Role of phospholipase A(2) and tyrosine kinase in Clostridium difficile toxin A-induced disruption of epithelial integrity, histologic inflammatory damage and intestinal secretion

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dc.contributor.authorLima, Aldo A. M.
dc.contributor.authorNascimento, Nilberto R. F.
dc.contributor.authorFang, Guodong D.
dc.contributor.authorYotseff, Peter
dc.contributor.authorToyama, M. H. [UNESP]
dc.contributor.authorGuerrant, Richard L.
dc.contributor.authorFonteles, Manasses C.
dc.contributor.institutionUniversity of Virginia (UVA)
dc.contributor.institutionUniversidade Federal do Ceará (UFC)
dc.contributor.institutionUniv Estadual Ceara
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUniv Prebiteriana Mackenzie
dc.date.accessioned2014-05-20T13:12:22Z
dc.date.available2014-05-20T13:12:22Z
dc.date.issued2008-10-01
dc.description.abstractClostridium difficile-associated disease causes diarrhea to fulminant colitis and death. We investigated the role of phospholipase A(2) (PLA(2)) inhibitors, aristolochic acid (AA), bromophenacyl bromide BPB and quinacrine (QUIN) on the C. difficile toxin A-induced disruption of epithelial integrity, histologic inflammatory damage and intestinal secretion. Toxin A caused severe hemorrhagic and inflammatory fluid secretion at 6-8 h in rabbit ileal segments, an effect that was significantly inhibited by QUIN (71%, P < 0.01), AA (87%, P < 0.0001) or by BPB (51%, P < 0.01). The secretory effect of toxin A was also inhibited in segments adjacent to those with AA (89%, P < 0.01). Furthermore, QUIN or AA substantially reduced the histologic damage seen after 6-8 h in rabbit ileal segments. The cyclooxygenase inhibitor, indomethacin, also significantly inhibited (96%; n = 6) the secretory effects of toxin A in ligated rabbit intestinal segments. The destruction by toxin A of F-actin at the light junctions of T-84 cell monolayers was not inhibited by AA or BPB. AA or QUIN had no effect on the T-84 cell tissue resistance reduction over 8-24 h after toxin A exposure. All the inhibitors were shown to be effective in the doses administered direct in ileal loops to inhibit PLA(2) activity. The data suggest that PLA(2) is involved in the major pathway of toxin A-induced histologic inflammatory damage and hemorrhagic fluid secretion. Cop. right (C) 2008 John Wiley & Sons, Ltd.en
dc.description.affiliationUniv Virginia, Div Infect Dis & Int Hlth, Sch Med, Charlottesville, VA 22908 USA
dc.description.affiliationUniversidade Federal do Ceará (UFC), Clin Res Unit, Fortaleza, Ceara, Brazil
dc.description.affiliationUniversidade Federal do Ceará (UFC), Inst Biomed, Ctr Global Hlth, Fortaleza, Ceara, Brazil
dc.description.affiliationUniv Estadual Ceara, Vet Coll, Fortaleza, Ceara, Brazil
dc.description.affiliationUniv Estadual Ceara, Super Inst Biomed, Fortaleza, Ceara, Brazil
dc.description.affiliationUNESP, Unidade Sao Vicente, Sao Vicente, SP, Brazil
dc.description.affiliationUniv Prebiteriana Mackenzie, São Paulo, Brazil
dc.description.affiliationUnespUNESP, Unidade Sao Vicente, Sao Vicente, SP, Brazil
dc.description.sponsorshipRocke-feller Foundation (USA)
dc.description.sponsorshipNational Research Council (CNOq-Brazil)
dc.description.sponsorshipNIH (USA)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipIdNIH: T32-A107046
dc.format.extent849-857
dc.identifierhttp://dx.doi.org/10.1002/jat.1348
dc.identifier.citationJournal of Applied Toxicology. Chichester: John Wiley & Sons Ltd, v. 28, n. 7, p. 849-857, 2008.
dc.identifier.doi10.1002/jat.1348
dc.identifier.issn0260-437X
dc.identifier.lattes8573195327542061
dc.identifier.urihttp://hdl.handle.net/11449/345
dc.identifier.wosWOS:000260072900004
dc.language.isoeng
dc.publisherJohn Wiley & Sons Ltd
dc.relation.ispartofJournal of Applied Toxicology
dc.relation.ispartofjcr2.909
dc.rights.accessRightsAcesso restrito
dc.sourceWeb of Science
dc.subjectPLA(2)en
dc.subjecttoxin A enterotoxinen
dc.subjectC. difficileen
dc.subjectPLA(2) inhibitorsen
dc.subjectdiarrheaen
dc.subjectGTPasesen
dc.subjectF-actinen
dc.subjecttight junctionsen
dc.subjectcytoskeleton disruptionen
dc.subjecterbstatinen
dc.titleRole of phospholipase A(2) and tyrosine kinase in Clostridium difficile toxin A-induced disruption of epithelial integrity, histologic inflammatory damage and intestinal secretionen
dc.typeArtigo
dcterms.licensehttp://olabout.wiley.com/WileyCDA/Section/id-406071.html
dcterms.rightsHolderJohn Wiley & Sons Ltd
unesp.author.lattes8573195327542061
unesp.campusUniversidade Estadual Paulista (Unesp), Instituto de Biociências, São Vicentept

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Artigos - Ciências Biológicas - São Vicente