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

Experimental Physiopathology Laboratory, Universidade do Extremo Sul Catarinense, Criciúma; Departments of Biochemistry and Pharmacology, Institute for Basic Health Sciences, Graduate Program in Medical Sciences; Department of Internal Medicine, Academic Hospital, Federal University of Rio Grande do Sul; Center for Memory Research, Biomedical Research Institute, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre; and Department of Internal Medicine, Academic Hospital, São Paulo University, São Paulo, Brazil

Correspondence and requests for reprints should be addressed to Felipe Dal-Pizzol, M.D., Laboratório de Fisiopatologia Experimental, Universidade do Extremo Sul Catarinense, 1105, Avenida Universitária, 88006–000 Criciúma, SC, Brazil. E-mail: piz{at}unesc.net

Rationale: 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.

Objectives: 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.

Methods: 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- (TNF-), interleukin (IL)-1, IL-10, and nitric oxide release from activated macrophages.

Measurements and Main Results: The GRP antagonist attenuated LPS- or CLP-induced TNF-, IL-1, 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- and IL-1 levels and decreased myeloperoxidase activity in several organs.

Conclusions: 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.

Key Words: cytokine • gastrin-releasing peptide • lipopolysaccharide • macrophage • RC-3095

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