Drug Targeting Organ-Specific Strategies

174 7 Vascular Endothelium in Inflamed Tissue as a Target for Site Selective Delivery of Drugs
DR on T cells, B cells and synovial lining cells, indicating strong immunological activity. RA
is thought to be an autoimmune reaction, caused by an interaction between constitutional
and environmental factors [14].
In human biopsies of patients with RA, an increased expression of the adhesion molecules
E-selectin, VCAM-1, ICAM-1 and the CD11c integrin has been demonstrated [15,16]. Also,
soluble mediators produced by perivascular cells (e.g. the chemokines Macrophage Inflammatory
Protein (MIP)-1α and MIP-1β) or by endothelial cells themselves (e.g. IL-8 and IL-
15) are important in the regulation of leucocyte infiltration in RA [17].Tumour Necrosis Factor
α (TNFα) is thought to be a particularly important inflammatory mediator contributing
to the pathology of arthritis, as demonstrated by the beneficial effects of the TNFα-neutralizing
therapies that are currently being explored [18]. However, present therapies for RA
mainly aim at the inhibition of cyclooxygenase enzymes which are responsible for the overproduction
of inflammatory mediators like prostaglandin E 2 in arthritis-affected joints [19].
7.3.1.2 Atherosclerosis
Atherosclerosis is a generalized degenerative disease that affects large and medium-sized arteries.
The atherosclerotic plaque contains increased numbers of smooth muscle cells (which
are morphologically abnormal), increased connective tissue and lipid, mostly cholesterol.
Monocyte-derived macrophages and lymphocytes are also found in the plaques. Endothelial
damage is believed to be the essential trigger for the development of atherosclerosis. Once
injury of the endothelium has occurred, platelets and smooth muscle cells will adhere and aggregate.
Subsequently smooth muscle cells will proliferate, collagen and elastin production
will increase, and lipid is allowed to accumulate in the vessel wall through enhanced permeability
at the site of injury [14].
Two important molecular participants in the atherosclerotic process are the transcription
factor nuclear factor κB (NFκB) and the adhesion molecule CD40. Using immunohistochemical
techniques the activated form of NFκB has been shown to be present in human atherosclerotic
lesions in smooth muscle cells, macrophages and endothelial cells. In contrast, in
vessels lacking atherosclerotic processes little or no activated NFκB was present [20]. Recently,
there has been an increasing interest in the role of CD40 and CD40L (CD154), members
of the TNF receptor and TNF family respectively, in chronic inflammation. Ligation of
CD40 on vascular wall cells promotes upregulation of endothelial adhesion molecules such
as E-selectin, ICAM-1 and VCAM-1 [21]. Furthermore, it stimulates mononuclear cell recruitment,
participates in the weakening of the plaque and sets the stage for thrombosis by
inducing tissue factor expression [22]. Additionally, CD40 ligation signals pro-angiogenic
processes which are also prominent in atherosclerosis [23].
7.3.1.3 Inflammatory Bowel Disease
Inflammatory Bowel Disease (IBD) comprises several diseases, including ulcerative colitis
and Crohn’s disease. Ulcerative colitis is a disease of the colon, originating in the rectum and
extending proximally to a variable extent. It frequently affects the entire colon but never