G. RAMADORI, E. MORICONI, I. MALIK, J.

DUDAS
PHYSIOLOGY AND PATHOPHYSIOLOGY OE LIVER
INELAMMATION, DAMAGE AND REPAIR
Department oI Internal Medicine, Section oI Gastroenterology and Endocrinology,
Georg-August-University Goettingen, Goettingen, Germany
The liver is the largest organ oI the body. It is located between the portal and the
general circulation, between the organs oI the gastrointestinal tract and the heart. The
main Iunction oI the liver is to take up nutrients, to store them, and to provide
nutrients to the other organs. At the same time has the liver to take up potentially
damaging substances like bacterial products or drugs delivered by the portal blood or
microorganisms, which reach the circulation.
The liver is not only an important power and sewage treatment plant oI the body. In
Iact, the liver is probably the best example Ior a cheap recycling system. Both
parenchymal and nonparenchymal liver cells participate in the clearance activities.
The Iunction oI the liver as clearance organ, however, harbors the danger that the
substances that should be degraded and/or eliminated lead to tissue damage. Thus,
eIIective deIense mechanisms are necessary. Among the nonparenchymal cells
KupIIer cells, sinusoidal endothelial cells, and natural killer (NK) lymphocytes exert
cellular deIense Iunctions Ior the whole body but also Ior the liver itselI.
Eurthermore, each cell type oI the liver, including the hepatocytes, possesses its own
deIense apparatus.
Ke y wo r d s : liver, inflammation
LIVER INEAMMATION AND INJURY - BASICS AND ASPECTS
The classical picture oI acute inIlammation and damage in the liver is the
acute hepatitis caused by diIIerent noxae. It is thought that inIlammation not only
precedes but is also needed to generate damage oI "stressed" hepatocytes.
Hepatic Iibrosis is the common endpoint Ior most types oI chronic liver injury. It
JOURNAL OE PHYSIOLOGY AND PHARMACOLOGY 2008, 59, Suppl 1, 107117
www.jpp.krakow.pl
was considered to be an irreversible process, especially when the complete
picture oI cirrhosis is present.
When damage is Iollowed by elimination oI cellular debris and oI the
"stressing" agents regeneration and restitution oI integrity are the terminal
consequences. When elimination oI the agent is not possible inIlammation and
Iibrosis Iollow.
DiIIerent types oI disease may lead to diIIerent patterns oI Iibrosis during
disease progression (1, 2). DiIIerent Iibrogenic cells may predominate in diIIerent
types oI Iibrosis.
The classic Iorms oI acute viral hepatitis are Iollowed by complete recovery
oI the liver. The hallmarks oI chronic inIection, caused by inIection with
hepatotropic viruses (hepatitis C and hepatitis B virus) are inIlammation, the
death oI hepatocytes and Iinally liver Iibrosis (3).
Alcoholic hepatitis (due to alcohol abuse) and non-alcoholic steatohepatitis
(caused by insulin resistance and obesity, diabetes mellitus, and/or
hypertriglyceridemia, etc.) are associated with a change in hepatocyte lipids on
histology, hepatocyte ballooning/necrosis, neutrophil inIiltration and the
development oI a particular type oI Iibrosis.
Obstruction oI the biliary tree Ior several weeks to months, leads to hepatocyte
necrosis and to lobular bile inIarcts. A ductular reaction develops at the periphery
oI the portal tracts, extending towards the neighbouring portal tracts and into the
parenchyma. In this case an extensive proliIeration oI periductular
(myo)Iibroblasts can be observed (4).
CELLS IN LIVER INELAMMATION
Hepatocytes make up 70-80 oI the cytoplasmic mass oI the liver. These cells
are involved in protein synthesis, protein storage and transIormation oI
carbohydrates, synthesis oI cholesterol, bile salts and phospholipids, and
detoxiIication, modiIication and excretion oI exogenous and endogenous
substances. The hepatocyte also initiates the Iormation and secretion oI bile.
Hepatocytes display an eosinophilic cytoplasm, reIlecting numerous
mitochondria, and basophilic stippling due to large amounts oI rough
endoplasmic reticulum and Iree ribosomes. The average liIe span oI the
hepatocyte is 5 months; they are able to regenerate. Hepatocytes are organised
into plates separated by vascular channels (sinusoids) (5). The hepatocyte plates
are one cell thick in adult mammals. Hepatocytes are able to synthesize
hormones, like insulin-like-growth-Iactor IGE-1 (6), thrombopoietin (7), and also
erythropoietin (8). They also synthesize cytokines like interleukin (IL)-8 (9) and
respond to acute phase mediators like IL-6, with the synthesis oI acute phase
proteins like C-reactive protein (CRP) (10) or serum amyloid A (SAA) (11) and
108
many others. The cells possess diIIerent intracellular deIense proteins like heme-
oxygenase-1 (HO-1) (12).
