Thesis (Ph. D.)--University of Virginia, 2005. / CD-ROM has .tiff and .mov files. Includes bibliographical references (leaves 129-132). Also available online through Digital Dissertations.

Thèse (Ph. D.)--Université Laval, 2005. / Bibliogr.: f. 334-437. Publié aussi en version électronique.

Thesis (Ph. D.)--University of North Carolina at Greensboro, 2006. / Title from PDF title page screen. Advisor: Michael K. McIntosh; submitted to the School of Health and Human Performance. Includes bibliographical references (p. 133-151).

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xv, 152 p.; also includes graphics (some col.). Includes bibliographical references (p. 138-152). Available online via OhioLINK's ETD Center

Horses are at high risk to develop systemic inflammation due to the release of bacterial endotoxin from an inflamed gastrointestinal tract. Neutrophils are critical for mounting an immune response to bacterial endotoxins. Neutrophil activation following engagement of bacterial endotoxin expands their lifespan through suppression of their constitutive apoptosis. The prolonged lifespan of neutrophils propagates acute inflammation and delays the resolution of inflammation. Since equine neutrophil lifespan has not been well-studied, I investigated the occurrence of equine neutrophil apoptosis in vitro and in vivo. First, I investigated the effect of Escherichia coli lipopolysaccharide (LPS) treatment on the occurrence of equine neutrophil apoptosis in vitro. LPS treatment delayed in vitro equine neutrophil apoptosis in a dose-dependent manner at concentrations of 0.1-10 μg/ml through toll-like receptor (TLR)-4 signaling and down-regulation of the intrinsic pathway of apoptosis, specifically through reduced caspase-9 activity. Next, I found that ex vivo neutrophil apoptosis was delayed in two models of intestinal inflammation, jejunal ischemia and reperfusion (IR) and oligofructose-induced colitis, through down-regulation of both the intrinsic and extrinsic apoptosis pathways via reduced caspase-3, -8, and -9 activities. Pulmonary intravascular macrophages (PIMs) depletion with systemic gadolinium chloride (GC) prevented the prolongation of ex vivo neutrophil lifespan in horses undergoing jejunal IR through modulation of caspase-3, -8 and -9 activities. PIM depletion in IR horses resulted in an earlier and greater increase in tumor necrosis factor-alpha and a concomitant decrease in interleukin-10 to suggest an enhanced systemic pro-inflammatory response. I examined the effect of neutrophil concentration and co-incubation with aged, apoptotic neutrophils on the occurrence of neutrophil apoptosis in vitro. Neutrophil apoptosis was delayed with increasing concentrations of neutrophils in vitro, which may contribute to delayed neutrophil apoptosis in systemic inflammation. However, co-incubation with aged, apoptotic neutrophils did not alter in vitro neutrophil lifespan. Taken together, the data show that LPS delays equine neutrophils apoptosis in vitro in a TLR4-dependent manner through inhibition of caspase-9. Ex vivo neutrophil apoptosis was also delayed with systemic inflammation via down-regulation of caspase activity. A novel finding of this work was the reversal of delayed neutrophil apoptosis by depletion of PIMs in horses experiencing intestinal IR.

