Gastrin-releasing peptide receptor antagonist effects on an animal model of sepsis.
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.
Dal-Pizzol
Felipe
F
Laboratório de Fisiopatologia Experimental, Universidade do Extremo Sul Catarinense, 1105, Avenida Universitária, 88006-000 Criciúma, SC, Brazil. piz@unesc.net
Di Leone
Luciane Pons
LP
Ritter
Cristiane
C
Martins
Márcio Rodrigo
MR
Reinke
Adalisa
A
Pens Gelain
Daniel
D
Zanotto-Filho
Alfeu
A
de Souza
Luiz Fernando
LF
Andrades
Michael
M
Barbeiro
Denise Frediani
DF
Bernard
Elena Aida
EA
Cammarota
Martin
M
Bevilaqua
Lia R M
LR
Soriano
Francisco Garcia
FG
Cláudio
José
J
Moreira
Fonseca
F
Roesler
Rafael
R
Schwartsmann
Gilberto
G
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*
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