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Gastrin-releasing Peptide Receptor Antagonist Effects on an Animal Model of Sepsis

2005; American Thoracic Society; Volume: 173; Issue: 1 Linguagem: Inglês

10.1164/rccm.200507-1118oc

1535-4970

Felipe Dal‐Pizzol, Luciane Pons Di Leone, Cristiane Ritter, Márcio R. Martins, Adalisa Reinke, Daniel Pens Gelain, Alfeu Zanotto‐Filho, Luiz Fernando de Souza, Michael Éverton Andrades, Denise Frediani Barbeiro, Elena Aida Bernard, Martı́n Cammarota, Lia R. Bevilaqua, Francisco García Soriano, José Cláudio, Fonseca Moreira, Rafael Roesler, Gilberto Schwartsmann,

Inflammation biomarkers and pathways

Several new therapeutic strategies have been described for the treatment of sepsis, but to date none are related to alterations in the bombesin/gastrin-releasing peptide (GRP) receptor pathways.To determine the effects of a selective GRP receptor antagonist, RC-3095, on cytokine release from macrophages and its in vivo effects in the cecal ligation and puncture (CLP) model of sepsis and in acute lung injury induced by intratracheal instillation of LPS.We determined the effects of RC-3095 in the CLP model of sepsis and in acute lung injury induced by intratracheal instillation of LPS. In addition, we determined the effects of RC-3095 on tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-10, and nitric oxide release from activated macrophages.The GRP antagonist attenuated LPS- or CLP-induced TNF-alpha, IL-1beta, and nitric oxide release in cultured macrophages and decreased the mRNA levels of inducible nitric oxide synthase. The administration of RC-3095 (0.3 mg/kg) 6 h after sepsis induction improved survival in the CLP model, and diminished lung damage after intratracheal instillation of LPS. These effects were associated with attenuation on the circulating TNF-alpha and IL-1beta levels and decreased myeloperoxidase activity in several organs.We report that a selective GRP receptor antagonist attenuates the release of proinflammatory cytokines in vitro and in vivo and improves survival in "established" sepsis. These are consistent with the involvement of a new inflammatory pathway relevant to the development of sepsis.