Hepatic Fibrogenesis

• ABSTRACT
• PATHOLOGICAL ALTERATIONS IN HEPATIC FIBROSIS
• PATHOGENESIS OF HEPATIC FIBROSIS
• Fibrogenic Stimuli from Injured Liver
• OXIDATIVE STRESS
• HYPOXIA
• INFLAMMATION AND IMMUNE RESPONSES
• APOPTOSIS
• STEATOSIS
• Imbalance between the Accumulation and Degradation of ECM
• The Biological Activity of ECM in Fibrogenesis
• CELLULAR RESPONSES TO ECM
• ECM AND BOUND GROWTH FACTORS
• Cellular Behavior in Hepatic Fibrogenesis
• HEPATIC STELLATE CELLS
• OTHER FIBROGENIC CELLS
• ROLE OF OTHER RESIDENT LIVER CELL POPULATIONS IN FIBROGENESIS
• FIBROGENESIS-RELATED RECEPTORS AND SIGNALING PATHWAYS
• Toll-like Receptors
• TGF-β Receptor-Smad Signaling
• Integrins
• Wnt Signaling
• Cannabinoid Receptors
• Mammalian Target of Rapamycin and Hedgehog
• REVERSIBILITY OF LIVER FIBROSIS
• CONCLUSIONS
• i ACKNOWLEDGMENTS
• ABBREVIATIONS
• REFERENCES

ABSTRACT

Hepatic fibrogenesis represents a wound-healing response of liver to a variety of insults, ultimately leading to decompensated cirrhosis in many patients and accounting for extensive morbidity and mortality worldwide. The net accumulation of extracellular matrix (ECM) in liver injury arises from increased synthesis by activated hepatic stellate cells and other hepatic fibrogenic cell types, as well as from bone marrow and circulating fibrocytes. Concurrently, degradation of ECM by matrix metalloproteinases (MMPs) fails to keep pace with increased synthesis, in part due to sustained expression of MMP inhibitors (e.g., tissue inhibitors of metalloproteinases). A growing list of circulating, paracrine, and autocrine mediators have been identified that amplify the fibrogenic response of liver. Combined with accelerating knowledge about signaling pathways and genetic determinants, major advances are anticipated in new diagnostics and therapies that will transform the care of patients with chronic liver diseases in the coming years.

The field of hepatic fibrogenesis has enjoyed explosive growth over the past 5 to 10 years, built upon sustained advances in our understanding of pathogenic mechanisms, combined with the realization that fibrosis represents a common pathway of chronic injury that may be amenable to therapy. As a result, progress has accelerated, and new insights into the key mediators of fibrosis progression and regression have set the stage for an exciting new era in the treatment of chronic liver diseases. This review will encompass the key basic and translational advances that underlie the growing optimism about treating hepatic fibrosis.

PATHOLOGICAL ALTERATIONS IN HEPATIC FIBROSIS

Hepatic fibrosis refers to the accumulation of interstitial or “scar” extracellular matrix (ECM) following either acute or chronic liver injury. Regardless of the etiology, cirrhosis or end-stage fibrosis is characterized by a distortion of hepatic architecture and the formation of septae, or broad bands of scar-encircling nodules of hepatocytes, and associated with alterations in microvascular structure. These pathological changes impair liver function and can lead to portal hypertension.

The quality, quantity, and distribution of ECM components in the liver undergo dramatic changes during fibrogenesis.[1] The accumulating interstitial ECM constituents that collectively form the hepatic scar replace the low-density type IV collagen within the normal subendothelial space of Disse. These interstitial fibril-forming collagens (especially types I and III collagens) become distributed primarily in the connective septa surrounding the regenerative hepatic nodules. Cirrhotic liver may contain up to six times more collagen and proteoglycan than a healthy organ.[2] Moreover, collagen type I increases more significantly than type III collagen, such that their ratio of 1:1 in normal liver exceeds 1:1 in cirrhotic liver. In addition, non-fibril-forming collagens, including collagen type IV and laminin, which are indispensable components of basement membranes, are also increased. These components, along with matrix glycoconjugates, including proteoglycans, fibronectin, and hyaluronic acid, contribute to the capillarization of the sinusoids. Moreover, the cross-linking of collagen fibrils by tissue transglutaminase increases, which renders the fibrous septae more insoluble and thus more resistant to proteolysis by matrix metalloproteinases (MMPs).

In the fibrotic milieu, the fenestrae of normal sinusoidal endothelial cells are markedly decreased in number and size, leading to decreased porosity of the endothelial barrier.[3] Additionally, a discontinuous basement membrane on the basal side of sinusoidal endothelial cells is replaced by a continuous basement membrane, accompanied by abundant collagen fibers that accumulate in the space of Disse. Another microvascular change is altered topography of the vascularized fibrotic septa, leading to the establishment of intrahepatic shunts between afferent (portal vein and hepatic artery) and efferent (hepatic vein) vessels of the liver.[4] [5] Both the reduced porosity and intrahepatic shunts impair the free exchange of metabolites between the interlobular (pseudolobular) hepatocytes and the perfused plasma in the liver, thus contributing to a hypoxic milieu surrounding hepatocytes (particularly in pericentral zones), which may further impair liver function.

