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Glucocorticoids exert direct toxicity on microvasculature: analysis of cell death mechanisms
Ikram El Zaoui1, Francine Behar-Cohen2, Alicia Torriglia3
1*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.
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.
Insights
Glucocorticoids (GCs) can harm ocular microvasculature. This study found GC toxicity varies by cell type and formulation, highlighting risks for retinal vascular health.
Area of Science:
- Ophthalmology
- Vascular Biology
- Pharmacology
Background:
- Glucocorticoids (GCs) are widely used for ocular diseases.
- Their impact on retinal microvasculature toxicity remains understudied.
- Understanding GC-induced vascular damage is crucial for patient safety.
Purpose of the Study:
- To investigate the in vitro and ex-vivo toxicity of various GCs on ocular and skin microvasculature.
- To elucidate the mechanisms of GC-induced endothelial cell death.
- To assess the implications for clinical use and intraocular device development.
Main Methods:
- In vitro evaluation of hydrocortisone, dexamethasone, dexamethasone-phosphate, and triamcinolone acetonide on human skin microvascular endothelial cells and bovine retinal endothelial cells.
- Ex-vivo assessment on flat-mounted rat retinas.
- Analysis of cell death pathways (caspase activation, leukocyte elastase inhibitor/L-DNase II pathways).
Main Results:
- GC toxicity differed based on endothelial cell type and GC properties.
- Skin microvascular cells exhibited higher toxicity compared to retinal cells.
- Hydrophobic GC formulations and specific GCs (hydrocortisone, triamcinolone acetonide) induced cell death via distinct pathways.
- Observed cell death mechanisms in vitro mirrored those in retinal explants.
Conclusions:
- GCs pose potential risks to the retinal microvasculature.
- Toxicity is influenced by formulation and cell type, necessitating careful clinical consideration.
- Particular attention is required for sustained-release intraocular GC devices due to potential vascular side effects.
