title: Neutrophil recruitment is critical for 5-fluorouracil-induced diarrhea and the decrease in aquaporins in the colon.
abstract: Diarrhea is a common side effect experienced by cancer patients undergoing clinical chemotherapy, such as with 5-fluorouracil (5-FU). However, the precise mechanisms underlying 5-FU-induced diarrhea remain unclear. In the present study, we examined the role of neutrophil in 5-FU-induced diarrhea. Mice were given 5-FU (50mg/kg, i.p.) daily for 4 days. Sivelestat sodium (100 or 300 mg/kg, i.p., neutorophil elastase inhibitor) or SB225002 (3 or 9 mg/kg, i.p., CXCR2 antagonist) was administered before the administration of 5-FU. Gene expression levels of aquaporin (AQP) 4 and 8, CXCL1, CXCL2, CXCL3, neutrophil elastase (Elane) and myeloperoxidase (MPO) in the colon were examined by real-time RT-PCR. The neutrophil (Ly-6G positive cell) number in the mucosa of colon was measured by flow-cytometric analysis. Administration of 5-FU induced diarrhea and decreased the expression levels of AQP 4 and 8 in the colon. Under the present conditions, the expression levels of CXCL1, CXCL2, CXCL3, the neutrophil markers Elane and MPO, as well as Ly-6G-positive neutrophils, in the colon were significantly increased by 5-FU. Neutrophil recruitment with decreased levels of AQP 4 and 8 were dramatically inhibited by either sivelestat sodium or SB225002. Furthermore, these reagents reduced the 5-FU-induced body weight loss and diarrhea. These findings provide evidence that neutrophil recruitment and neutrophil elastase may decrease the levels of AQP 4 and 8 in the colon of mice treated with 5-FU and contribute to the pathophysiology of 5-FU-induced body weight loss and diarrhea.
authors: Department of Pharmacology, Hoshi University, Tokyo, Japan; Division of Pharmacy Professional Development and Research, Hoshi University, Tokyo, Japan. Electronic address: sakai@hoshi.ac.jp.
authors: Hiroyasu
authors: H
authors: Sakai
authors: Department of Pharmacology, Hoshi University, Tokyo, Japan.
authors: Atsunobu
authors: A
authors: Sagara
authors: Department of Pharmacology, Hoshi University, Tokyo, Japan; Laboratory of Pharmacology, Josai International University, Chiba, Japan; Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors: Kenjiro
authors: K
authors: Matsumoto
authors: Department of Pharmacology, Hoshi University, Tokyo, Japan.
authors: Ara
authors: A
authors: Jo
authors: Department of Pharmacology, Hoshi University, Tokyo, Japan.
authors: Akiko
authors: A
authors: Hirosaki
authors: Department of Pharmacology, Hoshi University, Tokyo, Japan.
authors: Kazuhide
authors: K
authors: Takase
authors: Department of Pharmacology, Hoshi University, Tokyo, Japan.
authors: Ryoto
authors: R
authors: Sugiyama
authors: Department of Pharmacology, Hoshi University, Tokyo, Japan; Division of Pharmacy Professional Development and Research, Hoshi University, Tokyo, Japan.
authors: Ken
authors: K
authors: Sato
authors: Department of Pharmacology, Hoshi University, Tokyo, Japan.
authors: Daigo
authors: D
authors: Ikegami
authors: Laboratory of Pharmacology, Josai International University, Chiba, Japan.
authors: Syunji
authors: S
authors: Horie
authors: Department of Palliative Medicine and Psychooncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors: Motohiro
authors: M
authors: Matoba
authors: Department of Pharmacology, Hoshi University, Tokyo, Japan. Electronic address: narita@hoshi.ac.jp.
authors: Minoru
authors: M
authors: Narita
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D051401:Aquaporin 4 / Q000235:genetics; D020346:Aquaporins / Q000235:genetics; D054360:Chemokine CXCL1 / Q000235:genetics; D054426:Chemokine CXCL2 / Q000235:genetics; D019743:Chemokines, CXC / Q000235:genetics; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology; D005472:Fluorouracil / Q000009:adverse effects*; D019272:Leukocyte Elastase / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D009195:Peroxidase / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D020346:Aquaporins; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C577095:Cxcl3 protein, mouse; D012333:RNA, Messenger; C108330:aquaporin 8; D009195:Peroxidase; D019272:Leukocyte Elastase; D005472:Fluorouracil
keywords: 5-Fluorouracil; Aquaporin; Colon; Diarrhea; Neutrophil elastase; Neutrophil recruitment