title: Glucocorticoids exert direct toxicity on microvasculature: analysis of cell death mechanisms.
abstract: Glucocorticoids (GCs) are routinely administered systemically or injected into the eye when treating numerous ocular diseases; however, their toxicity on the retinal microvasculature has not been previously investigated. In this article, the effects of hydrocortisone (Hydro), dexamethasone, dexamethasone-phosphate and triamcinolone acetonide (TA) were evaluated in vitro on human skin microcirculation cells and, bovine endothelial retinal cells, ex-vivo, on flat mounted rat retinas. The degree of GCs induced endothelial cell death varied according to the endothelial cell type and GCs chemical properties. GCs toxicity was higher in skin microvascular endothelial cells and for hydrophobic GC formulations. The mechanism of cell death differed between GCs, Hydro and TA activated the leukocyte elastase inhibitor/L-DNase II pathways but did not activate caspases. The mechanisms of cell death observed in cell cultures were similar to those observed in rat retinal explants. Taken together these results indicate that particular attention should be paid to the potential vascular side effects when administrating GCs clinically and in particular when developing sustained-release intraocular devices.
authors.affiliation: *INSERM UMRS 1138, Team 17 from Physiopathology of Ocular Diseases to Clinical Developments, Paris, France, Pierre et Marie Curie University, Paris Descartes University, UMRS 1138, Centre de Recherche des Cordeliers 75006, Paris, France and Hopital Ophtalmique Jules Gonin 1000, Lausanne, Switzerland *INSERM UMRS 1138, Team 17 from Physiopathology of Ocular Diseases to Clinical Developments, Paris, France, Pierre et Marie Curie University, Paris Descartes University, UMRS 1138, Centre de Recherche des Cordeliers 75006, Paris, France and Hopital Ophtalmique Jules Gonin 1000, Lausanne, Switzerland *INSERM UMRS 1138, Team 17 from Physiopathology of Ocular Diseases to Clinical Developments, Paris, France, Pierre et Marie Curie University, Paris Descartes University, UMRS 1138, Centre de Recherche des Cordeliers 75006, Paris, France and Hopital Ophtalmique Jules Gonin 1000, Lausanne, Switzerland.
authors.forename: Ikram
authors.initials: I
authors.lastname: El Zaoui
authors.affiliation: *INSERM UMRS 1138, Team 17 from Physiopathology of Ocular Diseases to Clinical Developments, Paris, France, Pierre et Marie Curie University, Paris Descartes University, UMRS 1138, Centre de Recherche des Cordeliers 75006, Paris, France and Hopital Ophtalmique Jules Gonin 1000, Lausanne, Switzerland *INSERM UMRS 1138, Team 17 from Physiopathology of Ocular Diseases to Clinical Developments, Paris, France, Pierre et Marie Curie University, Paris Descartes University, UMRS 1138, Centre de Recherche des Cordeliers 75006, Paris, France and Hopital Ophtalmique Jules Gonin 1000, Lausanne, Switzerland *INSERM UMRS 1138, Team 17 from Physiopathology of Ocular Diseases to Clinical Developments, Paris, France, Pierre et Marie Curie University, Paris Descartes University, UMRS 1138, Centre de Recherche des Cordeliers 75006, Paris, France and Hopital Ophtalmique Jules Gonin 1000, Lausanne, Switzerland *INSERM UMRS 1138, Team 17 from Physiopathology of Ocular Diseases to Clinical Developments, Paris, France, Pierre et Marie Curie University, Paris Descartes University, UMRS 1138, Centre de Recherche des Cordeliers 75006, Paris, France and Hopital Ophtalmique Jules Gonin 1000, Lausanne, Switzerland.
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
authors.affiliation: *INSERM UMRS 1138, Team 17 from Physiopathology of Ocular Diseases to Clinical Developments, Paris, France, Pierre et Marie Curie University, Paris Descartes University, UMRS 1138, Centre de Recherche des Cordeliers 75006, Paris, France and Hopital Ophtalmique Jules Gonin 1000, Lausanne, Switzerland *INSERM UMRS 1138, Team 17 from Physiopathology of Ocular Diseases to Clinical Developments, Paris, France, Pierre et Marie Curie University, Paris Descartes University, UMRS 1138, Centre de Recherche des Cordeliers 75006, Paris, France and Hopital Ophtalmique Jules Gonin 1000, Lausanne, Switzerland *INSERM UMRS 1138, Team 17 from Physiopathology of Ocular Diseases to Clinical Developments, Paris, France, Pierre et Marie Curie University, Paris Descartes University, UMRS 1138, Centre de Recherche des Cordeliers 75006, Paris, France and Hopital Ophtalmique Jules Gonin 1000, Lausanne, Switzerland alicia.torriglia@inserm.fr.
authors.forename: Alicia
authors.initials: A
authors.lastname: Torriglia
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002417:Cattle; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects / Q000648:ultrastructure; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D005938:Glucocorticoids / Q000633:toxicity*; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D055806:Microvessels / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology; D012867:Skin / Q000098:blood supply
chemical_list: D005938:Glucocorticoids
keywords: apoptosis; dermic endothelial cell; endothelial cell; glucocorticoids; retinal microvasculature