الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
The liver, the largest organ in the body, weighs 1200 – 1500 g. It
is relatively larger in infancy, comprising one - eighteenth of the birth
weight. This is mainly due to a large left lobe.
Normal liver has a connective tissue matrix which includes type
IV collagen, glycoproteins and proteoglycans. These constituents
comprise the low - density basement membrane in the space of Disse,
which separates the hepatocytes from the sinusoidal endothelium.
The basement membrane allows unimpeded transport of solutes and
growth factors between sinusoid and hepatocytes.
Fibrogenesis is the natural wound healing response to tissue
injury. Scar tissue is produced in an effort to limit and encapsulate the
area of damage. While acute hepatocellular injury activates fibrogenic
pathways, it is persistent, significant fibrosis accumulates ultimately
leading to the development of cirrhosis.
The transformation of normal to fibrotic liver and then cirrhosis is
a complex process involving key components, including both hepatic
parenchymal and non - parenchymal cells, the immune system,
cytokines, proteinases and their inhibitors.
After hepatic injury there is a three - to eightfold increase in
extracellular matrixcomposed predominantly of high - density
interstitial fibril - forming collagens (types I and III, rather than type IV)
as well as cellular fibronectin, hyaluronic acid and other matrix
proteoglycans. In addition, there is loss of endothelial cell fenestrations
and hepatocyte microvilli associated with this capillarization of
sinusoids, which impedes the metabolic exchange between blood and
liver cells. The gradual accumulation of type I collagen results from both
Summary
increased synthesis and reduced degradation, which is the hallmark of
fibrogenesis.
The hepatic stellate cell (also called lipocyte, fat - storing cell, Ito
cell, pericyte) is the principal cell involved in fibrogenesis. It lies within
the space of Disse and in direct contact with hepatocytes, endothelial
cells, inflammatory cells and nerve fibres. In the normal liver, these cells
have intracellular droplets containing vitamin A. They contain 40 – 70%
of the body stores of retinoids.
In its quiescent state the HSC produces predominantly type IV
collagen, the collagen characteristic of a normal basement membrane.
With injury, it undergoes phenotypic changes referred to as activation,
characterized by loss of retinoid droplets, cellular proliferation, increased
endoplasmic reticulum, increased contractility with expression of smooth
muscle specifi α - actin, and secretion of cytokines/ chemokines. This
phenotypic switch is also characterized by production of type I collagen,
the high - density interstitial collagen characteristic of the cirrhotic liver,
as well as matrix - degrading enzymes.
Stellate cell activation is a central event in hepatic fibrosis and can
be conceptualized as occurring in at least two stages: (1) initiation and
(2) perpetuation
Initiation refers to early events, including rapid changes in gene
expression and a cellular phenotype that renders HSCs responsive to
cytokines and other stimuli. Initiation is provoked by different factors
depending on disease aetiology. Stimuli include oxidant stress signals
(reactive oxygen intermediates), apoptotic bodies and
lipopolysaccharide. Moreover, the rapid, disruptive effects of liver injury
Summary
result in early changes in the extracellular matrix composition and alter
the homeostasis of neighbouring cells such as hepatic macrophages
(Kupffer cells), sinusoidal endothelium and hepatocytes, resulting in
paracrine stimuli that stimulate the HSC to respond to a host of growth
factors and cytokines.
Perpetuation involves cellular events that amplify the activated
phenotype through enhanced cytokine expression and responsiveness,
and the acquisition of features critical to the development of fibrosis.
These signals provide the impetus for scar formation through:
• Enhanced HSC proliferation, contractility and fibrogenesis;
• Altered matrix degradation;
• HSC chemotaxis;
• Direct interactions between HSCs and the immune system;
• Secretion of proinflammatory mediators.
Once the initiating injury signal is eliminated (i.e. treatment of
underlying disease, discontinuation of hepatotoxins such as ethanol),
HSCs either revert to the quiescent phenotype or are removed from the
liver through programmed cell death, or apoptosis. This paradigm has
provided the framework for the development of numerous antifibrotic
approaches.