Role of platelet-activating factor in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice.

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(-/-)).
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.
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.
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.
AuthorsPedro M G Soares, Roberto C P Lima-Junior, José Maurício S C Mota, Priscilla F C Justino, Gerly Anne C Brito, Ronaldo A Ribeiro, Fernando Q Cunha, Marcellus H L P Souza
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 68 Issue 3 Pg. 713-20 (Sep 2011) ISSN: 1432-0843 [Electronic] Germany
PMID21153821 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimetabolites, Antineoplastic
  • Cytokines
  • Ginkgolides
  • Lactones
  • Platelet Activating Factor
  • ginkgolide B
  • Peroxidase
  • Receptors, Platelet-Derived Growth Factor
  • Fluorouracil
  • Animals
  • Antimetabolites, Antineoplastic (toxicity)
  • Cytokines (metabolism)
  • Duodenum (metabolism)
  • Fluorouracil (toxicity)
  • Ginkgolides (pharmacology)
  • Intestinal Diseases (chemically induced, pathology)
  • Intestinal Mucosa (pathology)
  • Lactones (pharmacology)
  • Leukocyte Count
  • Leukopenia (blood, chemically induced)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mucositis (chemically induced, pathology)
  • Peroxidase (metabolism)
  • Platelet Activating Factor (antagonists & inhibitors, genetics, physiology)
  • Receptors, Platelet-Derived Growth Factor (genetics)

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