Proliferation of Guinea Pig Tracheal Epithelial Cells Induced by Calcitonin Gene-related Peptide

White, Steven R.; Hershenson, Marc B.; Sigrist, Kirsten; Zimmermann, Anne; Solway, Julian

doi:10.1165/ajrcmb/8.6.592

Cited by 67 publications

(38 citation statements)

References 25 publications

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“…tor cells. Interestingly, the mitogenic effect of CGRP on guinea pig tracheal epithelial cells has been shown to be lost after 3 days of exposure (28), supporting the notion that sustained CGRP signals in CF SMGs could alter the phenotype of slow-cycling progenitor cells in the glandular niche.…”

Section: Figure 10mentioning

confidence: 58%

“…CGRPs have been shown to stimulate the proliferation of airway epithelial cells in vitro (27,28). Given this finding, we hypothesized that induction of glandular CGRP might be involved in signaling progenitor cell expansion in SMGs following airway injury and that dysregulation of this mechanism in CF may be responsible for formation of a facultative slow-cycling progenitor cell niche in the SAE.…”

Section: Glandular Cgrp Expression Is Activated Following Tracheal Inmentioning

confidence: 97%

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CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice

Xie¹,

Fisher²,

Lynch³

et al. 2011

J. Clin. Invest.

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In cystic fibrosis (CF), a lack of functional CF transmembrane conductance regulator (CFTR) chloride channels causes defective secretion by submucosal glands (SMGs), leading to persistent bacterial infection that damages airways and necessitates tissue repair. SMGs are also important niches for slow-cycling progenitor cells (SCPCs) in the proximal airways, which may be involved in disease-related airway repair. Here, we report that calcitonin gene-related peptide (CGRP) activates CFTR-dependent SMG secretions and that this signaling pathway is hyperactivated in CF human, pig, ferret, and mouse SMGs. Since CGRP-expressing neuroendocrine cells reside in bronchiolar SCPC niches, we hypothesized that the glandular SCPC niche may be dysfunctional in CF. Consistent with this hypothesis, CFTR-deficient mice failed to maintain glandular SCPCs following airway injury. In wild-type mice, CGRP levels increased following airway injury and functioned as an injury-induced mitogen that stimulated SMG progenitor cell proliferation in vivo and altered the proliferative potential of airway progenitors in vitro. Components of the receptor for CGRP (RAMP1 and CLR) were expressed in a very small subset of SCPCs, suggesting that CGRP indirectly stimulates SCPC proliferation in a non-cell-autonomous manner. These findings demonstrate that CGRP-dependent pathways for CFTR activation are abnormally upregulated in CF SMGs and that this sustained mitogenic signal alters properties of the SMG progenitor cell niche in CF airways. This discovery may have important implications for injury/repair mechanisms in the CF airway.

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Section: Figure 10mentioning

confidence: 58%

Section: Glandular Cgrp Expression Is Activated Following Tracheal Inmentioning

confidence: 97%

CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice

Xie¹,

Fisher²,

Lynch³

et al. 2011

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…In an in vitro model using lung buds, treatments with bombesin resulted in increasing branching morphogenesis (King et al, 1995). CGRP causes proliferation of guinea pig tracheal epithelial cells in primary culture through stimulation of a specific receptor (White et al, 1993). We have identified these peptides in NEBs surrounded by clusters of CCSPimmunolabeled cells.…”

Section: Discussionmentioning

confidence: 92%

Ontogeny of Clara cell-specific protein and its mRNA: their association with neuroepithelial bodies in human fetal lung and in bronchopulmonary dysplasia.

Khoór

Gray

Singh³

et al. 1996

J Histochem Cytochem.

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Clara cell-specific 1o-m protein (CCSP) is an abundant product of nonciliated bronchiolar epithelial (Clara) cells in the lung. We have determined the temporal-spatial distribution of CCSP and its mRNA in developing human lung and in neonatal lung disease, using immunohistochemistry and in situ hybridization. CCSP immunoreactivity was found in noncitiated bronchiolar epithelial cells from 12 weeks of gestation onward. Tracheal and bronchial epithelia showed positive immunoreactivity at each gestational week after 15 weeks and 14 weeks, respaaively. CCSP mRNA was seen in the bronchial and bronchiolar epithelia from 16 weeks onward and was detected in the trachea from 19 through 23 weeks ofgestation. CCSPimmunodvity andmRNAwere present in nonciliated single ails of bronchial and bronchio-

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“…CGRP induces degranulation in human neutrophils; promotes neutrophil adherence to endothelial cells (Richter et al 1992;Zimmerman, Anderson, and Granger 1992); and modulates migration and proliferation of cells, including tracheal epithelial cells (White et al 1993;Mikulec and Tanelian 1996;Kim et al 1995).…”

Section: Introductionmentioning

confidence: 99%

Activation of Calcitonin Gene-Related Peptide Receptor during Ozone Inhalation Contributes to Airway Epithelial Injury and Repair

et al. 2009

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The authors investigated the importance of the neuropeptide, calcitonin gene-related peptide (CGRP), in epithelial injury, repair, and neutrophil emigration after ozone exposure. Wistar rats were administered either a CGRP-receptor antagonist ) or saline and exposed to 8 hours of 1-ppm ozone or filtered air with an 8-hour postexposure period. Immediately after exposure, ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, airway dissected lung lobes were stained for 5'-bromo-2'-deoxyuridine, a marker of epithelial proliferation. Positive epithelial cells were quantified in specific airway generations. Rats treated with CGRP 8-37 had significantly reduced epithelial injury in terminal bronchioles and reduced epithelial proliferation in proximal airways and terminal bronchioles. Bronchoalveolar lavage and sections of terminal bronchioles showed no significant difference in the number of neutrophils emigrating into airways in CGRP 8-37 -treated rats. The airway epithelial cell line, HBE-1, showed no difference in the number of oxidant stress positive cells during exposure to hydrogen peroxide and a range of CGRP 8-37 doses, demonstrating no antioxidant effect of CGRP . We conclude that activation of CGRP receptors during ozone inhalation contributes to airway epithelial injury and subsequent epithelial proliferation, a critical component of repair, but does not influence neutrophil emigration into airways.

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Proliferation of Guinea Pig Tracheal Epithelial Cells Induced by Calcitonin Gene-related Peptide

Cited by 67 publications

References 25 publications

CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice

CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice

Ontogeny of Clara cell-specific protein and its mRNA: their association with neuroepithelial bodies in human fetal lung and in bronchopulmonary dysplasia.

Activation of Calcitonin Gene-Related Peptide Receptor during Ozone Inhalation Contributes to Airway Epithelial Injury and Repair

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