title: Role of platelet-activating factor in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice.
abstract: OBJECTIVE
  Gastrointestinal mucositis is a common side effect of cancer chemotherapy. Platelet-activating factor (PAF) is produced during gut inflammation. There is no evidence that PAF participates in antineoplastic-induced intestinal mucositis. This study evaluated the role of PAF in 5-fluorouracil (5-FU)-induced intestinal mucositis using a pharmacological approach and PAF receptor knockout mice (PAFR(-/-)).
  
  
  METHODS
  Wild-type mice or PAFR(-/-) mice were treated with 5-FU (450 mg/kg, i.p.). Other mice were treated with saline or BN52021 (20 mg/kg, s.c.), an antagonist of the PAF receptor, once daily followed by 5-FU administration. After the third day of treatment, animals were sacrificed and tissue samples from the duodenum were removed for morphologic evaluation. In addition, myeloperoxidase activity and the cytokine concentration were measured.
  
  
  RESULTS
  5-FU treatment decreased the duodenal villus height/crypt depth ratio, increased MPO activity, and increased the concentration of TNF-α, IL-1β and KC in comparison with saline-treated animals. In PAFR(-/-) mice and PAFR antagonist-treated mice, 5-FU-dependent intestinal damage was reduced and a decrease in duodenal villus height/crypt depth ratio was attenuated. However, the 5-FU-dependent increase in duodenum MPO activity was not affected. Without PAFR activation, 5-FU treatment did not increase the TNF-α, IL-1β and KC concentration.
  
  
  CONCLUSIONS
  In conclusion, our study establishes the role of PAFR activation in 5-FU-induced intestinal mucositis. This study implicates treatment with PAFR antagonists as novel therapeutic strategy for this condition.
authors.affiliation: Department of Morphology, Federal University of Ceara, Fortaleza, CE, Brazil. pedrogsoares@ufc.br
authors.forename: Pedro M G
authors.initials: PM
authors.lastname: Soares
authors.forename: Roberto C P
authors.initials: RC
authors.lastname: Lima-Junior
authors.forename: José Maurício S C
authors.initials: JM
authors.lastname: Mota
authors.forename: Priscilla F C
authors.initials: PF
authors.lastname: Justino
authors.forename: Gerly Anne C
authors.initials: GA
authors.lastname: Brito
authors.forename: Ronaldo A
authors.initials: RA
authors.lastname: Ribeiro
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Marcellus H L P
authors.initials: MH
authors.lastname: Souza
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D005472:Fluorouracil / Q000633:toxicity*; D046934:Ginkgolides / Q000494:pharmacology; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000473:pathology*; D007413:Intestinal Mucosa / Q000473:pathology; D007783:Lactones / Q000494:pharmacology; D007958:Leukocyte Count; D007970:Leukopenia / Q000097:blood / Q000139:chemically induced; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D052016:Mucositis / Q000139:chemically induced* / Q000473:pathology*; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D046934:Ginkgolides; D007783:Lactones; D010972:Platelet Activating Factor; C045856:ginkgolide B; D009195:Peroxidase; D017479:Receptors, Platelet-Derived Growth Factor; D005472:Fluorouracil