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.


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.
Chang
C K
CK
Department of Surgery, Finch University of Health Sciences/The Chicago Medical School at Mount Sinai Hospital Medical Center, California Avenue at 15th Street, Chicago, Illinois, 60608, USA.
Albarillo
M V
MV
Schumer
W
W
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D002432:Cecum; D002467:Cell Nucleus / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007813:Laparotomy; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D010538:Peritonitis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D000975:Antioxidants; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D018799:Intercellular Adhesion Molecule-1; D004121:Dimethyl Sulfoxide