Hearing loss or deafness, in its most serious form, affects an estimated 28 million people in America. One of the forms of hearing loss, known as ototoxicity, refers to damage to the ear (-oto) due to xenobiotics. Cisplatin is the most widely used antineoplastic agent in the treatment of various solid tumors. Cisplatin toxicity can lead to severe effects on the kidneys, nervous system and auditory system which significantly reduce the quality of life of cancer patients. While nephrotoxicity could be alleviated by hydration and diuresis, cisplatin-induced ototoxicity is permanent and there is currently no approved treatment for this condition. Previous studies have shown that the generation of reactive oxygen species (ROS) is a critical event that initiates damage to the outer hair cells (OHCs), stria vascularis (SVA) and spiral ganglion cells (SG) of the cochlea, leading to hearing loss after cisplatin treatment. However, the mechanism(s) underlying the transition from ROS generation to the manifestation of ototoxicity is (are) not clearly defined. Recent studies have also implicated inflammatory pathways in cisplatin-induced cell death. Various transcription factors have been linked to the induction of inflammation mediated by cisplatin in the cochlea. Recent study demonstrate that cisplatin activates signal transducer and activator of transcription 1 (STAT1) a transcription factor implicated in inflammation, which mediates damage to utricular hair cell and could also confer cisplatin-induced hearing loss. The aim of this study is to further define a role of STAT1 in cochlear inflammation and in cisplatin-mediated ototoxicity. Based on preliminary data, we hypothesize that STAT1 plays an integral role in cisplatin-mediated inflammation and hearing loss. Our data show that STAT1 couples ROS to the inflammatory process in the cochlea. The major source of ROS appears to be the NOX3 NADPH oxidase system, knockdown of which by short interfering (si)RNA reduces STAT1 activation by cisplatin and alleviates hearing loss. Activation of STAT1 by cisplatin involves phosphorylation of Serine 727 by mitogen activated protein kinases such as extracellular signal regulated kinase (ERK) 1/2 and p38. Knockdown of STAT1 by trans-tympanic administration of siRNA reduces damage to OHCs and protects against cisplatin-induced hearing loss in rats. STAT1 siRNA attenuates the production of inflammatory mediators, such as tumor necrosis factor- α (TNF-α), and reduces the recruitment of inflammatory cells to the cochlea. Furthermore, inhibition of TNF-α by trans-tympanic administration of etanercept, a clinically used TNF-α antagonist, protects against OHC damage and cisplatin-induced hearing loss. These data suggest that targeting STAT1 or the inflammatory genes it regulates could serve as useful strategies for preventing cisplatin-induced hearing loss and improve the overall quality of life of cancer patients.

INTRODUCTION: Diet induced obesity (DIO) is a major driving force responsible for low-grade inflammation mediated immune system decline. Impaired immune defenses lead to a number of chronic diseases and ultimately to an increased mortality. DISCUSSION: Over half a billion people worldwide are considered overweight or obese. It has been estimated that $190 billion dollars was spent in the US on obesity-related healthcare costs just in 2005. Lower productivity, lost wages, higher insurance costs, and an increased strain on the healthcare system as a whole, are the hallmarks of the obesity epidemic. Considerable body of epidemiologic evidence implicates DIO as the major cause of numerous pathologies. The obese population doesn't just suffer increased mortality from chronic conditions such as, cardiovascular disease, pulmonary diseases, Type 2 diabetes, various cancers, hyperlipidemia, hypertension, non-alcoholic fatty liver disease (NAFLD), renal failure, osteoarthritis and many other slow-onset diseases. Obese individuals also have increased mortality for more acute conditions such as N1H1 influenza virus, allergic diseases, and post-surgical complications while also lowering the efficacy for vaccinations and Helicobacter pylori eradication therapies. Today scientists recognize adipose tissue as the largest endocrine organ in the human body, releasing a myriad of paracrine and endocrine molecular factors. During DIO these adipocytokines induce a proinflammatory switch in the adipose tissue machinery, initiating chronic low-grade inflammation. Sensing an ongoing attack the immune system responds trying to maintain homeostasis. DIO however, initiates a positive feedback loop, which perpetuates inflammation and further decimates immune system's capacity to resist threats and to restore order. CONCLUSION: While the basic obesity-inflammation-disease road map has been outlined, many questions remain. Multiple areas of immunometabolism and meta inflammation require deeper understanding, but two key recommendations for future studies stand out. First, since it is easier to prevent obesity than to reverse it, attention should be focused on elucidating the endocrine role of foodstuff. Second, to find cures for chronic conditions of the ever growing obese population, scientists must elucidate the mechanism of obesity-induced inflammation's function in diminishing immune system's capacity.

