Hyperplasia of Alveolar Neuroendocrine Cells in Rat Lung Carcinogenesis by Silica with Selective Expression of Proadrenomedullin-Derived Peptides and Amidating Enzymes

Elizegi, Eider; Pino, Irene; Vicent, Silvestre; Blanco, David; Saffiotti, Umberto; Montuenga, Luis M.

doi:10.1038/labinvest.3780376

Cited by 17 publications

(12 citation statements)

References 50 publications

(59 reference statements)

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“…Experimentally induced hyperplasia of PNECs has been observed to occur in response to various toxic gases or carcinogenic stimuli [37]. Depending on the specific stimulus, the proliferative effect may be specifically restricted to a certain airway region [38,39]. PNEC proliferation was also seen in a number of non-neoplastic human lung diseases [37].…”

Section: Discussionmentioning

confidence: 98%

Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo

Fehrenbach

Fehrenbach²,

Pan³

et al. 2002

European Respiratory Journal

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Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo. H. Fehrenbach, A. Fehrenbach, T. Pan, M. Kasper, R.J. Mason. #ERS Journals Ltd 2002. ABSTRACT: Keratinocyte growth factor (KGF) is a potent mitogen of pulmonary bronchial and alveolar epithelial cells. However, it is unclear which type(s) of airway epithelial cells (AEC) proliferate(s) in response to KGF.AEC proliferation was induced in rats by either endobronchial instillation of 5 mg recombinant human (rHu) KGF per kg body weight or by adenoviral transfer of the human KGF gene (Ad5-HuKGF). Alterations in terminal airway AEC were followed for up to 7 days after rHuKGF, and for up to 28 days after Ad5-HuKGF.Cell proliferation, as assessed by immunohistochemistry (IHC) for incorporated 5-bromo-29-deoxyuridine (BrdU) and quantified by stereology, peaked at days 1-2 and was resolved by day 7 after rHuKGF and by day 21 after Ad5-HuKGF. Double immunofluorescence labelling for BrdU or Ki-67 on the one hand, and for Clara cell specific protein 10 (CC10) and calcitonin-gene related peptide on the other hand, demonstrated that Clara cells, not pulmonary neuroendocrine cells, proliferated in response to human KGF. TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling) method in conjunction with IHC for MNF116 failed to detect significant numbers of apoptotic AEC. IHC in conjunction with stereology revealed transient phenotypic alterations with a decrease in CC10, an increase in surfactant protein D and an increase in CD44v6 in AEC.The authors conclude that Clara cells responded to human keratinocyte growth factor in vivo by proliferation as well as by changes in protein expression, whereas no significant response was observed in pulmonary neuroendocrine cells. As Clara cells are intimately involved in airway epithelial repair, ion and fluid transport, and modulate lung inflammation, the potential of human keratinocyte growth factor to protect the lung may in part rely on the response of Clara cells.

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Section: Discussionmentioning

confidence: 98%

Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo

Fehrenbach

Fehrenbach²,

Pan³

et al. 2002

European Respiratory Journal

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“…In neuroendocrine cells of the larynx and trachea, serotonin could not be demonstrated, whereas in the lung, serotonin-containing cells were seen. (Adriaensen et al 2001;Boorman, Morgan, and Uraih 1990;Dungworth, Ernst, et al 1992;Dungworth et al 2001;Elizegi et al 2001;Gopinath, Prentice, and Lewis 1987;Haworth et al 2007;Karube et al 1989;Kasacka and Sawicki 2004;Kerns et al 1983;Larson et al 2004;Lauweryns and Van Ranst 1988;Lauweryns et al 1987;D. Lewis 1991;Luts et al 1991;Maronpot et al 1986;McBride et al 1990;Montuenga et al 1992;Pack, Al-Ugaily, and Morris 1981;Rehm and Kelloff 1991;Shimosegawa and Said 1991;Takahashi, Iwasaki, and Ide 1985;Van Lommel 2001;Van Lommel et al 1999) Hyperplasia with Cellular Atypia (Dysplasia): Larynx, Trachea, Bronchi, Bronchioles Pathogenesis/cell of origin: Proliferation of respiratory epithelium, or submucosal glands.…”

Section: Larynx Trachea Bronchi and Bronchiolesmentioning

confidence: 96%

Proliferative and Nonproliferative Lesions of the Rat and Mouse Respiratory Tract

Renne¹,

et al. 2009

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The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the respiratory tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for respiratory tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

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“…[69][70][71][72][73] The role of growth factors and cytokines in the pathogenesis of silica-induced lung carcinogenesis has been the object of earlier studies. [20][21][22][74][75][76][77] It was shown that hyperplastic type II cells present in this model are sites of active production and secretion of TGF-b1. 21,76 In rat alveolar cells in culture, silica treatment induced a dramatic secretion of TGF-b1.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of adhesion molecules and epithelial–mesenchymal transition in silica-induced rat lung carcinogenesis

Blanco

Vicent

Elizegi

et al. 2004

Laboratory Investigation

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Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelialmesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during lung cancer progression are still not well understood. We have used a rat model for multistep lung carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, a-catenin and b-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. a-and b-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear b-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat lung carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell-cell adhesion molecules are an early event in lung carcinogenesis, while EMT occurs at a later stage.

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Hyperplasia of Alveolar Neuroendocrine Cells in Rat Lung Carcinogenesis by Silica with Selective Expression of Proadrenomedullin-Derived Peptides and Amidating Enzymes

Cited by 17 publications

References 50 publications

Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo

Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo

Proliferative and Nonproliferative Lesions of the Rat and Mouse Respiratory Tract

Altered expression of adhesion molecules and epithelial–mesenchymal transition in silica-induced rat lung carcinogenesis

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