When however the deIense mechanisms are not suIIicient to withstand the
damaging attacks cells start to synthesize chemokines (CXC-chemokines like:
monokine-induced by gamma interIeron (MIG) (13), gamma-interIeron-inducible
protein (IP-10) (13), cytokine-induced neutrophil chemoattractant (KC) and
macrophage inIlammatory proteins (MIPs) (MIP-1, MIP-2, MIP-3) (14), which
are supposed to be responsible Ior attraction oI inIlammatory cells like
granulocytes and mononuclear phagocytes and to activation oI resident
macrophages (Table 1, Fig. 1). In the attempt to eliminate the damaging noxae the
deIense response however leads to death oI the stressed hepatocyte.
Hepatic stellate cells (HSC) (and liver (myo)Iibroblasts) have modulatory
roles in inIlammatory conditions, based on their capability oI cytokine and
chemokine production. The quiescent Stellate (Ito) cells (HSC) store vitamin A,
but produce extracellular matrix and collagen when activated. They are located in
the space oI Disse between hepatocytes and endothelial cells (1,2,5,15).
Hepatic stellate cells might also play a role during liver inIlammation. ICAM-1
and VCAM-1 expression was present in HSC in vitro and in cells located in the
sinusoidal/perisinusoidal area oI normal liver. Growth Iactors, e.g., transIorming
growth Iactor-1, down-regulated ICAM-1- and VCAM-1-coding mRNAs and
stimulated N-CAM expression oI HSC. In contrast, inIlammatory cytokines like
tumor necrosis Iactor-alpha reduced N-CAM-coding mRNAs, whereas induced oI
ICAM-1- and VCAM-1-speciIic transcripts by several Iold. HSC might be important
during the onset oI hepatic tissue injury by modulating the recruitment and migration
oI mononuclear cells within the perisinusoidal space oI diseased livers (16).
In addition, the secretion oI several cytokines and chemokines was
demonstrated in hepatic stellate cells including MCP-1, RANTES, IL-8 (17-19)
(Table 1, Fig. 1).
Sinusoids display a discontinuous, Ienestrated endothelial cell lining. The
sinusoidal "wall" does not possess a basement membrane and the endothelial cells
are separated Irom the hepatocytes by the space oI Disse which drains lymph into
the portal tract lymphatics (5). Under normal conditions the hepatic sinusoidal
endothelial cells express low levels oI Rantes, macrophage-chemotactic-protein-
1 (MCP-1), IL-8 and MIP-1. These Iactors are involved in the routine leukocyte
109
Table 1. Induction oI chemical mediators in liver cells populations during liver inIlammation
Liver cells Mediators
Hepatocytes IL-8, IP-10, MIG, MIP-1, MIP-2, MIP-3, KC
Sinusoidal Endothelial Cells RANTES, MCP-1, IL-8, MIP-1, MIP-1;
MIG, ITAC
KupIIer Cells IL-1, IL-6, IL-10, IL-18, TNE-, TGE-,
MIPs, IL-8, IP-109, KC/GRO, RANTES
Hepatic Stellate Cells IL8, RANTES, MCP-1
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Fig. 1. Scheme oI sinusoidal structure in normal liver (A) and in liver inIlammation (B). The
hepatocellular stress induced by hepatotoxins, or by viruses, may lead to activation oI liver resident
macrophages on one side and to the release oI chemokines on the other side. ProinIlammatory
cytokines are released by natural killer cells as well as by KupIIer cells. They induce an increased
expression oI cell adhesion molecules like intercellular cell adhesion molecule-1 (ICAM-1) and
vascular cell adhesion molecule-1 (VCAM-1) on the portal and/or sinusoidal endothelial cells and a
downregulation oI platelet endothelial cell adhesion molecule (PECAM-1). These molecules allow the
recruitment and sinusoidal transmigration oI inIlammatory cells toward their target, the hepatocyte.
A: Sinusoidal structure in normal liver
B: Changes in liver inIlammation
recirculation and immunological surveillance. During inIlammation the
chemokine expression proIile oI the normal hepatic endothelium changes. These
changes are characterized by expression oI high levels oI MIP-1, IP-10, MIG
and IEN-gamma-inducible T cell alpha chemoattractant (ITAC) (Table 1, Fig. 1).
