Effects of cyclosporine or FK506 in chronic colitis.
The objective of this study was to quantitatively characterize the effects FK506 on the pathophysiology observed in a model of chronic granulomatous colitis in rats and compare these effects to those obtained with cyclosporin A (CyA). Chronic granulomatous colitis was induced in female Lewis rats via intramural (subserosal) injections of peptidoglycan/polysaccharide (PG/PS) into the distal colon. Rats then received daily injections (i.m.) of either vehicle for CyA (0.5 ml/kg cremophor), CyA in vehicle (25 mg/kg), saline (0.5 ml/kg) or FK506 (1 mg/kg in saline), beginning 7 days after PG/PS injection and continuing for an additional 2 weeks. On day 21, we found that the intramural injection of PG/PS produced a chronic colitis that was associated with hepatic and splenic granulomatous inflammation. Daily treatment with CyA or FK506 beginning 7 days after the induction of colitis resulted in significant inhibition in colonic mucosal permeability, colonic myeloperoxidase activity and plasma nitrate/nitrite levels when compared with their vehicle or untreated controls. In some instances, we noticed a significant vehicle-dependent anti-inflammatory activity. The incidence of peritoneal adhesions as well as the presence of hepatic and splenic granulomas induced by PG/PS were also significantly reduced in both the CyA- and FK506-treated groups. Taken together, these data suggest that immunosuppressive therapy is effective at attenuating both the colitis as well as the extraintestinal inflammation induced by PG/PS. We conclude that FK506 may be useful in the treatment of certain types of inflammatory bowel disease.
Aiko
S
S
Department of Physiology and Biophysics, Louisiana State University Medical Center, Shreveport 71130, USA.
Conner
E M
EM
Fuseler
J A
JA
Grisham
M B
MB
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D003106:Colon / Q000473:pathology* / Q000503:physiopathology; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000473:pathology / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000473:pathology* / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009929:Organ Size; D010457:Peptidoglycan; D011134:Polysaccharides / Q000633:toxicity; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000187:drug effects / Q000473:pathology*; D016559:Tacrolimus / Q000494:pharmacology*
D009566:Nitrates; D009573:Nitrites; D010457:Peptidoglycan; D011134:Polysaccharides; D016572:Cyclosporine; D016559:Tacrolimus