Drug Targeting Organ-Specific Strategies

4.2.2.2 Phagocytosis and Transcytosis
SECs are normally able to internalize only small particles (up to 0.23 µm). In conditions of
impaired KC function, however, they have also been found to phagocytose larger particles
[23]. They are also responsible for the receptor-mediated transcytosis of several compounds,
such as insulin [24] and transferrin [25].
4.2.2.3 Regulation of the Inflammatory Process by SECs
Exposure of the SECs to pathogens or cytokines produced by other cells during stress induces
activation of the SECs and subsequent production of cytokines, eicosanoids, and/or
adhesion molecules. For instance, after activation with LPS, a main component of the walls of gramnegative
bacteria and a major inducer of inflammation and non-specific immune functions
[20], SECs produce a number of pro- and anti-inflammatory cytokines. Pro-inflammatory cytokines
shown to be produced were: tumour necrosis factor alpha (TNFα) [26]; interleukin-1
alpha/beta(IL-1α/β) [27]; the major inducer of acute phase proteins interleukin-6 (IL-6) [28];
and the neutrophil chemo-attractant interleukin-8 (IL-8) [29]. Anti-inflammatory cytokines
shown to be produced were: interleukin-10 (IL-10) [27] and hepatocyte growth factor (HGF) [30].
Eicosanoids are the oxidative metabolites derived from the cell membrane component
arachidonic acid. Arachidonic acid is released from the cell membrane by phospholipase A 2
and enzymatically converted to either prostaglandins (PGs) by cyclo-oxygenase or
leukotrienes (LTs) by lipoxygenase. Eicosanoids is the collective name of prostaglandins and
leukotrienes. SECs and KCs are the major sources of eicosanoids, whereas the PCs are considered
to be the most important target cells for them. The main eicosanoid produced by
SECs was found to be PGE 2 [31], although PGD 2 has also been reported to be a major product
[32]. The type of PG released may be a result of the difference in the induction stimulus
used. Eicosanoid production is induced by many circulating substances; LPS, interferon gamma
(IFNγ), TNFα, and platelet activating factor (PAF). PGE 2 is postulated to be involved in
liver regeneration [33] and inhibition of hormone-stimulated glycogenolysis [31], PGD 2 was
found to induce glycogenolysis [34].
SECs, like the vascular endothelium, play an active part in the control of leucocyte recruitment
in cases of acute and chronic inflammatory conditions. Leucocyte recruitment
from the blood compartment is a crucial determinant for the induction of immunity and inflammation.
SECs control this process by producing cytokines that activate leucocytes and by
expressing adhesion molecules. Under inflammatory conditions upregulation of intracellular
adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) was found
[35;36], as well as expression of E-selectin and P-selectin [37]. Together with the expression
of CD4 on SECs it has been postulated that these adhesion molecules might also be involved
in the adhesion of KC cells to the sinusoidal wall [20].
4.2.3 The Kupffer Cell (KC)
4.2 The Liver 93
Kupffer cells are the largest reservoir of fixed-tissue macrophages and are quantitatively the
most important cell type for the removal of circulating microorganisms, LPS, tumour cells,