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Int. J. Mol. Sci. 2014, 15(6), 10578-10604; doi:10.3390/ijms150610578
Abstract: Hepatic fibrosis is a wound-healing response to various chronic stimuli, including viral hepatitis B or C infection. Activated myofibroblasts, predominantly derived from the hepatic stellate cells (HSCs), regulate the balance between matrix metalloproteinases and their tissue inhibitors to maintain extracellular matrix homeostasis. Transforming growth factor-β and platelet-derived growth factor are classic profibrogenic signals that activate HSC proliferation. In addition, proinflammatory cytokines and chemokines coordinate macrophages, T cells, NK/NKT cells, and liver sinusoidal endothelial cells in complex fibrogenic and regression processes. In addition, fibrogenesis involves angiogenesis, metabolic reprogramming, autophagy, microRNA, and epigenetic regulations. Hepatic inflammation is the driving force behind liver fibrosis; however, host single nucleotide polymorphisms and viral factors, including the genotype, viral load, viral mutation, and viral proteins, have been associated with fibrosis progression. Eliminating the underlying etiology is the most crucial antifibrotic therapy. Growing evidence has indicated that persistent viral suppression with antiviral therapy can result in fibrosis regression, reduced liver disease progression, decreased hepatocellular carcinoma, and improved chances of survival. Preclinical studies and clinical trials are currently examining several investigational agents that target key fibrogenic pathways; the results are promising and shed light on this debilitating illness.
Fibrotic diseases account for up to 45% of the total deaths in developed countries . However, active antifibrotic therapies for established cirrhosis are currently unavailable, leaving the needs of cirrhosis patients unmet. Understanding the molecular mechanisms of liver fibrogenesis can shed light on how to ameliorate this debilitating disease.
Chronic hepatitis B and C are major causes of liver fibrosis progression and cirrhosis worldwide. Long-term hepatic necroinflammation is the main contributor to both fibrogenesis and carcinogenesis of the liver. However, growing lines of evidence indicate that successful antiviral therapy may halt or reverse liver fibrosis, especially in the early stages. Several molecular target agents (e.g., sorafenib) have been shown to improve experimental liver fibrosis. Targeted therapies using these agents against fibrogenesis may be the next step in the discovery of an antifibrotic treatment.
In this paper, we review and discuss the pathobiology of liver fibrosis, the clinical aspects and molecular mechanisms of viral-hepatitis-related fibrosis and cirrhosis, and the benefits of antiviral therapy. Finally, we evaluate and explore potential molecular target therapies for liver fibrosis.
2. Pathobiology for Liver Fibrogenesis and Regression
Hepatic fibrosis is a wound-healing response to various chronic stimuli, including hepatitis viral infection, metabolic disorders, alcohol abuse, and autoimmune attacks in liver (Table 1). During the course of fibrogenesis, various mediators, which are mainly produced by Kupffer cells, resident hepatic cells, and infiltrating inflammatory cells,, activate myofibroblasts, causing excess extracellular matrix (ECM) accumulation. Fibrosis is the resulting imbalance between ECM production and resolution. The excessive ECM deposition (especially type 1 collagen deposition) disorders the normal architecture of the liver, resulting in fibrosis progression and subsequent cirrhosis . At least five responses to injury-induced functional or physical disruption of epithelial cells can provoke tissue fibrosis, including cell death, dysregulation of metabolic pathways (resulting in cell stress, endoplasmic reticulum stress, and the generation of reactive oxygen species), epithelial-to-mesenchymal transition (EMT), transforming growth factor (TGF)-β activation, and immunological responses .
