Ozone induces synthesis of systemic prostacyclin by cyclooxygenase-2 dependent mechanism in vivo

Abstract

Under certain pathological conditions, e.g., infectious or neoplastic diseases, application of ozone exerts therapeutic effects. However, pharmacological mechanisms are not understood. Since an interaction with the arachidonic acid metabolism is suggested we investigated the effect of intraperitoneal insufflation of ozone on prostanoid system in vivo. Upon ozone application (4 mg/kg) to rats we observed an approximate 3-fold increase in excretion rate of 6-keto-prostaglandin (PG) F 1α and of 2,3-dinor-6-keto-PGF 1α, the measurable stable products of prostacyclin. In plasma and vessel tissue 6-keto-PGF 1α concentration was also significantly increased. In contrast, excretion rates for PGE 2 and thromboxane (TX) B 2 did not change. F2-isoprostanes, regarded as endogenous indicators of oxidative stress, were also unaffected by ozone application. Oxygen insufflation used as control was without any effect on prostanoid levels. Ozone caused increase in 6-keto-PGF 1α by arterial but not by venous vessel tissues with peak activity 6–9 h following insufflation. The increase in PGI 2 synthesis was dependent on cyclooxygenase (COX)-2 activity, demonstrated by its sensitivity towards COX-2 inhibition, and by enhanced COX-2 mRNA and protein expression in vessels. Ozone exerted no rise in excretion rate of prostacyclin metabolites in COX-2 −/− but in COX-1 −/− mice. Enzymatic activity and mRNA expression of vascular PGI 2 synthase (PGIS) was unaffected by ozone treatment. In summary our study shows for the first time that ozone insufflation causes enhanced expression of COX-2 in the vessel system leading to exclusive elevation of systemic PGI 2 levels. We assume that PGI 2 stimulation may contribute to the beneficial effects of ozone treatment.