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Am J Physiol Lung Cell Mol Physiol ; 313(3): L491-L506, 2017 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-28572154

RESUMEN

Individuals with intrauterine growth restriction (IUGR) are at risk for chronic lung disease. Using a rat model, we showed in our previous studies that altered lung structure is related to IL-6/STAT3 signaling. As neuropeptide Y (NPY), a coneurotransmitter of the sympathetic nervous system, regulates proliferation and immune response, we hypothesized that dysregulated NPY after IUGR is linked to IL-6, impaired myofibroblast function, and alveolar growth. IUGR was induced in rats by isocaloric low-protein diet; lungs were analyzed on embryonic day (E) 21, postnatal day (P) 3, P12, and P23. Finally, primary neonatal lung myofibroblasts (pnF) and murine embryonic fibroblasts (MEF) were used to assess proliferation, apoptosis, migration, and IL-6 expression. At E21, NPY and IL-6 expression was decreased, and AKT/PKC and STAT3/AMPKα signaling was reduced. Early reduction of NPY/IL-6 was associated with increased chord length in lungs after IUGR at P3, indicating reduced alveolar formation. At P23, however, IUGR rats exhibited a catch-up of body weight and alveolar growth coupled with more proliferating myofibroblasts. These structural findings after IUGR were linked to activated NPY/PKC, IL-6/AMPKα signaling. Complementary, IUGR-pnF showed increased survival, impaired migration, and reduced IL-6 compared with control-pnF (Co-pnF). In contrast, NPY induced proliferation, migration, and increased IL-6 synthesis in fibroblasts. Additionally, NPY-/- mice showed reduced IL-6 signaling and less proliferation of lung fibroblasts. Our study presents a novel role of NPY during alveolarization: NPY regulates 1) IL-6 and lung STAT3/AMPKα signaling, and 2) proliferation and migration of myofibroblasts. These new insights in pulmonary neuroimmune interaction offer potential strategies to enable lung growth.


Asunto(s)
Retardo del Crecimiento Fetal/patología , Pulmón/crecimiento & desarrollo , Neuropéptido Y/metabolismo , Sistema Nervioso Simpático/inmunología , Sistema Nervioso Simpático/patología , Adenilato Quinasa/metabolismo , Animales , Animales Recién Nacidos , Apoptosis/genética , Biomarcadores/metabolismo , Movimiento Celular/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Dieta , Retardo del Crecimiento Fetal/inmunología , Regulación de la Expresión Génica , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmón/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Miofibroblastos/metabolismo , Neurotransmisores/metabolismo , Proteína Quinasa C/metabolismo , Ratas Wistar , Receptores de Neuropéptido Y/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Aumento de Peso
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