Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.

The Republican Movement, 'Disappearing' and Framing the Past in Northern Ireland

Despite a rich body of research on the conflict and peace process in Northern Ireland, the ‘disappearances’ carried out by Republican armed groups have so far escaped scrutiny. In this article I examine how the Republican movement has framed the rationale behind ‘disappearing’ as a rational response to informing and as an example of historical continuity. In doing so, Republicans appear to attempt to confer legitimacy on their choice of target and normalize the use of the practice within a Republican framework. However, these rationales incorporate techniques of neutralization and attempts to contextualize the ‘disappearances’ in such a way as to distance the Irish Republican Army from agency. Such distancing speaks to a third, overarching rationale for ‘disappearing’: the avoidance of an embarrassment that has continued into the postconflict period. I consider why Republicans persist in claiming the ‘disappeared’ were legitimate targets, killed by a method for which there is historical precedent, when such framing left them open to criticism at a time when they were seeking to demonstrate that they had left violence behind. I conclude that Republican attempts to satisfy two audiences resulted in a gulf between their engagement in the process of recovering remains and their rhetoric surrounding this issue. In so doing, light is shed on some of the challenges the Republican movement faced in their transition away from violence. More broadly, the value of unpicking the framing of key actors in transitional processes is illuminated.