The patterns of fibrosis as the disease progresses are determined primarily by the nature of the hepatic injury. These patterns can be divided into portal-based (e.g., chronic viral hepatitis, chronic cholestatic diseases, and hemachromatosis) and central-based (e.g., steatohepatitis, and chronic venous outflow obstruction) fibrosis. Additionally, the fibrotic septae can be divided into those that are porto-portal (e.g., cholestatic liver injuries), portal-central (e.g., viral hepatitis), or central-portal (e.g., alcoholic liver disease). The different patterns are likely to reflect the locus of injury and inflammation conferred by the specific underlying disease, although the distribution pattern of fibrosis alone can rarely be used to establish a specific etiology in the absence of other clinical or laboratory evaluation.

PATHOGENESIS OF HEPATIC FIBROSIS

Typically, hepatic injury leads to initiation of fibrogenesis; this injury is multifactorial and often disease-specific. Stimuli may include hepatocyte necrosis, apoptosis, inflammatory cell infiltration, and ECM alterations. Both parenchymal and nonparenchymal cells participate in the response to injury, which relies on a convergence of cytokines and other extracellular signals, including reactive oxygen species (ROS). These stimuli provoke a fibrogenic response, resulting over time in an overall net accumulation of ECM proteins within the liver due to an imbalance between the deposition and degradation of ECM constituents (Fig. [1]).

Fibrogenic Stimuli from Injured Liver

OXIDATIVE STRESS

Oxidative stress plays an important role in producing liver damage and initiating hepatic fibrogenesis. Increased ROS, reactive nitrogen species (RNS), lipid peroxidative products such as malonaldehyde, 4-hydroxynonenal, products of protein and carbohydrate oxidation, and oxidative DNA damage (8-hydroxyguanosine) are commonly detected in the livers of patients with chronic liver diseases and in most types of experimental liver fibrosis.[6] [7] Oxidative stress occurs through the production of oxidants (e.g., O₂·^-, H₂O₂, ·OH, RO·, ROO·, ONOO^-), derived primarily from “leaking” or damaged mitochondria of hepatocytes, activated inflammatory cells, and products of specific cytochrome P450s (especially CYP2E1).[8] These accumulating ROS progressively overcome the antioxidant capacity of the liver, which includes catalase, reduced glutathione peroxidases, superoxide dismutases, and nonenzymatic components including α-tocopherol, reduced glutathione, β-carotene, bilirubin, and flavonoids (reviewed by Parola and Robino[7]). Oxidative disruption of lipids, proteins, and DNA induces necrosis and apoptosis of hepatocytes and amplifies the inflammatory response, resulting in the initiation of fibrosis. ROS also stimulate the production of profibrogenic mediators from Kupffer cells and both resident and circulating-inflammatory cells. These ROS are also directly fibrogenic and proliferative toward hepatic stellate cells (HSCs).[9]

HYPOXIA

Hypoxia has been recognized as a critical, early fibrogenic stimulus and may result from several mechanisms: reduced sinusoidal porosity associated with capillarization of the sinusoids, intrahepatic shunting, vasoconstriction, compression and thrombosis, and increased metabolic demands, especially in alcoholic liver injury. Hypoxia compromises mitochondrial function and produces oxidative stress. Moreover, hypoxia up-regulates hypoxia-inducible factor 1 alpha expression by HSCs, which is a central regulator of cellular responses to hypoxemia. This in turn induces vascular endothelial cell growth factor (VEGF) and its receptors and stimulates type I collagen synthesis in HSCs.[4] [10] [11] Hypoxia also potentiates transforming growth factor (TGF-β1) expression,[12] contributing to both autocrine and paracrine loops that drive angiogenesis and fibrogenesis. Fibrosis and hypoxia amplify each other in the presence of persistent parenchymal injury, leading to a vicious cycle that disrupts normal tissue repair.

INFLAMMATION AND IMMUNE RESPONSES

Inflammation is an important element in the initiation and progression of hepatic fibrosis. Inflammatory cells belonging to both innate immunity (e.g., natural killer [NK] cells and macrophages) and adaptive immunity (e.g., T and B cells) are involved in the development of liver injury and liver fibrogenesis. They provide a wide repertoire of “beneficial” or “detrimental” functions including eliminating pathogens, cell killing (e.g., hepatocyte damage during antiviral immune reaction), regulating inflammatory cells, recruiting and activating myofibroblasts, and regulating spontaneous recovery of fibrosis (reviewed in Henderson and Iredale[13] and Mehal[14]).

