Freselestat

We developed a colitis model in Syrian hamsters (Mesocricetus auratus) to investigate the relationship between colitis and neutrophil elastase (NE). Colitis was induced by a single intracolonic dose of trinitrobenzene sulfonic acid (TNBS; 90 mg/ml) dissolved in 15% (vol/vol) ethanol. The ulcer area, tissue myeloperoxidase (MPO) activity, and luminal NE activity all were increased on Days 1 and 5, corresponding with the acute inflammatory histopathological changes. These acute inflammatory parameters subsequently decreased by Day 14, and chronic inflammatory histopathological changes became evident. Recurrence of inflammation was not observed during the period up to Day 28. To evaluate our colitis model, the effects of prednisolone were examined. Prednisolone was administered orally once on the day before induction of colitis, and animals were treated twice daily thereafter. Although prednisolone had little effect on the tissue MPO activity, prednisolone inhibited the ulcer area and NE activity. In addition, the effects of an NE-specific inhibitor (ONO-6818) on our TNBS-induced colitis model were examined. In the subcutaneous treatment study, ONO-6818 was administered once before the induction of colitis. Although ONO-6818 had little effect on the tissue MPO activity, the ulcer area and NE activity were decreased in the ONO-6818-treated group. The inhibitory effects on the ulcer area and NE activity were confirmed after oral treatment with ONO-6818 after induction of colitis. We conclude that our colitis model is useful for investigating the relationship between colitis and NE, and inhibition of NE activity can prevent the progression of ulceration.

Neutrophil elastase (NE) released from neutrophils during inflammation is related to tissue disturbance and organ failure. We investigated the effects of an orally active NE inhibitor, ONO-6818, on acetic acid induced colitis in Syrian hamsters. The ulcer area, hemoglobin level in the colonic lumen, NE activity, and tissue myeloperoxidase (MPO) activity in the colitis control animals were significantly increased compared to the normal control ones. Either oral or subcutaneous treatment with ONO-6818 had significant inhibitory effects on the ulcer area, hemoglobin level and NE activity in the colonic lumen, but ONO-6818 did not have a significant inhibitory effect on tissue MPO activity. We conclude that NE is closely related to the development of inflammation in acetic acid-induced colitis in Syrian hamsters and that the condition is improved by the inhibition of NE.