|Causes of Fibrosis||Specific Therapies for Underlying Etiology|
|Hepatitis B||Conventional and pegylated interferon, lamivudine, adefovir, telbivudine, entecavir, tenofovir|
|Hepatitis C||Conventional and pegylated interferon/ribavirin, boceprevir, telaprevir, simeprevir, sofosbuvir, daclatasvir/asunaprevir|
|Steatosis||Lifestyle modification, obeticholic acid|
|Primary biliary cirrhosis||Ursodeoxycholic acid|
|Primary sclerosing cholangitis||Ursodeoxycholic acid|
|Hemochromatosis||Therapeutic phlebotomy, deferoxamine|
|Wilson’s disease||Penicillamine, trientine hydrochloride, zinc|
2.1. The Major Factor of Fibrogenesis: Myofibroblasts and Hepatic Stellate Cells
The key factor of fibrogenesis, myofibroblasts, are highly proliferative cells that exhibit enhanced survival and migrate to and accumulate at sites of liver injury in response to the autocrine and paracrine stimuli of various growth factors, cytokines, lipid mediators, or adipokines produced by the injured liver . Heterogeneity among cell populations, including hepatic stellate cells, portal fibroblasts, and bone-marrow derived fibroblasts, is a relevant contributor to the myofibroblast pool . Previous studies have suggested that the EMT from cholangiocytes and hepatocytes contributes to hepatic fibrosis ; however, novel sophisticated fate tracing experiments have discounted the contribution of these epithelial cells to myofibroblasts [7,8]. Mederacke et al. used a novel LratCre-transgenic mouse that marked 99% of hepatic stellate cells (HSCs), revealing that HSCs account for 82% to 96% of the myofibroblasts in models of toxic, cholestatic, and fatty liver disease . Their study confirmed that HSCs are the major contributors to fibrogenesis.
HSCs account for 5% to 8% of total liver cells , and their functions include vitamin A homeostasis ; ECM synthesis and degradation; sinusoidal blood flow regulation ; erythropoietin expression in the perinatal period ; contribution to the plasminogen activation system ; and secretion of paracrine, juxtacrine, autocrine, and chemoattractant mediators.
Responding to various stimuli from parenchymal injury, the inflammatory reaction generates large panels of profibrogenic signals (transcriptional factors and morphogens), and, subsequently, quiescent HSCs are primed and activated by the signals of persistent tissue injury . The myofibroblastic phenotype of these activated HSCs is characterized by the expression of α-smooth muscle actin (α-SMA); a parallel loss of retinoids and lipid droplets; a reduction in the expression of adipogenic/lipogenic factors; and a de novo expression of receptors for fibrogenic, chemotactic, and mitogenic factors . The balance between matrix metalloproteinases (MMPs, ECM degrading enzymes) and tissue inhibitors of the metalloproteinase family (TIMPs) is strongly regulated by HSCs. At the early stages of fibrogenesis, HSCs express MMPs, but not TIMPs, causing the liver ECM to degrade. However, fully activated HSCs express TIMPs and inhibit MMPs, thereby inhibiting ECM degradation . In addition, the ECM molecules, matrix stiffness, and collagen cross-linking promote the HSC activation process through integrin-mediated pathways .
2.2. Inflammation: The First Step of Fibrogenesis
Interaction with macrophages and inflammatory signals drives HSC activation. Lipopolysaccharide (LPS) originating from intestinal microflora can activate HSCs through the toll-like receptor 4 signaling pathway, , which increasingly express proinflammatory cytokines and chemokines (e.g., CCL2, CCL4, and CX3CL1) [17,18]. CCL2 (MCP-1) recruits inflammatory Gr1+/Ly6C+-expressing monocytes from the peripheral blood into the injured liver and promotes hepatic fibrosis , and CX3CL1 (fractalkine) protects against hepatic fibrosis by controlling the differentiation of infiltrating monocytes into proinflammatory macrophages and the survival of infiltrating monocytes . CCR1 and CCR5 play distinct roles in promoting hepatic fibrosis in Kupffer cells and HSCs . RANTES (regulated on activation normal T cell expressed and secreted), CCR1, and CCR5 are appreciably up-regulated in patients with hepatic cirrhosis, indicating the activation of the CC chemokine system in human fibrogenesis .
HSCs reside within the perisinusoidal space of Disse in close proximity to liver sinusoidal endothelial cells (LSECs), Kupffer cells, and dendritic cells; therefore, HSCs may indirectly influence the antigen-presenting function. Prior studies have demonstrated that HSCs express MHC-class II molecules and may present antigens to induce T-cell responses . However, in a recent study, highly purified HSCs did not present antigens to naive MHC-II-restricted CD4 T cells . HSCs function indirectly by mediating retinoid acid and TGF-β dependent regulatory T (Treg)-cell induction and the inhibition of Th17 cells primed by other antigen-presenting cells. These findings suggest that HSCs serve as regulatory bystanders that can enhance the differentiation and accumulation of regulatory T cells .
