Lipid signaling is an essential biological event/process in a plethora of pathophysiological conditions. The underlying idea of this thesis is that many of the roles and the complex interplay of... Show moreLipid signaling is an essential biological event/process in a plethora of pathophysiological conditions. The underlying idea of this thesis is that many of the roles and the complex interplay of the individual signaling lipids in inflammatory processes and related conditions in health and disease is not well known, and therefore has to be studied integrally as a complex network. In order to study this complex interplay, an improved broad analytical method is necessary to analyze a wide range of different signaling lipid classes such as oxylipins, (nitro) free fatty acids, endocannabinoids, bile acids and different subclasses of lysophospholipids. Therefore, the aim of this thesis is to develop a better method to study signaling lipids, and to apply it to study the role of these molecules in several relevant biological questions for a better understanding of inflammation related pathophysiology including autoimmune diseases, neurodegeneration and regulatory effect of exercise training. Show less
Mast cells are potent actors involved in inflammatory reactions in various tissues, including both in the intimal and the adventitial layers of atherosclerotic arteries. In the arterial intima, the... Show moreMast cells are potent actors involved in inflammatory reactions in various tissues, including both in the intimal and the adventitial layers of atherosclerotic arteries. In the arterial intima, the site of atherogenesis, mast cells are activated to degranulate, and thereby triggered to release an abundance of preformed inflammatory mediators, notably histamine, heparin, neutral proteases and cytokines stored in their cytoplasmic secretory granules. Depending on the stimulus, mast cell activation may also launch prolonged synthesis and secretion of single bioactive molecules, such as cytokines and derivatives of arachidonic acid. The mast cell-derived mediators may impede the functions of different types of cells present in atherosclerotic lesions, and also compromise the structural and functional integrity of the intimal extracellular matrix. In the adventitial layer of atherosclerotic coronary arteries, mast cells locate next to peptidergic sensory nerve fibers, which, by releasing neuropeptides may activate mast cells to release vasoactive compounds capable of triggering local vasoconstriction. The concerted actions of arterial mast cells have the potential to contribute to the initiation and progression of atherosclerosis, and ultimately to destabilization and rupture of an advanced atherosclerotic plaque with ensuing atherothrombotic complications Show less
This thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of... Show moreThis thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of circulating adiponectin can predict radiographic progression in patients with early RA. In contrast, in patients with hand OA, this association appears protective. Therefore, to obtain insight into the mechanisms underlying these associations, we investigated the high-molecular-weight isoform of adiponectin (hmwAPN), which is one of the most biologically active isoforms of adiponectin. We show that the associations of total adiponectin with radiographic progression are not mediated by hmwAPN, in either RA or HOA. In the second part, we present the immunological characterization of the infrapatellar fat pad (IFP), a joint associated adipose tissue, in patients with advanced knee OA. We observed profound differences in secreted inflammatory factors and immune cell composition between the IFP and paired subcutaneous adipose tissue samples. Interestingly, we observed obesity-related changes in the IFP phenotype, and in macrophages and adipocytes, Therefore, we investigated the modulatory effects of adipocytes on the phenotype of human macrophages in vitro and we observed that adipocyte-derived lipids can mediate the obesity-related changes in the phenotype of adipose tissue macrophages in humans Show less
