CD10/neutral endopeptidase 24.11 in developing human fetal lung. Patterns of expression and modulation of peptide-mediated proliferation.

Sunday, Mary E.; Hua, Jinping; Torday, John S.; Reyes, Bernadette; Shipp, Margaret A.

doi:10.1172/jci116145

Cited by 91 publications

(61 citation statements)

References 44 publications

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“…We performed additional experiments treating newborn mice with GRP, NMB, and a synthetic BRS3 ligand, (DTyr 6 ,[R-Apa 11 , Phe 13 , Nle 14 ]Bombesin- [6][7][8][9][10][11][12][13][14]) (31), using doses that are equimolar to 200 g/kg bombesin (detailed in the online supplement). GRP has the same effects on alveolarization as bombesin ( Figure 6F).…”

Section: Alveolarizationmentioning

confidence: 99%

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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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Section: Alveolarizationmentioning

confidence: 99%

“…BLP can promote growth and maturation of developing fetal lung in humans, nonhuman primates, rats, and mice (8)(9)(10). Levels of GRP receptor (GRPR) and GRP mRNAs peak during the canalicular phase, then fall to much lower levels during normal alveolarization after birth (8,11).…”

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confidence: 99%

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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“…CD10, also known as the common acute lymphocytic leukemia antigen (CALLA) or neutral endopeptidase, is a cellsurface zinc metalloendopeptidase (1,2). The ability of CD10 to cleave signal peptides at the cell surface can affect cell proliferation, differentiation, and migration (2)(3)(4). Expression of CD10 can be used as a diagnostic marker for a variety of cancers (5)(6)(7)(8)(9).…”

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confidence: 99%

“…2 Supported by National Institutes of Health NHLBI Hematology Training Grant T32 HL007501. 3 Supported by a pre-doctoral fellowship from the National Science and Engineering Research Council of Canada. 4 Supported by an undergraduate award from the Beckman Foundation Scholars Program.…”

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confidence: 99%

NF-κB Down-regulates Expression of the B-lymphoma Marker CD10 through a miR-155/PU.1 Pathway

Thompson¹,

Herscovitch²,

Zhao

et al. 2011

Journal of Biological Chemistry

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The NF-B signaling pathway is misregulated in a variety of human diseases including many chronic inflammatory diseases and cancers. As such, an understanding of the molecular details of NF-B-dependent gene networks has implications for improved disease diagnoses and therapies. CD10, also known as the common acute lymphocytic leukemia antigen (CALLA) or neutral endopeptidase, is a cellsurface zinc metalloendopeptidase (1, 2). The ability of CD10 to cleave signal peptides at the cell surface can affect cell proliferation, differentiation, and migration (2-4). Expression of CD10 can be used as a diagnostic marker for a variety of cancers (5-9). Relevant to this study, CD10 is highly expressed in the germinal center B-cell (GCB) 6 molecular subtype of diffuse large B-cell lymphoma (DLBCL), whereas CD10 expression is low in the activated B-cell (ABC) subtype of DLBCL (8, 9). ABC DLBCLs also have a high NF-B gene expression profile and a poorer clinical prognosis as compared with GCB DLBCLs (10). As such, reduced expression of CD10 and high NF-B activity are both correlated with a less favorable DLBCL patient outcome (10 -12).The correlation between high NF-B activity and reduced CD10 expression has been observed in several other settings as well. We previously showed that overexpression of an activated mutant of the NF-B family transcription factor REL in the GCB-like B-lymphoma cell line BJAB leads to reduced expression of CD10 (13). Infection of cells with Epstein-Barr virus (EBV) or human cytomegalovirus, both inducers of NF-B, causes reduced expression of CD10 (14, 15). Taken together, such results suggested to us that NF-B or a target of NF-B is involved in repressing CD10 gene/protein expression in certain B-cell lymphomas.Little is known about the control of CD10 transcription. Sequence analysis of the CD10 promoter/enhancer region revealed the presence of three consensus binding sites for transcription factor PU.1 (16). PU.1 is a member of the Ets family of transcription factors and is required for proper Bcell development and differentiation (17). Additionally, increased PU.1 expression has been correlated with the GCB subtype of DLBCL (8). Therefore, we were interested in investigating whether PU.1 contributes to the regulation of CD10 expression in B-cell lymphoma.In this report, we provide evidence for a functional link between activation of NF-B and reduced expression of CD10. We show that activation of NF-B in the GCB-like DLBCL cell line BJAB leads to reduced CD10 expression. Our data are consistent with a pathway in which NF-B-induced up-regulation of micro-RNA miR-155 leads to down-regulation of PU.1 protein levels, and consequently, reduced levels of * This work was supported, in whole or in part, by National Institutes of Health Grant CA047763 and American Recovery and Reinvestment Act of 2009 supplement Grant CA047763021S3 (to T. D. G.). □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Fig. S1

