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

• Published in: American journal of respiratory and critical care medicine Vol. 173; no. 1; pp. 84 - 90
• Main Authors: Dal-Pizzol, Felipe, Di Leone, Luciane Pons, Ritter, Cristiane, Martins, Marcio Rodrigo, Reinke, Adalisa, Pens Gelain, Daniel, Zanotto-Filho, Alfeu, de Souza, Luiz Fernando, Andrades, Michael, Barbeiro, Denise Frediani, Bernard, Elena Aida, Cammarota, Martin, Bevilaqua, Lia R. M, Soriano, Francisco Garcia, Claudio, Jose, Moreira, Fonseca, Roesler, Rafael, Schwartsmann, Gilberto
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 01-01-2006; American Lung Association; American Thoracic Society
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Bombesin - analogs & derivatives; Bombesin - pharmacology; Bronchoalveolar Lavage Fluid - immunology; Cytokines - biosynthesis; Disease Models, Animal; Emergency and intensive care: infection, septic shock; Ileum - drug effects; Ileum - immunology; Intensive care medicine; Kidney - drug effects; Kidney - immunology; Liver - drug effects; Liver - immunology; Lung - drug effects; Lung - immunology; Macrophage Activation - drug effects; Macrophage Activation - immunology; Male; Medical sciences; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Wistar; Receptors, Bombesin - antagonists & inhibitors; Receptors, Bombesin - immunology; Respiratory Distress Syndrome, Adult - immunology; Sepsis - immunology; Infection; Sepsis syndrome; RC-3095; Animal model; Intensive care; Cytokine; gastrin-releasing peptide; Lipopolysaccharide; Resuscitation; Macrophage
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200507-1118OC

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.