O diabetes mellitus tipo I (DMI) é uma doença crônica autoimune caracterizada por hiperglicemia devido à destruição das células beta pancreáticas produtoras de insulina. Ao final de 30 dias da indução do diabetes por estreptozotocina, os macrófagos peritoneais residentes dos animais diabéticos apresentaram aumento de RNAm de citocinas e quimiocinas inflamatórias, secreção de óxido nítrico, expressão de NLRP3, iNOS e PARP1 e da atividade da via glicolítica. Perfil pró-inflamatório também foi observado em macrófagos peritoneais de animais NOD (non-obese diabetic). Camundongos diabéticos deficientes em NLRP3 (NLRP3 KO) apresentaram diminuição na expressão de iNOS, PARP1 e na produção de NO em relação aos macrófagos dos animais diabéticos selvagens. O estado diabético tipo I influenciou o perfil dos macrófagos peritoneais residentes, causando aumento na produção de NO, via NLRP3-PARP1-iNOS, expressão de citocinas pró-inflamatórias, receptores de quimiocinas e da atividade glicolítica. O tratamento com DHA (ômega-3) ex-vivo reverteu este perfil e atenuou o quadro pró-inflamatório por diminuição da produção de NO e da expressão de citocinas pró-inflamatórias. / Type I diabetes mellitus (DMI) is a chronic autoimmune disease characterized by hyperglycemia due to the destruction of insulin-producing pancreatic beta cells. At the end of 30 days after type I diabetes induced by streptozotocin, macrophages from diabetic animals had increased expressions of inflammatory cytokines and chemokines, secretion of nitric oxide, expression of NLRP3, iNOS and PARP1, and glycolytic activity compared to the cells from control animals. Proinflammatory features was also observed in peritoneal macrophages of NOD (non-obese diabetic) animals. Macrophages from NLRP3 deficient diabetic mice (NLRP3 KO) had decreased expression of iNOS, PARP1 and of NO production when compared to cells from wild type animals. The type I diabetic state led to a proinflammatory feature in resident peritoneal macrophages by increasing NO production, via the NLRP3-PARP1-iNOS pathway, expressions of proinflammatory cytokines, chemokine receptors and glycolytic activity. In contrast, ex-vivo treatment with DHA (omega-3) reversed this profile and attenuated the proinflammatory state by reducing NO production and expression of proinflammatory cytokines.

Diss. (sammanfattning) Stockholm : Karol inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2004. / Härtill 6 uppsatser.

O diabetes mellitus tipo I (DMI) é uma doença crônica autoimune caracterizada por hiperglicemia devido à destruição das células beta pancreáticas produtoras de insulina. Ao final de 30 dias da indução do diabetes por estreptozotocina, os macrófagos peritoneais residentes dos animais diabéticos apresentaram aumento de RNAm de citocinas e quimiocinas inflamatórias, secreção de óxido nítrico, expressão de NLRP3, iNOS e PARP1 e da atividade da via glicolítica. Perfil pró-inflamatório também foi observado em macrófagos peritoneais de animais NOD (non-obese diabetic). Camundongos diabéticos deficientes em NLRP3 (NLRP3 KO) apresentaram diminuição na expressão de iNOS, PARP1 e na produção de NO em relação aos macrófagos dos animais diabéticos selvagens. O estado diabético tipo I influenciou o perfil dos macrófagos peritoneais residentes, causando aumento na produção de NO, via NLRP3-PARP1-iNOS, expressão de citocinas pró-inflamatórias, receptores de quimiocinas e da atividade glicolítica. O tratamento com DHA (ômega-3) ex-vivo reverteu este perfil e atenuou o quadro pró-inflamatório por diminuição da produção de NO e da expressão de citocinas pró-inflamatórias. / Type I diabetes mellitus (DMI) is a chronic autoimmune disease characterized by hyperglycemia due to the destruction of insulin-producing pancreatic beta cells. At the end of 30 days after type I diabetes induced by streptozotocin, macrophages from diabetic animals had increased expressions of inflammatory cytokines and chemokines, secretion of nitric oxide, expression of NLRP3, iNOS and PARP1, and glycolytic activity compared to the cells from control animals. Proinflammatory features was also observed in peritoneal macrophages of NOD (non-obese diabetic) animals. Macrophages from NLRP3 deficient diabetic mice (NLRP3 KO) had decreased expression of iNOS, PARP1 and of NO production when compared to cells from wild type animals. The type I diabetic state led to a proinflammatory feature in resident peritoneal macrophages by increasing NO production, via the NLRP3-PARP1-iNOS pathway, expressions of proinflammatory cytokines, chemokine receptors and glycolytic activity. In contrast, ex-vivo treatment with DHA (omega-3) reversed this profile and attenuated the proinflammatory state by reducing NO production and expression of proinflammatory cytokines.

For most children, occult vascular damage is minimal and has a slow rate of progression likely due to the existence of healthy lifestyles and the prevalence of preventative behaviours. However, there is evidence to suggest a marked increase in the prevalence of traditional and emerging cardiovascular risk factors in children with chronic inflammatory conditions due to the common aetiology pathways of inflammation and atherosclerosis. In the current cross-sectional study, a comprehensive vascular assessment was conducted on 21 children with various chronic inflammatory conditions including juvenile idiopathic arthritis (JIA), cystic fibrosis (CF), type I diabetes mellitus (T1DM) and inflammatory bowel disease (IBD) (CIC, 12.7 ± 2.3 years) compared to 9 healthy, age and sex- matched controls (CON, 13.1 ± 1.8 years). B-mode ultrasound images were used to assess carotid artery intima media thickness (cIMT) as well as local arterial stiffness through measurement of compliance and distensibility with the use of concurrent applanation tonometry. Whole-body arterial stiffness was measured by assessing pulse wave velocity (PWV) between the carotid and dorsalis pedis arteries. A brachial flow mediated dilation (FMD) test was implemented to assess endothelial function of the brachial artery. Twelve hour-fasted blood samples were collected and analyzed for blood lipids and an acute inflammatory marker, C-reactive protein (CRP). There were no group differences in cIMT (p=0.18), distensibility (p=0.40), compliance (p=0.88), whole body PWV (p=0.74) or LDL- cholesterol (p=0.99). The CIC group demonstrated significantly lower FMD when iii compared to CON (p=0.01). There were no group differences in inflammatory levels, as indicated by concentration of CRP (p=0.63). Sub-analyses revealed similar cIMT, distensibility, compliance, PWV and LDL levels between children with JIA (n=11, 12.6 ± 2.9 years), CON (n=9, 13.1 ± 1.8 years) and the other inflammatory conditions (INFL, n=10, 12.4 ± 1.7 years). Both JIA and INFL reported lower FMD when compared to CON (p=0.04). INFL had lower BMI compared to JIA and CON (p=0.02). The primary findings from this study suggest that arterial structure is similar between children with a CIC and their healthy peers; however, arterial function, as indicated by FMD (%), was reduced in the CIC group. This finding is essential in that it helps to identify an area for targeted intervention and/or prevention of future CV events as endothelial dysfunction is known to be an early event in the pathophysiology of atherosclerosis. / Thesis / Master of Science (MSc)