Pathogenesis Of Liver Fibrosis

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Ayman Alsebaey, MD.
Lecturer of Hepatology,
National Liver Institute.

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 It is a reversible wound-healing response to either acute or chronic
cellular injury that reflects a balance between liver repair and scar
formation.
 Acute conditions e.g. hepatitis is associated with transient and
reversible changes in liver architecture.
 Chronic conditions unfortunately is characterized by progressive
substitution of the liver parenchyma by scar tissue.
 The continuous hepatocyte regeneration stand for the progressive
scar formation.
 Liver fibrosis is a dynamic process in which increased synthesis of
matrix components and a failure of physiological mechanisms of matrix
turnover.
What is liver fibrosis?

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Hepatitis, NASH
ASH, Hemochromatosis
DILI, Wilson, Autoimmune, PSC
PBC
Hepatocyte Injury
HSCs activationFibrosis
Cirrhosis

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 Fibrosis provides mechanical stability.
 Inflammatory cells contribute to the removal of cellular
debris.
 Inflammatory signals also exert important functions in
the promotion of liver regeneration.
Is liver fibrosis beneficial?

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 It’s a constellation of extracellular molecules secreted by the cells to do
structural and biochemical support.
 it is present between the hepatocytes and liver sinusoidal endothelial cells
“LSECs”
 ECM is formed of interlocking mesh of fibrous proteins and
glycosaminoglycan.
 SIMPLY it is the road and the streets around the home “cells”. If
blocked, not paved the home begins troubles.
 The homeostasis of ECM is dependent on the balance of:
 matrix metalloproteinases (MMPs)  ECM
 tissue inhibitors of matrix metalloproteinases (TIMPs) ECM.
What is extracellular matrix [ECM]?

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 How is altered?
 Marked increase of TIMP 1 and 2.
 TIMP-1 is anti-apoptotic effects on HSCs  survival with progressive
fibrosis.
 Accumulation of other matrix proteins e.g. elastin, hyaluronan,
proteoglycans and fibronectin.
 What is the impact of ECM alternation:
 Endothelial cells alternation “capillarization”  impaired transport of
solutes from the sinusoid to the hepatocytes  hepatocyte dysfunction
“altered cell behaviour”.
 Altered ECM is a signal for more fibrosis.
What is the impact of ECM alternation?

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What are the implicated or accused cells of liver fibrosis?
Liver
fibrosis
Hepatic
stellate cells
(HSCs)
Portal
fibroblasts
Fibrocytes
Bone
marrow-
derived
mesenchym
al stem cells
(MSCs)
Epithelial to
Mesenchymal
Transition
(EMT)
Myofibrocyte
“MFs”

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 Portal fibroblasts
 They are implication in liver fibrosis due to biliary and cholestatic liver
injuries.
 They are activated to MFs.
 They have different genetic profiles and signaling responses than the HSCs.
 Fibrocytes
 Fibrocytes originate from hematopoietic stem cells and migrate to the liver,
proliferate and secrete growth factors that promote deposition of the ECM.
 Bone marrow-derived MFs
 Bone marrow-derived mesenchymal stem cells (MSCs)  myofibrocytes.
 Epithelial to Mesenchymal Transition (EMT)
 Hepatocytes and cholangiocytes  undergo EMT  acquire mesenchymal
features “MFs”.
 A lot of debate is present especially against it.

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 We are cells that live in the space of Disse as perisinusoidal cells in the
subendothelial space between hepatocytes and sinusoidal endothelial
cells.
 We are derived from mesodermal-derived multipotent mesenchymal
progenitor cells (MMPC) so we express neural and mesenchymal lineage
markers.
 Our functions are:
 Activation of the immune system by through secretion of cytokines and
chemokines and interacting with immune cells.
 Angiogenesis.
 Regulation of oxidant stress.
How HSCs introduce themselves?

