Noninvasive molecular imaging reveals role of PAF in leukocyte-endothelial interaction in LPS-induced ocular vascular injury
ABSTRACT Uveitis is a systemic immune disease and a common cause of blindness. The eye is an ideal organ for light-based imaging of molecular events underlying vascular and immune diseases. The phospholipid platelet-activating factor (PAF) is an important mediator of inflammation, the action of which in endothelial and immune cells in vivo is not well understood. The purpose of this study was to investigate the role of PAF in endothelial injury in uveitis. Here, we use our recently introduced in vivo molecular imaging approach in combination with the PAF inhibitors WEB 2086 (WEB) and ginkgolide B (GB). The differential inhibitory effects of WEB and GB in reducing LPS-induced endothelial injury in the choroid indicate an important role for PAF-like lipids, which might not require the PAF receptor for their signaling. P-selectin glycoprotein ligand-1-mediated rolling of mouse leukocytes on immobilized P-selectin in our autoperfused microflow chamber assay revealed a significant reduction in rolling velocity on the cells' contact with PAF. Rolling cells that came in contact with PAF rapidly assumed morphological signs of cell activation, indicating that activation during rolling does not require integrins. Our results show a key role for PAF in mediating endothelial and leukocyte activation in acute ocular inflammation. Our in vivo molecular imaging provides a detailed view of cellular and molecular events in the complex physiological setting.
SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), a dual-function molecule with adhesive and enzymatic properties, is expressed on the surface of vascular endothelial cells of mammals. It also exists as a soluble form (sVAP-1), which is implicated in oxidative stress via its enzymatic activity and can be a prognostic biomarker. Recent evidence suggests that VAP-1 is an important therapeutic target for several inflammation-related ocular diseases, such as uveitis, age-related macular degeneration (AMD), and diabetic retinopathy (DR), by involving in the recruitment of leukocytes at sites of inflammation. Furthermore, VAP-1 plays an important role in the pathogenesis of conjunctival inflammatory diseases such as pyogenic granulomas and the progression of conjunctival lymphoma. VAP-1 may be an alternative therapeutic target in ocular diseases. The in vivo imaging of inflammation using VAP-1 as a target molecule is a novel approach with a potential for early detection and characterization of inflammatory diseases. This paper reviews the critical roles of VAP-1 in ophthalmological diseases which may provide a novel research direction or a potent therapeutic strategy.Journal of Ophthalmology 06/2013; 2013:925267. DOI:10.1155/2013/925267 · 1.94 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Objective: To investigate the role of Platelet Activating Factor (PAF) in the pathogenesis and development of Age-Related Macular Degeneration (ARMD). Research design and methods: Fifty six patients with ARMD (24 patients with dry ARMD and 32 patients with wet ARMD) and 25 age-matched control participants underwent ophthalmological examination, including visual acuity measurement and evaluation of the retina. The participants were classified into three groups according to their retinal status, based on indirect fundoscopy, Optical Coherence Tomography and fluorescein angiography findings. In order to evaluate the concentrations of PAF in serum, blood samples were collected from all participants and were analyzed with ELISA technique. Results: The concentrations of PAF differed significantly according to macular lesions and were found to be lower in patients with ARMD than control participants. Conclusions: PAF levels are decreased along with the severity of ARMD. Understanding the role of PAF in pathogenesis of ARMD could be the impetus for the development of new therapies field of treatment of ARMD or even other retinal diseases.Expert Opinion on Therapeutic Targets 07/2014; 18(9):1-11. DOI:10.1517/14728222.2014.930439 · 4.90 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Diabetic retinopathy (DR) is a microvascular complication of diabetes and a leading cause of vision loss. Biomarkers and methods for early diagnosis of DR are urgently needed. Using a new molecular imaging approach, we show up to 94% higher accumulation of custom designed imaging probes against vascular endothelial growth factor receptor 2 (VEGFR-2) in retinal and choroidal vessels of diabetic animals (P<0.01), compared to normal controls. More than 80% of the VEGFR-2 in the diabetic retina was in the capillaries, compared to 47% in normal controls (P<0.01). Angiography in rabbit retinas revealed microvascular capillaries to be the location for VEGF-A-induced leakage, as expressed by significantly higher rate of fluorophore spreading with VEGF-A injection when compared to vehicle control (26±2 vs. 3±1 μm/s, P<0.05). Immunohistochemistry showed VEGFR-2 expression in capillaries of diabetic animals but not in normal controls. Macular vessels from diabetic patients (n=7) showed significantly more VEGFR-2 compared to nondiabetic controls (n=5) or peripheral retinal regions of the same retinas (P<0.01 in both cases). Here we introduce a new approach for early diagnosis of DR and VEGFR-2 as a molecular marker. VEGFR-2 could become a key diagnostic target, one that might help to prevent retinal vascular leakage and proliferation in diabetic patients.-Sun, D., Nakao, S., Xie, F., Zandi, S., Bagheri, A., Kanavi, M. R., Samiei, S., Soheili, Z.-S., Frimmel, S., Zhang, Z., Ablonczy, Z., Ahmadieh, H., Hafezi-Moghadam, A. Molecular imaging reveals elevated VEGFR-2 expression in retinal capillaries in diabetes: a novel biomarker for early diagnosis.The FASEB Journal 06/2014; 28(9). DOI:10.1096/fj.14-251934 · 5.48 Impact Factor