Similarly to the chemokine proIile the expression pattern oI adhesion molecules
also changes in the endothelial cells (20). Under normal conditions the hepatic
sinusoidal endothelial cells express platelet endothelial cell adhesion molecule-1
(PECAM-1), vascular adhesion protein-1 (VAP-1) and intercellular cell adhesion
molecule-2 (ICAM-2). During inIlammation this expression pattern changes,
characterized by the downregulation oI PECAM-1, and upregulation oI ICAM-1,
oI vascular cell adhesion molecule VCAM-1, and oI P and E selectins (20).
KupIIer cells are scattered within the liver sinusoid, they are the major part oI
the reticuloendothelial system and phagocytose spent erythrocytes. KupIIer cells
are the specialized macrophages oI the liver that Iorm the major part oI the
reticuloendothelial system (mononuclear phagocyte system). The cells were Iirst
observed by Karl Wilhelm von KupIIer in 1876 (21). In 1898, aIter several years
oI research, Tadeusz Browicz, a polish scientist, identiIied them correctly as
macrophages (22-23).
Their development begins in the bone marrow with the genesis oI
promonocytes and monoblasts into monocytes and then on to peripheral blood
monocytes completing their diIIerentiation into KupIIer cells (24).
The red blood cell is broken down by phagocytic action and the hemoglobin
molecule is split. The globin chains are reutilized while the iron containing portion
or heme is Iurther broken down into iron which is reutilized and bilirubin, which
is conjugated with glucuronic acid within hepatocytes and secreted into the bile.
Helmy et al. (25) identiIied a receptor present in KupIIer cells, the
complement receptor oI the immunoglobulin Iamily (CRIg). Mice without CRIg
could not clear complement system-coated pathogens. CRIg is conserved in mice
and humans and is a critical component oI the innate immune system (25).
During liver injury induced by hepatotoxins or by Gram-negative bacterial
lipopolysaccharide (LPS), or in association with sensitizers such as D-
galactosamine, CCl
4
, dimethylnitrosamine, acetaminophene, alcohol, etc. the
KupIIer cells get activated. Activation oI KupIIer cells results in secretion oI a large
number oI chemical mediators (cytokines: IL-1, IL-6, IL-8, TNE-, etc. chemokines:
C-X-C chemokines: MIP-2, IP-109, KC/GRO; C-C chemokines: MIP-1, MCP-1,
RANTES), most oI which can induce liver injury either by acting directly on the
liver cells or via chemoattraction oI extrahepatic cells (e.g. neutrophils and
lymphocytes) (20) (Table 1, Fig. 1). During inIlammatory conditions the expression
pattern oI adhesion molecules is also changed in the KupIIer cells, similarly to the
sinusoidal endothelial cells. The most characteristic change is the downregulation oI
PECAM-1 and the upregulation oI ICAM-1 (Fig. 1) (26).
In addition to KupIIer cells the liver hosts a lymphocyte subpopulation termed pit
cells. (27) Their number in the liver is about 1 oI the non-parenchymal cell
111
population (28). The pit cells correspond to the natural killer NK cells in other
organs. Together they constitute the Iamily oI the large granular lymphocytes (LGL).
They probably originate Iorm the bone marrow, circulate through the blood
and marginate in the liver, where they develop into pit cells by lowering their
density and increasing the number oI granules. Pit cells remain in the liver about
two weeks and their survival is dependent on the presence oI KupIIer cells (29).
Besides synthesis oI IEN- upon triggering by the damaging noxae, the most
important Iunction oI the NK cells is the destruction oI virus-inIected and malignant
cells without previous activation. NK cells are able to migrate and transmigrate
through epithels. NK cells can be activated by interleukin-2. The resulting cell
population is known as lymphokine-activated killer cells (LAK) (2, 15).
The chemical mediators released by KupIIer cells and by hepatocytes attract
extrahepatic cells to the liver. Neutrophils (PMN) are the characteristic cellular
compound oI the chemoattracted cells, and are involved in the acute inIlammation
(Fig. 1). They are always present in the inIlammatory inIiltrate oI chronic liver
disease. However, neutrophil inIiltration is most prominent in alcoholic hepatitis
and extravasation and transmigration oI neutrophils into the liver tissue are
critical Ior neutrophil-induced injury and cytotoxicity.
Up to now the role oI T-lymphocytes in liver disease is still ill-understood.
Previously a role was suggested oI T-cells in liver injury by activating KupIIer
cells to produce TNE- (30) However there is also a considerable amount oI data
demonstrating that T-cell activation against liver antigens (aIter a transient
cellular immune attack) induces tolerance and not immunity (31) and a recent
study suggests that at least natural killer T-cells might not concert in immune-
mediated liver injury (32). Eurthermore, other studies described the liver as
graveyard Ior T-cells (33).