2.3. Molecular Mechanisms of Fibrogenesis
TGF-β1 is a common major profibrogenic cytokine in liver disease, promoting HSC activation, hepatocyte apoptosis, and ECM formation and inducing several profibrogenic mediators such as TIMP-1 . TGF-β1 is regulated by stimulatory activators (Smad 2 and 3) and inhibitory signals (Smad 7) . However, studies have suggested that the TGF-β1 secreted from Treg cells functions as an antiinflammatory and antifibrotic mediator . Several clinical studies have reported that patients with chronic HBV or HCV infections have elevated TGF-β1 serum levels [26,27].
The N-terminal latency-associated peptide domain of TGF-β cross-links with latent TGF-β binding proteins and the ECM. Upon liver injury, cholangiocytes express high levels of integrin αvβ6, which binds to the LAP portion of TGF-β1 and TGF-β3 . Myofibroblast activation involves the activation of the platelet-derived growth factor (PDGF) and connective tissue growth factor (CTGF), as well as TGF-β .
The PDGF receptor pathway is another key mitogen in HSC proliferation . PDGF stimulation can activate mitogen-activated protein kinase (MAPK) signaling involving the activation of Ras–Rac–Raf followed by the activation of mitogen-induced extracellular kinase, and extracellular signal-regulated kinase (ERK) and C-Jun nuclear kinase. In addition, PDGF stimulation can activate either the matrix-associated focal adhesion kinase or the phosphatidylinositol 3-kinase–Akt–p70S6 kinase-signaling pathway, leading to the activation of downstream kinases such as Akt and p70S6K .
2.4. Microenvironment Involving Fibrogenesis
2.4.1. Macrophage Polarization
Resident and recruited macrophages, which are key components in the liver homeostasis process, have dual roles in matrix deposition and remodeling, and regulate activated myofibroblasts (and their precursor populations) and endothelial cells . The activated macrophages produce TNF-α and IL-1, which, in turn, activate fibroblasts and induce the overproduction of ECM proteins .
Previous studies have demonstrated that the phagocytosis of apoptotic hepatocytes and cholangiocytes by macrophages can eliminate fibrosis [31,32]. Macrophages can also directly clear excess collagen . In response to environmental stimulation, macrophages undergo polarized activation, attaining an M1, M2, or M2-like activation status . The M1 subtype consists of a classically activated macrophages that exhibit inflammatory and microbicidal activity; the M2 subtype consists of alternatively activated macrophages, or wound-healing macrophages, that function in tissue repair and exhibit profibrotic activities; and the M2-like subtype consists of regulatory macrophages that contribute to the resolution of inflammation and fibrosis [3,35].
The key regulator of macrophage polarization belongs to the interferon regulatory factor (IRF)-signal transducer and activator of transcription (STAT)-suppressor of cytokine signaling (IRF-STAT-SOCS) families. Interferon-γ and the TLR-activated IRF-STAT signaling pathway activate the M1 phenotype through STAT1. IL-4 and IL-13 mediate STAT6 activation, and IL-3 mediates STAT5 activation to promote M2 polarization. IL-10 activates the M2-like phenotype through STAT3 [34,36]. Because of the secretion of IL-13 signals, Th2 cells can drive M2 polarization to produce TGF-β, which is activated by MMP-9  and subsequently activates HSCs to promote fibrosis. The Th1 responses drive M1 polarization and are associated with antifibrotic activity [5,30]. Subpopulations of macrophages can either mediate the destruction of ECMs directly or indirectly by inducing the release of MMPs (M1) or support cellular proliferation, stimulate the production of deposited ECM proteins, and promote the synthesis and secretion of new ECM molecules (M2) .
