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Alan W. Stitt, Paul Canning, Philip J. Luthert, Josephiine V. Glenn, Lynsey-Dawn Allen, Vivien Prise, Peter S. Adamson; Lipoprotein-associated Phospholipase Inhibition Regulates Retinal Vasopermeability During Experimental Diabetes. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5765.
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Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a major role in macrophage infiltration, pro-inflammatory cytokine expression and adhesion molecule upregulation in macrovascular disease. Since diabetic macular edema (DME) is recognised to have an inflammation-linked aetiology it was hypothesized that inhibition of this enzyme could be protective against blood retinal barrier (BRB) breakdown.
Localization of Lp-PLA2 in human retina was analyzed by immunohistology. In parallel, brown Norwegian (BN) rats had diabetes induced using streptozotocin (65mg/Kg). After 4 weeks hyperglycemia, animals were treated for 4 weeks with either vehicle or SB435495 (a specific inhibitor of Lp-PLA2)(10mg/Kg/day) by intra-peritoneal injection. An additional group of hyperglycemic animals were maintained treatment free for 4 weeks prior to initiating the 4 wk treatment regimen. An age and sex-matched group of non-diabetic NDb) BN rats were used as controls. Following drug treatment, BRB function was determined by retinal fluorescein angiography (FA) using a scanning laser ophthalmoscope (SLO), quantification of Evan’s blue (EB) leakage or immunoreactivity of blood-borne and extravasated rat albumin in the retinal neuropile.
Lp-LPA2 was localized to the retinal vascular endothelium of humanretinal capillaries although there was also evidence of immunoreactivity inouter layers of vessels suggesting localization to pericytes and/or perivascular macrophages. Mean HbA1c for NDb rats was 5.54%+/-0.23 this was markedly elevated in Db rats to 14.82%+/- 0.59. There was no difference in HbA1c between drug and placebo-treated Db rats at either 4 or 8 weeks of hyperglycemia. SB435495-treatment after 4 or 8 weeks of prior diabetes resulted in less vascular leak during FA when compared to the placebo-treated Db controls. EB leakage was also elevated in the placebo-treated Db group when compared to NDb counterparts. 4 weeks treatment with SB435495 significantly prevented this response after either 4 or 8 weeks prior diabetes. In placebo-treated Db rats, albumin immunoreactivity was apparent in the neuropile and leakage appeared to emanate from both superficial and deep capillary plexi which were identified using isolectin. By contrast, in SB435495-treated Db rats, albumin was co-localised with isolectin-labelled blood vessels in an immunoreactivity pattern that was very similar to NDb controls.
Lp-PLA2 is expressed by the retinal capillary endothelium and other vascular cells. Inhibition of this enzyme in a preclinical model can prevent diabetes-mediated breakdown of the inner BRB. Lp-PLA2 may be a useful target for preventing DME.
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