Colonic Ulceration and Increase of Neutrophil Elastase Activity in the Acetic Acid-Induced Colitis Model in Syrian Hamsters

Abstract

ABSTRACT. A novel colitis model using Syrian hamsters was developed. Colitis was induced by intracolonic administration of 1% acetic acid, and the ulcer area, tissue myeloperoxidase (MPO) activity, and luminal neutrophil elastase (NE) activity of the colon were determined at 1, 3, 8, 24 and 48 hr after colitis induction. The histopathological changes of the colon were also examined in this m odel. An increase of tissue MPO activity and NE activity was evident at 3 hr after induction of colitis, peaked at 24 hr, and decreased subsequently. The increase of luminal NE activity was well correlated with the colonic ulcer area. In histopathological examination, ulceration, erosion, crypt abscesses, neutrophil infiltration, hemorrhage, and edema were seen. The effects of prednisolone were examined to evaluate the adequacy of our colitis model. Syrian hamsters were treated orally with prednisolone at 18 and 1 hr before and at 6 hr after induction of colitis, and the ulcer area, tissue MPO activity, and luminal NE activity were evaluated at 24 hr after colitis induction. Prednisolone therapy had little effect on the tissue MPO activity. However, the NE activity of the prednisolone-treated group was significantly decreased. In addition, although prednisolone did not significantly decrease the ulcer area, a tendency toward decrease was noted. We conclude that this new model of experimental colitis in Syrian hamsters is useful for investigating the pathophysiology of colitis, especially useful for studying the relationship between colitis and NE activity. KEY WORDS: acetic acid, colitis model, neutrophil elastase, Syrian hamster.J. Vet. Med. Sci. 66(4): 417-422, 2004 Inflammatory bowel disease (IBD) is a general term for a group of chronic inflammatory conditions of the gastrointestinal tract, including ulcerative colitis and Crohn's disease. These are intractable inflammatory diseases of unknown etiology that are characterized by repeated exacerbations and remissions. The symptoms include diarrhea, bloody stools, and abdominal pain, while the histological findings are ulceration, inflammatory cell infiltration, and accumulation of neutrophils in the intestinal crypts (socalled crypt abscesses) [3,5]. Although numerous authors have discussed the pathogenesis of IBD, the precise mechanisms of onset and exacerbation have not been clarified. Recently, toxic products of neutrophils such as reactive oxygen species (ROS) and proteases, including cathepsin and elastase, have been suggested to play an important role in the pathogenesis of IBD [10,13,[19][20][21].Neutrophil elastase (NE) is a protease found in neutrophil granules that is known to have a broad-spectrum proteolytic activity against various proteins, such as elastin and type I-IV collagen. Release of NE during inflammation is related to degradation of connective tissues and an increase of vascular permeability, thus causing tissue damage and organ failure [6,7]. It has been reported that α1-protease inhibitor (α1-PI), an endogenous inhibitor of NE, is inactivated by...

Effects of the Neutrophil Elastase Inhibitor (ONO-6818) on Acetic Acid Induced Colitis in Syrian Hamsters

“…This experimental colitis model shows similar histopathological features to human IBD, and the increase in luminal NE activity in the colon is closely correlated with the colonic ulcer area [5].…”

“…reduced at 30 and 100 mg/kg, and the colonic NE activity was also significantly inhibited. In addition, prednisolone, which is a glucocorticoid clinically used as a therapeutic agent for IBD [7], inhibits NE activity and the ulcer area in this colitis model, but has little effect on the tissue MPO activity [5]. These facts suggest that colonic tissue damage and hemorrhage were presumably inhibited because ONO-6818 or prednisolone blocked the NE activity.…”

“…We previously demonstrated that the ulcer area, colonic tissue MPO activity and NE activity were increased in a 1% AA-induced colitis model in Syrian hamsters [5]. These parameters peaked at 24 hr after induction of colitis, and acutely decreased toward the normal range by 48 hr.…”

Neutrophil Elastase Inhibitor Suppresses Il-17 Based Inflammation of Murine Experimental Colitis

“…The protective effects of NE inhibitors were first documented in acute lung injury associated with systemic inflammation response, which may occur after infection, surgical intervention, or traumatic or burn injury 21) . Although NE activity was elevated in colon and serum in IBD patients 10,11) , and some have shown the benefits of targeting NE in colitis models 22,23) , the details remain unclear. Therefore, we used a commercially available NE inhibitor, SNa, in DSS -induced colitis in an attempt to assess the mechanisms of inflammation inhibition.…”

Neutrophil elastase in colitis: more than a marker of disease activity?

“…NE activity was well correlated with the colonic ulcer area in an acetic acid-induced colitis model in the Syrian hamster. 10 In addition, an orally active NE inhibitor, ONO-6818, significantly inhibited colitis as well as luminal NE activity. 11 ONO-5046, another, nonsynthetic NE inhibitor, is a competitive inhibitor against NE in many kinds of animals.…”