title: ExoU-induced redox imbalance and oxidative stress in airway epithelial cells during Pseudomonas aeruginosa pneumosepsis.
abstract: ExoU is a potent proinflammatory toxin produced by Pseudomonas aeruginosa, a major agent of severe lung infection and sepsis. Because inflammation is usually associated with oxidative stress, we investigated the effect of ExoU on free radical production and antioxidant defense mechanisms during the course of P. aeruginosa infection. In an experimental model of acute pneumonia, ExoU accounted for increased lipid peroxidation in mice lungs as soon as 3 h after intratracheal instillation of PA103 P. aeruginosa strain. The contribution of airway cells to the generation of a redox imbalance was assessed by in vitro tests carried out with A549 airway epithelial cells. Cultures infected with the ExoU-producing PA103 P. aeruginosa strain produced significantly increased concentrations of lipid hydroperoxides, 8-isoprostane, reactive oxygen intermediates, peroxynitrite and nitric oxide (NO), when compared to cells infected with exoU-deficient mutants. Overproduction of NO by PA103-infected cells likely resulted from overexpression of both inducible and endothelial NO synthase isoforms. PA103 infection was also associated with a significantly increased activity of superoxide dismutase (SOD) and decreased levels of reduced glutathione (GSH), a major antioxidant compound. Our findings unveil another potential mechanism of tissue damage during infection by ExoU-producing P. aeruginosa strains.
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade do Estado do Rio de Janeiro, Av. 28 de Setembro, 87, Fundos, 3° andar, Vila Isabel, Rio de Janeiro, RJ, 20.551-030, Brazil.
authors.forename: Luiz Gonzaga
authors.initials: LG
authors.lastname: da Cunha
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade do Estado do Rio de Janeiro, Av. 28 de Setembro, 87, Fundos, 3° andar, Vila Isabel, Rio de Janeiro, RJ, 20.551-030, Brazil.
authors.forename: Miriam Francisca
authors.initials: MF
authors.lastname: Ferreira
authors.affiliation: Laboratório de Farmacologia Celular e Molecular, Departamento de Biologia Celular, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: João Alfredo
authors.initials: JA
authors.lastname: de Moraes
authors.affiliation: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Patricia Alves
authors.initials: PA
authors.lastname: Reis
authors.affiliation: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Hugo Caire
authors.initials: HC
authors.lastname: Castro-Faria-Neto
authors.affiliation: Laboratório de Farmacologia Celular e Molecular, Departamento de Biologia Celular, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Christina
authors.initials: C
authors.lastname: Barja-Fidalgo
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade do Estado do Rio de Janeiro, Av. 28 de Setembro, 87, Fundos, 3° andar, Vila Isabel, Rio de Janeiro, RJ, 20.551-030, Brazil.
authors.forename: Maria-Cristina
authors.initials: MC
authors.lastname: Plotkowski
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade do Estado do Rio de Janeiro, Av. 28 de Setembro, 87, Fundos, 3° andar, Vila Isabel, Rio de Janeiro, RJ, 20.551-030, Brazil. alessandrasaliba@hotmail.com.
authors.forename: Alessandra Mattos
authors.initials: AM
authors.lastname: Saliba
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D015227:Lipid Peroxidation; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D018410:Pneumonia, Bacterial / Q000378:metabolism* / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000382:microbiology*; D018805:Sepsis; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001426:Bacterial Proteins; C111749:pseudomonas exoprotein A protein, Pseudomonas aeruginosa; D002374:Catalase; D013482:Superoxide Dismutase
keywords: ExoU; Lipid peroxidation; NO synthase; Oxidative stress; Pneumosepsis; Pseudomonas aeruginosa