LIVER INELAMMATION
Liver inIlammation not only in many animal models (e. g. aIter CCl
4
or
thioacetamide (TAA) administration) but also in humans may not be initiated by
the death oI (apoptosis or necrosis) oI liver parenchymal cells but by liver
resident and by recruited inIlammatory cells. The hepatocellular stress induced by
hepatotoxins, or by viruses, may lead to activation oI liver resident macrophages
on one side and to the release oI chemokines on the other side (1, 2, 15).
ProinIlammatory cytokines are Interleukin-1, InterIeron-gamma (IEN-), whose
tissue concentration increases early aIter toxin administration (34), Iollowed by
Tumor Necrosis Eactor-, and Interleukin-6 in a similar kinetics, which are
released by natural killer cells as well as by KupIIer cells. They induce an
increased expression oI cell adhesion molecules like ICAM-1 and VCAM-1 on
the portal and/or sinusoidal endothelial cells and a downregulation oI PECAM-1
112
(2). These molecules allow the recruitment and sinusoidal transmigration oI
inIlammatory cells toward their target, the hepatocyte (Fig. 1).
InIlammation perpetuates as long as the damaging noxae remain present or are
repeatedly administered. Leukocytes may enter the liver tissue mainly through
the portal tract, where the inIlammation mainly initiates. The hepatic inIiltrate
may include granulocytes, macrophages, but also T-lymphocytes, B-
lymphocytes, plasma cells (35). Resident and recruited inIlammatory
macrophages can stimulate matrix synthesis by activated mesenchymal cells and
its deposition by the action oI cytokines or growth Iactors, especially TNE-,
TGE-, and reactive oxygen intermediates/lipid peroxides (1, 2, 15).
COMPARISON OE CARBON-TETRACHLORIDE (CCL
4
)-INDUCED
LIVER DAMAGE WITH X-RAY-INDUCED LIVER INJURY
In an attempt to understand the mechanisms leading to recruitment oI
inIlammatory cells into the liver parenchyma we compared two models oI liver
insult in the rat: administration oI CCl
4
on one side, and -irradiation applied
directly to the liver on the other.
AIter the administration oI CCl
4
, levels oI IEN-gamma rose 3-24 hours aIter
the treatment, Iollowed immediately by TNE- 6-24 hours aIter the treatment, the
levels oI TGE- were enhanced later 9-24 hours aIter the treatment (Table 2).
PECAM-gene expression was downregulated 24-48 hours aIter the treatment, and
ICAM was upregulated 9-48 hours aIter the treatment. IEN-gamma-treatment
decreased PECAM-1-gene-expression in isolated sinusoidal endothelial cells and
mononuclear phagocytes (MNPs) in parallel with an increase in ICAM-1-gene-
expression in a dose and time dependent manner. In contrast, TGE--treatment
increased PECAM-1-expression. Additional administration oI IEN- to CCl
4
-
113
Table 2. Comparison oI the regulation oI some inIlammatory Iactors in CCl
4
-induced and X-ray-
irradiation induced liver damage.
Mediators and Adhesion CCl
4
-induced rat X-ray-induced rat
molecules liver damage liver injury
IL-1
TNE-
IL-6
TGE- late early
CINC-1
IP-10
MIP-3
KC
PECAM-1 no change -
ICAM-1
VCAM-1
treated rats and observations in IEN-
-/-
mice conIirmed the eIIect oI IEN- on
PECAM-1 and ICAM-1-expression observed in vitro and increased the number
oI ED1-expressing cells 12 h aIter administration oI the toxin. The early decrease
oI PECAM-1-expression and the parallel increase oI ICAM-1-expression
Iollowing CCl
4
-treatment is induced by elevated levels oI IEN- in livers and may
Iacilitate adhesion and transmigration oI inIlammatory cells. The up-regulation oI
PECAM-1-expression in sinusoidal endothelial cells and mononuclear
phagocytes aIter TGE--treatment suggests the involvement oI PECAM-1 during
the recovery aIter liver damage (26).
Similarly to CCl
4
administration, a single irradiation oI the rat liver induced
increase oI several chemokines (e. g. CINC1 (IL-8), IP-10, MCP1, MIP-3, MIP-
3, MIG and ITAC) gene expression (Table 2). Moreover, CINC1 (IL8), MCP1
and IP-10 serum levels were signiIicantly increased. In Iact, irradiation oI the
liver induces up-regulation oI the genes oI the main proinIlammatory
chemokines, probably through the action oI locally synthesized proinIlammatory
cytokines. Nevertheless, the recruitment oI inIlammatory cells is not observed to
the irradiated rat liver (36).