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 HSC is the primary effector cell, orchestrating the deposition of
ECM in normal and fibrotic liver.
 They lay fibrous tissue and have receptors for inflammatory signals.
 Inactive HSCs are characterized by:
 A lot of retenoids “Vitamin retinyl esters” storage.
 Lipid droplets so its old name was Ito and lipocytes.
 Synthesis of glial fibrillary acidic protein (GFAP).
 On activation to myofibrocytes
 There are loss of the above, de novo expression of receptors for
fibrogenic, chemotactic, and mitogenic factors and expression of α-
smooth muscle actin so being contractile.
Let us navigate with HSCs

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Life cycle of activated HSCs
Quiescent
inactive HSCs
Active HSCs Resolution
HSCs
InitiationActive HSCs
Senescence
Apoptosis
Proliferation, chemotaxis,
fibrogenesis, contractility,
matrix degradation, retinoid
loss, and WBC chemo-
attractant/cytokine release
Removal of injurious agent

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 Initiation (pre-inflammatory stage):
 It is the early changes in gene expression and phenotype.
 The HSCs is activated in auto and paracrine manner from the
neighboring injured cells.
 Perpetuation:
 The continuous presence of inflammatory milieu cause prolonged
survival of the HSCS “perpetuation”.
 It lays down the fibrous tissue with accumulation of extracellular
matrix.
 Proliferation, chemotaxis, fibrogenesis, contractility, matrix
degradation, retinoid loss, and WBC chemo-attractant/cytokine release.
 Resolution phase if the injury subsides:
 HSCs go to apoptosis, senescence, or quiescence.

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Who and how do activate the HSCs?
Hepatocytes Reactive oxygen species
Natural killer cells
Platelets
Leucocytes
Lymphocytes
Kupffer Cells
Liver sinusoidal
endothelial cells Toll-like receptors
Epigenetics
Genes
Nuclear Receptors
MicroRNAs
DNA demethylation
Growth factor signaling
Neuroendocrine
signaling
SIGNALING
Adipokine signaling
Chemokine signaling
Fibrogenic signaling

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 Hepatocytes:
 The injured hepatocytes undergo apoptosis (Fas and TRAIL mediated) with release of apoptotic
bodies, DNA, fibrogenic lipid peroxides and DAMPs.
 All of them activate the HSCs.
 Liver sinusoidal endothelial cells (LSECs):
 The endothelial injury causes loss of the fenestrations which activate the HSCs.
 Kuppfer cells (KCs):
 They are indwelling liver macrophages.
 Together with the recruited monocytes, secrete cytokines that cause fibrosis progression,
 They express CCR1, CCR2, CCR6, CCR8, and CCR9 that are essential for conversion of
monocytes to proinflammatory macrophages that augment the fibrosis milieu.
 There is recruitment of high Gr1hi (Ly6chi) expression macrophages.
 Antifibrogenesis monocytes:
 Dendritic cells promote fibrosis resolution via the release of MMP-9, a gelatinase active on
collagens I, III, IV, and elastin.
 The Gr1lo monocyte subset expresses chemokine receptors with anti-inflammatory and
antifibrogenic functions, such as CXCR1 and CX3CR1.
Cellular activation of HSCs

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 Lymphocytes:
 CD4 T-helper lymphocytes secrete cytokines the activate the HSCs.
 Th2 is more fibrogenic than Th1.
 On the hand they also aid in the resolution of liver fibrosis
 Th1  INF-γ  apoptosis of the myofibrocytes.
 Th17  IL17 mainly, IL21, IL22
 It activates myofibrocytes and KCs
 It shifts macrophages from M2 "repair" to M1 "killer" macrophages.
 Despite this IL22 is hepatoprotective and antifibrogenic cytokine.
 B lymphocytes
 They fibrogenic but the mechanism is unknown.
 Treg:
 It is antifibrotic.
 Innate lymphoid cells (ILCs):
 A recently discovered cell population, which express many TH cell-associated cytokines, but no
cell-surface markers of known lymphoid lineage.
 Hepatocytes  IL33  ILC2 expansion  IL13 and activation of (STAT) 6 pathway  HSCs
activation.
Cellular activation of HSCs

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 Natural killer cells (NK)
 NK cells  inhibit and kill activated HSCs  antifibrotic effects.
 Retinoid [retinoic acid early inducible 1 (RAE1)] activate NK cells  secrete INF-γ plus
“FasL and TRAIL”  HSCs apoptosis.
 This effect is present on early activated HSCs as containing the retinoic acid but fully
active cells are devoid of it.
 NK T-cells:
 has diverse effects on liver fibrosis depending on the stage of the disease
 Leukocytes:
 Neutrophils  reactive oxygen species (ROS) and NO  counteract the effect of superoxide on
collagen production.
 Platelets:
 They produce TGF-β1, PDGF and epidermal growth factor (EGF)  paracrine stimuli in HSC
activation and fibrogenesis.
 On the other hand several studies have described antifibrotic effects of platelets [the more
the platelet count, the less the liver fibrosis].
Cellular activation of HSCs

