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Identifier

000389943

Title

Molecular inflammatory factors in diabetic retinopathy : role of azurocidin

Alternative Title

Μοριακοί παράγοντες φλεγμονής στη διαβητική αμφιβληστροειδοπάθεια:

Author

Σκόνδρα, Δήμητρα

Thesis advisor

Τσιλιμπάρης, Μιλτιάδης

Reviewer

Παπαβασιλείου, Ευστάθιος
Παλλήκαρης, Ιωάννης
Μπούμπας, Δημήτριος
Θερμού, Κυριακή
Γανωτάκης, Εμμανουήλ
Τσατσάνης, Χρήστος

Abstract

PURPOSE. Azurocidin, released by neutrophils during leukocyte-endothelial interaction, is a main cause of leukocyte-evoked vascular leakage. Its role in the retina, however, is unknown. METHODS. Brown Norway rats received intravitreal injections of azurocidin and vehicle control. Blood-retinal barrier (BRB) breakdown was quantified using the Evans blue (EB) dye technique 1, 3, and 24 hours after intravitreal injection. To block azurocidin, aprotinin was injected intravenously before the intravitreal injections. To investigate if azurocidin increases retinal leukostasis, number of adherent leukocytes in the retina 2 hours and 24 hours after azurocidin injection were quantified using the Concanavalin A perfusion technique. To investigate whether azurocidin plays a role in vascular endothelial growth factor (VEGF)- induced BRB breakdown, rats were treated intravenously with aprotinin, followed by intravitreal injection of VEGF164. BRB breakdown was quantified 24 hours later. To investigate whether azurocidin may mediate BRB breakdown in early diabetes, aprotinin or vehicle was injected intravenously each day for 10 days to streptozotocin-induced diabetic rats, and BRB breakdown was quantified. To investigate whether azurocidin may mediate BRB breakdown in endotoxin induced uveitis (EIU) as another model of leukocyte mediated retinal vascular leakage , EIU rats were treated with aprotinin or vehicle and BRB breakdown was quantified 24 hours after the EIU induction. RESULTS. Intravitreal injection of azurocidin (20 μg) induced a 6.8-fold increase in vascular permeability compared with control at 1–3 hours (P ΄&λτ 0.05), a 2.7-fold increase at 3-5 hours (P ΄&λτ 0.01), and a 1.7-fold increase at 24 hours (P ΄&λτ 0.05). Azurocidin did not increase static retinal leukostasis at 2 hours after the intravitreal injection or 24 hours after the intravitreal injection. Aprotinin inhibited azurocidin-induced BRB breakdown by 98% (P ΄&λλτ 0.05). Furthermore, treatment with aprotinin significantly suppressed VEGF-induced BRB breakdown by 93% (P ΄&λτ 0.05) , BRB breakdown in early experimental diabetes by 40.6% (P ΄&λτ 0.05) and BRB breakdown in EIU by 73% (P΄&λτ0.05) CONCLUSIONS. Azurocidin increases retinal vascular permeability and is effectively blocked by aprotinin. The inhibition of VEGF-induced, early diabetic BRB breakdown and EIU retinal vascular leakage with aprotinin indicates that azurocidin may be an important mediator of leukocyte-dependent BRB breakdown especially in a disease model like diabetes that leukostasis is crucial in pathogenesis. Azurocidin may become a new therapeutic target in the treatment of retinal vascular leakage, diabetic retinopathy and diabetic macular edema.

Language

English

Subject

Diabetic retinopathy

Inflammation

Διαβητική αμφιβληστροειδοπάθεια

Φλεγμονή

Issue date

2014-12-03

Collection

School/Department--School of Medicine--Department of Medicine--Doctoral theses

Type of Work--Doctoral theses