation.

We hypothesize that drugs with anticholinergic properties will induce inflammation in the brain. MCP1 and IL 6 are chemokines that contribute to neuroinflammation. We investigated the influence of diphenhydramine (Benadryl) on the production of MCP1 and IL-6 in Normal Human Astrocytes and Paroxetine on the production of MCP1 in Normal Human Astrocytes and Normal …

Examining The Relationship Between Yoga Participation And Health. You Down, Dog?, Bethany Forseth Hanson

Theses and Dissertations

The prevalence of debilitating chronic diseases, such as cardiovascular disease (CVD) and Alzheimer’s disease, are increasing in the United States. Inflammation, mitochondrial dysfunction, stress and depression are common pathologies associated with these chronic diseases. Many individuals engage in yoga because they believe it will improve their health. However, research examining the impact of yoga on markers of health associated with chronic diseases is limited and often reports conflicting results. Therefore, the purpose of this dissertation is to examine the relationship between yoga and inflammation, protein content of oxidative phosphorylation complexes, stress and depression, which may support the use of lifestyle …

Macrophages And Associated Inflammation Differentially Impact Obesity, Colorectal Cancer And Obesity-Enhanced Colorectal Cancer, Jackie Bader

Theses and Dissertations

Colorectal Cancer (CRC) is the third-most common malignancy for men or women, with chronic inflammation considered as a primary risk factor. Obesity is also considered a chronic inflammatory disease and is associated with increased CRC incidence. Further, obesity and CRC occur in men and women differently with the highest incidence of either disease found in men, suggesting that female sex hormones may play a protective role in inflammatory diseases. Macrophages can promote inflammation and are a driving force in obesity-associated metabolic dysfunction. Conversely, macrophages also contribute to pro-tumoral responses including, proliferation, angiogenesis and tissue remodeling. This heterogeneity of macrophage behavior …

Role Of Epigenome And Microbiome In Endocannabinoid-Mediated Regulation Of Inflammation During Diet-Induced Obesity, Kathryn Miranda

Theses and Dissertations

Obesity is an inflammatory disease involving accumulation of adipose tissue, gut microbiota dysbiosis, and over-activation of the endocannabinoid system (ECS). Mechanisms involved in ECS regulation of obesity-induced inflammation are not well understood. Presented here are three chapters involving microRNA (miR) regulation of inflammatory adipose tissue macrophages (ATM) during high-fat diet (HFD)-induced obesity and cannabinoid receptor-mediated regulation of gut microbiota dysbiosis.

ATMs are innate immune cells that drive chronic low-grade inflammation during obesity. Polarization between pro-(M1) and anti-(M2-like) inflammatory phenotypes influence insulin sensitivity and energy expenditure; however, the mechanisms involved are unclear. In study one, we characterized miRs involved in ATM …

The Role Of Sphingosine Kinase 2 In Alcoholic Liver Disease, Eric K. Kwong

Theses and Dissertations

Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide characterized by the accumulation of lipids within the liver, inflammation and the possibility of progressing to cirrhosis and liver failure. More importantly, there are currently no effective treatments for ALD and liver transplantation remains the only therapeutic option for end-stage liver disease. Previous studies have shown that ALD is a result of a combination of endoplasmic reticulum (ER) stress, lipid metabolism dysregulation and inflammation. It has been previously reported that alcohol disrupts gut microbiota homeostasis and causes increased endotoxins that contribute to the pathology of ALD. However, …

Counterregulatory Effects Of Ptx3 On Inflammation And Cellular Aging, Aaron L. Slusher

Theses and Dissertations

Pentraxin 3 (PTX3) is a vital regulator of innate immune function that has been shown to counterregulate pro-inflammatory signaling and protect against the development of cardiovascular disease (CVD). Less is known about how PTX3 may mitigate against CVD risk by regulating the pro-inflammatory response at the cellular level. Therefore, this dissertation details four manuscripts which aimed to examine the capacity of PTX3 to regulate the innate immune response of peripheral blood mononuclear cells (PBMCs) isolated from healthy adults. Manuscript 1 examined the capacity of PTX3 to alter the inflammatory milieu following in vitro stimulation of isolated PBMCs with the pro-inflammatory …

The Role Of Human Msc Derived Exosomes In The Treatment Of Periodontal Diseases, Sonia S. Talegaonkar