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“…21 Thus, NEP contributes to the maintenance of a delicate balance of neuropeptides in the lung and elsewhere; disruption of that balance could alter susceptibility to hypoxic injury. 22,23 The role of NEP in chronic hypoxic PHTN remains uncertain. Early studies, conducted with inhibitors of NEP, suggested that this peptidase may contribute to chronic hypoxic PHTN.…”

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confidence: 99%

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

Dempsey

Wick

Karoor³

et al. 2009

The American Journal of Pathology

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Neprilysin is a transmembrane metalloendopeptidase that degrades neuropeptides that are important for both growth and contraction. In addition to promoting carcinogenesis, decreased levels of neprilysin increases inflammation and neuroendocrine cell hyperplasia, which may predispose to vascular remodeling. Early pharmacological studies showed a decrease in chronic hypoxic pulmonary hypertension with neprilysin inhibition. We used a genetic approach to test the alternate hypothesis that neprilysin depletion increases chronic hypoxic pulmonary hypertension. Loss of neprilysin had no effect on baseline airway or alveolar wall architecture, vessel density, cardiac function, hematocrit, or other relevant peptidases. Only lung neuroendocrine cell hyperplasia and a subtle neuropeptide imbalance were found. After chronic hypoxia, neprilysin-null mice exhibited exaggerated pulmonary hypertension and striking increases in muscularization of distal vessels. Subtle thickening of proximal media/adventitia not typically seen in mice was also detected. In contrast, adaptive right ventricular hypertrophy was less than anticipated. Hypoxic wild-type pulmonary vessels displayed close temporal and spatial relationships between decreased neprilysin and increased cell growth. Smooth muscle cells from neprilysin-null pulmonary arteries had increased proliferation compared with controls, which was decreased by neprilysin replacement. These data suggest that neprilysin may be protective against chronic hypoxic pulmonary hypertension in the lung, at least in part by attenuating the growth of smooth muscle cells. Lung-targeted strategies to increase neprilysin levels could have therapeutic benefits in the treatment of this disorder. Chronic hypoxic pulmonary hypertension (PHTN) is a major clinical problem, complicating most lung and heart disorders. 1,2 In large animal models of chronic hypoxic PHTN that closely resemble human disease, the earliest pulmonary artery (PA) smooth muscle cell (SMC) proliferative changes occur at the medial/adventitial border. 3 Growth and migration of SMC and myofibroblasts in distal vessels is also a prominent feature. 4,5 These structural changes, together with derangements in vascular tone, are major contributors to the severity of chronic hypoxic PHTN. [1][2][3][4][5][6] However, mechanisms that regulate susceptibility to, and severity of, chronic hypoxic PHTN and vascular remodeling remain poorly understood. Currently available treatments for chronic hypoxic PHTN are also inadequate.

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CD10/neutral endopeptidase 24.11 in developing human fetal lung. Patterns of expression and modulation of peptide-mediated proliferation.

Cited by 91 publications

References 44 publications

Bombesin Inhibits Alveolarization and Promotes Pulmonary Fibrosis in Newborn Mice

Bombesin Inhibits Alveolarization and Promotes Pulmonary Fibrosis in Newborn Mice

NF-κB Down-regulates Expression of the B-lymphoma Marker CD10 through a miR-155/PU.1 Pathway

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

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