Gastrin-releasing Peptide Receptor Antagonist Effects on an Animal Model of Sepsis

Dal‐Pizzol, Felipe; Leone, Luciane Pons Di; Ritter, Cristiane; Martins, Márcio Rodrigo; Reinke, Adalisa; Gelain, Daniel Pens; Zanotto-Filho, Alfeu; Souza, Luiz Carlos Bento de; Andrades, Michael Éverton; Barbeiro, Denise Frediani; Bernard, Elena Aida; Cammarota, Martı́n; Bevilaqua, Lia R.; Soriano, Francisco Garcia; Cláudio, José; Moreira, Fonseca; Roesler, Rafaël; Schwartsmann, Gilberto

doi:10.1164/rccm.200507-1118oc

Cited by 58 publications

(55 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, here we demonstrate the proinflammatory activity of the neuropeptide GRP. Our results also provide a unique candidate mechanism for the antiinflammatory effect of the GRPR antagonist RC-3095 in models of arthritis (9) and sepsis (10). We can also extend our model to explain the proinflammatory effect of GRP, because a GRP blocking agent effectively prevented asthma exacerbation in animal models (12).…”

Section: Discussionmentioning

confidence: 74%

“…Previous studies revealed an antiinflammatory effect of RC-3095 in murine arthritis (9) and sepsis models (10). This effect was attributed to the inhibition of IL-1β and TNF-α production.…”

Section: Neutrophil Migration Toward Synovial Fluid (Sf) Of Rheumatoidmentioning

confidence: 89%

“…It has been previously shown that GRPR antagonist RC-3095 has antiinflammatory activity in animal models of inflammation (9,10,16). We hypothesized that GRP could have proinflammatory potential, so we tested whether GRP would have a dose-dependent effect on neutrophil recruitment in vivo.…”

Section: Grp Induces Neutrophil Migration In Vivomentioning

confidence: 98%

See 2 more Smart Citations

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Czepielewski

Porto

Rizzo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC-β2, PI3K, ERK, p38 and independent of Gαi protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095. We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders.

show abstract

Section: Discussionmentioning

confidence: 74%

Section: Neutrophil Migration Toward Synovial Fluid (Sf) Of Rheumatoidmentioning

confidence: 89%

See 1 more Smart Citation

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Czepielewski

Porto

Rizzo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have demonstrated that increased BLP levels in baboons with BPD are directly linked to oxidant exposure, because treatment of animals with a novel antioxidant abrogates these increased BLP levels (18,44). Similarly, GRP may have a role in acute lung injury (16,45). In view of the fact that BPD is a multifactorial disorder, it remains surprising that several characteristic histopathologic features of BPD can be induced by a single peptide in a simple newborn mouse model.…”

Section: Discussionmentioning

confidence: 99%

Bombesin Inhibits Alveolarization and Promotes Pulmonary Fibrosis in Newborn Mice

