Digital Commons Network^™

The Effects Of Diesel Exhaust Particle Exposure On Adipos Mitochondrial Bioenergetics And Inflammation, Cali Elizabeth Warren

Theses and Dissertations

Fine particulate matter (PM2.5) constitutes a significant component of ambient air pollution that has been implicated in the pathogenesis of metabolic disorders, including insulin resistance and type 2 diabetes. Among PM2.5 constituents, diesel exhaust particles (DEP) are prevalent particulates that infiltrate the bloodstream to drive systemic pathologies. The purpose of this study was to characterize the metabolic response of adipose tissue to DEP. We aimed to provide a comprehensive understanding by exploring mitochondrial bioenergetics, characterizing the inflammatory marker profile, including adipokines, and conducting a detailed histological analysis of adipocytes to provide valuable insights to the evolving understanding of the intricate …

Dynamic Mathematical Approaches To Understanding Pain In Sickle Cell Disease, Quindel Jones

Theses and Dissertations

In the last 50 years, pain in Sickle Cell Disease (SCD) has become more widely studied thanks to advancements in technology and awareness. Clinical studies, population surveys, pharmaceutical trials, and computational models have been created and conducted to elucidate the mechanisms, treatments, and prediction of Sickle Cell disease pain episodes. Computational models have become quite useful in unraveling disease pathology with the rise in data collection accessibility and advanced computational power. In particular, dynamic mathematical models have been used to investigate Sickle Cell disease pathology and treatment. In this work we conduct a literature review of mathematical models used in …

Osteoarthritis And Cartilage Insult: Elucidation Of Molecular Interplay And Attempted Interventions, Brandon James Rose

Theses and Dissertations

Osteoarthritis (OA) is a common and incapacitating joint disease beginning with breakdown of articular cartilage and extending into subchondral bone. At present, the processes through which the disease occurs are poorly understood, and interventions are limited to pain relief and eventual joint replacement. OA is commonly associated with obesity and corresponding pathologies, and as OA is demonstrably not a product of passive erosion of cartilage over time or under increased loads there must needs be some other mechanistic link between the two conditions. We hypothesize that the production of ceramides, a hallmark of the insulin resistance syndrome underlying many obesity-related …

Diagnosis And The Role Of Chemokine Receptors In Alzheimer's Disease, Josue David Gonzalez Murcia

Theses and Dissertations

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is the main cause of dementia in the elderly population. AD is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles that results in neurodegeneration and loss of memory function. However, diagnosis of AD and characterization of biological mechanisms that lead to pathology and modulate risk for disease has proven to be extremely difficult. Cerebrospinal fluid (CSF) contains critical biomarkers for AD such as levels of amyloid beta (Aβ) phosphorylated-tau (p-tau), total-tau (t-tau), and neurofilament light chain (NfL). The CSF levels of these biomarkers are useful in determining …

Rage And Gas6/Axl Signaling In Obstetric Complications, Kelsey May Hirschi Budge

Theses and Dissertations

Current research spans a wide range of objectives whose diversity includes the understanding of global epidemiology and the detailing of molecular interactions leading to specific pathologies. This work aligns more closely with the goal of mechanistic clarity by elucidating several aspects of signaling pathways involved in inflammatory and obstetric pathologies. Prior research has confirmed the role of Receptors for Advanced Glycation End-Products (RAGE) activation in signaling leading to chronic inflammation such as that observed in chronic obstructive pulmonary disease (COPD). RAGE activation has also been identified in other disease states including diabetes, Alzheimer’s disease, osteoarthritis, and cancers. We examined the …

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 …

An Assessment Of Bsa Protein Hydrogel Biocompatibility In The Vertebrate Intestinal Tract, Ryan Joseph Garde

Theses and Dissertations

The fields of biomedicine and pharmacology have a mission to design methods to treat disease while minimizing adverse side effects using novel drug delivery systems. In developing new therapeutic systems, it is crucial to test that drug delivery systems target pathological cells and tissue and is non-toxic in healthy tissue. One promising method for targeted drug delivery is the use of hydrogels as carriers. Here, we studied the effects of bovine serum albumin (BSA) hydrogel consumption to assess the potential for hydrogel use in treating intestinal disease via oral administration. We investigated intestinal architecture and cell populations following hydrogel treatments …

