| Abstract |
Hepatic stellate cells are pericytes which are situated around liver sinusoids in
the space of Disse and are intimately associated with sinusoidal endothelial cells
and hepatocytes. In the healthy liver they store retinol esters, regulate sinusoidal
blood flow and have improtant immunologic functions acting as dedicated antigen
presenting cells. Following noxious stimuli in the liver they can transdifferentiate
into myofibroblasts with intensely inflammatory phenotype and exhibit increased
mobility, proliferation and produce many proinflammatory and profibrotic factors.
This transdifferentiation has been termed activation and plays a crucial role in the
inflammatory and regenerative response in the liver following injury.
Hepatic stellate cells produce collagen along with other components of extracellular
matrix in the liver as well as the enzymes responsible for the degradation of these
components, such as matrix metaloproteases (MMPs) and their inhibitors (TIMPs).
Thus, they are cells of great importance in chronic liver diseases as they are responsible
for the remodelling of the hepatic fibrous skeleton and the production of fibrous
tissue. Stimuli that lead to increased activation and proliferation of hepatic stellate
cells and increased production of collagen and TIMPs lead to increased fibrosis
whilst those that lead to increased apoptosis or increased expression of MMPs and
decreased expression of collagen and other components of extracellular matrix
have been shown in in vivo models of hepatic fibrosis to favor the reversal and
resolution of fibrosis even when it has progressed to the early stages of cirrhosis.
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Based on these observations, hepatic stellate cells are under intense research as
they are regarded as potential therapeutic targets against hepatic fibrosis and cirrhosis.
Somatostatin is a neuropeptide with vast biological actions both in the CNS
and in peripheral tissues. It mediates its effects through 5 distinct receptor types
SSTR1-5 the precise biological functions of which are still incompletely understood.
In this work we studied the expression of the various subtypes of somatostatin
receptors in rat hepatic stellate cells as well as the actions of octreotide, a synthetic
somatostatin analogue with different affinity for the different subtypes of SSTRs,
in regard to production of α1-procollagen and MMP expression from activated
hepatic stellate cells as well as the proliferation of these cells. We also studied the
effect of the proinflammatory and profibrotic cytokines TNFα, PDGF and TGFβ
in regard to the above mentioned actions as well as the effect of their combination
with octreotide in various concentrations.
Quiescent hepatic stellate cells do not express any subtype of somatostatin
receptor. Activated cells express the subtypes SSTR1, 2A, 2B, 3 and 4. Receptor
expression level is influenced by different cytokines, mainly PDGF which increases
the expression of SSTR1, 3 and 4 and IFNγ which increases the expression of
SSTR4.
TNFα inhibits the production of α1-procollagen as well as proliferation of
activated hepatic stellate cells, while it up-regulates the production of MMP-2 and
MMP-9. PDGF increases the expression of α1-procollagen and is also the most
potent mitotic stimulus for these cells. It also up-regulates ΜΜP-2 and MMP-
9 expression. TGFβ is the most potent profibrotic stimulus for activated hepatic
stellate cells and strongly induces the production of α1-procollagen. Octreotide
differentially modulates the effects of the three cytokines. By itself it dose dependently
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decreases the production of α1-procollagen and has no effect on MMP production
or proliferation. Under the co-stimulus of TNFα though, it up-regulates α1-procollagen
and increases proliferation. It down-regulates α1-procollagen expression under
the co-stimulus of TGFβ and it acts synergistically to the increased proliferation
induced by PDGF.
To study the effect of phosphotyrosine phosphatases (PTP) and serine/threonine
phosphatases (STP) in α1-procollagen and MMP production and cellular proliferation,
we employed the PTP inhibitor sodium orthovanadate and the STP inhibitor okadaic
acid. Sodium orthovanadate showed synergistic action to octreotide in inducing
MMP-2 and MMP-9 in TNFα and PDGF treated cells while okadaic acid reduced
proliferation, α1-procollagen production and potently up-regulated MMP-2 and
MMP-9 production regardless of cytokine treatment, thus exhibiting strong antifibrotic
action.
In conclusion, the actions of the somatostatinergic system in activated rat hepatic
stellate cells is strongly dependent on the signalling context the cell finds itself
into, with different cytokines inducing different actions. The SSTR intracellular
signalling is influenced by both PTP and STP, and the latter could potentially be
an important target for antifibrotic treatments in the future.
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Επίδραση της σωματοστατίνης επί των αστεροειδών κυττάρων του ήπατος