Damaged hepatocytes, Kupffer cells, and HSCs contribute to the induction of inflammation. These complicated cellular interactions also lead to recruitment of other inflammatory cells. Locally released tissue factors from damaged hepatocytes (e.g., apoptotic bodies and lipid peroxide), as well as degraded ECM components (e.g., degraded collagen, elastin, fibronectin, and hyaluronic acid) stimulate the expression of chemotactic cytokines and chemokines that amplify inflammatory activity.

Kupffer cells, the liver's tissue-specific macrophage population, are key effector cells in the hepatic inflammatory response. HSCs also act as important effectors of the liver's inflammatory response rather than simply targets of inflammation (more description is provided later). They all signal through nuclear factor kappa B (NF-κB) activation to express several inflammatory mediators, including inflammatory chemokines.[15] [16] [17] [18]

APOPTOSIS

Apoptosis or programmed cell death is a common feature of chronic liver disease, particularly apoptosis of hepatocytes.[19] Apoptosis results in the generation of apoptotic bodies, which are then cleared by phagocytosis. Although apoptosis was often thought to be noninflammatory, in fact it is a proinflammatory and fibrogenic stimulus. Kupffer cells secrete death ligands and tumor necrosis factor (TNF)-α after engulfing apoptotic bodies.[20] Similarly, the engulfment of apoptotic bodies by HSCs triggers a profibrogenic response with production of oxidative radicals and up-regulation of both TGF-β1 and collagen I expression.[21] [22]

STEATOSIS

Hepatic steatosis reflects a complex pathophysiology that most commonly arises from insulin resistance and mitochondrial dysfunction.[23] [24] [25] The steatosis in chronic hepatitis C, alcoholic steatohepatitis, and nonalcoholic steatohepatitis are all risk factors for fibrosis.[26] [27] [28] Steatosis also increases resistance to antiviral therapy in patients with hepatitis C virus (HCV).[29] [30]

Even in simple steatosis, there is evidence of HSC activation as assessed by expression of α smooth muscle actin in a study of patients with alcoholic fatty liver.[31] Although steatosis may be not sufficient to perpetuate fibrosis by itself, it represents a “first hit” that renders hepatocytes susceptible to a “second hit” (e.g., oxidative stress, viral infection, or lipopolysaccharide [LPS]), which propagates damage and provokes sustained fibrosis.[32] [33] Several pathways may contribute to steatosis-related fibrogenesis in liver. These include: (1) enhanced oxidative stress; (2) increased susceptibility to apoptosis; (3) a dysregulated response to cellular injury; (4) peroxisome proliferator-activated receptor signaling and activity; (5) dysregulation of leptin expression and signaling.

Imbalance between the Accumulation and Degradation of ECM

Hepatic fibrosis results from a net increase in ECM synthesis compared with ECM degradation. In reality, both are induced significantly during liver injury, and as a result, matrix still accumulates slowly despite active fibrogenesis in patients with chronic liver disease. Over time, however, ECM degradation does not keep pace with ongoing fibrogenesis and matrix steadily accumulates. Continued thickening of fibrotic septae, combined with chemical cross-linking of collagen, renders the ECM increasingly insoluble and resistant to protease digestion.[34] Ultimately, in advanced cirrhosis, ECM accumulation becomes truly irreversible, although the point at which this occurs and the determinants of irreversibility are not fully defined.

ECM degradation is mediated by MMPs, a family of zinc-dependent enzymes grouped into collagenases, gelatinases, stromelysins, and membrane-type MMPs (Table [1]).[35] [36] [37] Tissue inhibitors of metalloproteinases (TIMPs) bind in a substrate- and tissue-specific manner to MMPs and membrane-type 1 metalloproteinase in a trimolecular complex, which blocks their proteolytic activity. During fibrosis, TIMP mRNA and protein levels dramatically increase, and MMP levels increase modestly or remain relatively static.[37] An exception is MMP2, which dramatically increases during fibrogenesis and is involved in degrading normal liver architecture.[35] Of note, TIMP-1 represents a critical switch because it both inhibits matrix proteases and promotes survival of fibrogenic cells, in part through induction of the antiapoptotic protein Bcl-2.[38] [39] [40] As such, TIMP-1 is an attractive target for antifibrotic treatment, particularly because its expression is restricted to activated stellate cells among liver cell populations, and little is expressed in normal liver.[41]

The Biological Activity of ECM in Fibrogenesis

ECM is actively involved in the regulation of would-healing response and fibrogenesis through its interaction with the peripheral environment and cells. ECM is comprised of precisely organized molecular networks that determine the specific histoarchitecture of tissues. The structural ECM molecules include collagens, noncollagenous glycoproteins and proteoglycans, and growth factors and MMPs that are sequestered by ECM.[1] Some of the matrix components such as galectins that distribute at the cell surface can modulate cell signaling by cross-linking with target molecules, leading to the proliferation and activation of HSCs.[42] [43] ECM provides cells with positional signals and a mechanical scaffold for polarization, adhesion, migration, proliferation, survival, and differentiation. In addition, ECM transfers specific biological signals to cells that act in concert with growth factors/cytokines. ECM-derived peptides can also modulate angiogenesis or availability and activity of growth factors and MMPs.