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Origin Cell Type Target Cell/Mechanisms of Action
BM
Macrophages
 Promote HSC survival by cytokines - Up-regulate TIMP-1 by cytokines
 Promote liver fibrosis as demonstrated by genetic or pharmacological ablation
 Promote fibrosis regression through MMP-12- and MMP-13-mediated ECM degradation and through killing of
HSCs by TRAIL
NK cells
 Active killing of HSCs by FasL and TRAIL
 Reduction of liver fibrosis in mice treated with poly I:C–activated NK cells
 Increased fibrosis in SCID-BEIGE mice lacking NK cells
NKT cells  Promote liver fibrosis through CXCL16-CXCR6- αGalCer treatment enhances NKT cell-mediated liver fibrosis
B lymphocytes  Promotion of collagen, but not α-SMA, expression in HSCs - Effects independent of Ig
T lymphocytes  No decrease in fibrosis observed in mice lacking CD4+ T cells, CD8+ T cells, and γ-δ T cells
Neutrophils
 Recruited in a TLR2-CXCL2-S100A9–dependent manner
 Play minor roles for liver fibrosis
ILC2  In response to IL-33, ILC2 expand and promote HSC activation and liver fibrosis through IL-13
Platelets
 Increased fibrosis in thrombocytopenic mice
 Decreased fibrosis in SCID mice receiving human platelets
 Repression of HSC activation by platelets through Met
Hepatocytes
 Promotion of HSC activation and liver fibrosis through heptocyte-secreted IL-33
 Apoptotic hepatocytes promote HSC activation through phagocytosis.
 Apoptotic hepatocytes increase inflammatory and profibrogenic cytokines in macrophages.
Liver
resident
Cholangiocytes
 Promotion of portal fibroblast activation by cholangiocyte-secreted CCL2
 Promotion of cholangiocyte proliferation through hyaluronan from myofibroblasts
LSECs
 LSECs from normal liver suppress HSC activation.
 LSECs from fibrotic liver lose the ability to suppress HSC activation.
 LSECs from fibrotic liver promote HSC activation depending on CXCR4 and FGFR-1 expression on LSECs.

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 ROS:
 Hepatocytes, macrophages, cholangiocytes and inflammatory cells  lipid
peroxidation especially in the presence of PDGF, TGF-β leptin and Angiotensin II 
ROS release  HSCs activation.
 NADPH oxidase is implicated in ROS formation  Homologs of NADPH oxidase
(NOX)  HSCs and KCs activation.
 Antioxidants and CYP2E1 inhibitors   liver fibrosis.
 Toll-like receptors (TLRs):
 CLD   intestinal permeability   portal flow of gut-derived microbial products
e.g. lipopolysaccharides (LPS)  activate TLR4, TLR9 and TLR2  activate HSCs
and KCs   BAMBI   TGF-β   liver fibrogenesis.
 High mobility group box 1 protein (HMGB1) is endogenous ligand that may activate
the above cascade without the need of LPS.
Molecular activation of HSCs

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 Gene transcription:
 There are increase gene transcription of factors of fibrogenesis and their downstream targets.
  Type 1 collagen, α-SMA, TGF-β-1, TGF-β receptors, MMP-2, TIMPs 1 and 2.
  downstream targets; Ets-1, Mef2, CREB, Egr-1, Vitamin D receptor, Foxf1, JunD and
C/EBPβ.
 Nuclear receptors:
 PPARγ  down-regulates HSC activation  fibrogenesis.
 RXR an FXP  collagen production.
 Steroids and antibiotics  PXR  dimerizes RXR to induce cytochrome p450 
fibrogenesis.
 MicroRNAs:
 TGF-β and LPS in cultured HSCs   mi-R29  ECM proteins, including collagens.
 miR-221/222  fibrogenesis.
 MiR-19b  TGF-β signaling. It was found to that its expression is decreased in patients with
advanced fibrosis.
Gene regulations in activated HSCs

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 DNA methylation and histone modifications:
 DNA methylation of genes expressed in quiescent HSCs contributes to
the maintenance of the quiescent phenotype.
 During activation  HSCs express DNA-methyl binding proteins
(MeCP2)  silencing of antifibrogenic genes and increase the
expression of histone methyl transferases, leading to enhanced
transcription of collagen, TIMP-1 and TGF-β.
 Epigenetics
 Epigenetic changes  modulate fibrosis susceptibility.
 Offspring from the progeny of male fibrotic rat ancestors are found
to be more resistant to liver fibrosis than their counterparts with no
previous history of fibrosis.
Gene regulations in activated HSCs

