Aiko S, Conner E M, Fuseler J A, Grisham M B
Department of Physiology and Biophysics, Louisiana State University Medical Center, Shreveport 71130, USA.
J Pharmacol Exp Ther. 1997 Feb;280(2):1075-84.
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.
本研究的目的是定量表征FK506对大鼠慢性肉芽肿性结肠炎模型中观察到的病理生理学的影响，并将这些影响与环孢素A（CyA）所获得的影响进行比较。通过向雌性Lewis大鼠远端结肠壁内（浆膜下）注射肽聚糖/多糖（PG/PS）诱导慢性肉芽肿性结肠炎。然后，从PG/PS注射后7天开始，大鼠每天接受一次肌肉注射，分别为CyA的赋形剂（0.5 ml/kg聚氧乙烯蓖麻油）、含CyA的赋形剂（25 mg/kg）、生理盐水（0.5 ml/kg）或FK506（1 mg/kg生理盐水），并持续额外2周。在第21天，我们发现壁内注射PG/PS导致了慢性结肠炎，伴有肝脏和脾脏的肉芽肿性炎症。与它们的赋形剂或未治疗的对照组相比，在结肠炎诱导后7天开始每天用CyA或FK506治疗，导致结肠黏膜通透性、结肠髓过氧化物酶活性和血浆硝酸盐/亚硝酸盐水平受到显著抑制。在某些情况下，我们注意到有显著的依赖赋形剂的抗炎活性。在CyA和FK506治疗组中，PG/PS诱导的腹膜粘连发生率以及肝脏和脾脏肉芽肿的存在也显著降低。综上所述，这些数据表明免疫抑制疗法在减轻PG/PS诱导的结肠炎以及肠外炎症方面是有效的。我们得出结论，FK506可能对治疗某些类型的炎症性肠病有用。
