Anti-inflammatory properties have been ascribed to a series of N-(fluorenyl-9-methoxycarbonyl)
amino acids called leumedins that inhibit the activity of granulocytes and T-lymphocytes. We evaluated one of these leumedins, N-(fluorenyl-9-methoxycarbonyl)
leucine (
NPC 15199), in a model of
ileitis in guinea pigs.
Ileitis was induced by intraluminal
trinitrobenzenesulfonic acid (TNBS 30 mg/kg in 50%
ethanol) in anesthetized guinea pigs.
NPC 15199 was administered daily (10 or 100 mg/kg, s.c.). After 7 days, the guinea pigs were anesthetized, and saline was administered intraluminally into an ileal loop created at the site of TNBS administration and was withdrawn after 30 min. The changes in lavage
protein,
nitrite levels,
myeloperoxidase (MPO) activity and mast cell numbers were used as indices of
inflammation and injury.
NPC 15199 (10 or 100 mg/kg) attenuated or abolished TNBS-induced elevations in lavage
protein and
nitrite content. Only the high dose of
NPC 15199 (100 mg/kg) attenuated ileal MPO activity and mast cell
hyperplasia. Histological disturbances induced by TNBS administration included crypt
hypertrophy, mucosal and submucosal
fibrosis and smooth-muscle
hyperplasia. These disturbances were reversed by high-dose
NPC 15199 (100 mg/kg) but were minimally affected by low-dose
NPC 15199 (10 mg/kg). We conclude that
NPC 15199 prevents mucosal injury and dysfunction in this model of intestinal
inflammation. Inhibition of granulocyte infiltration does not appear to be essential for the beneficial effects of
NPC 15199 and suggests that the alternative actions of
NPC 15199 may be pertinent to this model.