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

BACKGROUND

Dimethyl sulfoxide (DMSO) is a potent antioxidant which protects against endotoxemia and septic shock in animal models. We investigated the therapeutic effect of DMSO on intercellular adhesion molecule 1 (ICAM-1) gene expression and activation of nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) in a rat model of peritonitis sepsis. This postchallenge model simulates the clinical treatment of ruptured viscus peritonitis.

MATERIALS AND METHODS

Peritonitis was produced by subjecting rats to laparotomy, followed by a 1-cm cecal incision (CI) to produce fecal soilage of the 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 activation 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 expression 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 90 min post-CI surgery. At 6 h post-CI surgery (late sepsis), DMSO administered at 30, 60, or 90 min post-CI surgery significantly inhibited ICAM-1 mRNA expression and NF-kappaB activation but not AP-1 activation.

CONCLUSIONS

Therapeutic treatment of DMSO inhibited sepsis-induced activation of NF-kappaB and AP-1, resulting in the suppression of ICAM-1 gene expression in the livers of peritonitis septic rats. This finding suggests that reactive oxidants are involved in the signal transduction pathways for activation of NF-kappaB and AP-1. Thus, antioxidants which inhibit NF-kappaB and AP-1 activation may be beneficial in treating sepsis and septic shock.