Little is known about the endothelial mechanisms involved in the anti-inflammatory effects of interleukin 10 (IL-10). The goal of this study was to evaluate the effects of IL-10 on endothelial oxidative stress and endothelial inflammation induced by tumor necrosis factor α (TNF-α). Production of reactive oxygen species (ROS) in perfused human umbilical vein endothelial cells (HUVECs) was studied by fluorescent microscopy using dichlorodihydrofluorescein diacetate. Tumor necrosis factor α (1 ng/mL) was added to the perfusion medium in the absence and presence of IL-10 (1 ng/mL). The role of phosphatidylinositol 3-kinase (PI3-kinase) was assessed using wortmannin and LY 2940002 (inhibitors of PI3-kinase). Specific inhibition of p110 α and p110 γ/δ PI3-kinase subunits was studied using A66 and TG100-115. As well, levels of ceramide and intercellular adhesion molecule 1 (ICAM-1) expression were measured. Finally, the effect of IL-10 on TNF-α-induced leukocyte/endothelium interaction was examined using an ex vivo perfused vessel model. Interleukin 10 significantly reduced dichlorodihydrofluorescein diacetate fluorescence induced by TNF-α in HUVECs (12.5% ± 3.2% vs. 111.7% ± 21.6% at 60 min). Pretreatment by LY2940002 or wortmannin restored ROS production induced by TNF-α in the presence of IL-10. In HUVECs treated by TNF-α + IL-10, inhibition of p110 α PI3-kinase subunit significantly increased ROS production, whereas p110 γ/δ inhibition did not have a significant effect. Pretreatment with IL-10 significantly decreased TNF-α-induced increased levels of ceramide (TNF-α vs. TNF-α + IL-10: 6,278 ± 1,013 vs. 1,440 ± 130 pmol/mg prot), as well as ICAM-1 expression and leukocyte adhesion (TNF-α vs. TNF-α + IL-10: 26.8 ± 2.6 vs. 6.7 ± 0.4 adherent leukocytes/field at 15 min). Interleukin 10 decreases the level of inflammation induced by TNF-α in endothelial cells by reducing the TNF-α-induced ROS production, ICAM-1 expression, and leukocyte adhesion to the endothelium. The antioxidant effect of IL-10 is mediated through PI3-kinase and is paralleled by a decrease in ceramide synthesis induced by TNF-α.

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RAS inhibition by losartan or perindopril prevented cardiac rupture at the acute phase of MI through blockade of splenic release of monocytes and neutrophils and consequently attenuation of systemic and regional inflammatory responses.

A variety of blood constituents were injected into an isolated segment of rabbit aorta to determine which elements might be involved in early endothelial injury. Test materials consisted of platelet rich plasma (P. R. P.) alone; P. B. P. plus adenosine diphosphate (A. D. P.); P. R. P. plus tendon extract; P. B. P. plus thrombin; ultrasonicated P. R. P. alone; platepoor plasma (P. P. P.) alone and thrombin in saline. Each experimental mixture was left in the aorta for 15 minutes, followed by reflow for 20 min. The vessel was then flex by glutaraldehyde perfusion. Thick sections of the entire circumference of the aorta were taken for phase contrast microscopy and representative areas were selected for electron microscopy. In control experiments and with sonicated P. R. P. and P. R. P. plus tendon extract, the endothelium was normal. With P. R. P. alone, P. P. P. alone and with P. R. P. plus A. D. P. there were occasional subendothelial vesicles. When P. R. P. plus thrombin and P. P. P. plus thrombin were injected separately to form a thrombus or when thrombin in saline was used, there was extensive subendothelial vesiculation with focal ulceration and adherence of thrombus to endothelium. Severe injury was associated with the presence of thrombin initiating the polymerization of fibrinogen to fibrin. Electron micrographs demonstrate the earliest lesion as a disruption of the superficial fibrillary elastica with separation of overlying endothelium.Additional Key Words: Plasminogen activation, turbulent flow, atherosclerosis, encrustation.