Abstract
Leukocyte-endothelial cell interactions and leukocyte activation are important factors for vascular diseases including nephropathy, retinopathy and angiopathy. In addition, endothelial cell dysfunction is reported in vascular disease condition. Endothelial dysfunction is characterized by increased superoxide (O2 •−) production from endothelium and reduction in NO bioavailability. Experimental studies have suggested a possible role for leukocyte-endothelial cell interaction in the vessel NO and peroxynitrite levels and their role in vascular disorders in the arterial side of microcirculation. However, anti-adhesion therapies for preventing leukocyte-endothelial cell interaction related vascular disorders showed limited success. The endothelial dysfunction related changes in vessel NO and peroxynitrite levels, leukocyte-endothelial cell interaction and leukocyte activation are not completely understood in vascular disorders. The objective of this study was to investigate the role of endothelial dysfunction extent, leukocyte-endothelial interaction, leukocyte activation and superoxide dismutase therapy on the transport and interactions of NO, O2 •− and peroxynitrite in the microcirculation. We developed a biotransport model of NO, O2 •− and peroxynitrite in the arteriolar microcirculation and incorporated leukocytes-endothelial cell interactions. The concentration profiles of NO, O2 •− and peroxynitrite within blood vessel and leukocytes are presented at multiple levels of endothelial oxidative stress with leukocyte activation and increased superoxide dismutase accounted for in certain cases. The results showed that the maximum concentrations of NO decreased ∼0.6 fold, O2 •− increased ∼27 fold and peroxynitrite increased ∼30 fold in the endothelial and smooth muscle region in severe oxidative stress condition as compared to that of normal physiologic conditions. The results show that the onset of endothelial oxidative stress can cause an increase in O2 •− and peroxynitrite concentration in the lumen. The increased O2 •− and peroxynitrite can cause leukocytes priming through peroxynitrite and leukocytes activation through secondary stimuli of O2 •− in bloodstream without endothelial interaction. This finding supports that leukocyte rolling/adhesion and activation are independent events.
Highlights
Leukocyte-endothelial cell interactions and leukocyte activation are important factors for onset and progression of vascular diseases including nephropathy, retinopathy, cardiomyopathy, neuropathy and angiopathy [1,2,3,4]
We examined the biochemical aspects of oxidative stress distribution during the presence of leukocytes along the endothelium to understand the effects of leukocyte-endothelium interaction on nitric oxide (NO), O2N2 and peroxynitrite profiles
The model used in this study predicts the steady state NO, O2N2 and peroxynitrite concentration distribution and radial profiles under normal and oxidative stress conditions in the presence of three leukocytes located along the luminal surface of the endothelium
Summary
Leukocyte-endothelial cell interactions and leukocyte activation are important factors for onset and progression of vascular diseases including nephropathy, retinopathy, cardiomyopathy, neuropathy and angiopathy [1,2,3,4]. Vascular disease conditions increase oxidative stress in endothelial cells, resulting in endothelial dysfunction [11]. Endothelial dysfunction is characterized by increased superoxide (O2N2) production from endothelium and a reduction in NO bioavailability [11,12]. The increased oxidative stress increases cytokines, inflammatory agents and adhesion molecules expression on the endothelial cell surface and their ligands expression on the surface of the leukocytes [15,16] resulting in recruitment of leukocytes to the endothelium [2,15,16,17]
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