Hepatic Fibrosis -- Role of Hepatic Stellate Cell Activation

Scott L. Friedman, MD

Disclosures
In This Article

Therapy of Hepatic Fibrosis

General Considerations

Antifibrotic therapy for chronic liver disease is an emerging reality, although no agents are yet approved for this indication. Combination therapies may prove synergistic rather than additive, but agents must first be tested individually to establish safety and "proof-of-principle."

Antifibrotic Therapies -- Rationale and Specific Agents

The paradigm of stellate cell activation provides an important framework for defining sites/targets of antifibrotic therapy (Table; see [54] for review). These strategies include: (A) curing the primary disease to prevent injury; (B) reducing inflammation or the host response in order to avoid stimulating stellate cell activation; (C) directly downregulating stellate cell activation; (D) neutralizing proliferative, fibrogenic, contractile, and/or proinflammatory responses of stellate cells; (E) stimulating apoptosis of stellate cells; and (F) increasing the degradation of scar matrix, either by stimulating cells that produce matrix proteases, downregulating their inhibitors, or by direct administration of matrix proteases. The following sections explore each of these strategies in greater depth. A. Cure the primary disease. The most effective way to eliminate hepatic fibrosis is to clear the primary cause of liver disease. The latter includes abstinence in the case of alcoholic liver disease, removal of excess iron or copper in precirrhotic genetic hemochromatosis or Wilson's disease, clearance of HBV or HCV in chronic viral hepatitis, eradication of organisms in schistosomiasis, or decompression in mechanical bile duct obstruction.

B. Reduce inflammation and immune response. A number of agents have anti-inflammatory activity in vitro and in vivo that may eliminate the stimuli to stellate cell activation. Corticosteroids have been used for decades to treat several types of liver disease; their activity is solely as anti-inflammatory agents, with no direct antifibrotic effect on stellate cells.[55] Antagonists to TNF-alpha have some rationale in inflammatory liver disease, and have shown acceptable safety profiles in rheumatoid arthritis and Crohn's disease, but must be tested directly in hepatic fibrosis. Other efforts to neutralize inflammatory cytokines include an IL-1 receptor antagonist that has shown modest efficacy in rats with dimethylnitrosamine-induced liver injury,[56] as well as RGD (ie, Arg-Gly-Asp, a major cell adhesive ligand of ECM) antagonists that may limit TNF-related immunologic injury.[57,58]

Ursodeoxycholic acid has a beneficial effect on fibrosis in primary biliary cirrhosis,[59,60] possibly in part due to its anti-inflammatory activity. Similarly, a NO-releasing derivative of ursodeoxycholic acid reduces inflammation, fibrosis, and portal pressure in an animal model.[61]

Drugs that dampen the allergic response are also under study. Tranilast[62] and captopril,[63] an angiotensin-converting enzyme (ACE) inhibitor, have antifibrotic activity attributed to reduced mast cell and eosinophil accumulation. ACE inhibitors also may have direct antifibrotic activity in liver, as has been recently demonstrated in cardiac and renal fibrosis. Given their safety, and encouraging results in animals,[64] human trials can be anticipated.

D. Inhibit stellate cell activation. Reducing the transformation of quiescent stellate cells to activated myofibroblasts is a particularly attractive strategy given its central role in the fibrotic response. The most practical approach is to reduce oxidant stress, which is an important stimulus to activation. Antioxidants, including alpha-tocopherol (vitamin E), suppress fibrogenesis in some[65] but not all[66] studies of experimental fibrogenesis. Other antioxidants can also reduce stellate cell activation in culture,[67] and provide a rationale for antioxidant trials in humans.

