Prostaglandins and Isoprostanes in Relation to Risk Factors for Atherosclerosis Role of Inflammation and Oxidative Stress

Sammanfattning: Inflammation and oxidative stress may be involved in atherogenesis. This thesis describes clinical studies of prostaglandin F2? (PGF2?), an inflammatory mediator, and the isoprostane 8-iso-PGF2?, a reliable indicator of oxidative stress, and cytokine-related inflammatory mediators and indicators in healthy subjects and in a population-based cohort of Swedish men. PGF2? and 8-iso-PGF2? formation in healthy subjects varied considerably between days with a mean intra-individual coefficient of variation of 41 % and 42 %, respectively. A morning urine sample reflected the basal level of 8-iso-PGF2? formation as accurately as a 24-hour urine collection, and represents a more practical alternative to the 24-hour urine collection in clinical studies. PGF2? formation (as measured by urinary 15-keto-dihydro-PGF2?) was increased in patients with type 2 diabetes and in smokers independent of other cardiovascular risk factors. These results indicated an on-going cyclooxygenase (COX)-mediated inflammatory reaction related to these conditions. Further, an increased formation of isoprostanes (as measured by urinary 8-iso-PGF2?) was found in patients with type 2 diabetes and in smokers, indicating a high level of oxidative stress in these men. The smokers had also increased levels of the cytokine interleukin-6, indicating an on-going cytokine-related inflammatory reaction. The inflammatory indicators C-reactive protein and serum amyloid A were related to overweight but not independently associated to type 2 diabetes. High levels of serum selenium in middle-aged men predicted reduced formation of PGF2? and 8-iso-PGF2? 27 years later.In summary, low-grade, chronic COX-mediated and possibly cytokine-related inflammation, and oxidative stress, seem to be joint features of type 2 diabetes and smoking, two major risk factors of atherosclerosis, in elderly men. Inflammation and oxidative stress may represent a possible common pathogenetic link between established risk factors for atherosclerosis and atherogenesis.