Hepatic macrophages enhance myofibroblast survival in a manner dependent on nuclear factor (NF)-κB, thereby promoting liver fibrosis . The proinflammatory and profibrogenic Gr1hi/Ly6Chi monocytes express CCR1, CCR2, CCR6, CCR8, and CCR9. After activation of these receptors, the infiltrating monocytes differentiate into proinflammatory macrophages and drive HSC activation [39,40]. The Gr1l monocyte subset expresses antiinflammatory and antifibrogenic chemokines, such as CXCR1 and CX3CR1 . The CX3CR1-CX3CL1 interaction promotes macrophage survival, inhibits inflammatory properties in macrophages, and results in a reduction of liver inflammation and fibrosis . The MMP-13 and MMP-9 produced by macrophages and dendritic cells facilitate fibrosis resolution [42,43].
2.4.2. T Cells and NK/NKT Cells
CD4+ lymphocytes, including Th1, Th2, Th17, and Treg cells, play vital roles in immune responses controlling fibrogenesis. Th1 cells release IFN-γ, reducing liver fibrogenesis by inhibiting the TGF-β-induced transduction cascade . Th2 cells promote liver fibrosis by producing IL13 . The number of Th17 cells, or IL17-positive lymphocytes, increases in patients with chronic hepatitis B or alcoholic liver disease and correlates with the severity of liver fibrosis [45,46]. In one study, hepatic IL-17 levels were elevated in experimental liver fibrosis . IL-17 directly induced the production of type I collagen in HSCs by activating the STAT3 signaling pathway. Furthermore, mice devoid of STAT3 signaling in HSCs (GFAP-STAT3−/− mice) were less susceptible to fibrosis compared with wildtype controls .
In addition to antiviral and antitumor properties, liver-specific NK and NKT cells exhibit antifibrotic effects. For example, NK cells can induce apoptosis in early-activated HSCs or promote senescence through a TRAIL-medicated pathway .
2.4.3. Liver Sinusoidal Endothelial Cells
The early activation of LSECs with loss of fenestration, production of TGF-β or PDGF-BB, and secretion of ECM proteins (e.g., type 1 collagen) contributes to HSC activation . Moreover, restoration of LSEC differentiation promotes the HSC quiescence and subsequent fibrosis regression . Using an acute and chronic liver injury murine model, Ding et al. recently demonstrated that differential recruitment of proregenerative CXCR7-Id1 differs from that of profibrotic FGFR1-CXCR4 angiocrine pathways in LSECs to facilitate balance between liver regeneration and fibrosis .
In the microenvironment of liver fibrosis with hepatic vasculature and tissue hypoxia alterations, HSCs produce multiple angiogenic factors, including vascular endothelial growth factor (VEGF), PDGF-BB, and angiopoietin 1 or 2, and express angiopoietin 1 receptors [51,52,53]. These angiogenic signals contribute to angiogenesis from neighboring endothelial cells by emitting paracrine signals and enhance HSC-induced fibrogenesis.
2.5. Reprogramming Metabolic Control to Regulate Hepatic Stellate Cells
Quiescent HSCs are similar to differentiated adipocytes in that they have abundant lipid droplets and they express lipogenic genes and transcriptional factors, which are downregulated upon HSC activation [54,55]. Recent data has shown that the transdifferentiation of quiescent HSCs into myofibroblasts induces glycolysis and causes lactate accumulation, which requires hedgehog signaling and the induction of HIF1-α for metabolic reprogramming of HSCs . Hedgehog signaling controls the fate of the HSCs by regulating metabolism, engendering highly proliferative myofibroblastic phenotypes .
2.6. Autophagy, MicroRNA, and Epigenetic Regulation in Fibrogenesis
The activation of HSCs induces the loss of intracellular lipid droplets, the autophagic digestion of which may provide energy for cellular functions. A recent study demonstrated that hepatic fibrogenesis in mice requires the autophagy of activated HSCs . Genetic and pharmacological inhibition of autophagy leads to the growth inhibition and downregulation of the fibrogenic properties of HSCs .
