Gastrin-releasing peptide receptor antagonism induces protection from lethal sepsis: involvement of toll-like receptor 4 signaling.
In sepsis, toll-like receptor (TLR)-4 modulates the migration of neutrophils to infectious foci, favoring bacteremia and mortality. In experimental sepsis, organ dysfunction and cytokines released by activated macrophages can be reduced by gastrin-releasing peptide (GRP) receptor (GRPR) antagonist RC-3095. Here we report a link between GRPR and TLR-4 in experimental models and in sepsis patients. RAW 264.7 culture cells were exposed to lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α and RC-3095 (10 ng/mL). Male Wistar rats were subjected to cecal ligation and puncture (CLP), and RC-3095 was administered (3 mg/kg, subcutaneously); after 6 h, we removed the blood, bronchoalveolar lavage, peritoneal lavage and lung. Human patients with a clinical diagnosis of sepsis received a continuous infusion with RC-3095 (3 mg/kg, intravenous) over a period of 12 h, and plasma was collected before and after RC-3095 administration and, in a different set of patients with systemic inflammatory response syndrome (SIRS) or sepsis, GRP plasma levels were determined. RC-3095 inhibited TLR-4, extracellular-signal-related kinase (ERK)-1/2, Jun NH(2)-terminal kinase (JNK) and Akt and decreased activation of activator protein 1 (AP-1), nuclear factor (NF)-κB and interleukin (IL)-6 in macrophages stimulated by LPS. It also decreased IL-6 release from macrophages stimulated by TNF-α. RC-3095 treatment in CLP rats decreased lung TLR-4, reduced the migration of cells to the lung and reduced systemic cytokines and bacterial dissemination. Patients with sepsis and systemic inflammatory response syndrome have elevated plasma levels of GRP, which associates with clinical outcome in the sepsis patients. These findings highlight the role of GRPR signaling in sepsis outcome and the beneficial action of GRPR antagonists in controlling the inflammatory response in sepsis through a mechanism involving at least inhibition of TLR-4 signaling.
Graduate Program in Health Sciences, Universidade do Sul de Santa Catarina, Tubarão, Brazil.
Fabricia
F
Petronilho
Francieli
F
Vuolo
Letícia Selinger
LS
Galant
Larissa
L
Constantino
Cristiane Damiani
CD
Tomasi
Vinicius Renne
VR
Giombelli
Cláudio Teodoro
CT
de Souza
Sabrina
S
da Silva
Denise Frediani
DF
Barbeiro
Francisco Garcia
FG
Soriano
Emílio Luiz
EL
Streck
Cristiane
C
Ritter
Alfeu
A
Zanotto-Filho
Matheus Augusto
MA
Pasquali
Daniel Pens
DP
Gelain
José Luiz
JL
Rybarczyk-Filho
José Cláudio Fonseca
JC
Moreira
Norman L
NL
Block
Rafael
R
Roesler
Gilberto
G
Schwartsmann
Andrew V
AV
Schally
Felipe
F
Dal-Pizzol
D000328:Adult; D000818:Animals; D001839:Bombesin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D019886:Gastrin-Releasing Peptide / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism
D018925:Chemokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D012333:RNA, Messenger; D018004:Receptors, Bombesin; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D019886:Gastrin-Releasing Peptide; D001839:Bombesin