Anti-inflammatory effect of aldose reductase inhibition in murine polymicrobial sepsis.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Reddy
Aramati B M
AB
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Srivastava
Satish K
SK
Ramana
Kota V
KV
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000032:analysis / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D048289:Imidazolidines / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018746:Systemic Inflammatory Response Syndrome / Q000503:physiopathology / Q000517:prevention & control*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D000449:Aldehyde Reductase; C026411:sorbinil