Contractile effect of bombesin on guinea pig lung in vitro: involvement of gastrin-releasing peptide-preferring receptors

Lach, Estelle; Haddad, El-Bdaoui; Gies, Jean-Pierre

doi:10.1152/ajplung.1993.264.1.l80

Cited by 24 publications

(23 citation statements)

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“…Direct effects are also likely in airway smooth muscle constriction (21,22), endothelial cell activation and angiogenesis (20,41), and epithelial cell and fibroblast proliferation (6, 31, 52) during remodeling. Indirect effects due to increased cytokine production could occur in parallel, some cytokines being secreted earlier due to direct binding of GRP to GRPR on target cells, amplifying proinflammatory signals via multiple cytokinespecific receptors.…”

Section: Discussionmentioning

confidence: 99%

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RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

Zhou¹,

Potts

Cuttitta

et al. 2011

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

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Gastrin-releasing peptide (GRP) is synthesized by pulmonary neuroendocrine cells in inflammatory lung diseases, such as bronchopulmonary dysplasia (BPD). Many BPD infants develop asthma, a serious disorder of intermittent airway obstruction. Despite extensive research, early mechanisms of asthma remain controversial. The incidence of asthma is growing, now affecting >300 million people worldwide. To test the hypothesis that GRP mediates asthma, we used two murine models: ozone exposure for air pollution-induced airway hyperreactivity (AHR), and ovalbumin (OVA)-induced allergic airway disease. BALB/c mice were given small molecule GRP blocking agent 77427, or GRP blocking antibody 2A11, before exposure to ozone or OVA challenge. In both models, GRP blockade abrogated AHR and bronchoalveolar lavage (BAL) macrophages and granulocytes, and decreased BAL cytokines implicated in asthma, including those typically derived from Th1 (e.g., IL-2, TNFα), Th2 (e.g., IL-5, IL-13), Th17 (IL-17), macrophages (e.g., MCP-1, IL-1), and neutrophils (KC = IL-8). Dexamethasone generally had smaller effects on all parameters. Macrophages, T cells, and neutrophils express GRP receptor (GRPR). GRP blockade diminished serine phosphorylation of GRPR with ozone or OVA. Thus, GRP mediates AHR and airway inflammation in mice, suggesting that GRP blockade is promising as a broad-spectrum therapeutic approach to treat and/or prevent asthma in humans.

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Section: Discussionmentioning

confidence: 99%

“…Several observations led to our hypothesis that GRP contributes to asthma. Bombesin and GRP are potent, immediate bronchoconstrictors, 10-fold more potent than substance P and 100-fold more than histamine in vitro (21,22). In guinea pigs, systemic immunization elicits PNEC hyperplasia, and PNEC degranulation follows aerosol challenge (23).…”

mentioning

confidence: 99%

RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

Zhou¹,

Potts

Cuttitta

et al. 2011

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

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“…Our observations are consistent with numerous pharmacokinetic studies indicating that GRP and bombesin are nearly identical in mammalian systems, due to their shared bioactive amidated carboxyterminal sequence, both binding to the same high-affinity bombesin/GRP-preferring receptor. In fact, amphibian bombesin binds to and functions better at the mammalian bombesin/GRP receptor than does GRP itself, probably due to conformational differences related to its smaller molecular weight that permit greater access to the cell-surface GRPR in tissues (23)(24)(25). Three of the four amino acids required for high-affinity bombesin binding to GRPR are also required for high-affinity GRP binding (34,35).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, amphibian bombesin binds and functions approximately fourfold better than GRP itself at the mammalian bombesin/GRP receptor, apparently due to conformational differences related to its lower molecular weight that permit greater access to GRPR cell-surface receptors in tissues (23)(24)(25). Cumulatively, these observations provided our rationale for choosing bombesin as well as GRP for the present studies.…”

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confidence: 95%

Bombesin Inhibits Alveolarization and Promotes Pulmonary Fibrosis in Newborn Mice

Ashour

Lin

Lee

et al. 2006

Am J Respir Crit Care Med

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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...

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“…Whether these in vivo effects are mediated by a direct effect on ASM contraction is not completely clear as GRP blockage also abrogates the inflammatory response. However, GRP contracts ASM more potently than substance P, a prototypical spasmogen (Lach et al 1993).…”

Section: Stomach and Intestinesmentioning

confidence: 91%

Endocrine regulation of airway contractility is overlooked

Bossé

2014

Journal of Endocrinology

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Asthma is a prevalent respiratory disorder triggered by a variety of inhaled environmental factors, such as allergens, viruses, and pollutants. Asthma is characterized by an elevated activation of the smooth muscle surrounding the airways, as well as a propensity of the airways to narrow excessively in response to a spasmogen (i.e. contractile agonist), a feature called airway hyperresponsiveness. The level of airway smooth muscle (ASM) activation is putatively controlled by mediators released in its vicinity. In asthma, many mediators that affect ASM contractility originate from inflammatory cells that are mobilized into the airways, such as eosinophils. However, mounting evidence indicates that mediators released by remote organs can also influence the level of activation of ASM, as well as its level of responsiveness to spasmogens and relaxant agonists. These remote mediators are transported through circulating blood to act either directly on ASM or indirectly via the nervous system by tuning the level of cholinergic activation of ASM. Indeed, mediators generated from diverse organs, including the adrenals, pancreas, adipose tissue, gonads, heart, intestines, and stomach, affect the contractility of ASM. Together, these results suggest that, apart from a paracrine mode of regulation, ASM is subjected to an endocrine mode of regulation. The results also imply that defects in organs other than the lungs can contribute to asthma symptoms and severity. In this review, I suggest that the endocrine mode of regulation of ASM contractility is overlooked.

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Contractile effect of bombesin on guinea pig lung in vitro: involvement of gastrin-releasing peptide-preferring receptors

Cited by 24 publications

References 0 publications

RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

Bombesin Inhibits Alveolarization and Promotes Pulmonary Fibrosis in Newborn Mice

Endocrine regulation of airway contractility is overlooked

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