Drug Targeting Organ-Specific Strategies

96 4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Cells
platelet derived growth factor (PDGF) receptor, the collagen type VI receptor, and the insulin-like
growth factor II/mannose-6-phophate receptor (IGFII/M6P). For reviews on this
subject see Beljaars et al. [63], Li et al. [64], and Bissell [65].
4.3 Hepatic Inflammation and Fibrosis
Virtually any insult to the liver can cause hepatocyte destruction and parenchymal inflammation.
If the insult is minor and occurs only once, local restoration mechanisms will suffice
to repair the damage. If, however, the insult is major or persistent, an inflammatory response
will be generated. This inflammation is the result of cytokine-mediated activation of sinusoidal
cells, their subsequent release of pro-inflammatory cytokines and their expression of
adhesion molecules for the recruitment of circulating leucocytes. Once the damage is under
control and the inciting insult has been eliminated, the inflammatory process will end and local
mechanisms will proceed until the damage is repaired. Usually little scar tissue will be detectable,
because of extracellular matrix remodelling. During conditions of chronic liver injury,
however, the repair process does lead to scar tissue formation, which is deposited within
the liver until impairment of liver function occurs. This process is called liver fibrogenesis
and the end stage, or irreversible stage, is referred to as liver cirrhosis (Figure 4.2).
Figure 4.2. Diagram outlining the pathogenesis of liver fibrosis. Injury to parenchymal cells (PC) results
in the activation of Kupffer cells (KC) and sinusoidal endothelial cells (SEC) and the recruitment of
inflammatory cells (IC). These cells release cytokines, growth factors and reactive oxygen species that
induce activation and proliferation of hepatic stellate cells (HSC). HSCs gradually transform into
myofibroblasts (MF), the major producers of extracellular matrix (ECM) proteins.