Theses and Dissertations

Periodontal disease affects 47% of Americans over 30. Characterized by microbial dysbiosis and unregulated inflammation, severe periodontitis causes degradation of bone and soft tissue around teeth. Current treatments have limited regenerative outcomes and frequent reinfection by harmful bacteria. Human mesenchymal stem cells (hMSCs) have been shown to promote wound healing and tissue regeneration. Many therapeutic benefits of hMSCs are due to their secretome products, like exosomes. Our long-term goal is to develop periodontal therapies with hMSC exosomes. The objectives of this study were to determine the effect of hMSC-derived exosomes on cellular activity of hMSCs and investigate whether hMSC exosome …

Characterization Of The Role Of Insulin-Like Growth Factor Binding Protein 7 (Igfbp7) Using A Genetic Knockout Mouse Model, Maaged A. Akiel

Theses and Dissertations

In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/- ) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops …

The Role Of Inflammation In Atherosclerosis, Fatma Saaoud

Theses and Dissertations

Atherosclerosis is both a chronic inflammatory disease and lipid deposition disorder characterized by accumulation of lipids, fibrous tissue, and inflammatory cells in the arterial wall. Thus, investigating the role of inflammation and the immune system in the progression of atherosclerosis may help in the development of novel therapeutics for atherosclerotic disease. Current atherosclerosis therapy is aimed at lipid targets and focused primarily on reducing plasma cholesterol levels. Clinical and experimental data support the critical role of inflammation in atherosclerosis and suggest that reducing inflammation even without affecting lipid levels may reduce the event rate of cardiovascular disease. Yet, no pure …

Resolution Of Inflammation Rescues Axon Initial Segment Disruption, Nicholas M. George

Theses and Dissertations

Axonal domains are required for proper neuron function. These domains are unstable and degenerate concurrent with the inflammation in multiple sclerosis (MS) and the inflammatory disease models experimental autoimmune encephalomyelitis (EAE) and lipopolysaccharide (LPS) induced inflammation. Previous studies from our laboratory have shown that the axon initial segment (AIS) is maintained independently of the presence of myelin, but that AIS disruption is seen in MS as well as EAE and LPS-mediated inflammation. AIS loss can be interrupted in the early stage of EAE using the anti-inflammatory drug Didox. However, the potential for Didox directed repair of the AIS in later …

Post-Tbi Hippocampal Neurogenesis In Different Tbi Models, Kaushal S. Patel

Theses and Dissertations

Traumatic brain injury (TBI) leads to short-term and long-term consequences that can cause many different life-long disorders. Studies of TBI have generally focused on the acute stage; however, it is now becoming important to investigate chronic responses following TBI as clinical reports of dementia and cognitive impairments have been linked to a history of TBI. Recent data have established that cognitive function is associated with hippocampal neurogenesis. Chronic injury induced changes in the brain may affect this endogenous process. Chronic responses following TBI include cell death pathways and inflammatory responses that are persistent in the brain for months to years …

The Role Of Enteric Glia In Opioid-Induced Constipation, Sukhada Bhave

Theses and Dissertations

Morphine is one of the most widely used drugs for the treatment of pain but its clinical efficacy is limited by adverse effects including persistent constipation and colonic inflammation. Morphine-induced colonic inflammation is facilitated by microbial dysbiosis and bacterial translocation. In this study, we demonstrate that secondary inflammation and persistent constipation are modulated by enteric glia. In chronic morphine treated mice (75 mg morphine pellet/5 days), ATP-induced currents were significantly enhanced in enteric glia isolated from the mouse colon myenteric plexus. Chronic morphine resulted in significant disruption of the colonic epithelium and increased Il-1β in the myenteric plexus. The increase …

