The involvement of heme oxygenase-1 activity in the therapeutic actions of 5-aminosalicylic acid in rat colitis.
The mechanism of action of 5-aminosalicylic acid (5-ASA), the active therapeutic moiety of a number of clinically used anti-colitic agents, is unclear. The present study investigates whether the beneficial effects in vivo could involve induction of the heat shock protein, heme oxygenase-1 (HO-1), known to provide endogenous anti-oxidant and anti-inflammatory moieties which can modulate colonic inflammation. The effects of 5-ASA on the colonic expression and activity of HO-1 along with its effect on the inflammatory damage have been evaluated in the colitis provoked by instillation of trinitrobenzene sulphonic acid (TNBS) over 48 h in the rat. Intracolonic administration of 5-ASA (8, 25 and 75 mg/kg/day) dose-dependently reduced the TNBS-provoked macroscopic colonic inflammatory injury, myeloperoxidase (MPO) activity and TNF-alpha levels, while also dose-dependently increasing colonic heme oxygenase enzyme activity. Colonic HO-1 protein expression, determined by Western blot analysis in this colitis model, was likewise further induced by 5-ASA. Intracolonic administration of 5-ASA alone under unchallenged conditions also induced colonic HO-1 protein expression and stimulated heme oxygenase enzyme activity. Administration of zinc protoporphyrin (50 micromol/kg/day, s.c.), which prevented the increase in colonic heme oxygenase activity, abolished the anti-colitic effect of 5-ASA. These results suggest that 5-ASA may exert its colonic anti-oxidant and anti-inflammatory effects in vivo in part through the up-regulation of HO-1 enzyme expression and activity.
Horváth
Krisztina
K
Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
Varga
Csaba
C
Berkó
Anikó
A
Pósa
Anikó
A
László
Ferenc
F
Whittle
Brendan J R
BJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D003092:Colitis / Q000188:drug therapy*; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019804:Mesalamine / Q000008:administration & dosage / Q000494:pharmacology*; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D011524:Protoporphyrins; D014409:Tumor Necrosis Factor-alpha; C017803:zinc protoporphyrin; D019804:Mesalamine; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D051547:Heme Oxygenase-1