Microglia, the innate immune cells of the brain, are not only immune surveyors, but also play important roles in neural development and maintenance. Microglial aberrations, including changes in morphology, gene expression, and phagocytic activity, have been observed in humans and animal models of pathologies involving cognitive and behavioral consequences. However, the precise contribution of microglial biology is not well characterized. Expression profiling of microglia and neural stem cells, co-culture assays, and transgenic mice were used to identify microglial micro-RNAs and genes, and study their roles in neural development. The results show that a specific micro-RNA, miR-155, participates in the neurogenic deficits induced by inflammation, and microglia-derived Wnt5a is essential for neural differentiation and maturation. This indicates the potential involvement of abnormal microglia in neurodevelopmental disorders such as autism spectrum disorders (ASDs). ASDs are group of debilitating disorders characterized by behavioral symptoms, including social and communication deficits and repetitive or restricted behaviors. I hypothesize that aberrant microglial biology plays a role in neurogenic and behavioral deficits in a mouse model of ASD. I performed a time-course study of microglial gene expression profiling, neural and microglial morphology, neurophysiology, and behavior in the maternal immune activation (MIA) model of ASD induced by the innate immunity ligand polyinosinic:polycytidylic acid. Microglia in MIA offspring displayed altered expression of 22 genes including 14 involved in cell-cell interaction, increased complexity of branching, and increased interactions with dendritic spines of cortical layer V pyramidal neurons. Microglial abnormalities were associated with neurophysiological alterations, measured by whole-cell patch clamp recordings, increased neuronal spine density, and ASD-like behaviors. MIA offspring treated with a colony stimulating factor -1 receptor inhibitor, to deplete and replenish microglia, showed correction of specific behaviors, microglial gene expression and branching, microglia-spine interactions, and spine density, and partial correction of neurophysiology. The data presented here shed new insight into the functional effects of microglia gene and microRNA expression in neurodevelopment. Furthermore, inflammation induces microglial aberrations that lead to altered neurodevelopment; this strongly supports the idea that targeting specific microglial genes and miRNAs will be a worthwhile approach to pursue for molecular intervention in ASD and related disorders. / 2018-11-02T00:00:00Z

Orientador: Guilherme José Pimentel Lopes de Oliveira / Resumo: O objetivo deste estudo foi avaliar o efeito do extrato de óleo insaponificável de abacate e soja (ASU) sobre a doença periodontal experimental em ratos com artrite induzida por antígenos. A artrite foi induzida através da imunização (duas aplicações subcutâneas - 500µg de mBSA) e dois desafios intra-articulares do antígeno albumina de soro bovino metilada (10µg/cavidade articular - mBSA). No estudo 1 os animais foram distribuídos aleatoriamente em 3 grupos de acordo com a condição sistêmica: CTR(controle- solução salina), ART(artrite-solução salina), ART/ASU. No dia da remoção das ligaduras os animais receberam a administração do ASU e da solução salina de forma diária por gavagem até o dia da eutanásia dos animais, que ocorreu nos períodos de 7, 15 e 30 dias após a remoção das ligaduras (n=5 animais/grupo). No estudo 2, os animais foram randomicamente distribuídos em 4 grupos de acordo com o tipo de tratamento e a condição sistêmica dos animais: CTR: Animais saudáveis em que foi administrado solução salina; ASU: Animais sem artrite em que foram administrados o ASU; ART/ASU: Animais com artrite induzida em que foi administrado o ASU; ART: Animais com artrite induzida em que foi administrado o solução salina. A periodontite e a artrite foram induzidas da mesma forma que no estudo 1. A periodontite foi tratada no dia da remoção das ligaduras por meio da raspagem com instrumentos manuais. A solução salina e o ASU foram administrados diariamente por gavagem até a eutanásia dos a... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The objective of this study was to evaluate the effect of the avocado/soybean unsaponifiables (ASU) on experimental periodontal disease in rats with antigen - induced arthritis. Arthritis was induced by immunization (two subcutaneous applications - 500 μg mBSA) and two intra-articular challenges with methylated bovine serum albumin antigen (10 μg / joint cavity - mBSA). In study 1, the animals were randomly assigned to 3 groups according to the systemic condition: CTR (control-saline solution), ART (arthritis-saline solution), ART / ASU. At the day of the ligature removal, the ASU and saline were administrated daily by gavage until the euthanasia day of the animals, which occurred at 7, 15 and 30 days after ligature removal (n = 5 animals / group). In the study 2, the animals were randomly distributed into 4 groups according to the type of treatment and the systemic condition of the animals: CTR: Healthy animals in which saline was administered; ASU: Healthy animals in which the ASU was administered; ART / ASU: Animals with induced arthritis in which ASU was administered; ART: Animals with induced arthritis in which saline solution was administered. Periodontitis and arthritis were induced in the same manner as in study 1. Periodontitis was treated on the day of ligature removal by scaling with hand instruments. Saline and ASU were administered daily by gavage until euthanasia of the animals occurred at 7, 15 and 30 days after the scraping procedure (n = 5 animals / group). I... (Complete abstract click electronic access below) / Doutor

