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Modulation of radiation injury response in retinal endothelial cells by quinic acid derivative KZ-41 involves p38 MAPK.
Toutounchian, Jordan J; Steinle, Jena J; Makena, Patrudu S; Waters, Christopher M; Wilson, Matthew W; Haik, Barrett G; Miller, Duane D; Yates, Charles R.
Afiliación
  • Toutounchian JJ; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
  • Steinle JJ; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Department of Anatomy and Neurobiology, Univer
  • Makena PS; Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
  • Waters CM; Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
  • Wilson MW; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
  • Haik BG; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
  • Miller DD; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
  • Yates CR; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
PLoS One ; 9(6): e100210, 2014.
Article en En | MEDLINE | ID: mdl-24956278
Radiation-induced damage to the retina triggers leukostasis, retinal endothelial cell (REC) death, and subsequent hypoxia. Resultant ischemia leads to visual loss and compensatory retinal neovascularization (RNV). Using human RECs, we demonstrated that radiation induced leukocyte adhesion through mechanisms involving p38MAPK, p53, and ICAM-1 activation. Additional phenotypic changes included p38MAPK-dependent tyrosine phosphorylation of the focal adhesion scaffolding protein, paxillin (Tyr118). The quinic acid derivative KZ-41 lessened leukocyte adhesion and paxillin-dependent proliferation via inhibition of p38MAPK-p53-ICAM-1 signaling. Using the murine oxygen-induced retinopathy (OIR) model, we examined the effect of KZ-41 on pathologic RNV. Daily ocular application of a KZ-41-loaded nanoemulsion significantly reduced both the avascular and neovascular areas in harvested retinal flat mounts when compared to the contralateral eye receiving vehicle alone. Our data highlight the potential benefit of KZ-41 in reducing both the retinal ischemia and neovascularization provoked by genotoxic insults. Further research into how quinic acid derivatives target and mitigate inflammation is needed to fully appreciate their therapeutic potential for the treatment of inflammatory retinal vasculopathies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácido Quínico / Traumatismos Experimentales por Radiación / Retina / Enfermedades de la Retina / Vasos Retinianos / Sistema de Señalización de MAP Quinasas / Proteínas Quinasas p38 Activadas por Mitógenos / Rayos gamma Límite: Animals / Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácido Quínico / Traumatismos Experimentales por Radiación / Retina / Enfermedades de la Retina / Vasos Retinianos / Sistema de Señalización de MAP Quinasas / Proteínas Quinasas p38 Activadas por Mitógenos / Rayos gamma Límite: Animals / Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos