Functional facets of the pulmonary neuroendocrine system

Linnoila, R. Ilona

doi:10.1038/labinvest.3700412

Cited by 176 publications

(155 citation statements)

References 188 publications

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“…The reduced proliferation and apoptosis of Gfi1 À/À airway epithelium was associated with a profound impairment in the absolute levels of NE marker expression and BrdU þ CGRP þ cells. Although these results might support a previously hypothesized paracrine and growth stimulatory role of PNEC, 7 we found no difference in the post-naphthalene induced rate of proliferation and apoptosis in wt vs Gfi1 À/À terminal airway epithelial cells. Moreover, regeneration of the CC10 þ cells was virtually identical between wt and Gfi1 À/À littermates.…”

Section: Discussioncontrasting

confidence: 52%

“…[2][3][4][5] Pulmonary damage caused by chronic lung diseases, hypoxia, hyperoxia, extended exposure to environmental pollutants such as tobacco smoke, nitrosamines, ozone and naphthalene induces PNEC proliferation. 6,7 Naphthalene is an aromatic hydrocarbon that is a constituent of tobacco smoke. 8 Naphthalene specifically ablates the non-ciliated epithelial Clara cells that are most abundant in the bronchiolar epithelium.…”

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confidence: 99%

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Loss of GFI1 impairs pulmonary neuroendorine cell proliferation, but the neuroendocrine phenotype has limited impact on post-naphthalene airway repair

Linnoila

Jensen-Taubman

Kazanjian

et al. 2007

Laboratory Investigation

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Naphthalene exposure kills lung airway epithelial (Clara) cells, but is rapidly followed by Clara cell reconstitution coincident with proliferation of pulmonary neuroendocrine cells (PNEC). Although a role for mature PNEC in the reconstitution process has been excluded, the reconstituting progenitor cells have been suggested to enter a transient neuroendocrine (NE) differentiation phase before differentiating to Clara cells. Furthermore, these progenitors were suggested to be the target population for transformation to a NE tumor; small cell lung cancer (SCLC). Although the NE phenotype is central to SCLC oncogenesis, the relevance of NE differentiation to post naphthalene reconstitution remains to be determined. The Growth factor independent-1 (Gfi1) transcription factor is expressed in SCLC and is required for the NE differentiation of PNEC. Gfi1 À/À mice display a 70% reduction in airway cells that express NE markers, and cells that stain for NE markers show weak expression of some markers. Therefore, to determine the relevance of the NE phenotype to post-naphthalene reconstitution, we examined post-naphthalene reconstitution in Gfi1 À/À mice. Our analyses indicate that the post-naphthalene regeneration process includes both airway epithelial proliferation and apoptosis. Gfi1 deletion lowered both airway epithelial proliferation and apoptosis; however, the post-naphthalene rate of increase in growth and apoptosis was not significantly different between Gfi1 À/À mice and wild-type littermates. Moreover, the timing and extent of CC10 þ cell regeneration was unaffected by Gfi1 deletion. These data suggest that neither Gfi1 nor the NE phenotype play a dominant role in the regeneration process. However, the few Gfi1 À/À cells capable of NE differentiation show a significant reduction in post-naphthalene proliferation. The modest proliferation seen in Gfi1 À/À NE cells is consistent with the previously proposed role for Gfi1 in controlling neuroendocrine cancer growth.

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Section: Discussioncontrasting

confidence: 52%

mentioning

confidence: 99%

Loss of GFI1 impairs pulmonary neuroendorine cell proliferation, but the neuroendocrine phenotype has limited impact on post-naphthalene airway repair

Linnoila

Jensen-Taubman

Kazanjian

et al. 2007

Laboratory Investigation

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“…13,14 Furthermore, these vCE cells are harbored and maintained within a microenvironment or niche, which is provided by PNECs/NEBs through the paracrine secretion of various neuropeptides and bioactive amines. 48 It has also previously been shown that acute naphthalene toxicity results in PNEC/NEB hyperplasia in mice, 49 and after examination of PNECs/NEBs in our study, we found no observable difference in the extent of PNEC/NEB hyperplasia between Elf3 þ / þ and Elf3À/À mice after naphthalene exposure (data not shown).…”

Section: Discussioncontrasting

confidence: 41%

Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury

Oliver

Kushwah

et al. 2011

Laboratory Investigation

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“…However, we cannot rule out similar regulatory functions for other PNEC-derived neuropeptides. PNECs have been implicated as regulators of ventilationperfusion mismatches in response to hypoxia (16,58). Bronchoconstrictor and vasoconstrictor responses could be homeostatic in normal lung, maintaining optimal ventilation-perfusion matching despite regional hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…In lung, only PNECs produce GRP (16). GRP is present at high levels in human and mouse fetal lung (17,18), and GRP regulates normal development (18,19).…”

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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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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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Functional facets of the pulmonary neuroendocrine system

Cited by 176 publications

References 188 publications

Loss of GFI1 impairs pulmonary neuroendorine cell proliferation, but the neuroendocrine phenotype has limited impact on post-naphthalene airway repair

Loss of GFI1 impairs pulmonary neuroendorine cell proliferation, but the neuroendocrine phenotype has limited impact on post-naphthalene airway repair

Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury

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

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