CELLULAR RESPONSES TO ECM

Changes in the composition of the ECM can directly stimulate fibrogenesis.[1] After liver damage, a provisional matrix is established at the site of injury that derives from circulating proteins (e.g., fibrin, fibronectin) and macromolecules produced by HSCs and sinusoidal endothelial cells. The rapid release by endothelium of a splice variant of cellular fibronectin, and the activation of latent cytokines such as TGF-β1 by urokinase type plasminogen activator, stimulate resident HSCs. Clearance of matrix substrates from the injured environment by MMPs and serine proteases such as plasminogen may be important factors maintaining the activated HSC phenotype. Defective plasmin-driven proteolysis leads to accumulation of nonfibrin matrices and persistent activation of HSCs within areas of defective repair.[44] In addition, fibrillar collagens can bind and stimulate HSCs via discoidin domain tyrosine kinase receptor 2 and integrins.[45] [46] Moreover, ECM degradation can serve as activator of innate immune receptors located on the surface of almost all types of liver cells.

In addition to a large amount of interstitial collagen, activated HSCs secrete MMPs, which induce three-dimensional changes in ECM. On the other hand, the expression of TIMPs (especially TIMP-1 and TIMP-2) from HSCs increases, which promotes ECM accumulation by inhibiting matrix degradation.

ECM AND BOUND GROWTH FACTORS

ECM can serve as a reservoir for growth factors and MMPs. They normally combine with heparin and heparin sulfate in latent forms. The alteration of ECM may control both the release and activation of these growth factors and MMPs, thereby modulating fibrogenesis.[1]

Cellular Behavior in Hepatic Fibrogenesis

The fibrogenic process results from proliferation and accumulation of myofibroblastic cells (MFBs) arising from different cell populations including local sources (e.g., HSCs and portal mesenchymal cells) as well as from outside the liver (e.g., bone marrow and circulating fibrocytes). It is unknown, however, whether the relative contributions of each source are the same in all forms of liver injury, as they may differ based on the underlying etiology and region(s) of injury within the liver. No endogenous marker(s) have been identified that enable investigators to discriminate the source of myofibroblasts with certainty in an injured liver, but there is increasing reliance on use of genetic models in which cells can be “marked” to define their origin(s), for example from bone marrow.[47] [48] In other tissues, epithelial-mesenchymal cell transition (EMT) is also increasingly appreciated as a source of tissue myofibroblasts,[49] [50] particularly in kidney and lung. In liver, the contribution of EMT to the total mesenchymal cell population may exist but varies with the disease etiology and stage, as it has only been evidenced in bile duct ligation model of fibrosis.[51]

Myofibroblasts have several characteristic properties not only in liver but also in all tissues that display a wound-healing response. Their most classic feature is expression of smooth muscle α-actin (α-SMA), a contractile filament that in liver is a marker of fibrogenic cells and that may predict fibrosis progression.[52] Myofibroblasts also synthesize an array of ECM components, metalloproteinases and their inhibitors, and release a range of cytokines and chemokines.

HEPATIC STELLATE CELLS

In normal liver, HSCs are resident perisinusoidal cells that store vitamin A. Over the past two decades, the isolation and analysis of HSCs led to a more fundamental understanding of hepatic fibrosis and the conclusion that HSCs are the major fibrogenic cell type in injured liver.[53] The fundamental features of HSC activation appear to be similar regardless of the initial cause of injury, although increasingly, disease-specific mechanisms of HSC activation have begun to emerge as well, especially for HCV infection[54] [55] and nonalcoholic steatohepatitis.[56] [57] Conceptually, activation occurs in two phases, initiation and perpetuation, followed by resolution if liver injury is abrogated. Initiation refers the earliest events that render cells responsive to cytokines. It is mediated primarily by paracrine stimuli (oxidative stress, apoptotic fragments, and cytokines) from injured neighboring liver cells and infiltrating inflammatory cells. Perpetuation connotes those responses to cytokines that collectively enhance scar formation (see later). Resolution refers to the fate of activated stellate cells when the primary insult is withdrawn or attenuated (reviewed by Friedman[58] and Iredale[59]).

The perpetuation of stellate cell activation can be further subdivided into at least seven distinct events that can occur simultaneously. Specific pathways and mediators contributing to these responses are described in more detail below. (1) Proliferation is due to several mitogenic cytokines, including platelet-derived growth factor (PDGF),[60] fibroblast growth factor, thrombin,[61] and VEGF. (2) Chemotaxis and migration are equally important mechanisms of stellate cell accumulation, which has been attributed to cytokines (e.g., PDGF, TGF-β1, endothelin-1 [ET-1]), altered cell-matrix interactions,[62] [63] and Rho signaling.[64] (3) Fibrogenesis is largely driven by the cytokine TGF-β1, whose activity is amplified by increased production, increased activation of the latent form,[65] enhanced receptor expression, and down-regulation of a pseudoreceptor. (4) Release of proinflammatory, profibrogenic, and promitogenic cytokines, in particular monocyte chemotactic protein-1 (MCP-1), increase the accumulation of inflammatory cells and stimulate ECM production via autocrine pathways, especially through the actions of TGF-β1 and PDGF.[66] (5) Contractility confers upon the cells the potential to constrict sinusoids and reduce blood flow. Actions of ET-1 are key components of this response, which likely contributes to increased portal pressure in patients with chronic liver disease.[67] (6) Degradation of the liver's normal matrix disrupts the delicate scaffolding required to preserve liver function (see Iredale[68] for review). (7) Loss of vitamin A droplets, whose functional role is not clear, may involve altered retinoid receptor signaling.[69] [70] [71]