Uveal melanoma is a highly malignant intraocular tumor with quite homogeneous tumor tissue and a diffuse leukocytic infiltration. In contrast with many other malignancies, the presence of... Show moreUveal melanoma is a highly malignant intraocular tumor with quite homogeneous tumor tissue and a diffuse leukocytic infiltration. In contrast with many other malignancies, the presence of infiltrating macrophages and T cells is associated with a poor prognosis rather than a good one. The clear link between inflammation and this malignancy provides a paradigm for macrophage plasticity and function. Macrophages in uveal melanoma have an M2-like phenotype and are associated with the loss of one specific chromosome - monosomy 3. The central players involved in this process and discussed include macrophages, T lymphocytes, chemokines and cytokines, including the macrophage-attraction molecules. When a tumor acquires the ability to release significant amounts of macrophage-attraction molecules it causes the expansion of a population of myeloid immature cells that may not only help the tumor to suppress immune reactions but also aid in the construction of new blood vessels for tumor growth. A better understanding of the molecular basis of a local myelomonocytic cell population will bring a better understanding of the immunopathology of this disease and will lead to therapeutic interventions in uveal melanoma. This thesis focuses on the roles of the local inflammatory microenvironment in the development and progression of uveal melanoma. Show less
Overgewicht en obesitas kunnen leiden tot insulineresistentie (type 2 diabetes mellitus) en hyperlipidemie, een risicofactor voor atherosclerose (aderverkalking). Obesitas gaat ook gepaard met de... Show moreOvergewicht en obesitas kunnen leiden tot insulineresistentie (type 2 diabetes mellitus) en hyperlipidemie, een risicofactor voor atherosclerose (aderverkalking). Obesitas gaat ook gepaard met de ontwikkeling van een chronische ontsteking in vetweefsel en lever. Met dit promotieonderzoek laten we met behulp van onderzoek in muizen zien dat ontsteking een belangrijke rol speelt in het metabolisme en transport van vetten. We bekijken ook welk effect dit heeft op de ontwikkeling van atherosclerose en type 2 diabetes. In het eerste deel van dit promotieonderzoek laten we zien dat ontsteking een belangrijke rol speelt in vetmetabolisme en atherosclerose. De ontstekingsremmer aspirine zorgde voor een verlaging van de hoeveelheid vet in het bloed. Activatie van een onsteking in de lever leidde juist tot een verhoging van vet in het bloed, wat de ontwikkeling van atherosclerose in de vaatwand verergerde. In het tweede deel van dit promotieonderzoek bestuderen we het belang van het inflammasoom/caspase-1 complex (betrokken bij ontstekingsprocessen) in obesitas, insulineresistentie en vetmetabolisme. We laten zien dat muizen die een deel van dit eiwit-complex missen, beschermt zijn tegen de ontwikkeling van obesitas en insulineresistentie. Het inflammasoom/caspase-1 complex lijkt daarmee een potentieel target voor de behandeling van obesitas, insulineresistentie en type 2 diabetes. Show less
The aim of the studies presented in this thesis is to test potential treatment options in an animal model of bronchopulmonary dysplasia (BPD). BPD is a chronic lung disease in very preterm infants... Show moreThe aim of the studies presented in this thesis is to test potential treatment options in an animal model of bronchopulmonary dysplasia (BPD). BPD is a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome (RDS). BPD is characterized by an arrest in alveolar and vascular lung development, complicated by inflammation, abnormal coagulation, oxidative stress, and at later stages by pulmonary hypertension (PAH). The inflammatory process is one of the major players in experimental BPD and we explored the effect of phospohodiesterase type 4 (PDE4) inhibitors on this process. We investigated the effect of PDE4 inhibition on the cardiopulmonary aspect of experimental BPD. The arrest in alveolar development is currently lack effective therapy, therefore we explored the therapeutic potential on alveologenesis of apelin and PDE5 inhibitor sildenafil, both very potent pro-angiogenic and vasodilative agents. We investigated the therapeutic potential of stem cell therapy in an animal model of PAH by mimicking autologous MSC therapy. Our data warrant clinical investigation of sildenafil as a potential drug to prevent or treat PAH and RVH, and the arrest in lung development, which plays a pivotal role in poor outcome in the neonatal intensive care nursery. Show less
This thesis describes the role of the immune system as an important phenomenon in the most frequently occurring form of eye cancer in adults, namely in uveal melanoma. We show that the immune... Show moreThis thesis describes the role of the immune system as an important phenomenon in the most frequently occurring form of eye cancer in adults, namely in uveal melanoma. We show that the immune system can be the cause of the tumor, and also plays a role in the development of a tumor, and may be an entry for therapy. In the first chapters of this thesis, we describe the phenomenon of "an inflammatory phenotype" in uveal melanoma. It appears that when this type of cancer shows more inflammation, the survival of patients decreases. A possible explanation for this observation is that one of the key players among the immune cells, the macrophage, plays an essential role in intra-ocular tumor growth. We demonstrate this in patient material, but also in experimental studies; we are able to inhibit tumor growth when we modulate the presence of macrophages. In this thesis, we also show that the immune system can be used effectively to eradicate eye melanomas in experimental models. T cell vaccination in combination with monoclonal antibodies gave promising results for treating eye cancer. Further research has to be performed to translate this into the clinic. Show less
The aim of this thesis was to investigate the pathofysiology of neuropsychiatric symptoms in the auto immune disease Systemic Lupus Erythematosus (SLE) using magnetic resonance imaging (MRI) of the... Show moreThe aim of this thesis was to investigate the pathofysiology of neuropsychiatric symptoms in the auto immune disease Systemic Lupus Erythematosus (SLE) using magnetic resonance imaging (MRI) of the brain. To this end MRI abnormalities in SLE patients with neuropsychiatric symptoms were compared with clinical symptoms and serological markers of disease. This thesis shows that immune abnormalities have an influence on the central nervous system in SLE (chapter 3&4). Reversible abnormalities in quantitative brain MRI in NPSLE are associated with clinical symptoms (chapter 2). These abnormalities are associated with neuroimaging features which may be interpreted as reversible axonal and/ or neuronal dysfunction (chapter 5). In line with this, severe ischemia does not appear to play a major role in NPSLE patients without obvious infarction on conventional MRI (chapter 6). Chapter 3 suggests that the influence of auto-immune antibodies is similar to the influence of auto-immune antibodies found in mouse models of NPLSE affecting specific locations of the brain. Using advanced MRI techniques and statistical analysis in chapter 7 suggests that the influence of auto-antibodies in human NPSLE also extends to white matter. Hopefully, these findings will facilitate earlier detection and treatment of neuropsychiatric symptoms in SLE. Show less
The main objective of this thesis was to study the association between nutritional status and survival in end-stage renal disease patients who are maintained on a chronic dialysis treatment. Where... Show moreThe main objective of this thesis was to study the association between nutritional status and survival in end-stage renal disease patients who are maintained on a chronic dialysis treatment. Where as obesity is an established risk factor for morbidity and mortality in the general population, many survival studies in hemodialysis patients have indicated reverse associations of obesity with mortality. We showed, however, that the association between BMI and mortality in the hemodialysis population was similar, and not reversed compared with the general population of equal baseline age and duration of follow-up. Independent from BMI, weight loss and muscle mass depletion were both associated with an increased mortality risk in hemodialysis patients. Furthermore, we observed an interaction effect between protein-energy wasting, inflammation and cardiovascular disease, resulting in excess mortality in chronic dialysis patients. Finally, compared with a normal nutritional status, the short-term impact of protein-energy wasting on mortality appeared more important than the long-term effect. The results of this thesis emphasize the importance of maintaining a good nutritional status in chronic dialysis patients. The nutritional status of dialysis patients should be assessed regularly, at least every 6 months. In clinical practice, the 7-point Subjective global assessment can be used for this. Show less
The main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e.... Show moreThe main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e. transgenic and knock-out mouse models). Many of these genes exert their role in atherosclerosis development as a result of effects on lipoprotein metabolism and inflammation. Transgenic mouse models have also been proven to be suitable for evaluating the mechanisms underlying the anti-atherosclerotic action of experimental drugs aimed to reduce atherogenic lipoprotein levels. However, thus far no suitable animal model was present to evaluate the mechanism of action of anti-atherosclerotic effect of HDL-raising therapeutic strategies. In this thesis, we further explored the role of apolipoprotein CI (apoCI) and cholesteryl ester transfer protein (CETP) in lipoprotein metabolism, inflammation, and atherosclerosis. Furthermore, we developed a mouse model that will be suitable for testing potential high-density-lipoprotein (HDL) raising therapies as a novel strategy to treat CVD. Show less