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Detailed Life cycle of activated HSCs
Quiescent
inactive HSCs
Active HSCs Resolution
HSCs
InitiationActive HSCs
Senescence
Apoptosis
Proliferation, chemotaxis,
fibrogenesis, contractility,
matrix degradation, retinoid
loss, and WBC chemo-
attractant/cytokine release
Removal of injurious agent

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 HSCs proliferation:
 PDGF is the most potent mitogen.
 PDGF also stimulates Na+/H+ exchange.
 Other mitogens: VEGF, thrombin and its receptors, transforming growth factor α
(TGFα), epidermal growth factor (EGF), keratinocyte growth factor, and bFGF.
 Downstream pathways:
 PI3 kinase and ERK/MAP kinase
 PDGF antagonism  potential anti-fibrotic strategy.
 Sorafenib  a multiple receptor tyrosine kinase inhibitor targeting the PDGF
receptor and the Raf/ERK signaling pathway  is effective in advanced HCC
patients.
 Sorafenib  displays anti-fibrotic activity.
 HSC remodels the ECM into one rich in fibril-forming collagens, particularly types I
and III.
 The ECM components in turn act in a positive feedback loop by releasing
additional matrix-bound growth factors resulting from increased protease activity, as well
as increasing liver stiffness, both of which propagate HSC migration and contraction.

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 HSCs chemotaxis:
 Usually there is chemotaxis of the HSCs to the site of injury.
 The usual chemokines are including VEGF, PDGF, MCP-1, CXCR4,
CXCR3 and CCR5 and its ligand RANTES.
 Hypoxia:
 Is another activator of HSC migration via VEGF and ROS.
 ECM:
 Cellular fibronectin containing an alternatively spliced domain A
(EIIA) has been shown to induce motility of HSCs.
 Adenosine:
 Enhanced adenosine signaling  stimulates HSC fibrogenesis.
 Caffeine   adenosine signaling  antifibrotic effect.

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 HSCs in fibrogenesis:
 ECM:
 In the normal liver  ECM is composed of collagens IV and VI.
 Fibrosis  ECM is composed of collagens I and III and cellular fibronectin.
 HSCs  secrete collagen type I  fibrosis.
 It is mediated by TGF-β, retinoids and angiotensin II.
 TGF-β:
 TGF-β is the most profibrogenic cytokine in the liver.
 It stimulates the production of collagen type I, cellular fibronectin and proteoglycan.
 TGF-β is produced by Kupffer cells, liver sinusoidal endothelial cells, hepatocytes and HSCs
and has paracrine/autocrine effects on HSCs.
 It stimulates SMADs signaling.
 TGF-β1 may also contribute to liver homeostasis during regeneration, therapeutic
antagonization of TGF-β1 is challenging.
 Connective tissue growth factor (CTGF/CCN2):
 It is released in response to hyperglycemia, hyperinsulinemia and alcohol-induced cellular
injury.
 It stimulates the HSCs independent of TGF-β unlike the hepatocyte.

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 Adipokines:
 There is similarity between the adipocyte and the HSCs as containing LDs.
 Leptin:
 Leptin  leptin receptor (OB-R)  JAK 2 and STAT 3 pathway  HSC fibrogenesis and
activates Kupffer cells, macrophages and endothelial cells to produce TGF-β1.
 Leptin partially suppresses PPARγ, which can reverse HSC activation and maintain
senescence.
 Leptin   norepinephrine activity  fibrogenesis.
 Adiponectin:
 Is a counter-regulatory hormone of leptin, inhibits hepatic fibrogenesis both in vivo and in
vitro.
 Neurochemical and neurotrophic factors:
 Activated HSCs express specific endocannabinoid receptors CB1 and CB2 with 2
opposing effects.
 CB1 stimulation   fibrogenesis
 CB2 stimulation   fibrogenesis  hepatoprotective.
 Serotonin and thyroid hormones are also involved in fibrogenesis.