The Effect Of Arsenic On Type 2 Diabetes And Inflammation, Kayla Penta

Theses and Dissertations

Arsenic, a ubiquitous environmental contaminant, has been shown to cause a number of health effects. At high concentrations the inorganic form is a well-known toxin, but at lower concentrations the effects range from various cancers, to cardiovascular disease and type 2 diabetes. At higher concentrations of arsenic (500- 1000μg/L) there have been epidemiological studies conducted demonstrating an increased risk in the development of type 2 diabetes with this exposure. At lower levels of arsenic exposure (<500 μg/L) the epidemiological results are inconclusive. Arsenic is also an immunotoxicant, meaning that it will cause changes in the immune response. The changes in the immune response will vary depending on a number of variables, including amount of arsenic exposure, forms of exposure and route of exposure. We wanted to determine if arsenic could modulate the immune system, and if this change could lead to an increase in susceptibility to type 2 diabetes development. We chose to examine this in C57BL/6 and db/+ mice – two non-susceptible strains. After 8 weeks (4 weeks old to 12 weeks old) of low dose inorganic arsenic exposure (50 μg/kg or 500 μg/kg) we evaluated changes in body composition, glucose tolerance and immune response. We saw that there were differences based on sex, genotype and treatment group present after the 8-week treatment period in body composition, while there were minimal changes in glucose tolerance. Finally, the immune response showed great variability depending on sex, genotype and treatment group. This project has demonstrated that while we are trying to compare differences in in vivo and epidemiological studies to find a link between arsenic and type 2 diabetes, there may be deeper levels of complications based on individual variability to arsenic exposure.

The Effects Of 830nm Light On Inflammation In Retinitis Pigmentosa, Krystal Marie Bach

Theses and Dissertations

Purpose: Retinitis Pigmentosa (RP) is an inherited retinal degenerative disease and the most common cause of blindness in developed countries, affecting approximately 1 in 4,000 people. RP is characterized by photoreceptor cell death and recent studies suggest that chronic inflammation may play a key role in the pathogenesis of RP. Currently, there are no known treatments or preventive measures to delay or halt the loss of photoreceptor cells. Photobiomodulation (PBM) by light in the far-red or near-infrared (NIR) range of the light spectrum has been documented to help promote cell survival and reduce inflammation in several disease states. Recent studies …

The Mechanism Of Suppression By A Protective Peptide In A Mouse Model Of Multiple Sclerosis, Alaa Mansour Almatrook

Theses and Dissertations

Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). MS is characterized by an immune response directed against myelin sheath. This immune response results in demyelination, which leads to the clinical symptoms of MS. It is accepted that MS is mediated by T helper 1/ T helper 17 immune responses. However, the role of B cells and antibodies (Abs) are still under debate. The primary animal model for MS is the experimental autoimmune encephalomyelitis (EAE) that is induced by immunizing animals with one of the myelin components. We previously showed that immunizing mice with the …

The Effects Of Antibodies In Disease Progression Of Mog-Induced Experimental Autoimmune Encephalomyelitis, Melissa Marie Riter

Theses and Dissertations

Abstract: Multiple sclerosis (MS) is an auto-inflammatory disease of the central nervous system (CNS), affecting over 400,000 people in the US. MS is primarily studied in the animal model experimental autoimmune encephalomyelitis (EAE). MS is a T cell mediated disease but there is mounting evidence for a role for B cells in MS. Previous studies have established that rMOG Induction depends on the presence of B cells, while induction using the MOG peptide covering amino acids 35-55 does not require B cells to cause disease. When plasma from the rMOG and MOG35-55 immunized WT mice was analyzed by ELISA there …

Effects Of Tgf-Β1 And Il-33 On Mast Cell Function, Victor S. Ndaw

Theses and Dissertations

TGFβ is involved in many pathological conditions, including autoimmune disorders, cancer, and cardiovascular and allergic diseases. We have previously found that TGFβ can suppress IgE-mediated mast cell activation in human and mouse mast cells in vitro. IL-33 is a recently discovered member of the IL-1 family capable of inducing mast cell responses and enhancing IgE-mediated activation. In this study, we investigated the effects of TGFβ on IL-33-mediated mast cell activation. Bone marrow-derived mast cells cultured in TGFβ -1, -2, or -3 showed reduced IL-33-mediated production of TNF, IL-6, IL-13 and MCP-1, in a concentration-dependent manner. Furthermore, TGFβ also reduced …

Vitamin C: A Potential Regulator Of Inflammatory Response, Bassem M. Mohammed

Theses and Dissertations

Introduction: Neutrophils (PMNs) and Macrophages are the first responders recruited consecutively to the site of injury/inflammation. PMNs’ response/fate as well as macrophage reprogramming ultimately determine the course of resolution of inflammation. Physiologic wound healing has a significant inflammatory component. An exaggerated inflammation however is self-defeating leading to delayed healing. Parenteral vitamin C (VitC) attenuated inflammation in murine sepsis models and in patients with sepsis. However information about the mechanisms by which VitC regulates these events is limited.

