Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice.

Abstract

Although NADPH oxidase 1 (NOX1) has been shown to be highly expressed in the gastrointestinal tract, the physiological and pathophysiological roles of this enzyme are not yet fully understood. In the present study, we investigated the role of NOX1 in the pathogenesis of intestinal mucositis induced by the cancer chemotherapeutic agent 5-fluorouracil (5-FU) in mice. Intestinal mucositis was induced in Nox1 knockout (Nox1KO) and littermate wild-type (WT) mice via single, daily administration of 5-FU for 5 days. In WT mice, 5-FU caused severe intestinal mucositis characterized by a shortening of villus height, a disruption of crypts, a loss of body weight, and diarrhea. In Nox1KO mice, however, the severity of mucositis was significantly reduced, particularly with respect to crypt disruption. The numbers of apoptotic caspase-3- and caspase-8-activated cells in the intestinal crypt increased 24 h after the first 5-FU administration but were overall significantly lower in Nox1KO than in WT mice. Furthermore, the 5-FU-mediated upregulation of TNF-α, IL-1β, and NOX1 and the production of reactive oxygen species were significantly attenuated in Nox1KO mice compared with that in WT mice. These findings suggest that NOX1 plays an important role in the pathogenesis of 5-FU-induced intestinal mucositis. NOX1-derived ROS production following administration of 5-FU may promote the apoptotic response through upregulation of inflammatory cytokines.

• Authors: Masashi Yasuda, Shinichi Kato, Naoki Yamanaka, Maho Iimori, Daichi Utsumi, Yumeno Kitahara, Kazumi Iwata, Kuniharu Matsuno, Kikuko Amagase, Chihiro Yabe-Nishimura, Koji Takeuchi
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 302 Issue 10 Pg. G1133-42 (May 15 2012) ISSN: 1522-1547 [Electronic] United States
• PMID: 22403796 (Publication Type: Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Cflar protein, mouse
• Cytokines
• Reactive Oxygen Species
• NADH, NADPH Oxidoreductases
• NADPH Oxidase 1
• NOX1 protein, mouse
• Casp3 protein, mouse
• Caspase 3
• Fluorouracil

Topics

• Animals
• Antimetabolites, Antineoplastic (adverse effects)
• CASP8 and FADD-Like Apoptosis Regulating Protein (analysis)
• Caspase 3 (analysis)
• Cytokines (biosynthesis)
• Fluorouracil (adverse effects)
• Intestinal Mucosa (drug effects, enzymology, pathology)
• Mice
• Mice, Knockout
• Mucositis (chemically induced, enzymology, pathology)
• NADH, NADPH Oxidoreductases (genetics, metabolism)
• NADPH Oxidase 1
• Reactive Oxygen Species (metabolism)
• Severity of Illness Index
• Up-Regulation (drug effects)
• Weight Loss