Pharmacological Targeting of Neutrophil Serine Proteases Prevents Lethality in Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice

Background and aims: In recent years the number of patients with inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis has been on the rise. Neutrophils are thought to be first cells to colonize disease-state colon tissue. Neutrophil elastase (NE) and cathepsin-G (Cat-G) are major secretory products from activated neutrophils and a major contributor to tissue destruction in inflammatory diseases. We predicted that inhibiting neutrophils and their proteases would improve ulcerative colitis. Methods: Acute colitis was induced in mice by oral administration of 2% DSS for 7 days. In the first experiment, an inhibitor of Gr-1, a key neutrophil protein, was administered. In the second, the respective antagonists for NE and Cat-G, proteinases secreted by neutrophils, were administered, and the conditions of DSS-induced colitis were evaluated for improvement. Blood samples were collected and analyzed for levels of cytokines. Results: The survival rate and pathology were improved in the Gr-1 inhibition experiments. In addition, administration of inhibitors of NE and Cat-G also resulted in clinical improvement. However, elevation of TNF-α, a key cytokine, was not suppressed in either experiment. Conclusion: The proteolytic environment of neutrophils is associated with colonic inflammation. Disruption of the neutrophil proteases NE and Cat-G might therefore be a strategy for treatment of colitis regardless of TNF-α suppression.