Therapeutic effect of dimethyl sulfoxide on ICAM-1 gene expression and activation of NF-kappa B and AP-1 in septic rats

Background. Dimethyl sulfoxide (DMSO) is a potent antioxidant which protect s against endotoxemia and septic shock in animal models. We investigated th e therapeutic effect of DMSO on intercellular adhesion molecule 1 (ICAM-1) gene expression and activation of nuclear factor-kappaB (NF-kappaB) and act ivating protein-1 (AP-1) in a rat model of peritonitis sepsis. This postcha llenge model simulates the clinical treatment of ruptured viscus peritoniti s. Materials and methods. Peritonitis was produced by subjecting rats to lapar otomy, followed by a 1-cm cecal incision (CI) to produce fecal soilage of t he peritoneum. Rats were subjected to laparotomy only for the sham-operated group. For the protection study, DMSO (6 ml/kg) was injected ip at 30, 60, or 90 min post-CI surgery. The levels of ICAM-1 mRNA expression and activa tion of NF-kappaB and AP-1 in Livers were determined at 3 and 6 h post-CI. Results. At 3 h post-CI surgery (early sepsis), DMSO treatment at 30 and 60 min post-CI surgery significantly inhibited sepsis-induced ICAM-1 mRNA exp ression and activation of NF-kappaB and AP-1. DMSO has no effect on ICAM-1 gene expression and activation of NF-kappaB and AP-1 when administered at 9 0 min post-CI surgery. At 6 h post-CI surgery (late sepsis), DMSO administe red at 30, 60, or 90 min post-CI surgery significantly inhibited ICAM-I mRN A expression and NF-kappaB activation but not AP-1 activation. Conclusions. Therapeutic treatment of DMSO inhibited sepsis-induced activat ion of NF-kappaB and AP-1, resulting in the suppression of ICAM-1 gene expr ession in the livers of peritonitis septic rats. This finding suggests that reactive oxidants are involved in the signal transduction pathways for act ivation of NF-kappaB and AP-1. Thus, antioxidants which inhibit NF-kappaB a nd AP-1 activation may be beneficial in treating sepsis and septic shock. ( C) 2000 Academic Press.