title: 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.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yasuda
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kato
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamanaka
authors.forename: Maho
authors.initials: M
authors.lastname: Iimori
authors.forename: Daichi
authors.initials: D
authors.lastname: Utsumi
authors.forename: Yumeno
authors.initials: Y
authors.lastname: Kitahara
authors.forename: Kazumi
authors.initials: K
authors.lastname: Iwata
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Matsuno
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amagase
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000032:analysis; D053148:Caspase 3 / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis; D005472:Fluorouracil / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052016:Mucositis / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D017382:Reactive Oxygen Species / Q000378:metabolism; D012720:Severity of Illness Index; D015854:Up-Regulation / Q000187:drug effects; D015431:Weight Loss
chemical_list: D000964:Antimetabolites, Antineoplastic; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D016207:Cytokines; D017382:Reactive Oxygen Species; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; D005472:Fluorouracil