Biomedical Engineering Reference
In-Depth Information
disease today is liver organ transplantation. However, experimental and clinical
data indicate that earlier events of the perpetuated fibrogenic process in the liver
can be stopped or even reversed.
There is now experimental evidence that several endogenous factors/cytokines
play important roles in regulation of liver fibrogenesis. The use of interferon alpha
-2a and -2b is nowadays the main therapeutic strategy for the treatment of chronic
viral hepatitis and compensated viral liver cirrhosis [
81
,
82
]. In addition to
decreasing viremia in HBV and HCV infections, it also may lead to reduced liver
fibrosis.
New therapeutic targets interfering with fibrogenesis are emerging from
translational research and have been recently addressed in clinical trials. Inter-
feron-gamma1b (IFN-c1b) is a pleiotropic cytokine that displays antifibrotic,
antiviral, and antiproliferative activity. Initial studies conducted in patients with
HCV-related liver diseases have shown a fibrosis reduction in some of the patients
[
83
]. In particular, patients with elevated interferon-inducible T cell-alpha che-
moattractant (ITAC) levels in their blood and, perhaps less advanced disease
stages, may best be suited for IFN-gamma1b based therapy [
84
].
Interleukin-10 (IL-10) was first described as a cytokine synthesis inhibitory
factor for T lymphocytes produced from T helper 2 cell clones. In fact various cell
populations produce IL-10 in the body, including T cell subsets, monocytes,
macrophages, and also various other cell types present in organs such as the liver.
IL-10 gene polymorphisms are possibly associated with liver disease susceptibility
or severity. Recombinant human IL-10 is currently tested in clinical trials in
patients not responding to standard Peg-IFN a therapy.
PDGF is the most potent mitogen for hepatic stellate cell-derived myofibro-
blasts and levels of the growth factor have been shown to increase in liver diseases.
Autocrine signaling by PDGF was the first cytokine loop discovered in hepatic
stellate cell activation and is among the most potent ones [
85
]. Hepatic PDGF-a
overexpression using the CRP-gene promoter was accompanied by a significant
increase in hepatic procollagen III mRNA expression as well as TGF-b1 expres-
sion. Liver histology showed increased deposition of extracellular matrix in
transgenic but not in wildtype mice. These results point to a mechanism of fibrosis
induction by PDGF-a via the TGF-b1 signaling pathway [
86
]. On the other hand,
Dominant-negative soluble PDGF receptor beta is currently investigated as a
possible new antifibrogenic target.
TGFb1 remains, however, the classic fibrogenic cytokine. TGF b1 activates
stellate cells via the SMAD proteins pathway and also stimulates collagen
expression in stellate cells through a hydrogen peroxide and C/EBPb -dependent
mechanism. There is experimental evidence that hepatocyte-specific overexpres-
sion of TGFb1 in transgenic mice increases fibrosis in vivo, and that soluble TGFb
receptor type II treatment inhibits fibrosis in vivo. Also, it has been shown that
adenovirus encoding antisense TGFb mRNA inhibits fibrogenesis in vivo.
More experimental strategies aim to reduce extracellular matrix deposition by
overexpression of MMP's. Siller-Lopez et al. have used an extrahepatic human
neutrophil collagenase complementary MMP-8 DNA cloned in an adenovirus
