Abstract
Inflammatory bowel diseases (IBD) are chronic and relapsing gastrointestinal disorders, where a significant proportion of patients are unresponsive or lose response to traditional and currently used therapies. In the current study, we propose a new concept for anti-inflammatory treatment based on a selective acidic mammalian chitinase (AMCase) inhibitor. The functions of chitinases remain unclear, but they have been shown to be implicated in the pathology of various inflammatory disorders regarding the lung (asthma, idiopathic pulmonary fibrosis) and gastrointestinal tract (IBD and colon cancer). The aim of the study is to investigate the impact of AMCase inhibitor (OAT-177) on the dextran sulfate sodium (DSS)-induced models of colitis. In the short-term therapeutic protocol, OAT-177 given intragastrically in a 30 mg/kg dose, twice daily, produced a significant (p < 0.001) anti-inflammatory effect, as shown by the macroscopic score. Additionally, OAT-177 significantly decreased TNF-α mRNA levels and MPO activity compared to DSS-only treated mice. Intraperitoneal administration of OAT-177 at a dose of 50 mg/kg caused statistically relevant reduction of the colon length. In the long-term therapeutic protocol, OAT-177 given intragastrically in a dose of 30 mg/kg, twice daily, significantly improved colon length and body weight compared to DSS-induced colitis. This is the first study proving that AMCase inhibitors may have therapeutic potential in the treatment of IBD.
Highlights
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic and relapsing intestinal disorders characterized by prolonged inflammation of the digestive tract
We demonstrate the efficacy of a selective murine acidic mammalian chitinase (AMCase) inhibitor, compound OAT-177, in the dextran sulfate sodium (DSS)-induced mouse models of colitis
The net result of such a compensation mechanism is an exacerbation of the disease observed at higher doses of mAMCase inhibitor
Summary
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic and relapsing intestinal disorders characterized by prolonged inflammation of the digestive tract. The precise etiology of IBD remains unknown despite ongoing studies. It is believed that besides the genetic and environmental factors, a dysregulated immune system, intestinal microbiota, and dysfunction in the mucosal barrier are involved [1,2]. Treatment strategies currently used in IBD rely mainly on reduction of inflammation by administration of aminosalicylates, corticosteroids, and immunomodulators, or inhibition of TNFα [3]. A significant proportion of patients are unresponsive or lose response to these traditional therapies.
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