Extravasation surface

Factors known to influence the clearance of drugs from interstitial sites, following extravasation or parenteral interstitial or transepithelial administration, include size and surface characteristics of particles, formulation medium, the composition and pH of the interstitial fluid, and disease within the interstitium. Studies indicate that soluble macromolecules smaller than 30 nm can enter the lymphatic system, whereas particulate materials larger than 50 nm are retained in the interstitial sites and serve as a sustained-release depot. The use of lipids or an oil in a formulation and the presence of a negative surface charge all appear to... 

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... 

There is an increased blood flow in brain tumors (ref. 589), and the blood-brain barrier is leaky in and around 9L tumors because the blood vessels associated with these (ref. 568), and other (ref. 565-567), tumors are fenestrated. This well-known leakiness of tumor capillaries, which in the case of brain tumors includes breaches in the blood-brain barrier (ref. 566,568 cf. Section 12.2), would allow extravasation of small particulate matter (cf. ref. 590-594) or LCM. Once in the tumor area, LCM remain there because of an affinity for tumor cell surface components (cf. ref. 531 see also Chapter 14). At least 4 different types of experimental tumors in rats (C6 glioma, 9L gliosarcoma, Novikoff hepatoma, and Walker-256 carcinosarcoma), as well as several spontaneous tumors in dogs (ref. 570), do interact with LCM in a preferential manner (cf. Chapters 12 and 13), suggesting that LCM affinity may be for tumor cells in general (ref. 531). 

The inflammation response to tissue injury involves infiltration of damaged areas by leukocytes from the blood stream (1-4). Unregulated extravasation of leukocytes can result in inflammatory disorders such as reperfusion injuries, stroke, psoriasis, rheumatoid arthritis and respiratory diseases. An early step in the cascade of events leading to influx of leukocytes is the recognition of the tetrasaccharide sLex 1 (found on the terminus of leukocyte surface glycoproteins), by E, P and L selectins that are expressed by endothelial cells... 

Fig. 16.5 Numerous, partially ruptured lymphcysts (light red, dot-like ruptured openings) on the liver surface with extravasation of protein-rich lymph (so-called liver weeping ) in alcoholic cirrhosis...

The inflammatory response is initiated by stimuli released from sites of tissue injury that results in the expression of selectins on the endothelial layer. These selectins (E(endothelial)-selectin and P(platelet)-selectin) function through recognition of oligosaccharides on the opposing leukocyte cell surface [194]. This interaction eventually weakly tethers the leukocyte to the endothelial layer, at which point integrin binding events lead to firm adhesion and extravasation of the leukocyte into the tissue. In certain disease processes, excessive leukoc)4e infiltration becomes deleterious to the body, and inhibitors of this process are desirable. Rheumatoid arthritis, asthma, organ transplant rejection, and reperfusion injury are just a few of the cases in which these events occur [27]. 

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). 

Stimulation of cultured endothelial cells with thrombin, histamine, or H202 results in a rapid (within minutes) translocation of P-selectin (CD62P) to the cell surface from secretory granules known as Weibel-Palade bodies. In contrast, induction of endothelial E-selectin (CD62E) expression is dependent upon de novo synthesis following stimulation with cytokines such as IL-1 a and TNF-a.57 58 P- and E-selectin are only transiently expressed on the cell surface, during which time they bind to the sialylated Lewis X antigens of neutrophils and monocytes.59-61 Both selectins are implicated in leucocyte extravasation associated with the acute inflammatory response.62-63... 

In summary, the process of leucocyte extravasation, from initial attachment to endothelium to the final entry into the surrounding tissue, involves the sequential utilisation of an array of cell surface adhesion molecules. The important features of these adhesion molecules are that whilst some are constitutively expressed, others are induced, upregulated, or converted to a fully functional form only upon activation of endothelial cells or leucocytes. At present, it is not clear whether the arrival of distinct populations of blood leucocytes to an inflammatory lesion depends upon an initial recognition on the endothelial surface of a combination of known adhesion... 

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