Extravasation Vascular endothelial cell

IFN-y also induces the costimulatory molecules on the macrophages, which increases cell-mediated immunity. As a consequence, there is activation and increase in the tumoricidal and antimicrobial activity of mononuclear phagocytes, granulocytes and NK cells. The activation of neutrophils by IFN-y includes an increase in their respiratory burst. IFN-y stimulates the cytolytic activity of NK cells. It is an activator of vascular endothelial cells, promoting CD4+ T lymphocyte adhesion and morphological alterations, which facilitates lymphocyte extravasation. IFN-y promotes opsonization by stimulating the production of IgG subclasses that activate the complement pathway. A summary of the characteristics of selected cytokines is shown in Table 2.3. 

The vascular endothelial growth factor is produced by tumor cells, macrophages, and endothelial and smooth muscle cells. It induces vascular endothelial cell migration, enhances vascular permeability, and promotes extravasation of plasma proteins from tumor vessels to form an extracellular matrix, facilitating inward migration of endothelial cells (Callagy et al., 2000). These characteristics impart selectivity to VEGF for endothelial cells. 

In order to understand how blood leucocytes adhere to cerebral endothelium prior to extravasation across the BBB, it is necessary to consider in general terms the mechanisms by which blood leucocytes recognise and bind to molecules expressed on the luminal surface of vascular endothelial cells. Leucocyte-endothelial interaction is a multistep process28 in which families of cell adhesion molecules regulate different stages of adhesion that culminate in migration across the vessel wall (see Table 6.1). 

The endothelium has many diverse functions that enable it to participate in in-flammatoiy reactions (H27). These include modulation of vascular tone, and hence control of local blood flow changes in structure that allow leakage of fluids and plasma proteins into extravascular tissues local accumulation and subsequent extravasation into tissues of leukocytes and synthesis of surface molecules and soluble factors involved in leukocyte activation (B43). The endothelial cells themselves can modulate vascular tone by the release of vasoactive substances such as prostacyclin, nitric oxide (NO), ET. Endothelium-derived vasoactive substances... 

Apart from inducing vascular damage via infiltration and degranulation of various blood cells, PAF and TNF exert also direct effects in the endothelium. In vitro, both substances cause contraction of endothelial cells, which may partially account for the increased vascular permeability and plasma extravasation observed in many species following PAF or TNF administration [311]. While it has been known for some time that endothelial cells produce PAF when stimulated with various agonists such as thrombin, it has recently been established that TNF and IL-1 also induce cultured endothelial cells to synthesize PAF, the majority of which remains associated with the cells [317]. 

Extravasation requires the successive formation and breakage of cell-cell contacts between leukocytes in the blood and endothelial cells lining the vessels. Some of these contacts are mediated by selectins, a family of CAMs that mediate leukocyte-vascular cell interactions. A key player in these Interactions is P selectin, which is localized to the blood-facing surface of endothelial cells. All selectins contain... 

Figure 3.4 Examples of targeted systems [63]. Right Particles passively extravasate through the leaky vasculature that is present in many solid tumours and inflamed tissue, and accumulate through the EPR effect. Middle Ligands on the particle surface actively target receptors, thus enhancing accrunulation and uptake. Left Vascular targeting of endothelial cells. Reproduced with permission from O.C. Farokhzad, and R. Langer, ACS Nano, 2009, 3,16. 2009, ACS...

FIGURE 83.2 Extravasation of liposomes in normal and tumor tissues. The fluorescently labeled liposomes are shown as bright pixels and some of them are indicated by the arrows. Panel (a) shows that liposomes accumulate only in perivascular regions in solid tumors. Bar, 100 pm. Panel (b) shows that two vascular networks on the surface of a tumor have different patterns of liposome accumulation, indicating that microvascular permeability is heterogeneous in solid tumors. Bar, 400 pm. Panel (c) shows that extravasated liposomes are mostly located near the roots of capillary sprouts (bottom), while the capillary sprouts per se (top) are nearly impermeable to liposomes. Bar, 200 pm. Panel (d) shows that liposome accumulation in normal subcutaneous tissues occurs only in endothelial cells in postcapillary and collecting venules (6-25 pm in diameter). The letters a, c, and v represent arteriole, capillary, and venule, respectively. Bar, 100 pm. (Reprinted from Yuan F et al. Cancer Res 1994 54 3352-3356. With permission.)... 

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