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- Title
Gastrin-Releasing Peptide Receptor Antagonism Induces Protection from Lethal Sepsis: Involvement of Toll-like Receptor 4 Signaling.
- Authors
Petronilho, Fabricia; Vuolo, Francieli; Galant, Letícia Selinger; Constantino, Larissa; Tomasi, Cristiane Damiani; Giombelli, Vinicius Renne; de Souza, Cláudio Teodoro; da Silva, Sabrina; Barbeiro, Denise Frediani; Soriano, Francisco Garcia; Streck, Emílio Luiz; Ritter, Cristiane; Zanotto-Filho, Alfeu; Pasquali, Matheus Augusto; Gelain, Daniel Pens; Rybarczyk-Filho, José Luiz; Moreira, José Cláudio Fonseca; Block, Norman L.; Roesler, Rafael; Schwartsmann, Gilberto
- 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)-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.
- Subjects
DRUG antagonism; SEPSIS; MACROPHAGE activation; TOLL-like receptors; CYTOKINE genetics
- Publication
Molecular Medicine, 2012, Vol 18, Issue 8, p1209
- ISSN
1076-1551
- Publication type
Article
- DOI
10.2119/molmed.2012.00083