Background: Mounting evidence suggests that inflammation is involved in the pathophysiology of both Major Depressive Disorder (MDD) and schizophrenia. The presence of inflammation in the brain, however, is less clear. Microglial activation, a measure of neuroinflammation, can be quantified using PET ligands that bind to the Translocator Protein (TSPO) which is overexpressed by activated microglia. Previous PET studies using TSPO radioligands have shown some evidence for neuroinflammation in both MDD and schizophrenia. However some of these studies have been confounded by antidepressant/antipsychotic medication, low numbers and mild severity. We aimed to address some of these issues and investigate the relationship between neuroinflammation and peripheral inflammation, medication status, symptom severity and cognitive function. Method: Fourteen patients in a Major Depressive Episode (MDE) of at least moderate severity, sixteen patients with a diagnosis of schizophrenia of at least moderate severity and a total of eighteen age and gender-matched healthy volunteers underwent a 60 minute dynamic PET scan with the TSPO radioligand [11C](R)-PK11195 on the High Resolution Research Tomograph (HRRT). Parametric maps of binding potential (BPND) were generated using the simplified reference tissue model and a grey matter cerebellum input function. All of the MDD patients were antidepressant-free for at least eight months prior to scanning. Of the sixteen schizophrenia patients, eight were antipsychotic-free (for at least twelve months) and eight were on a long-acting injection of risperidone or paliperidone. All patients and healthy volunteers were medically healthy and had drug or alcohol abuse within the previous year. Results: We found a 26% mean increase in BPND values, indicative of microglial activation, in MDD patients compared to healthy volunteers. Exploratory analysis revealed significantly higher [11C](R)-PK11195 binding in the anterior cingulate cortex (ACC). We found no significant correlations between [11C](R)-PK11195 binding and peripheral markers of inflammation or with symptom severity. We also found a mean 27% increase in BPND values in the schizophrenia patients compared to healthy volunteers. There were significant correlations between [11C](R)-PK11195 and negative symptoms across multiple brain regions. When breaking the cohort down according to medication status, there was no difference between antipsychotic-free patients and healthy volunteers. However, mean BPND values were 30% higher in the ACC. The medicated patients exhibited higher BPND values than healthy volunteers, with a mean increase of 48%. Exploratory t-tests revealed significant increases in dorsolateral prefrontal cortex and ACC.Conclusions: Our findings are largely consistent with previous PET findings of increased microglial activation in a sample of antidepressant-free patients in a moderate-to-severe MDE, suggesting that neuroinflammation is present in MDD. We also investigated neuroinflammation in antipsychotic-free patients for the first time and found no evidence of microglial activation. However it is likely that the subgroup sample was underpowered. The medicated patients exhibited a 48% increase in [11C](R)-PK11195 binding compared to controls, suggesting that either medication or duration of illness might potentiate microglial activation. Our findings also point to an association between neuroinflammation and the negative symptoms of schizophrenia. The PET findings from both cohorts are largely overlapping, suggesting that neuroinflammation is not specific to either disorder but rather a common mechanism. This could reflect a common aetiology and/or an overlap in symptoms. Our findings suggest that inflammation could be used as a potential biomarker as well as a target for novel treatment strategies in both MDD and schizophrenia.