title: Modulation of radiation injury response in retinal endothelial cells by quinic acid derivative KZ-41 involves p38 MAPK.
abstract: 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.
authors: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Jordan J
authors: JJ
authors: Toutounchian
authors: 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, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Jena J
authors: JJ
authors: Steinle
authors: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Patrudu S
authors: PS
authors: Makena
authors: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Christopher M
authors: CM
authors: Waters
authors: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Matthew W
authors: MW
authors: Wilson
authors: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Barrett G
authors: BG
authors: Haik
authors: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Duane D
authors: DD
authors: Miller
authors: 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.
authors: Charles R
authors: CR
authors: Yates
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D005720:Gamma Rays / Q000009:adverse effects*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D012160:Retina / Q000201:enzymology / Q000473:pathology; D012164:Retinal Diseases / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D012171:Retinal Vessels / Q000201:enzymology / Q000473:pathology; D016159:Tumor Suppressor Protein p53; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C573420:ICAM1 protein, human; C569814:KZ 41 compound; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011801:Quinic Acid; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases