Thesis (M.S.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 140-168).

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2009. / Härtill 4 uppsatser.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

ADM is a 52-amino acid peptide which carries out multiple biological functions in cardiovascular system such as vasodilation and hypotension, and is a prognostic marker for cardiovascular diseases. Recent studies show that its plasma level is elevated in diabetes, however the reason and significance for such an increase has not been understood. Recent research has proposed that inflammation and oxidative stress both contribute to the pathogenesis of diabetes. If ADM is a marker in diabetes, it is possible that ADM is regulated by these two mechanisms, and so this project aims to investigate how these mechanisms could affect ADM expression. Recent studies have demonstrated that advanced glycation endproducts (AGEs) could lead to development of various diabetic complications. AGEs are formed as intermediate product in the non-enzymatic glycation of reducing sugars. Formation of these products is stimulated by hyperglycemia and oxidative stress, which could also induce ADM expression. Hence one of the studies investigated the direct effect of AGEs on ADM expression in an in vitro model. A rat macrophage cell line NR8383 was used to investigate the dose-response and time-point responses of macrophage cells in expressing ADM stimulated by AGEs. 6 hours of AGEs treatment resulted in no significant effect on ADM gene expression. The gene expression increased in all time points in which the change was at maximum after 1 hour of AGE treatment compared with other time points (P<0.05). However the time-dependent effect on ADM gene expression was insignificant compared with controls. How oxidative stress could lead to increased ADM expression deserves further investigation. ADM plays a role in inflammation that it could influence IL-6 and adiponectin expressions. This project also investigated whether IL-6 and adiponectin could affect ADM levels on the opposite. The associations between IL6 and adiponectin single nucleotide polymorphisms (SNPs) with plasma ADM levels were studied using a cohort of 476 subjects from the Cardiovascular Risk Factor Prevalence Study (CRISPS). Specific tagging SNPs were genotyped for the 476 subjects. Significant associations were identified for the IL6 SNP rs17147230 and adiponectin SNP rs182052 with plasma ADM levels in additive model (β=-0.096, P=0.034, and β=0.104, P=0.023 respectively adjusting for age and sex). The associations remained significant after adjusting for various covariates (P<0.05). Genotypic model shows that the minor alleles of rs17147230 and rs182052 resulted in 12.8% decrease and 17.7% increase in plasma ADM levels. These findings show that ADM level could be regulated by IL-6 which is an inflammatory cytokine, and adiponectin which is a protective peptide in inflammation. Reducing inflammation could lower ADM level and adiponectin might be a therapeutic candidate. / published_or_final_version / Medicine / Master / Master of Philosophy

published_or_final_version / Surgery / Master / Master of Surgery

published_or_final_version / Medicine / Master / Doctor of Medicine

No description available.

No description available.

Chronic inflammation in response to Aß peptide deposits is a pathological hallmark of Alzheimer's disease (AD). The inflammatory environment includes populations of reactive and proliferating microglia and astrocytes and perturbed vasculature. However, the association between activated glial cells and cerebrovascular dysfunction remain largely unknown. This study has used Aß1-42 intrahippocampal injection as an animal model of inflamed AD brain to characterize mechanisms of glial-vasculature responses as a basis for chronic inflammation. Preliminary findings suggested Aß1-42-injected brain demonstrated vascular remodeling including evidence for formation of new blood vessels (angiogenesis). This result led to study of the effects of the anti-angiogenic/anti-inflammatory compound, thalidomide on activated glial cells and perturbations in the vasculature in an Aß1-42 peptide-injected rat model. First, Aß1-42 injection was found to cause perturbations in vasculature including new blood vessel formation and increased BBB leakiness. Second, thalidomide decreased the vascular perturbations and the glial reactivity and conferred neuroprotection. Overall, these results suggest that altered cerebral vasculature is integral to the overall inflammatory response induced by peptide. Experiments then examined the level of parenchymal plasma proteins in brain tissue from AD and nondemented (ND) individuals. AD, but not ND, brain tissue demonstrated high levels of fibrinogen immunoreactivity (ir). Aß1_42 injection into the rat hippocampus increased the level of parenchymal fibrinogen, which was reduced by treatment with the defibrinogenating agent, ancrod. In addition, ancrod also attenuated microglial activation and prevented neuronal injury. Overall, these results demonstrate that extravasation of blood protein and a leaky BBB are important in promoting and amplifying inflammatory responses and causing neuronal damage in inflamed AD brain. Microglial chemotactic responses to VEGF (vascular endothelial growth factor) receptor Flt-1 were next studied. Treatment with a monoclonal antibody to Flt-1 (anti-Flt-1 Ab) in the peptide-injected hippocampus diminished microglial reactivity and provided neuroprotection. Secondly, anti-Flt-1 Ab inhibited the AI3142-induced migration of human microglia. These results suggest critical functional roles for Flt-1 in mediating microglial chemotaxis and inflammatory responses in AD brain. The overall conclusion from my work is that AP deposits induce microglial reactivity which subsequently causes vascular remodeling resulting in an amplified inflammatory microenvironment which is damaging to bystander neurons.

Mast cells reside at tissue sites closely interfacing the environment and play a role in host defense against pathogens. Mast cell responses to respiratory syncytial virus (RSV), a major cause of severe respiratory tract infections and subsequent bronchiolitis, are not fully elucidated. Human cord blood-derived mast cells (CBMCs) and the HMC-1 mast cell line supported low levels of RSV antigen expression as compared with airway epithelial cells. RSV inoculated mast cells up-regulated the expression of several chemokines such as CCL4, CCL5 and CXCL10, as well as type I and III interferons. Type I interferon receptor blockade on RSV-inoculated HMC-1 cells had no effect on chemokine production or viral antigen expression. These data show that mast cells respond to RSV by expressing various cytokines and chemokines that may enhance inflammation and effector cell recruitment during RSV disease.