Although the fibrogenic potential of HSCs is now well characterized, several new and intriguing features of the cell type have also begun to emerge, in particular their role in immunoregulation and inflammatory signaling. HSCs interact with inflammatory signaling pathways in several ways: (1) They signal through NF-κB to release several chemokines including MCP-1 and macrophage inflammatory protein-2 (MIP-2),[17] [18] which recruit and activate macrophages. (2) They express Toll-like receptor (TLR) 2 and 4 and produce inflammatory cytokines when stimulated by their ligands,[72] [73] for example, LPS for TLR4,[72] [74] which enhances fibrogenesis (see next section). (3) They also display features of professional antigen-presenting cells, stimulate lymphocyte proliferation, and activate T-cell responses.[75] [76] (4) HSCs interact directly with Kupffer cells during activation. (5) HSCs are activated by specific T-cell subsets, with CD8 ⁺ cells harboring more fibrogenic activity than CD4 ⁺ cells.[77] (6) HSCs can be cleared through their killing by NK cells and are particularly susceptible to NK cell-mediated attack when activated.[13] [14] [78] [79]

The embryonic origin of HSCs has remained uncertain despite the initial descriptions of HSCs by von Kupffer in 1876 as liver sternzellen (star-shaped cells), and by Ito and Nemoto as fat-storing cells in 1952.[80] HSCs have features indicating either a mesenchymal (i.e., expressing vimentin), endodermal (i.e., coexpressing hepatoblast markers cytokeratins 8 and 18 during rat embryonic development), and even neuroectodermal origin (i.e., expressing several neural crest markers, such as glial fibrillary acidic protein, and neurohumoral factors and their receptors adrenoreceptors).[81] However, a recent study using fate mapping techniques strongly supports their derivation from septum transversum rather than neural crest.[82] On the other hand, a population of CD34 ⁺ CK7/8 ⁺ cells has been identified in the human fetal liver that appear to be embryonic stellate cell precursors that are of endodermal origin and are distinct from cells of the hematopoietic lineage.[83] In aggregate, the findings suggest that HSCs may be heterogeneous both in their sources and fates, possibly even with pleuripotent features allowing them to differentiate into endothelial or hepatocyte lineages.[84]

OTHER FIBROGENIC CELLS

As noted above, there are other sources of ECM-producing fibroblasts cells in injured liver besides those derived from activated HSCs. Different subpopulations of mesenchymal cells may be recruited depending on the main site of injury within the liver lobule (e.g., cholestatic versus parenchymal). For example, there is a prominent accumulation of portal myofibroblasts (devoid of lipid droplets, desmin negative) compared with HSCs (desmin positive) in ischemic and biliary fibrosis.[85]

Some fibrogenic cells in liver may also have a hematopoietic origin. When mice or humans receive a bone marrow transplant that is traceable (e.g., male marrow into female recipient, or bone marrow cells from green fluorescent protein transgenic animals), cells from the transplanted marrow can be identified in the recipient mouse liver and in human fibrotic bands.[47] [48] [86] [87] Bone marrow cells may contribute to populations of the HSCs (glial fibrillary acidic protein or desmin positive) and myofibroblasts (α-SMA positive) in the fibrotic livers of transplanted mice. The infiltration of marrow-derived myofibroblasts does not appear to involve cell fusion. However, it is unknown what proportion of myofibroblasts/fibrocytes are derived from bone marrow or circulating fibrocytes, whether myofibroblasts of these origins transition through a stellate cell phenotype, and what happens to activated myofibroblasts from various sources when liver injury resolves.

Although the conversion of hepatocytes to fibroblasts through EMT has not yet been quantified, colocalization of α-SMA and cytokeratin-19 (a biliary epithelial marker) in bile duct epithelium has been observed in fibrotic liver induced by bile duct ligation, suggesting the possibility of biliary epithelial to myofibroblast transition after bile duct ligation.[51]

ROLE OF OTHER RESIDENT LIVER CELL POPULATIONS IN FIBROGENESIS

There is a complex interplay among different hepatic cell types during hepatic fibrogenesis.