Methods: Humanized mice lacking VitC synthesis capability (Gulo^-/-) were used. VitC sufficient and deficient mice were challenged with sterile inflammation, or …

Mcp-1 In Colorectal Cancer: Benefits Of Exercise, Jamie Lee Mcclellan

Theses and Dissertations

The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental factors. However, only about 20% have a familial basis with the largest fraction being attributed to environmental causes that can lead to chronic inflammation. Tumors associated macrophages drive the pro-inflammatory response in the tumor micro-environment and are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. In chapter 1, we examined the timing and magnitude of the intestinal inflammatory cytokine response in relation to tumorigenesis in …

Role Of Chronic Inflammation On Liver Function During Cachexia Progression In The ApcMin/+ Mouse Model, Aditi Narsale

Theses and Dissertations

Cachexia is a multifactorial syndrome that manifests during the advanced stage of chronic diseases and is characterized by a progressive loss of body mass sustained by underlying inflammation. The ApcMin/+ mouse is an established model of cachexia that exhibits a gradual loss of body mass correlating with increasing tumor burden and plasma IL – 6 levels. Moreover it also mimics other secondary characteristics observed in cachectic patients like splenomegaly, elevated plasma endotoxin levels, gut barrier dysfunction, hypogonadism and an overall hypermetabolic state. Liver controls the energy metabolism in the body by regulating glucose and lipid metabolism, glycogen storage, filtration of …

Symptoms, Cytokines, And Quality Of Life Of Patients With Chronic Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation, Debra Kelly

Theses and Dissertations

Introduction: Chronic graft-versus-host disease (cGVHD) is a serious complication following allo-HSCT characterized by immune dysregulation, organ dysfunction, risk for infection, and distressing symptoms. Complications may include scleroderma, hepatic dysfunction and bronchiolitis obliterans. Advances in allo-HSCT for many hematologic dyscrasias (e.g. acute and chronic leukemias, aplastic anemia, and myelodysplastic syndrome) have improved survival which has generated a renewed focus on survivorship issues. Distressing symptoms are noted as negatively impacting quality of life (QoL). The relationship between inflammation and behavioral responses may impact symptoms. Examining patterns and levels of inflammation with symptoms is relevant. Objective: The aims of this study were to …

The Effect Of Obesity On Il-1Β, Il-1ra, And Leptin Following Acute Mental Stress, Heather Caslin

Theses and Dissertations

Research regarding the development of cardiovascular disease (CVD) is important because CVD is the leading cause of death in the United States (US) and many countries abroad. Risk factors, such as obesity and psychological stress, should be studied in order to understand contributing factors for CVD and the cellular mechanisms which link risk factors with the development of disease. Specifically, the combined influence of multiple risk factors on inflammation is of interest because many individuals have more than one risk factor, which additively increases an individual’s risk for CVD. Obesity is already characterized by disordered inflammation, which suggests that the …

Transformation Of Human Mast Cells By Interferon-Gamma And The Potential Role Of Myeloid Derived Suppressor Cells In Mastocytosis., Sahar Lotfi-Emran

Theses and Dissertations

Mast cells respond to a variety of signals, are associated with both increased inflammation and regulation of the immune response, and are able to interact with a variety of hematopoietic and non-hematopoietic cells. The majority of the work that highlights mast cell pleiotropic abilities has been completed in murine models. Though these models have significantly advanced our understanding of what mast cells can do, they cannot inform us as to what mast cells actually do in human beings. The goal of this dissertation is to assess fully mature, primary human mast cell function beyond the well-defined type 1 hypersensitivity function …

Epigenetic Alterations Of Toll-Like Receptors By Tet2 In Spontaneous Preterm Labor, Anuja Chumble

Theses and Dissertations

Increasing evidence implicates the presence of bacteria in intrauterine tissues as an important risk factor for spontaneous preterm labor. Epigenetic alterations of innate immunity genes may increase the mother’s sensitivity to subclinical levels of bacteria. This study examined the presence of TET2, TLR-2, and TLR-9 in intrauterine tissue, and evaluated whether epigenetic alterations of these genes, as well as IL-8, changed their expression in human decidual tissue and a macrophage cell culture. Immunohistochemicalstaining was used to detect the presence of these proteins in intrauterine tissue. Gene expression changes were evaluated in stimulated monocytes and macrophages. Fluorescence immunohistochemistry was used to …