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 HSCs contractility:
 HSCs acquire contractility with  formation of the cytoskeletal protein α-smooth muscle actin
(α-SMA). This contractility  perisinusoidal constriction and portal hypertension. Endothelin-1 is
an agonist of contractility.
 Retinoid loss of HSCS:
 Retinoid is stored as retinyl esters "perinuclear droplets".
 Lecithin retinol acetyl transferase (LRAT) catalyzes the esterification of retinol into retinyl
ester in liver. Activated HSCs  retinyl esters hydrolysis  retinol release outside HSCs.
 PPARs:
 Their expression decreases with the activation of HSCs. Forced expression of PPARγ  
TGF-β1 signaling   collagen expression.
 Adipose differentiation related protein (ADRP):
 an intracellular lipid storage protein. Its expression is reduced during HSC activation.
 Autophagy:
 It produces energy for activated HSCs by digestion of intracellular lipids "LD".
 HSCs in inflammation and WBCs chemoattraction
 HSCs may produce chemokines that amplify inflammatory responses by inducing migration of
inflammatory cells. HSCs promote ICAM-1- and VCAM-1-dependent adhesion and migration of
lymphocytes.

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The Gut Microbiota/TLR Pathway:
 Bacterial translocation is a cardinal feature of chronic liver disease. It produces
chronic inflammatory status.
 Microbiota  pathogen-associated molecular patterns (PAMPs) e.g. LPS 
stimulate TLR e.g. TLR4.
 TLR4 signaling   TGF-β decoy receptor, BMP and activin membrane bound
inhibitor (BAMBI)  TGF-β-mediated HSC activation.
 The HSCs activation   expression of chemokines and adhesion molecules 
recruitment of macrophages to sites of fibrogenesis
 Microbiota and HSCs activation  stimulate LSECs directly and indirectly through
fibronectin produced from HSCs.
 TLR9 is also profibrogenic.
 TLR3 and 7 prevent liver fibrosis by stimulation of the NK cells but it was found to
downregulated in liver fibrosis.
Triggers of Inflammatory Signaling

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Class Mediator Target Cell and Mechanisms of ActionGutmicrobiotaaxis/TLR
pathway
TLR4
 Directly stimulates HSC to down-regulate BAMBI and produce
chemokines in BDL and CCl4-induced liver fibrosis
 Stimulates KCs to produce proinflammatory and fibrogenic cytokines
that activate HSCs in ALD and NASH
 Stimulates LSECs to induce angiogenesis that promotes HSC
activation and fibrosis
TLR2
 Stimulates KCs to produce cytokines that activate HSCs in NASH-
Stimulates macrophages in intestine, which promote bacterial
translocation
TLR9
 Stimulates KCs to produce cytokines that activate HSCs in NASH-
Stimulates HSCs by host DNA released from apoptotic hepatocytes
TLR3
 Stimulates NK cells to produce IFN-γ that induces antifibrotic effect by
killing HSCs
TLR7  Stimulates DCs to produce type I IFN that inhibits liver fibrosis

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 Inflammatory Cytokines:
 IL-1β:
 IL-1β is secreted by the macrophages. It is powerful inflammatory cytokine.
 IL-1β   TIMP1 and  BAMI  fibrosis
 TNF-α:
 Main functions are hepatocyte apoptosis, immune cell activation, and HSC activation.
 TNF-α   TIMP1 and  BAMI  fibrosis
 IL-17:
 CD4+ Th17 T cells  secrete IL-17  activation of NF-κB and STAT3  17A stimulates both
KCs and HSCs to produce IL-6, TNF-α, and TGF-β.
 IL-20:
 It acts on both the hepatocytes and the HSCs.
 IL-20  promotes the activation, proliferation, and migration of HSCs.
Triggers of Inflammatory Signaling

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Inflammatory Cytokines:
 IL-22:
 IL-22 is implicated in the defense against bacterial infections by inducing antimicrobial
proteins, including β-defensin, as well as in cell proliferation, tissue repair, and wound healing.
 IL-22  HSC senescence.
 Liver cirrhosis is associated with  IL-22, especially complicated with ascites, hepatorenal
syndrome, spontaneous bacterial peritonitis, and reduced survival.
 IL-33:
 Injured hepatocytes  IL-33 secretion  ILC2  IL-13  HSCs activation.
 TGF-β:
 Macrophages  TGF-β  Smad pathway  HSCs activation  type I and III collagen
production.
 It represses NK cells  prevent HSCs apoptosis.
 TGF-β is secreted in inactive form that is activated with MMPs, pH, trombospondin-1, reactive
oxygen species (ROS), or αv integrins.
Triggers of Inflammatory Signaling

