title: Gastrin-releasing peptide receptor antagonist effects on an animal model of sepsis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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-alpha (TNF-alpha), interleukin (IL)-1beta, IL-10, and nitric oxide release from activated macrophages.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Laboratório de Fisiopatologia Experimental, Universidade do Extremo Sul Catarinense, 1105, Avenida Universitária, 88006-000 Criciúma, SC, Brazil. piz@unesc.net
authors.forename: Felipe
authors.initials: F
authors.lastname: Dal-Pizzol
authors.forename: Luciane Pons
authors.initials: LP
authors.lastname: Di Leone
authors.forename: Cristiane
authors.initials: C
authors.lastname: Ritter
authors.forename: Márcio Rodrigo
authors.initials: MR
authors.lastname: Martins
authors.forename: Adalisa
authors.initials: A
authors.lastname: Reinke
authors.forename: Daniel
authors.initials: D
authors.lastname: Pens Gelain
authors.forename: Alfeu
authors.initials: A
authors.lastname: Zanotto-Filho
authors.forename: Luiz Fernando
authors.initials: LF
authors.lastname: de Souza
authors.forename: Michael
authors.initials: M
authors.lastname: Andrades
authors.forename: Denise Frediani
authors.initials: DF
authors.lastname: Barbeiro
authors.forename: Elena Aida
authors.initials: EA
authors.lastname: Bernard
authors.forename: Martin
authors.initials: M
authors.lastname: Cammarota
authors.forename: Lia R M
authors.initials: LR
authors.lastname: Bevilaqua
authors.forename: Francisco Garcia
authors.initials: FG
authors.lastname: Soriano
authors.forename: José
authors.initials: J
authors.lastname: Cláudio
authors.forename: Fonseca
authors.initials: F
authors.lastname: Moreira
authors.forename: Rafael
authors.initials: R
authors.lastname: Roesler
authors.forename: Gilberto
authors.initials: G
authors.lastname: Schwartsmann
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001839:Bombesin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D007082:Ileum / Q000187:drug effects / Q000276:immunology; D007668:Kidney / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors* / Q000276:immunology; D012128:Respiratory Distress Syndrome / Q000276:immunology*; D018805:Sepsis / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D010446:Peptide Fragments; D018004:Receptors, Bombesin; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D001839:Bombesin