Gastrin-releasing peptide receptor antagonism induces protection from lethal sepsis: Involvement of toll-like receptor 4 signaling

Fabricia Petronilho, Francieli Vuolo, Letícia Selinger Galant, Larissa Constantino, Cristiane Damiani Tomasi, Vinicius Renne Giombelli, Cláudio Teodoro de Souza, Sabrina D. da Silva, Denise Frediani Barbeiro, Francisco Garcia Soriano, Emílio Luiz Streck, Cristiane Ritter, Alfeu Zanotto-Filho, Matheus Augusto Pasquali, Daniel Pens Gelain, José Luiz Rybarczyk-Filho, José Cláudio Fonseca Moreira, Norman L. Block, Rafael Roesler, Gilberto SchwartsmannAndrew V. Schally, Felipe Dal-Pizzol

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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 NH2-terminal kinase (JNK) and Akt and decreased activation of activator protein 1 (AP-1), nuclear factor (NF)-αB 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.

Original languageEnglish (US)
Pages (from-to)1209-1219
Number of pages11
JournalMolecular Medicine
Volume18
Issue number8
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Petronilho, F., Vuolo, F., Galant, L. S., Constantino, L., Tomasi, C. D., Giombelli, V. R., de Souza, C. T., da Silva, S. D., Barbeiro, D. F., Soriano, F. G., Streck, E. L., Ritter, C., Zanotto-Filho, A., Pasquali, M. A., Gelain, D. P., Rybarczyk-Filho, J. L., Moreira, J. C. F., Block, N. L., Roesler, R., ... Dal-Pizzol, F. (2012). Gastrin-releasing peptide receptor antagonism induces protection from lethal sepsis: Involvement of toll-like receptor 4 signaling. Molecular Medicine, 18(8), 1209-1219. https://doi.org/10.2119/molmed.2012.00083