Evidence of free radical–mediated injury (isoprostane overproduction) in scleroderma

Abstract

Objective. Free radical–induced oxidative stress with consequent lipid peroxidation and resultant tissue damage has been suggested as a potential mechanism of the pathogenesis of scleroderma. However, because reliable measurement of lipid peroxidation in vivo is difficult, it has not been possible to adequately examine this hypothesis. We have previously described a series of bioactive prostaglandin F2–like compounds, termed F2‐isoprostanes, produced in vivo in humans by the noncyclooxygenase, free radical–catalyzed, peroxidation of arachidonic acid and have shown them to be a reliable measure of lipid peroxidation in vivo. In the present study, we determined whether scleroderma is associated with enhanced oxidative stress.Methods. As a measure of oxidative stress, we determined urinary concentrations of a tetranordicarboxylic acid metabolite of F2‐isoprostanes (F2IP‐M) by mass spectrometry in 8 patients with scleroderma (representing a wide spectrum of disease, including limited disease with refractory digital ulceration or pulmonary hypertension, and diffuse disease) and in 10 healthy control subjects.Results. F2IP‐M concentrations were significantly higher in patients 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 in those with diffuse disease.Conclusion. The increased level of urinary F2IP‐M supports the hypothesis that free radical–induced oxidative injury occurs in scleroderma and provides a biologic marker whose relationship to disease activity and disease therapy may be important. These findings may also provide a rationale for exploring whether antioxidant therapy may influence the natural course of the disease.

The Isoprostanes: Unique Bioactive Products of Lipid Peroxidation

“…Not only can free radicals stimulate fibroblast proliferation and fibrosis, which characterizes this disease, they can also inhibit the action of NO resulting in enhanced vasoconstriction which is another hallmark of scleroderma. To examine whether there was evidence of oxidative stress in scleroderma, the excretion of F 2 -IsoPs urinary metabolites was measured in 10 healthy controls and 8 patients with scleroderma (representing a wide spectrum of disease severity ranging from limited to diffuse disease) [26]. The urinary excretion of F 2 -IsoP metabolites was elevated in scleroderma patients a mean of 2.8-fold above control.…”

Streamlined F2-Isoprostane Analysis in Plasma and Urine with High-Performance Liquid Chromatography and Gas Chromatography/Mass Spectroscopy

“…Some isoprostanes, e.g., 8-iso-PGF 2␣ , exhibit potent vasoconstrictor activity in lung and kidney (2) and stimulate mitogenesis in aortic smooth muscle (3). Elevated levels of F 2 -isoprostanes have been reported in conditions associated with increases in oxidative stress status, e.g., in smokers (4), hypercholesterolemia (5), hepatic cirrhosis (6), scleroderma (7), coronary reperfusion (8), and non-insulin-dependent diabetes mellitus (9). Levels of F 2 -isoprostanes can be reduced by the administration of dietary antioxidants (10,11).…”

Antioxidant effect of Iloprost: current knowledge and therapeutic implications for systemic sclerosis

“…Moreover, isoprostanes are more than inert markers of oxidative burden: they are proven to induce ROS production (40), to mediate vascular constriction (41, 42), endothelin-1 gene expression (43) and fibroblast proliferation (44) and to impair angiogenesis (45), all of them are well known specific features of SSc. Thus, is not surprising that raised isoprostanes levels have been demonstrated in different organic fluids (46)(47)(48)(49)(50) in SSc and are related to severity and extent of visceral (49) and vascular involvement (49,51). Of interest such an increase of F 2 -isoprostanes seems predominate in the early steps of SSc (50) highlighting the role of OS as a key factor in the induction of disease.…”