Determination Of Optimal Parameter Estimates For Medical Interventions In Human Metabolism And Inflammation, Marcella Torres

Theses and Dissertations

In this work we have developed three ordinary differential equation models of biological systems: body mass change in response to exercise, immune system response to a general inflammatory stimulus, and the immune system response in atherosclerosis. The purpose of developing such computational tools is to test hypotheses about the underlying biological processes that drive system outcomes as well as possible real medical interventions. Therefore, we focus our analysis on understanding key interactions between model parameters and outcomes to deepen our understanding of these complex processes as a means to developing effective treatments in obesity, sarcopenia, and inflammatory diseases.

We develop …

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, …

Repair And Adaptation Of Aged Skeletal Muscle To Nonpathological Muscle Damage: The Influence Of Macrophage Polarization, Jacob R. Sorensen

Theses and Dissertations

The age-related loss of skeletal muscle mass and function is accompanied by a decline in regenerative capacity. The processes that facilitate healthy muscle repair are complex, involving several phases of degradation and rebuilding of muscle tissue and the surrounding microenvironment. Specifically, myogenic progenitor cells known as satellite cells are the most influential in repairing damaged muscle tissue. Following injury, satellite cells become activated and migrate, proliferate and fuse with mature skeletal muscle fibers to restore homeostasis to the tissue. However, satellite cells do not act in isolation, a robust inflammatory response is necessary to facilitate successful and rapid healing. Macrophages …

The Effect Of Mechanical Load On Biomarkers Of Knee Joint Inflammation For Individuals Who Are Predisposed To Knee Cartilage Degeneration: An Exploratory Study, Alyssa Evans

Theses and Dissertations

Objective: Physical exercise decreases disability and pain associated with chronic articular cartilage degradation. However, understanding of the pathology is lacking. In this study, the levels of 17 biomarkers of inflammation and cartilage degradation were measured in synovial fluid (SF) before and after a 30-minute run in able-bodied and previously-injured individuals. Materials & Methods: Four able-bodied recreational runners (3 men and 1 woman: 24 ± 2 years, 68 ± 7 kg, and 173 ± 9 cm) and 4 recreational runners who had undergone a unilateral anterior cruciate ligament reconstruction (ACLr) (2 men and 2 women: 23 ± 1 years, 71 ± …

The Role Of T Cells In Muscle Damage Protective Adaptation, Michael Roger Deyhle

Theses and Dissertations

Skeletal muscle is prone to damage from a range of stimuli. The muscle repair process that ensues is complex, involving several phases and requiring the participation of many different cell types. Among the cells involved are various immune cells including neutrophils, macrophages, monocytes, and eosinophils. More recently, T cells were added to this list of immune cells known to participate in effective muscle repair from traumatic injuries in mice. We recently published data showing that T cells also accumulate in human muscle following contraction-induced damage. These data suggested that T cells might be involved an adaptation known as the repeated …

Complexities Of Chronic Opioid Exposure, Maciej Gonek

Theses and Dissertations

Studies on repeated exposure to opioids have been carried out for decades yet the mechanisms for certain phenomena such as tolerance are still not fully understood. Furthermore, different medications, such as frequently prescribed benzodiazepines, or different disease states, such as HIV, have their own effects and interactions with chronic opioid exposure that are not fully understood. The overall objective of this dissertation was to investigate the complexities of chronic opioid exposure and how different disease states and medications may modulate the effects of chronic opioids. Our findings demonstrate that the administration of diazepam, at doses that are not antinociceptive or …

Lps-Induced Inos Mrna And The Pro-Apoptotic Signaling Pathway In Leukocytes Of Fit And Unfit Males, Tiffany M. Zuniga

Theses and Dissertations

Overexpression of the enzyme iNOS induces apoptotic cellular death by increasing indices of pro-inflammation and oxidative stress. Aerobic physical activity has been known to have anti- inflammatory benefits and reduce oxidative stress. Purpose: Therefore, this study aimed to examine the impact of aerobic fitness on LPS-induced iNOS mRNA expression and the relationship of this expression with indices of oxidative stress, pro-inflammation and apoptosis in isolated leukocytes. Methods: Whole blood samples from aerobically fit and unfit males were stimulated with and without LPS. Thereafter, iNOS mRNA expression and MDA, TNF-α and p53 concentrations were analyzed. Results: iNOS mRNA expression levels following …

