Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights
J Gastroenterol
Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights
Thomas Greuter 0 1 2
Vijay H. Shah 0 1 2
0 & Vijay H. Shah
1 Gastroenterology Research Unit, Department of Gastroenterology and Hepatology, Mayo Clinic and Foundation , 200 First St. SW, Rochester, MN 55905 , USA
2 Division of Gastroenterology and Hepatology, University Hospital Zurich , Zurich , Switzerland
Changes of hepatic sinusoids are crucial in the pathogenesis of liver cirrhosis and portal hypertension. Liver injury leads to distinct morphological abnormalities such as loss of sinusoidal fenestration, vasoconstriction, and angiogenesis as well as molecular changes. Communication between the two key cells in this hepatic microenvironment-hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC)-has been studied for many years and several canonical pathways have been elucidated, such as decreased eNOS activity or increased PDGF and TGF-b production leading to activation and migration of HSC. In recent studies, alternative pathways of intercellular communication in liver diseases have been described such as cell-derived extracellular vesicles called exosomes, which deliver cell compounds to their target cells. Moreover, such extracellular vesicles may link injury to inflammation in alcoholic hepatitis. While inflammation leading to liver fibrosis has been studied in detail, in some circumstances pathways other than the known canonical inflammatory pathways may contribute to hepatic fibrogenesis. For example, in congestive hepatopathy, sinusoidal dilatation and fibrosis have been shown to be mediated by non-inflammatory mechanisms and associated with sinusoidal thrombi. A recently developed murine model further enables experimental studies of this disease entity. Increasing knowledge about these alternative disease pathways in liver injury, inflammation, and fibrosis may reveal possible target molecules for future therapies. This article builds upon a seminar given at the recent 3rd JSGE International Topic Conference in Sendai, Japan, and reviews the areas outlined above.
Sinusoidal epithelial cell; Hepatic stellate cell; Intercellular communication; Intrasinusoidal thrombosis; Exosome signaling; Microvesicles; Overview of changes in hepatic sinusoids in the pathogenesis of liver cirrhosis and portal hypertension
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The hepatic sinusoids with the involved hepatic sinusoidal
endothelial cells (SEC), smooth muscle cells, and
pericytelike hepatic stellate cells (HSC) form an intrahepatic
microcirculatory unit, where these cells are intimately
associated with one another and communicate through
paracrine and autocrine effects [
1
]. Changes in this
microenvironment are crucial in the early steps of
fibrogenesis and include sinusoidal remodeling,
vasoconstriction, endothelial dysfunction, and angiogenesis [
2
]. This
article provides background information pertaining to the
hepatic sinusoids and then focuses on recent developments
pertaining to sinusoidal pathobiology, as recently presented
at the 3rd JSGE International Topic Conference in Sendai,
Japan.
Sinusoidal endothelial cells
SEC have a very unique phenotype distinct from
conventional endothelial cells, characterized by multiple fenestrae
and the lack of a basement membrane [
3?5
]. Serving as a
mechanical sieve, fenestration permits steric selection of
transfer from sinusoidal space to hepatic parenchyma [
6,
7
]. In addition, SEC show constitutive expression of nitric
oxide (NO) synthase, which can be upregulated by
increased blood flow and shear stress [8] as well as
paracrine factors from other cells such as VEGF [
9, 10
].
Through this mechanism known as autoregulation, hepatic
sinusoids can adapt to increased intrahepatic blood flow
and decrease intrahepatic pressure [8]. Further
physiological functions of SEC are leukocyte diapedesis through
expression of adhesion molecules, endocytosis (known as
the hepatic reticuloendothelial system), and bacterial
processing [
5
]. As the first cells interacting with portal vein
components, SEC are exposed to different bacterial
compounds. Bacterially derived lipopolysaccharides (LPS)
bind to their receptor TLR-4 expressed on SEC, inducing
injury and inflammation [
11
]. Interestingly, recent studies
have shown that LPS can also induce fibrosis-associated
angiogenesis by interacting with TLR-4, highlighting the
role of SEC in the so-called gut?liver axis [
12, 13
].
In liver disease, the SEC phenotype changes
dramatically [
1, 14
]. Liver injury leads to endothelial dysfunction
with loss of fenestrae and deposition of a basement
membrane, a process that is known as capillarization [
6, 15, 16
].
Besides these morphological changes, changes in paracrine
and autocrine function are dramatic, too. NO production
usually decreases, leading to an increasing intrahepatic
pressure due to an inability to maintain intrasinusoidal
autoregulation by vasodilatation [
1, 17
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