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Abstract
Increased production of cytokines and chemokines in serum and tissues upon oxidative
stress caused by severe systemic infections are the major cause of sepsis. Aldose
reductase (AR) known to mediate oxidative stress-induced NF-kappaB activation and
transcription of cytokines and chemokines are the main mediator of bacterial endotoxin-induced
inflammatory response. Our aim is to investigate the effect of AR inhibitors on the
prevention of inflammatory cytokines in the cecum ligation and puncture (CLP) model
of polymicrobial sepsis which closely mimics the sepsis syndrome in humans.
Mice were rendered septic by CLP in the absence and presence of AR inhibitor, sorbinil.
The levels of cytokines, chemokines and other inflammatory markers in the plasma,
peritoneal fluid and heart of mice were significantly inhibited by sorbinil. Inhibition
of AR also prevented CLP-induced COX-2, iNOS and HMGB-1 in heart, kidney and spleen.
Our results showed that the inhibition of AR significantly prevented the polymicrobial
sepsis-induced increase in inflammatory markers and thus indicate the use of AR inhibitors
as anti-inflammatory agents.