Neutrophil recruitment is critical for 5-fluorouracil-induced diarrhea and the decrease in aquaporins in the colon

Area of Science:

• Gastroenterology
• Oncology
• Immunology

Background:

• Diarrhea is a common chemotherapy side effect, particularly with 5-fluorouracil (5-FU).
• The exact mechanisms of 5-FU-induced diarrhea are not fully understood.
• Neutrophils are implicated in inflammatory conditions.

Purpose of the Study:

• To investigate the role of neutrophils in 5-fluorouracil (5-FU)-induced diarrhea.
• To explore the impact of neutrophil elastase and CXCR2 antagonism on 5-FU-induced gastrointestinal side effects.

Main Methods:

• Mice were treated with 5-fluorouracil (5-FU) to induce diarrhea.
• Neutrophil elastase inhibitor (Sivelestat sodium) and CXCR2 antagonist (SB225002) were administered.
• Gene expression of aquaporins (AQP 4, 8), chemokines (CXCL1-3), and neutrophil markers (Elane, MPO) was analyzed.
• Neutrophil infiltration in the colon was quantified using flow cytometry.

Main Results:

• 5-FU induced diarrhea and reduced colonic AQP 4 and 8 expression.
• 5-FU significantly increased neutrophil markers (Elane, MPO) and neutrophil infiltration in the colon.
• Sivelestat sodium and SB225002 inhibited neutrophil recruitment and normalized AQP 4 and 8 levels.
• These treatments also reduced 5-FU-induced body weight loss and diarrhea.

Conclusions:

• Neutrophil recruitment and neutrophil elastase play a critical role in 5-FU-induced diarrhea.
• Decreased aquaporin levels in the colon contribute to the pathophysiology of 5-FU side effects.
• Targeting neutrophil activity may offer a therapeutic strategy for managing chemotherapy-induced diarrhea.