Kupffer cells are the resident macrophages in the liver. They release a variety of inflammatory mediators, free radicals, fibrogenic cytokines, as well as ECM proteinases that alter the original normal ECM structure during the early stage of liver injury, thus playing a critical role in promoting HSC activation.[88] However, conditional ablation (nontoxic, cell-type specific, temporally controlled deletion) of macrophages in animal studies of liver fibrosis indicates that there are functionally distinct subpopulations of macrophages harboring different phenotypes depending on the surrounding milieu.[13] [89] [90]

Hepatocytes are targets for most hepatic pathogens and hepatotoxic agents. Hepatocyte components may act as antigens that provoke immune responses, particularly in autoimmune hepatitis. More importantly, damaged hepatocytes also are sources of ROS, inflammatory and fibrogenic mediators, and apoptotic bodies that recruit inflammatory cells and activate HSCs.[21] [22]

Sinusoidal endothelial cells are involved in the activation of HSCs in part by producing a splice variant of cellular fibronectin (EIIIA isoform) at the early stage of fibrogenesis, as described previously.[91] They also synthesize type IV collagen and laminin, which are basement components of the capillarized sinusoidal. Sinusoidal endothelial cells also produce ET-1, which stimulates HSC contractility, thereby contributing to regulation of sinusoidal blood flow and resistance.

Bile duct epithelial cells play particularly important roles in fibrogenesis associated with cholestatic liver diseases, for example, primary biliary cirrhosis and sclerosing cholangitis. They produce profibrogenic cytokines, such as TGF-β1, PDGF-BB, and connective tissue growth factor, that stimulate myofibroblast activation in cholestatic models of these diseases.[92] [93] Moreover, there is cross talk between bile duct epithelium and portal fibroblasts involving nucleotides[94] and chemokines, especially MCP-1.[95]

T and B lymphocytes are both implicated in hepatic fibrosis.[13] Hepatic T cells possess characteristics distinct from those of circulating blood, including a high percentage with activation markers and a high basal apoptotic rate. B lymphocytes comprise as much as 50% of the entire lymphocyte pool in the liver. Hepatic B cells most closely resemble those of the spleen, based on their cell surface marker phenotype, and are derived from bone marrow. Mice genetically deficient in B cells have the same extent of injury following acute administration of CCl₄ but markedly reduced collagen deposition after 6-week treatment, raising the possibility that B cells could interact with fibrolytic pathways in the resolution of liver fibrosis; this B cell-mediated pathway is independent of antibody function.[96]

In addition, a large fraction of NK and NK T cells also characterizes the hepatic immune system. NK cells activated by hepatotrophic viruses play an essential role in recruiting virus-specific T cells, inducing antiviral immunity, and the cytolytic elimination of virus-infected hepatocytes. NK cells may be important for killing stellate cells in liver injury models, such that NK cell depletion or inactivation may augment fibrosis.[14] [78] [97] Pathways inhibited by HCV to counteract the antiviral innate immune system may interfere with mechanisms intended to limit liver fibrosis. One example is the ligation of CD81 by the HCV E2 protein, which could inhibit NK cell function[98] [99] and enhance survival of activated HSCs.[100]

FIBROGENESIS-RELATED RECEPTORS AND SIGNALING PATHWAYS

There has been remarkable progress in unraveling several key signaling pathways in hepatic fibrogenesis. The list below is not intended to be comprehensive, but rather to emphasize those systems where advances have been most noteworthy.

Toll-like Receptors

TLRs are a family of mammalian transmembrane pattern recognition receptors that recognize structural components unique to bacteria, fungi, and viruses. They signal and activate innate and adaptive inflammatory response.[101] [102] Ten family members of TLRs have been identified that have individual or shared substrates for activation. Double-stranded RNA produced during viral replication activates TLR3, whereas DNA viruses activate TLR9.

TLR signaling is mediated by NF-κB,[72] mitogen-activated protein kinase (MAPK), and PI3K-Akt,[103] with downstream products including: (1) proinflammatory cytokines (TNF-α, interleukin [IL]-1, IL-6); (2) chemotactic cytokines (MCP-1, macrophage inhibitory factor); (3) proinflammatory proteins (inducible nitric oxide synthase); (4) ROS; (5) adhesion molecules (intercellular adhesion molecule-1, vascular adhesion molecule-1); and (6) other effectors of the innate immune response (e.g., interferon-β). For TLR4, besides its natural exogenous substrate LPS, there are endogenous substrates that include low-molecular-weight hyaluronic acid,[104] saturated fatty acid,[105] fibrinogen,[106] fibronectin,[107] heat shock protein 60 and 70,[108] [109] and high-mobility group box-1.[110] In vivo, damage signals and intact extracellular matrix degradation also activate TLR4.[111]

In liver, TLR4 is expressed by most resident cells including Kupffer cells, HSCs, and hepatocytes, and TLR4 signaling contributes to hepatic inflammation and injury of many etiologies.[112] [113] Genetic deletion or mutation of TLR4 reduces macrophage infiltration and liver injury in animals with experimentally induced liver damage.[112] [114] [115] Moreover, recent findings suggest that TLR4 signaling in HSCs may be more important than in Kupffer cells in mediating fibrogenesis, in part by down-regulation of an inhibitory TGF-β pseudoreceptor, BAMBI.[116]

