Prolongation of alloskin graft survival by catalytic scavengers of reactive oxygen species.
ABSTRACT We tested the effects of salen manganese (Salen-Mn) complexes, which are scavengers of reactive oxygen species exhibiting superoxide dismutase and catalase activities on the rejection of and alloresponse to fully allogeneic skin grafts in mice. We showed that pre-transplant treatment of C57Bl/6 donor skin or of BALB/c recipients with Salen-Mn complexes significantly delayed allograft rejection. ELISPOT analysis of alloimmune response of treated mice revealed a significant reduction of the frequency of type 1 cytokine (pro-inflammatory) producing T-cells, while the number of activated T-cells producing type 2 cytokines was elevated. In addition, anti-oxidative treatment of graft recipients resulted in a profound inhibition of their donor-specific cytotoxic T-cell response. Our results indicate that salen manganese complexes mediate their effect on graft rejection both by reducing the susceptibility of graft tissue to ROS-mediated injury and by exerting an anti-inflammatory effect in recipients.
Article: Mitochondrial manganese superoxide dismutase mRNA expression in human chorioamniotic membranes and its association with labor, inflammation, and infection.[show abstract] [hide abstract]
ABSTRACT: Human parturition is characterized by the activation of genes involved in acute inflammatory responses in the fetal membranes. Manganese superoxide dismutase (Mn SOD) is a mitochondrial enzyme that scavenges reactive oxygen species (ROS). Mn SOD is up-regulated in sites of inflammation and has an important role in the down-regulation of acute inflammatory processes. Therefore, the aim of this study was to determine the differences in Mn SOD mRNA expression in the fetal membranes in patients with term and preterm labor (PTL) as well as in acute chorioamnionitis. Fetal membranes were obtained from patients in the following groups: (1) term not in labor (n = 29); (2) term in labor (n = 29); (3) spontaneous PTL with intact mebranes (n = 16); (4) PTL with histological chorioamnionitis (n = 12); (5) preterm prelabor rupture of the membranes (PPROM; n = 17); and (6) PPROM with histological chorioamnionitis (n = 21). Mn SOD mRNA expression in the membranes was determined by quantitative real-time reverse transcription-polymerase chain reaction. (1) Mn SOD mRNA expression was higher in the fetal membranes of patients at term in labor than those not in labor (2.4-fold; p = 0.02); (2) the amount of Mn SOD mRNA in the fetal membranes was higher in PTL than in term labor or in PPROM (7.2-fold, p = 0.03; 3.2-fold, p = 0.03, respectively); (3) Mn SOD mRNA expression was higher when histological chorioamnionitis was present both among patients with PPROM (3.8-fold, p = 0.02) and with PTL (5.4-fold, p = 0.02) than in patients with these conditions without histological chorioamnionitis; (4) expression of Mn SOD mRNA was higher in PTL with chorioamnionitis than in PPROM with chorioamnionitis (4.3-fold, p = 0.03). The increase in Mn SOD mRNA expression by fetal membranes in term labor and in histological chorioamnionitis in PTL and PPROM suggests that the fetus deploys anti-oxidant mechanisms to constrain the inflammatory processes in the chorioamniotic membranes.The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 11/2009; 22(11):1000-13. · 1.36 Impact Factor
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ABSTRACT: Salen Mn complexes, including EUK-134, EUK-189 and a newer cyclized analog EUK-207, are synthetic SOD/catalase mimetics that have beneficial effects in many models of oxidative stress. As oxidative stress is implicated in some forms of delayed radiation injury, we are investigating whether these compounds can mitigate injury to normal tissues caused by ionizing radiation. This review describes some of this research, focusing on several tissues of therapeutic interest, namely kidney, lung, skin, and oral mucosa. These studies have demonstrated suppression of delayed radiation injury in animals treated with EUK-189 and/or EUK-207. While an antioxidant mechanism of action is postulated, it is likely that the mechanisms of radiation mitigation by these compounds in vivo are complex and may differ in the various target tissues. Indicators of oxidative stress are increased in lung and skin radiation injury models, and suppressed by salen Mn complexes. The role of oxidative stress in the renal injury model is unclear, though EUK-207 does mitigate. In certain experimental models, salen Mn complexes have shown "mito-protective" properties, that is, attenuating mitochondrial injury. Consistent with this, EUK-134 suppresses effects of ionizing radiation on mitochondrial function in rat astrocyte cultures. In summary, salen Mn complexes could be useful to mitigate delayed radiation injury to normal tissues following radiation therapy, accidental exposure, or radiological terrorism. Optimization of their mode of delivery and other key pharmaceutical properties, and increasing understanding of their mechanism(s) of action as radiation mitigators, are key issues for future study.Anti-cancer agents in medicinal chemistry 04/2011; 11(4):359-72.