Raised levels of F 2-isoprostanes and prostaglandin F 2 á in di V erent rheumatic diseases

Objective—To evaluate oxidative injury and inflammatory status in various rheumatic diseases by measuring the levels of isoprostanes and prostaglandins in serum and synovial fluid. Methods—The concentrations of 8-isoPGF2á (F2-isoprostane indicating oxidative injury) and 15-keto-dihydro-PGF2á (a major metabolite of prostaglandin F2á) were measured in both serum and synovial fluid aspirated from 26 patients with various arthritic diseases, including rheumatoid arthritis (RA), reactive arthritis (ReA),psoriatic arthritis (PsA),and osteoarthritis (OA). These prostaglandin derivatives were also measured in serum samples collected from 42 healthy control subjects. Results—Overall, serum levels of 8-isoPGF2á and 15-keto-dihydro-PGF2á were much higher in patients with arthritic diseases than in the healthy control subjects. The levels of 8-iso-PGF2á and 15-ketodihydro-PGF2á in synovial fluid aspirated from knee joints were also high and varied among various types of arthritic patients. Although the synovial fluid level of these prostaglandin derivatives was sometimes higher than in the corresponding serum sample, this was not a consistent finding. Overall, there was no correlation between serum and synovial fluid levels of 8-isoPGF2á, or between serum and synovial fluid levels of 15-keto-dihydro-PGF2á. However, a strong relation was found between the levels of 8-iso-PGF2á and 15-keto-dihydro-PGF2á, in both serum (rs=0.53, p<0.001) and synovial fluid (rs=0.62, p<0.001). Conclusions—These data suggest that both free radical mediated oxidative injury and cyclo-oxygenase dependent inflammatory responses are closely correlated in various types of arthritis. (Ann Rheum Dis 2001;60:627–631) Reactive oxygen species and reactive nitrogen species have been shown to cause tissue injury and pathophysiological consequences in chronic inflammatory conditions such as rheumatoid arthritis and other rheumatic diseases. However, the degree of free radical injury and inflammatory response may vary in diVerent types of inflammatory arthritis and also in diVerent people depending on the severity and duration of these diseases. A major problem associated with the assessment of oxidative stress in inflammatory arthritis has been the limitation in available assay methods for in vivo measurement of free radical generation or end products of free radical catalysed oxidation of lipids. In 1990, Morrow, Roberts, and their colleagues reported the discovery of isoprostanes, a family of prostaglandin derivatives generated in vivo by non-enzymatic free radical catalysed oxidation of arachidonic acid. It has also been noted that one of the major isoprostanes, 8-isoprostaglandin F2á (8-iso-PGF2á, fig 1) is increased in several syndromes that are associated with oxidant injury, and the measurement of isoprostanes is widely regarded as a reliable biomarker for in vivo measurement of lipid peroxidation. Cyclo-oxygenase-2 (COX-2), an isoform of cyclo-oxygenase, has been shown to be expressed in macrophages, epithelial cells, and fibroblasts after exposure to several proinflammatory stimuli (for example, cytokines, growth factors), leading to the release of prostaglandins (fig 1). 15-Keto-13,14-dihydro-PGF2á (15-keto-dihydro-PGF2á), a major metabolite of prostaglandin F2á, is increased in the inflammatory response. 22 We recently developed a highly specific and sensitive radioimmunoassay (RIA) by raising antibodies in rabbits against both 8-iso-PGF2á (indicating oxidative injury) 23 and 15-ketodihydro-PGF2á (indicating inflammatory response). The antibodies clearly discriminate between these two closely related substances (fig 1). 23 By applying these parameters, we showed that oxidative modification of arachidonic acid, through both non-enzymatic lipid peroxidation and enzymatic (cyclo-oxygenase) pathways, is involved in endotoxin induced inflammation in septic shock, 17 hepatotoxin induced oxidative injury, and cerebral oxidative injury after resuscitation from cardiac arrest. These results suggest that oxidative injury and inflammation are closely associated in various syndromes. The proposed role of reactive oxygen species in inflammatory joint disease suggests the need for a marker of oxidative injury, such as 8-isoPGF2á. A previous study has shown that plasma 8-iso-PGF2á levels are raised in systemic lupus erythematosus and other rheumatic diseases with vascular involvement, though no increase was seen in patients with rheumatoid arthritis (RA). However, this particular study examined plasma levels only. We considered it likely that markers of oxidative injury are raised at local sites of inflammation. Patients with joint diseases who present with a synovial eVusion provide an opportunity to examine localised oxidative injury as well as systemic responses. Ann Rheum Dis 2001;60:627–631 627 Sections of Geriatrics and Clinical Nutrition Research, Faculty of Medicine, Uppsala University, Box 609, SE-751 25 Uppsala, Sweden