Ashour

Lin

Lee

et al. 2006

Am J Respir Crit Care Med

View full text Add to dashboard Cite

Rationale: Bombesin-like peptides promote fetal lung development. Normally, levels of mammalian bombesin (gastrin-releasing peptide [GRP]) drop postnatally, but these levels are elevated in newborns that develop bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by arrested alveolarization. In premature baboons with BPD, antibombesin antibodies reduce lung injury and promote alveolarization. Objectives: The present study tests whether exogenous bombesin or GRP given perinatally alters alveolar development in newborn mice. Methods: Mice were given peptides intraperitoneally twice daily on Postnatal Days 1-3. On Day 14 lungs were inflation-fixed for histopathologic analyses of alveolarization. Measurements and Main Results: Bombesin had multiple effects on Day 14 lung, when alveolarization was about half complete. First, bombesin induced alveolar myofibroblast proliferation and increased alveolar wall thickness compared with saline-treated control animals. Second, bombesin diminished alveolarization in C57BL/6 (but not Swiss-Webster) mice. We used receptor-null mice to explore which receptors might mediate these effects. Compared with wild-type littermates, bombesin-treated GRP receptor (GRPR)-null mice had increased interstitial fibrosis but reduced defects in alveolarization. Neuromedin B (NMB) receptor-null and bombesin receptor subtype 3-null mice had the same responses as their wildtype littermates. GRP had the same effects as bombesin, whereas neither NMB nor a synthetic bombesin receptor type 3 ligand had any effect. All effects of GRP were abrogated in GRPR-null mice. Conclusions: Bombesin/GRP can induce features of BPD, including interstitial fibrosis and diminished alveolarization. GRPR appears to mediate all effects of GRP, but only part of the bombesin effect on alveolarization, suggesting that novel receptors may mediate some effects of bombesin in newborn lung.Keywords: bronchopulmonary dysplasia; gastrin-releasing peptide; interstitial fibrosis; knock-out mice Bombesin is a 14-amino acid peptide originally identified in 1971 by Erspamer in skin of the frog Bombina bombina (1-3). Using antibodies to amphibian bombesin, a 27-amino acid mammalian homolog was identified by McDonald and termed gastrinreleasing peptide (GRP) (4). GRP and bombesin share a highly conserved seven-amino acid C-terminus, which is required for immunogenicity and high-affinity binding to physiologic receptors. Thus, bombesin and GRP are referred to collectively as "bombesin-like peptides" (BLPs), because both peptides bind to and elicit the same physiologic effects at mammalian bombesin/ GRP-preferring receptors. BLP immunoreactivity is widely distributed in the central nervous system, the lung, and the gut, but the highest levels occur in mid-gestation human fetal lung (2, 5).During lung development, the first epithelial cells to differentiate are the pulmonary neuroendocrine cells (6, 7), which contain high levels of BLP immunoreactivity. BLP can promote growth and maturation of developing fetal lung in hum...

show abstract

“…[6][7][8][9] More recently, it has been reported that releasing of GRP closely related to the progression and severity of chronic inflammatory diseases, including RA, and administration of GRPR antagonist have anti-inflammatory effects in inflammation models. 7,[10][11][12] RC-3095 is a synthetic polypeptide BN/GRP antagonist with the MW of Chemical and Pharmaceutical Bulletin Advance Publication 1106.32. Studies showed that RC-3095 could be an attractive and safe candidate compound for future trials in GRPR-related diseases, including specific types of cancer and chronic inflammatory diseases.…”

Section: Gastrin-releasing Peptide (Grp) Is the Mammalian Homologue Omentioning

confidence: 99%

Anti-inflammatory Effects of a Small Molecule Gastrin-Releasing Peptide Receptor Antagonist on Adjuvant-Induced Rheumatoid Arthritis in Rats

Mei

Yao

et al. 2018

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

SummaryThe anti-inflammatory effects of (R)-2-(1H-imidazol-1-yl) ethyl-3-(1H-indol-3-yl)-2-(2-p-tolylacetamido)propanamide (RH-1402), a previous designed small molecule Gastrin releasing peptide (GRP) antagonist were evaluated in adjuvant-induced arthritic model of rats, and the inhibitory effect on neutrophil migration induced by GRP was determined by a transwell system experiment in vitro. The arthritis was induced by injection of Complete Freund's Adjuvant (CFA) containing 10 mg/mL of heat killed mycobacterium into the left hind footpad. Experimental rats were randomly divided into 6 groups, including control, placebo, positive control group, RH-1402 of low/middle/high dose group. Disease incidence and severity was evaluated through scoring of the paw edema and histologic features of joint synovial. Blood of all experimental rats was collected for IL-1β and TNF-α cytokine levels. A transwell system was used to investigate whether RH-1402 would inhibit neutrophils migrating up a gradient of GRP in vitro. RH-1402 (5 and 10mg/kg) significantly decreased adjuvant induced increased arthritis index during the administration period (days 14-20). Significant inhibition of joint synovial histological features can be found in the RH-1402 treated group, including alleviated Hyperplasia, Inflammatory of infiltration and activation of pannus formation. It also suppressed TNF-α and IL-1β level. 5mg/kg and 10mg/kg of RH-1402 significantly inhibited the effect of GRP on neutrophil migration with a dose dependent relationship. These findings indicate that RH-1402 have potential protective anti-inflammatory effects on experimental models of arthritis.

show abstract

Gastrin-releasing Peptide Receptor Antagonist Effects on an Animal Model of Sepsis

Abstract: 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.

Cited by 58 publications

References 31 publications

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Bombesin Inhibits Alveolarization and Promotes Pulmonary Fibrosis in Newborn Mice

Anti-inflammatory Effects of a Small Molecule Gastrin-Releasing Peptide Receptor Antagonist on Adjuvant-Induced Rheumatoid Arthritis in Rats

Contact Info

Product

Resources

About