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IFNs
 Types:
 Type I IFNs (IFN-α and IFN-β) and type II IFN (IFN-γ).
 Antifibrotic effects:
 IFN-γ   proliferation and α-SMA expression. It also  NK cell activation.
 IFN-α  basal and TGF-β-induced collagen gene transcription in HSCs.
Triggers of Inflammatory Signaling

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Class Mediator Target Cell and Mechanisms of Action
Inflammatorycytokines
IL-1β
 Up-regulates TIMP-1 and down-regulates BAMBI in HSCs
 Promotes HSC survival
 Promotes lipid accumulation and cell death in hepatocytes during NASH and ALD
IL-33
 Secreted from damaged hepatocyte
 Stimulating ILC2 to produce IL-13 that, in turn, activates HSCs
TNF-α
 Induces hepatocyte apoptosis
 Up-regulates TIMP-1 and down-regulates BAMBI in HSCs
 Promotes HSC survival and proliferation
 Activates liver macrophages
IL-17
 Stimulates KCs and HSC to produce IL-6, TNF-α, and TGF-β
 Activates NF-κB and STAT3 in KCs and HSCs
 HSC activation through STAT3
IL-20
 Promotes activation, proliferation, and migration of HSCs
 Prevents hepatocyte injury
IL-22
 Induces HSC senescence through STAT3-p53
 HSC senescence inhibits liver fibrosis.
IFN-γ
 Suppresses HSC proliferation and activation
 Activates NK cells to promote HSC killing

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Chemokines:
 The main function is the recruitment of immune and nonimmune cells into the inflamed sites.
 CCL2:
 Is produced by the HSCs and the NK cells  recruitment of macrophages and the monocytes to
the liver.
 It induces also HSCs activation.
 CCL5:
 Activates its receptor (CCR1 and CCR5) on macrophages and HSCs  activation of HSCs.
 Chemokine (C-X3-C motif) ligand (CX3CL)1/chemokine (C-X3-C motif) receptor 1
interaction on liver macrophages negatively regulates liver inflammation
 Other cytokines:
 CXCL16 and its receptor, CXCR6, CCL20, and its receptor, CCR6, and CXCL9 and CXCL10
and their receptor, CXCR3,
Triggers of Inflammatory Signaling

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Class Mediator Target Cell and Mechanisms of Action
Chemokines
CCL2 (MCP-1)
Macrophage and HSC recruitment
HSC activation
CCL5
Macrophage and HSC recruitment
HSC activation
CXCL9
Suppresses HSC activation
Inhibits angiogenesis that inhibits liver fibrosis
CXCL10
Promotes hepatocyte death and HSC activation
Inhibits NK cell-mediated HSC inactivation
CX3CL1
Prolongs KC survival
Promotes anti-inflammatory property in KCs

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Downstream Signaling Pathways Linking Inflammation and Fibrosis
 NF-κB
 NF-κB is a transcription factor that acts as a key regulator of inflammation and cell death.
 It is stimulated by TLRs, IL-1β, and TNF-α.
 Effect of activation
 Physiological  prevents hepatocyte apoptosis.
 Pathological over-activation  liver inflammation by increased production of
proinflammatory, NF-κB-regulated cytokines, such as TNF-α, IL-1β, and IL-6.
 Effect on the HSCs:
 NF-κB   HSC survival  fibrogenesis.
 NF-κB  HSC survival   TLR4- and TNF-α-mediated down-regulation of BAMBI  
TGF-β   fibrogenesis.
Triggers of Inflammatory Signaling

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Downstream Signaling Pathways Linking Inflammation and Fibrosis
 c-Jun N-Terminal Kinases
 c-Jun N-terminal kinases (JNKs) are mitogen-activated protein kinases.
 They are activated by TLRs, IL-1β, TNF-α, ROS, and saturated free fatty acids (FFAs).
 In HSCs, JNK exerts a direct profibrogenic role by promoting PDGF, TGF-β, and angiotensin
II–induced proliferation, α-SMA expression, and/or collagen production.
 JNK plays important roles in TGF-β- and PDGF-mediated Smad2 and Smad3
phosphorylation.
 JNK also regulates hepatic steatosis, cell death in hepatocytes, and inflammatory gene
expression in immune cells, all of which modulate liver fibrosis.
Triggers of Inflammatory Signaling

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Ayman Alsebaey, MD.
Lecturer of Hepatology,
National Liver Institute.

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