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

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Abstract

Purpose

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.

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Acknowledgments

The authors gratefully acknowledge the financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil) and the technical assistance of Maria Silvandira Freire França. Drs. Brito, Ribeiro, Cunha, and Souza, who are recipients of CNPq fellowship.

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Authors and Affiliations

  1. Department of Morphology, School of Medicine, Federal University of Ceara, Rua Delmiro de Farias, s/n, Rodolfo Teófilo, Fortaleza, CE, 60.416-030, Brazil

    Pedro M. G. Soares & Gerly Anne C. Brito

  2. Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceara (UFC), Fortaleza, CE, Brazil

    Pedro M. G. Soares, Roberto C. P. Lima-Junior, José Maurício S. C. Mota, Priscilla F. C. Justino, Ronaldo A. Ribeiro & Marcellus H. L. P. Souza

  3. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Fernando Q. Cunha

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  1. Pedro M. G. Soares
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  8. Marcellus H. L. P. Souza
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Correspondence to Pedro M. G. Soares.

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Soares, P.M.G., Lima-Junior, R.C.P., Mota, J.M.S.C. et al. Role of platelet-activating factor in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice. Cancer Chemother Pharmacol 68, 713–720 (2011). https://doi.org/10.1007/s00280-010-1540-5

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  • DOI: https://doi.org/10.1007/s00280-010-1540-5

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