EVIDENCE OF FREE RADICAL-MEDIATED INJURY (ISOPROSTANE OVERPRODUCTION)IN SCLERODERMA

Objective. Free radical-induced oxidative stress with consequent lipid peroxidation and resultant tissue damage has been suggested as a pote ntial mechanism of the pathogenesis of scleroderma. However, because r eliable measurement of lipid peroxidation in vivo is difficult, it has not been possible to adequately examine this hypothesis. We have prev iously described a series of bioactive prostaglandin F-2-like compound s, termed F-2-isoprostanes, produced in vivo in humans by the non-cycl ooxygenase, free radical-catalyzed, peroxidation of arachidonic acid a nd have shown them to be a reliable measure of lipid peroxidation in v ivo. In the present study, we determined whether scleroderma is associ ated with enhanced oxidative stress, Methods. As a measure of oxidativ e stress, we determined urinary concentrations of a tetranordicarboxyl ic acid metabolite of F-2-isoprostanes (F2IP-M) by mass spectrometry i n 8 patients with scleroderma (representing a wide spectrum of disease , including limited disease with refractory digital ulceration or pulm onary hypertension, and diffuse disease) and in 10 healthy control sub jects. Results. F2IP-M concentrations were significantly higher in pat ients with scleroderma (mean +/- SEM 3.41 +/- 0.64 ng/mg of creatinine ) than in healthy controls (1.22 +/- 0.14 ng/mg of creatinine) (P = 0. 002). These elevations occurred in patients with limited disease and i n those with diffuse disease. Conclusion. The increased level of urina ry F2IP-M supports the hypothesis that free radical-induced oxidative injury occurs in scleroderma and provides a biologic marker whose rela tionship to disease activity and disease therapy may be important. The se findings may also provide a rationale for exploring whether antioxi dant therapy may influence the natural course of the disease.