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

Fabricia Petronilho, Francieli Vuolo, Galant LS, Larissa Constantino, Cristiane Daminai Tomasi, Giombelli VR, Claudio De Souza, Da Silva S, Barbeiro DF, Soriano FG, Emiilio Streck, Cristiane Ritter, Zanotto-Filho A, Mateus Augusto Pasquali, Gelain DP, Rybarczyk-Filho JL, José Claudio Moreira, Block NL, Rafael Roesler, Gilberto Schwartsmann, Schally AV, Felipe Dal-Pizzol

In sepsis, 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 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 LPS or TNF-α and, RC-3095 (10ng/ml). Male Wistar rats were subjected to CLP and RC-3095 was administered (3 mg/kg, subcutaneously); after 6 hours 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 SIRS or sepsis, GRP plasma levels were determined. RC-3095 inhibited TLR-4, ERK1/2, JNK, and Akt, decreased activation of AP-1, NF-kB and 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, 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.

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