MicroRNAs (miRNAs) represent a family of small noncoding RNAs that control the translation and transcription of various genes. Recently, researchers have suggested that miRNAs modulate cellular processes in the liver, such as hepatocarcinogenesis. Several miRNAs are expressed in HSCs, controlling the fibrogenic process. The miR-29 family is significantly downregulated in mice with experimental fibrosis and in patients with advanced fibrosis . In one study, this downregulation of miR-29 in cultured HSCs was mediated by TGF-β and the inflammatory signals LPS and NF-κB, and induced subsequent up-regulation of ECM genes . In vitro experiments have indicated that the miR-19b mimic negatively regulates the TGF-β signaling components by reducing TGF-β receptor II and Smad3 expression, blocking TGF-β-induced expression of α1(I) and α2(I) procollagen mRNAs, and reducing α-SMA expression . In addition, a study revealed that miR-19b expression is markedly downregulated in fibrotic rat and human livers . MiR-221/222 expression is up-regulated in the human liver to a degree corresponding to the degree of liver fibrosis progression. Therefore, miR-221/222 may be a new marker for HSC activation and liver fibrosis progression .
Studies have indicated that the DNA methylation of genes expressed in quiescent HSCs contributes to maintenance of the quiescent phenotype . A recently published study indicated that rat hepatic myofibroblasts induce heritable epigenetic changes in the sperm of the rats, thus attenuating fibrogenesis in their offspring. This result suggests that fibrogenic signals are epigenetically and genetically transmissible .
2.7. Microvesicles Containing Biomarkers for Fibrogenesis
Microvesicles (MVs) are 0.1- to 1.0-μm vesicles containing lipids, proteins, RNAs, and miRNAs that, which are formed by budding from the cellular plasma membrane. MVs have been implicated in many stages of liver disease, including liver fibrogenesis , and are possibly involved in fibrosis regression in the liver . In vitro studies have indicated that the MVs released from T cells fuse with HSC membranes, leading to an up-regulation of MMP (MMP1, MMP3, MMP9, and MMP13) gene expression, down-regulation of the gene encoding procollagen-α1(I), and amelioration of TGF-β1 profibrogenic activity . The CD147 molecule exposed on T-cell MVs contributes to HSC-induced fibrolytic activities . A study suggested that the miRNAs contained in MVs promote fibrolysis . Diehl et al. determined that cultured HSCs release MVs containing hedgehog ligands, which might promote fibrogenesis by increasing inducible nitric oxide synthase by primary sinusoidal endothelial cells in vitro .
2.8. Fibrosis Regression
Studies on rodent models have demonstrated that, once a liver injury is eliminated, fibrosis regression occurs. The restoration of fibrinolytic activities, such as the up-regulation of MMPs and downregulation of TIMPs, drives the reversal of fibrosis . The clearance of activated HSCs or myofibroblast through apoptosis , senescence , or reversion into quiescent phenotypes is also crucial in fibrosis resolution [68,69].
Monocytes can promote resolution of fibrotic disease by (1) differentiating into regulatory macrophages that produce suppressor cytokines (e.g., IL-10); (2) producing MMPs that can degrade interstitial collagen directly; (3) locally depleting essential amino acids required for T-cell and myofibroblast proliferation; (4) actively promoting the apoptosis of myofibroblasts; and (5) phagocytosing ECM and cellular debris that would otherwise stimulate inflammatory and fibrogenic cell activation .
Several mechanisms have been implicated in the apoptosis of active HSCs: (1) the activation of death-receptor-mediated pathways (Fas or TNFR-1 receptors) and caspases 3 and 8; (2) the up-regulation of proapoptotic proteins (p53, Bax, caspase 9); and (3) the reduction of prosurvival genes (Bcl-2) .
During the course of fibrosis regression, the apoptosis of previously activated fibrogenic cells, which promote a favorable shift in the balance between fibrolytic MMPs and their profibrotic inhibitors within the microenvironment, leads to partial or even complete resolution of excess ECM accumulation . In the recovery phase of liver fibrosis, macrophages harboring a distinct phenotype induce HSC apoptosis and produce active metalloproteinases to promote fibrosis resolution . After prolonged injury, a liver with advanced fibrosis and cirrhosis exhibits more difficulty in undergoing tissue fibrinolysis. The reversibility of fibrosis potential tends to decline at advanced stages . Although the limited resolution of advanced fibrosis is not well characterized, evidence has suggested that the fibrinolytic capability of MMPs decreases as the matrix stiffness and matrix cross-linking of collagen I in older septa increases . This pathophysiological state may lead to a “point of no return” for livers with fibrosis .