TGF-β Receptor-Smad Signaling

Latent TGF-β undergoes activation, then signals through a complex of two related but structurally and functionally distinct serine-threonine kinase receptors, the type I (TβRI) and type II (TβRII) receptors (see Breitkopf et al[117] and Inagaki and Okazaki[118] for reviews). Binding of the homodimeric TGF-β to TβRII enables the formation and stabilization of type I/type II receptor complexes. The TβRII kinase then phosphorylates TβRI and serves as the initiation point for downstream events that include phosphorylation and assembly of cytoplasmic Smad proteins. These activated Smads translocate into the nucleus, where they function as transcriptional regulators controlling the expression of several TGF-β-induced matrix proteins, including collagen type I, plasminogen activator inhibitor-1, as well as the inhibitory Smad7.

Interestingly, the time course of HSC culture activation differs for Smad2 and Smad3, suggesting that they subserve different functions, because overexpression of Smad2 in HSCs reduces proliferation whereas Smad3 enhances conversion to the activated phenotype.[119] Thus, the development of a selective small-molecule inhibitor of Smad3 merits exploration as a novel antifibrotic agent.

Integrins

Integrins are a group of heterodimeric transmembrane proteins composed of α and β subunits.[120] They mediate the interactions between cells and ECM. Many integrin ligands contain an Arg-Gly-Asp (RGD) tripeptide sequence, which is necessary but not sufficient for transmitting the signal to the cellular interior. The integrins α1β1, α2β1 (two major collagen binding integrins),[121] αvβ1, and α6β4 have been identified in HSCs and MFBs,[46] and some of their downstream signaling has been characterized, involving NF-κB, MAPK, and focal adhesion kinase.[122] Integrins can bind and activate latent TGF-β1.[123] In cultured stellate cells, integrins such as αvβ1 (a fibronectin receptor) recognize matrix constituents and are mechanotransducers, transmitting information to the cell about matrix “stiffness.”[124] The latter is a significant determinant of stellate cell activation in culture and possibly in vivo.

Wnt Signaling

Wnt signaling is essential for development and is also implicated in tumorigenesis. Wnt ligands bind to the receptor of frizzled family, which transduce signals to β-catenin, promoting its nuclear localization and participation in gene regulation. Microarray analysis of activated HSCs indicates that multiple ligands, receptors, and regulatory proteins of Wnt signaling are highly up-regulated.[125] Several of the Wnt target genes promote fibrosis. For example, WISP1 and WISP2 are members of the connective tissue growth factor family of cytokines, which stimulate angiogenesis, chondrogenesis, and osteogenesis, processes characterized by deposition of ECM.[126] Follistatin is an activin antagonist and modulates the actions of several members of the TGF-β family and, thus, is directly involved in the TGF-β response. Twist and pitx2 are two transcription factors that regulate the formation of mesoderm-derived tissue. Expression of Wnt5a and its receptor frizzled 2 are highly up-regulated in fibrotic livers. However, activation of HSCs in vivo is not accompanied by β-catenin activation, suggesting that the noncanonical Wnt pathway may be more important in HSC differentiation and liver fibrosis.[125]

Cannabinoid Receptors

Two G protein-coupled receptors of endogenous and exogenous cannabinoids, CB1 and CB2, are expressed by hepatic endothelial cells and MFBs and contribute to fibrogenesis.[127] Interestingly, CB1 is profibrogenic, whereas CB2 has antifibrogenic properties.[128] [129] CB1 receptor antagonism reduces matrix remodeling associated with acute liver injury, enhances apoptosis, and decreases proliferation of liver fibrogenic cells, thereby reducing accumulation of ECM in vivo. PI3K-Akt and ERK, two crucial regulatory pathways of growth and survival, mediate effects of CB1 receptor on hepatic MFBs. In addition, CB1 and CB2 receptors are expressed on immunocytes, where they influence immune regulation via suppression of cell activation, modulation of the Th1/Th2 balance, and induction of NF-κB-dependent apoptosis. Moreover, cannabinoids exert a range of peripheral and central effects on energy expenditure and metabolism, including the liver, and can modify adipokine secretion by adipose.[130] Thus, CB1 antagonism is an attractive therapeutic strategy in vivo.[131]

Mammalian Target of Rapamycin and Hedgehog

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that controls cell growth and proliferation. The activation of mTOR is PI3-K/Akt-dependent, and one of its downstream targets, the 70-kd ribosomal s6 kinase, is activated upon phosphorylation and plays a crucial role in HSC proliferation, collagen expression, and cell cycle control.[132] Inhibition of p70s6k phosphorylation by rapamycin inhibits cell cycle progression and posttranscriptional collagen 1 expression in isolated HSCs.[133] An in vivo study has shown that rapamycin attenuates liver fibrosis in experimental animals by down-regulating TGF-β expression, decreasing MMP-2 activity, and reducing the numbers of activated HSCs.[134]

Hedgehog (Hh) is a potential differentiation factor that regulates enteric nervous system development, endodermal differentiation, liver organogenesis, and maintenance of hepatic progenitors. HSCs express Hh ligands (Shh and Ihh) and multiple components of Hh pathway, which regulate their viability and activation.[133] The mechanism linking Hh activity to fibrosis might be Gli1, a known signaling component and transcriptional target of Hh signals that sensitizes the mTOR pathway.