The Interaction Between Ceramide-1-Phosphate And Group Iva Cytosolic Phospholipase A2 And Its Role In Wound Healing, Patrick Macknight

Theses and Dissertations

The sphingolipid, ceramide-1-phosphate (C1P), directly binds and activates Group IVA cytosolic phospholipase A₂ (cPLA₂a) to generate eicosanoids. Due to the role of eicosanoids in wound healing, we choose to use our novel genetic mouse model expressing cPLA₂a with an ablated C1P interaction site (KI) to examine the cPLA₂a/C1P interaction in wound healing. Wound closure rate was not affected, but wound maturation was dramatically enhanced by loss of the C1P/cPLA₂α interaction based on the following findings. Wounds in KI mice displayed: i) increased infiltration of dermal fibroblasts into the wound environment; ii …

Impact Of Aerobic Exercise On Monocyte Subset Receptor Expression And Macrophage Polarization, Anson M. Blanks

Theses and Dissertations

Atherosclerotic cardiovascular disease (CVD) is hallmarked by inflammatory immune activation, particularly by the induction of a response by monocytes. Classical (CD14⁺⁺CD16^-) are anti-inflammatory mediators under homeostatic conditions, while intermediate (CD14⁺⁺CD16⁺) and non-classical (CD14^LowCD16⁺⁺) monocytes promote inflammation following activation. Monocyte activation and functionality is dependent upon receptor expression and ligand production by a variety of cells, including monocytes. Alterations in the expression of surface receptors often have a direct impact upon monocyte function, such as the increased pro-inflammatory cytokine production in response to activation that accompanies elevated CD14 expression …

Are Cardiovascular Disease Inflammatory Markers Elevated In Those With Nonspecific Chronic Musculoskeletal Pain Compared To Nonpain Case Controls?, Jeffrey Ray Tolley

Theses and Dissertations

CONTEXT: Recent studies have considered the role of inflammation in the development of both cardiovascular disease (CVD) and musculoskeletal conditions, such as rheumatoid arthritis. Studies suggest that inflammation plays a significant role in the development of cardiovascular disease. In conditions of chronic pain, as with rheumatoid arthritis, inflammation has also been noted through elevated levels of inflammatory markers. There are currently no studies that examine the possible connection between inflammatory markers related to increased risk of cardiovascular disease and nonspecific chronic musculoskeletal pain (NCMP). OBJECTIVE: The purpose of this study was to determine whether urinary levels of microalbumin (MA) and …

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 …

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 …

Role Of Altered Gut Microbiota In Tumor Development, Mucus Production And Inflammation In Apc Min/+ Mouse Model, Kamaljeet Kaur

Theses and Dissertations

The microbiome forms an integral part of the gut microenvironment. Once ignored, the topic has gained momentum in research during the past decade, where studies have strongly suggested the association of microbiota with health and a misbalance thereof, to many disease conditions ranging from inflammation and colitis to diabetes, obesity and colon cancer. The Human Microbiome Project (HMP, NIH common fund - 2008) has used a variety of high throughput analyses in order to study gut microbiota in health. The consortium has so far been able to isolate and characterize more than 1,300 reference bacterial strains from the human body. …

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 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 …

The Recovery Of Gut Barrier Function With Selenium Rich Diet In Acute Dss-Induced Colitis, Sarah Depaepe

Theses and Dissertations

Background: Acute Dextran Sodium Sulfate (DSS)-induced colitis is an inflammatory ailment limited to the colon. It works to destroy the morphology and gut barrier goblet and epithelial cells that aid in providing homeostasis. Selenium (Se) is an essential micronutrient that has anti-inflammatory and antioxidant properties and is known to play a role in reducing inflammation in areas elsewhere in the body. The current study is focused on how Se alters gut barrier permeability and functionality related to the recovery of tight junction regulation and mucin secretion. Methods: C57BL/6 mice were randomly placed into control (normal water) and 2% DSS water …