4. Treatment for Viral Hepatitis-Related Liver Fibrosis and Cirrhosis
Several therapeutic strategies can be applied to treat hepatic fibrosis: eliminating the causes of injury and their mediators; reducing inflammation and the immune response; targeting specific signaling: receptor–ligand interaction and intracellular signaling; inhibiting matrix synthesis and increasing scar matrix degradation; and stimulating HSC apoptosis and providing bone marrow or cell transplantation . However, eliminating the underlying causes of liver diseases is the most crucial and effective antifibrotic therapy (Table 1).
4.4. Tissue-Specific Targeting
Targeting the core pathway in hepatic fibrogenesis is possible; however, researchers have been cautious because of the potential off-target effects in nonfibrotic or unaffected tissues. For example, targeting the TGF-β pathway would inhibit fibrogenesis, but could also cause chronic inflammation and even impair tumor suppression . Drugs can be designed to specifically target HSCs in higher doses to prevent toxicity from spreading to other cells. As HSCs take up vitamin A with a retinol-bound protein, Sato et al. showed that vitamin-A-coupled liposomes against gp46 successfully ameliorated collagen deposition in experimental liver fibrosis models . During liver fibrogenesis, mannose 6-phosphate (M6P)/insulin growth factor type II receptor was de novo expressed in activated HSCs. Moreno et al. incorporated losartan into M6P-modified human serum albumin for an antifibrotic treatment in an experimental liver fibrosis model and observed that this HSC-targeted losartan markedly reduced advanced liver fibrosis .
Various causes of hepatic fibrogenesis have been identified, including viral infection, alcohol abuse, steatohepatitis, metabolic disorders, and immune attack. The simplest approach to targeting liver fibrosis is disease prevention. For example, immunization can prevent hepatitis B, transmission precautions can be taken for hepatitis C, abstinence from alcohol can prevent alcoholic hepatitis, and a healthy diet, lifestyle modification and body weight reduction can prevent steatohepatitis. The next step in combatting liver diseases is to eliminate the underlying causes through medical control methods, such as antiviral therapy, which can control HBV or even eradicate HCV. Recently, the FLINT trial reported that NASH was successfully treated using obeticholic acid, reducing the NAFLD Activity Score by at least 2 points and yielding no exacerbation of fibrosis (ClinicalTrials.gov NCT01265498).
For established cirrhosis or diseases without a standardized therapy (e.g., alcoholic cirrhosis and cryptogenic cirrhosis), antifibrotic therapies targeting the central pathway of fibrogenesis are the only potential treatment. Although numerous studies have investigated the pathobiology of fibrogenesis and identified potential therapeutic targets, there is still a large gap between the bench and the bedside, and few clinical trials have explored positive preclinical signals. Several major obstacles to developing antifibrotic therapies include slow fibrogenesis progression, lacking validated biomarkers, and insensitive clinical endpoints . Nevertheless, antifibrotic therapy has recently become the focus of investigation and remains a critical unmet clinical need. Several new agents have been proved to exhibit antifibrotic efficacy in IPF [141,142,143,144,145]. In addition to antiviral therapies for controlling viral hepatitis, future clinical trials are required to investigate direct antifibrotic therapies that can halt fibrogenesis progression, HCC development, and death.
Viral hepatitis B and hepatitis C are major health problems worldwide that result in critical liver fibrosis or cirrhosis after long-term infection. Several viral and host factors have been identified to predict the disease progression. Growing evidence has suggested that current antiviral therapies can effectively control or even eradicate HBV and HCV, and subsequently ameliorate or even reverse cirrhosis, cirrhotic complications, and HCC. However, more effort should be exerted in developing direct antifibrotic agents for patients with established cirrhosis who cannot benefit from antiviral therapies.
The work was supported by grants from the Ministry of Science and Technology and the Ministry of Health and Welfare (102-2325-B-002-079); the Executive Yuan, Taiwan; and National Taiwan University and National Taiwan University Hospital, Taiwan (VN103-06).
Tung-Hung Su: draft of the manuscript, concept, and acquisition and interpretation of data; Jia-Horng Kao: concept and supervision; Chun-Jen Liu: concept, supervision, and critical revision.
Conflicts of Interest
The authors declare no conflict of interest.
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