Gastrin-releasing Peptide Receptor Antagonist Effects on an Animal Model of Sepsis
| Autor: | Luiz Fernando de Souza, Francisco Garcia Soriano, Michael Everton Andrades, Elena Aida Bernard, Lia R. M. Bevilaqua, Luciane Pons Di Leone, Rafael Roesler, Daniel Pens Gelain, Márcio R. Martins, Denise Frediani Barbeiro, Fonseca Moreira, Gilberto Schwartsmann, Cristiane Ritter, Alfeu Zanotto-Filho, Adalisa Reinke, Martín Cammarota, Felipe Dal-Pizzol, José Cláudio |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Pulmonary and Respiratory Medicine medicine.medical_specialty medicine.drug_class Anti-Inflammatory Agents Lung injury Kidney Critical Care and Intensive Care Medicine Nitric oxide chemistry.chemical_compound Ileum Sepsis Gastrin-releasing peptide Internal medicine Gastrin-releasing peptide receptor medicine Animals Rats Wistar Lung Respiratory Distress Syndrome biology business.industry Bombesin Macrophage Activation Receptor antagonist Peptide Fragments Rats Receptors Bombesin Nitric oxide synthase Disease Models Animal Endocrinology Liver chemistry biology.protein Cytokines Tumor necrosis factor alpha business Bronchoalveolar Lavage Fluid hormones hormone substitutes and hormone antagonists |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine. 173:84-90 |
| ISSN: | 1535-4970 1073-449X |
| DOI: | 10.1164/rccm.200507-1118oc |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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