REVERSIBILITY OF LIVER FIBROSIS

The hepatic response to injury is a dynamic, bidirectional process of progression and regression. The reversibility of liver fibrosis has been established in treated patients with chronic hepatitis B and C, secondary biliary cirrhosis, autoimmune liver diseases, and Wilson's disease, as well as in animal models,[135] [136] fueling the enthusiasm for antifibrotic therapies. The different extents to which fibrosis regression may be tracked range from histological regression alone, to regression associated with functional improvement (e.g., reduced portal pressure), to regression associated with reduced clinical events and prolonged survival. Substantial insights into how fibrosis might regress in patients have emerged from animal models, indicating that the reversibility can result from apoptosis of HSCs and degradation of a type I collagen-rich neomatrix due to a increased net MMP activity.[59] Other key determinants of reversibility are the eradication of the injurious agent and the regeneration of parenchymal cells.

Apoptosis of HSCs has the potential to remove the source of both the fibrotic neomatrix and TIMPs, as TIMP-1 expression is localized to the activated HSCs/myofibroblasts.[137] Stimulation of death receptors by activated HSCs and a decrease in survival factors, including TIMP-1, can precipitate HSC apoptosis.[39] Removal of activated HSCs by apoptosis precedes fibrosis resolution.

Although substantial improvement in function and structure may occur in advanced fibrosis, it is uncertain whether the architectural distortion and vascular derangements in advanced cirrhosis can return to a normal structure.[138] An incomplete but not total resolution of micronodular cirrhosis can be observed in experimental animals. Tissue transglutaminase-mediated cross-linking of fibrillar collagens may be a control point for matrix resorption,[34] rendering the hepatic scar resistant to degradation, especially as the local milieu becomes increasingly hypocellular.

CONCLUSIONS

With emerging new technologies and greatly refined methodologies, our knowledge about the natural history of liver fibrosis and its pathogenesis is continuously expanding in breadth and depth. However, many intriguing questions remain to be answered. For example, epigenetic mechanisms that act as major determinants of gene activation and repression in stellate cell biology may represent a fertile new area for study. Also, the origin(s) of ECM-producing myofibroblasts from sources other than HSCs remain(s) enigmatic. Future studies are required to characterize the different fibrogenic cell populations and their regulation in more detail and to identify cell-specific markers. Clinically, general and disease-specific pathogenic mechanisms need further clarification. Biomarkers and noninvasive tests that are sensitive and specific, and respond quickly to changes in fibrogenic activity are urgently needed. Genetic determinants of fibrosis progression and regression are also active areas of inquiry. Collectively, current and future basic and translational advances will continue to portend meaningful progress in the evaluation and treatment of patients with chronic liver disease.

ACKNOWLEDGMENTS

Jinsheng Guo, M.D., is a recipient of National Fund of Nature Science of P. R. China (No. 30570825). Work from Dr. Friedman's laboratory described in this article is supported in part by NIH Grant DK56621.

ABBREVIATIONS

• α-SMA α smooth muscle actin

• ECM extracellular matrix

• EMT epithelial mesenchymal transition

• ET-1 endothelin-1

• HCV hepatitis C virus

• Hh hedgehog

• HSC hepatic stellate cell

• IL interleukin

• LPS lipopolysaccharide

• MAPK mitogen-activated protein kinase

• MCP-1 monocyte chemotactic protein-1

• MFB myofibroblast

• MIP-2 macrophage inflammatory protein-2

• MMP matrix metalloproteinase

• mTOR mammalian target of rapamycin

• NF-κB nuclear factor kappa B

• NK natural killer

• PDGF platelet-derived growth factor

• RNS reactive nitrogen species

• ROS reactive oxygen species

• TβRI TGF-β type I receptor

• TβRII TGF-β type II receptor

• TGF transforming growth factor

• TIMP tissue inhibitor of metalloproteinase

• TNF tumor necrosis factor

• TLR Toll like receptor

• VEGF vascular endothelial cell growth factor

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Scott L FriedmanM.D. 

Division of Liver Diseases, Mount Sinai School of Medicine

Box 1123, 1425 Madison Avenue, Room 1170C, New York, NY 10029

Email: scott.friedman@mssm.edu

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Scott L FriedmanM.D. 

Division of Liver Diseases, Mount Sinai School of Medicine

Box 1123, 1425 Madison Avenue, Room 1170C, New York, NY 10029

Email: scott.friedman@mssm.edu