Diversity, Genetics, And Health Benefits Of Sorghum Grain, Davina Rhodes

Theses and Dissertations

Staple cereal crops provide the majority of nutrients to the world's population, and thus, can significantly impact human nutrition and health. Phenotypic and genetic diversity within a crop can be useful for biofortification and crop improvement, but quantitative phenotyping is needed to identify varieties with high or low concentrations of a nutrient of interest, and to identify alleles responsible for quantitative trait variation of the nutrient. Sorghum [Sorghum bicolor (L.) Moench] is a diverse and widely adapted cereal crop that provides food for more than 500 million people in sub-Saharan Africa and Asia, and is becoming increasingly popular in specialty …

Pharmacologic Immunomodulation Of Macrophage Activation By Caffeine, Ryan Perry Steck

Theses and Dissertations

Caffeine is one of the most widely used neurostimulants in the world and there is considerable debate on its effect in immune cells. One of its main targets is proposed to be adenosine receptors which mediate an anti-inflammatory switch in activated immune cells while another target is phosphodiesterase where it acts as an inhibitor. In macrophages, caffeine has been shown to cause both pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. If the primary effect of caffeine on macrophages were to antagonize adenosine receptors we would expect cells exposed to caffeine to have a prolonged M1 response. However, we show that caffeine …

Increased Circulatory Lipopolysaccharide From A High Fat Diet Aggravates Inflammation And Exacerbates Renal Failure, Samuel Righi

Theses and Dissertations

Kidney failure is frequently associated with the risk factors linked to metabolic syndrome. Lipopolysaccharide (LPS) is a potent inflammatory molecule, which has increased absorption from the gut into blood circulation following a high fat and high-energy diet. We hypothesized that LPS from a high fat diet can amplify inflammation, thereby exacerbating chronic kidney disease and associated disorders. We have found that adding a high fat diet to renal insufficient mice significantly progressed their kidney disease as well as associated disorders, compared to both a high fat diet and renal insufficiency alone. Additionally, we were able to demonstrate in vitro that …

The Effect Of Fluvastatin On Mast Cell Function: Genotype Dependence, Elizabeth M. Kolawole

Theses and Dissertations

Fluvastatin, the HMG-CoA reductase inhibitor known for its role in the treatment of hypercholesterolemia and cardiovascular disease, has more recently been shown to play a role in the immune response. Given the critical role that mast cells play in allergy and inflammatory diseases such as asthma, which effects one third of America’s population, we assessed the effect of fluvastatin on mast cell and basophils function. We demonstrate that fluvastatin downregulated IgE-mediated cytokine production. Additionally, in vivo studies showed that fluvastatin suppressed IgE-mediated anaphylaxis. Interestingly, the effects of fluvastatin showed dependence on genetic background, as C57BL/6 mast cells were sensitive, while …

The Effect Of Lactic Acid On Mast Cell Function, Andrew J. Spence

Theses and Dissertations

This study shows for the first time the effect that L-(+)-lactic acid has on mast cell activation. Lactic acid is a byproduct of anaerobic glycolysis and is associated with inflammatory environments such as wounds, tumors and, asthma. In this study, pre-treatment with lactic acid altered cytokine production by bone marrow-derived mast cells (BMMC). Specifically, lactic acid enhanced cytokine secretion following IgE cross-linking, but decreased IL-33 mediated cytokine production. These effects were altered by genetic background, since C57BL/6 mast cells demonstrated the aforementioned result, but lactic acid had no effect on IgE-mediated cytokine production in 129/SvJ mast cells. The affected cytokines …

The Group Iva Cytosolic Phospholipase A2/C1p Interaction And Its Role In Eicosanoid Synthesis And Inflammation, Jennifer A. Mietla

Theses and Dissertations

In the presented study, we demonstrate that the interaction of group IVA cytosolic phospholipase A2 and ceramide-1-phosphate is crucial for production of eicosanoid synthesis in inflammation. Inflammation is a critical component of many disease states including anaphylaxis, cancer, cardiovascular disease, rheumatoid arthritis, diabetes and asthma. Eicosanoids are well established mediators of inflammation, and the initial rate limiting step in the production of eicosanoids is the liberation of arachidonic acid (AA) from membrane phospholipids by a phospholipase A2 (PLA2). The major phospholipase involved in this liberation of AA during the inflammatory response is group IVA cytosolic phospholipase A2 (cPLA2α). Previous studies …