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1.
Respir Res ; 14: 108, 2013 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-24134692

RESUMEN

BACKGROUND: Receptors for advanced glycation end-products (RAGE) are cell surface receptors prominently expressed by lung epithelium. Previous research demonstrated that over-expression of RAGE by murine alveolar epithelial cells during embryogenesis caused severe lung hypoplasia and neonatal lethality. However, the effects of RAGE over-expression on adjacent matrix and endothelial cells remained unknown. METHODS: RAGE transgenic (TG) mice were generated that conditionally over-expressed RAGE in alveolar type II cells when fed doxycycline (dox) from conception to E18.5. To evaluate effects on the basement membrane, immunostaining and immunoblotting were performed for collagen IV and MMP-9, a matrix metalloprotease capable of degrading basement membranes. To assess changes in vasculature, immunostaining, immunoblotting and qRT-PCR were performed for Pecam-1, a platelet endothelial cell adhesion marker also known as CD31. Lastly, to characterize potential regulatory mechanisms of endothelial cell differentiation, immunoblotting and qRT-PCR for FoxM1, a key endothelium-specific transcription factor of the Forkhead Box (Fox) family, were completed. RESULTS: Qualitative immunostaining for collagen IV was less in RAGE TG mice compared to controls and immunoblotting revealed decreased collagen IV in the RAGE TG mouse lung. Additionally, elevated MMP-9 detected via immunostaining and immunoblotting implicated MMP-9 as a possible down stream effector in matrix destabilization mediated by RAGE signaling. Lastly, Pecam-1 assessment revealed a decrease in the prevalence of microvascular endothelial cells coincident with FoxM1 abrogation in RAGE TG mice compared to controls. CONCLUSIONS: RAGE over-expression by alveolar epithelium weakened the basement membrane and associated matrix via increased MMP-9 activity. Furthermore, over-expression of RAGE inhibited FoxM1, suggesting that anomalous transcriptional control contributes to decreased endothelial cell prevalence in the TG mouse lung.


Asunto(s)
Membrana Basal/metabolismo , Endotelio/patología , Alveolos Pulmonares/embriología , Alveolos Pulmonares/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Diferenciación Celular/fisiología , Colágeno/metabolismo , Endotelio/metabolismo , Epitelio/embriología , Epitelio/metabolismo , Factores de Transcripción Forkhead/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Animales , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/genética
2.
Respir Res ; 12: 82, 2011 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-21682884

RESUMEN

BACKGROUND: α5 nicotinic acetylcholine receptor (nAChR) subunits structurally stabilize functional nAChRs in many non-neuronal tissue types. The expression of α5 nAChR subunits and cell-specific markers were assessed during lung morphogenesis by co-localizing immunohistochemistry from embryonic day (E) 13.5 to post natal day (PN) 20. Transcriptional control of α5 nAChR expression by FoxA2 and GATA-6 was determined by reporter gene assays. RESULTS: Steady expression of α5 nAChR subunits was observed in distal lung epithelial cells during development while proximal lung expression significantly alternates between abundant prenatal expression, absence at PN4 and PN10, and a return to intense expression at PN20. α5 expression was most abundant on luminal edges of alveolar type (AT) I and ATII cells, non-ciliated Clara cells, and ciliated cells in the proximal lung at various periods of lung formation. Expression of α5 nAChR subunits correlated with cell differentiation and reporter gene assays suggest expression of α5 is regulated in part by FoxA2, with possible cooperation by GATA-6. CONCLUSIONS: Our data reveal a highly regulated temporal-spatial pattern of α5 nAChR subunit expression during important periods of lung morphogenesis. Due to specific regulation by FoxA2 and distinct identification of α5 in alveolar epithelium and Clara cells, future studies may identify possible mechanisms of cell differentiation and lung homeostasis mediated at least in part by α5-containing nAChRs.


Asunto(s)
Células Epiteliales Alveolares/metabolismo , Factor Nuclear 3-beta del Hepatocito/metabolismo , Inmunohistoquímica , Pulmón/metabolismo , Receptores Nicotínicos/metabolismo , Análisis de Varianza , Animales , Sitios de Unión , Diferenciación Celular , Línea Celular Tumoral , Factor de Transcripción GATA6/genética , Factor de Transcripción GATA6/metabolismo , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Edad Gestacional , Factor Nuclear 3-beta del Hepatocito/genética , Humanos , Pulmón/citología , Pulmón/embriología , Pulmón/crecimiento & desarrollo , Ratones , Ratones Endogámicos C57BL , Mutación , Organogénesis , Regiones Promotoras Genéticas , Receptores Nicotínicos/genética , Transcripción Genética , Transfección
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