Drug Targeting Organ-Specific Strategies

172 7 Vascular Endothelium in Inflamed Tissue as a Target for Site Selective Delivery of Drugs
PBMC
sLe x
selectins
1. 2.
integrins
IgSF
3.
4.
antigen is the recruitment of leucocyte subsets to the site of antigen presence or entry. The
immune system is subsequently capable of efficiently eliminating the antigen.
The recruitment and migration of leucocytes into inflamed tissues is a carefully orchestrated
process (Figure 7.1). It consists of sequential steps mediated by different families of
adhesion molecules expressed by both the leucocytes and the endothelial cells at the site of
inflammation [4]. Of these adhesion molecules, the selectin family mediates the initial contact
and subsequent rolling of the leucocyte on the endothelium. It consists of three members,
i.e. E- (endothelial), P- (platelet) and L- (leucocyte) selectin.Activated endothelial cells
express E- and P-selectin. P-selectin is also expressed on platelets, whereas L-selectin is only
expressed on subsets of leucocytes [5].
If during the rolling process the leucocyte is correctly activated, the affinity of the members
of the integrin family of adhesion molecules on the leucocyte membrane increases. Examples
of activating factors are cytokines such as interleukin (IL)-6 and IL-8, which can be
produced by the activated endothelial cells, and chemokines such as monocyte chemotactic
proteins (MCPs), growth related proteins (GROs) and interferon γ-inducible protein 10 (IP-
10) [6]. The so-called counter receptors for integrins on the endothelium are members of the
immunoglobulin superfamily (IgSF) and encompass Intercellular Adhesion Molecule-1
(ICAM-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1). These molecules are highly
expressed by activated endothelial cells in inflammatory sites.The interaction of integrins on
the leucocyte with the immunoglobulin superfamily members on the endothelium mediates
the firm attachment of the leucocyte, followed by transmigration into the tissue. In this latter
process Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1, CD31) and a variety of
matrix metalloproteases (MMPs) exert important functions. Although initially identified as
an IgSF member with a main function in cell–cell contact, PECAM-1 was recently shown to
be a modulator of vascular cell activation as well [7]. MMPs play a role in the degradation of
EC
Inciting stimulus
Figure 7.1. Leucocyte recruitment to sites of inflammation takes place via strictly regulated expression
of adhesion molecules by the leucocytes (peripheral blood mononuclear cells, PBMC) and endothelial
cells (EC). (1) Tethering of the leucocytes is mediated by interactions between members of the selectin
family and their sialyl Lewis X (sLe x ) counterparts. Subsequent chemokine-mediated cellular activation
leads to strong adhesion (2) and trans-endothelial migration (3) of the leucocytes into the underlying
tissue. These processes are mediated by members of the integrin and immunoglobulin superfamily
(IgSF) and homotypic interactions of the IgSF member CD31, among others. Cellular movement
through the extracellular matrix (4) is facilitated by interactions between integrins and their
extracellular matrix ligands, and a variety of chemokines and their respective receptors.