Interestingly, signiIicant radiation-induced increase oI ICAM-1, VCAM-1,
junctional adhesion molecule-1 (JAM-1), 1-integrin, 2-integrin, E-cadherin,
and P-selectin-gene-expression could be detected in vivo in the irradiated rat liver,
while PECAM-1-gene-expression remained unchanged. These Iindings suggest
that liver irradiation modulates adhesion-molecules-gene-expression probably
through acute-phase-cytokines. However, PECAM-1 gene expression is not
aIIected. This may be one reason Ior the lack oI the inIiltration oI extrahepatic
inIlammatory cells aIter irradiation in this model (37), when compared to the
CCl
4
or to acetaminophen induced inIlammation (38).
LIVER DAMAGE REPAIR
When the injury is recurrent (or "chronic"), matrix deposition occurs in excess
oI resorption as a result oI an imbalance between Iibrogenesis and Iibrolysis
leading to scar Iormation. Herein chronic tissue destruction with missing or slow
regeneration also providing the space Ior matrix deposition may be oI special
importance. As scarring progresses Irom bridging Iibrosis to the Iormation oI
complete nodules it results in an architectural distortion and ultimately in liver
cirrhosis. Liver Iibrosis is a common sequel to diverse liver injuries such as
chronic viral hepatitis, ethanol, biliary tract diseases, iron or copper
accumulation. Erom the
toxic animal models oI liver Iibrosis we have learnt that Iibrogenesis may
result Irom recurrent small liver injuries. These per se would result in complete
tissue repair, suggesting that activation oI the Iibrosis process with matrix
114
deposition may not be a primarily cellular problem but that oI a recurrence oI the
damaging noxae within a certain time window (2).
During liver damage a large number oI cytokines are synthesised locally
among which TGE-, TNE-, platelet-derived growth Iactor and insulin-like
growth Iactor-I are thought to be oI special importance Ior liver Iibrogenesis.
The processes oI liver repair and Iibrogenesis resemble that oI a wound-healing
process. Eollowing injury and acute inIlammation response takes place resulting in
moderate cell necrosis and extracellular matrix damage. AIter that tissue repair
takes place where dead cells are replaced by normal tissue with regeneration oI
specialised cells by proliIeration oI surviving ones or generation Irom stem cells,
Iormation oI granulation tissue, tissue remodelling with scar Iormation.
Liver Iibrosis is deIined as an abnormal accumulation oI extracellular matrix
in the liver. Its endpoint is liver cirrhosis which is responsible Ior a signiIicant
morbidity and mortality. Cirrhosis is an advanced stage oI Iibrosis, characterised
by Iormation oI regenerative nodules oI liver parenchyma separated by Iibrotic
septa, which result Irom cell death, aberrant extracellular matrix deposition and
vascular reorganisation. Advanced liver Iibrosis results in cirrhosis, liver Iailure,
and portal hypertension and oIten requires liver transplantation (1,2,15).
Accumulating data Irom clinical and laboratory studies demonstrate that even
advanced Iibrosis and cirrhosis are potentially reversible. The hepatic stellate cells
have been identiIied as the pivotal eIIector cells orchestrating the Iibrotic process
and, Iurthermore, reversibility appears to hinge upon their elimination (1, 2, 15).
Removing the insult and stopping the persistent inIlammatory stimuli is
probably the best way to prevent progression oI Iibrosis; this has been shown in
many patients with chronic hepatitis C and in smaller numbers oI patients with
autoimmune hepatitis. Clinical data conIirmed that, providing appropriate,
targeted treatment to patients with histologically advanced liver disease,
especially those with autoimmune hepatitis, may improve their long-term
outcome (39-41). Eurthermore, it was shown that, cirrhosis due to chronic
hepatitis B might be reversible in patients who respond to antiviral therapy (41).
Nevertheless, prevention oI the progression oI Iibrosis to cirrhosis remains the
major clinical goal. The poor prognosis oI cirrhosis is aggravated by the Irequent
occurrence oI hepatocellular carcinoma (2).
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Re c e i v e d : July 11, 2008
Ac c e p t e d : July 23, 2008
Author`s address: ProI. Dr. G. Ramadori, Department oI Internal Medicine, Section oI
Gastroenterology and Endocrinology, Georg-August-University Gttingen, Robert-Koch-Strae
40, 37075 Gttingen, Germany; phone:49-551-396301 Iax: 49-551-398596; e-mail:
gramadomed.uni-goettingen.de
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