The cytokines gamma interferon and hepatocyte growth factor (HGF) have inhibitory effects on stellate cell activation in animal models of fibrosis.[68,69] Trials of gamma interferon are under way for pulmonary fibrosis,[70] with similar efforts anticipated in liver fibrosis. The precise mechanism underlying the antifibrotic activity of HGF is uncertain, but may involve inhibition of TGF-beta 1 activity. A deletion variant of HGF is also effective, even when administered after the onset of fibrosis, a situation more akin to human liver disease.[71] Trials in large animals and humans are anticipated, with careful monitoring expected to avoid an increased risk of hepatocarcinogenesis, because TGF-beta 1 inhibits growth of hepatocytes.

PPAR-gamma nuclear receptors are expressed in stellate cells, and synthetic PPAR-gamma ligands (thiazolidinediones) downregulate stellate cell activation.[44,45] Given their widespread use in diabetes, clinical trials of second- and third-generation thiazolidinediones (ie, lacking the hepatotoxicity seen with first-generation agents such as troglitazone) merit consideration in clinical trials.

Leptin is produced by activated stellate cells,[72] which not only affects lipid metabolism, but also can directly influence wound healing.[73] In fact, animals deficient in leptin have reduced hepatic injury and fibrosis.[74] Thus, elucidation and manipulation of the actions of leptin in stellate cells may yield insights that can translate into new therapies.

Progress in understanding transcriptional regulation has offered the opportunity to block stellate cell activation by inhibiting the activity of histone deacetylases (HDACs), enzymes critical for modifying chromatin during gene transcription.[75] Highly specific HDAC inhibitors offer the potential for selectively blocking stellate cell activation, with tolerable safety and good efficacy.[76]

Herbal therapies and products derived from natural compounds that are commonly used in the Far East are increasingly being tested under controlled, scientifically rigorous conditions,[77] and some show promise of efficacy.[78,79,80]

D. Neutralize proliferative, fibrogenic, contractile, and/or proinflammatory responses of stellate cells. Significant advances in growth factor biology will benefit the treatment of hepatic fibrosis through the development of antagonists to cytokines and their receptors. In particular, many proliferative cytokines including PDGF, fibroblast growth factor, and TGF-alpha signal through tyrosine kinase receptors; inhibitors that block the activity of tyrosine kinases and the signaling pathways they activate are already undergoing clinical trials in other tissues.[81] Because the intracellular signaling pathways for these receptors are well understood, inhibitors to signaling models are being explored in vivo or in cultured stellate cells, including gamma-linoleic acid and lipoxygenase inhibitors,[82] and PPAR-gamma pathways.[83]

The recent success in developing a safe, effective small-molecule tyrosine kinase antagonist in human leukemia and mesenchymal cell tumors[84,85] bodes well for the potential of this approach in other indications, including liver fibrosis. Small-molecular-weight compounds are under development with the aim of blocking cytokine receptor or intracellular signaling. One such compound is a selective inhibitor of Rho-mediated focal adhesions, which can reduce experimental liver fibrosis.[86]

TGF-beta antagonists are currently undergoing extensive testing because neutralizing this potent cytokine would have the dual effect of inhibiting matrix production and accelerating its degradation.[87] Animal and culture studies using soluble TGF-betareceptors or other means of neutralizing the cytokine, including monoclonal antibodies and protease inhibitors to block TGF-beta activation, have established proof-of-principle. The latter include recombinant soluble mannose-6-phosphate (M6P) to compete with cell surface M6P receptor, which binds TGF-beta at the stellate cell surface during activation from the latent form.[88]

Because endothelin-1 is an important regulator of wound contraction and blood flow regulation mediated by stellate cells, antagonists have been tested as both antifibrotic and portal hypotensive agents. Alternatively, delivery of NO to injured liver may have the same therapeutic effect as inhibiting endothelin-1.[61]

Halofuginone, an anticoccidial compound, has antifibrotic activity by way of blocking collagen expression, and has been used in a number of models of tissue fibrosis, including liver.[89]

E. Stimulate stellate cell apoptosis. Attention is now increasingly focused on how liver fibrosis regresses, and in particular, on the fate of activated stellate cells as fibrosis recedes. Recent animal studies have used gliotoxin, which provokes selective apoptosis of stellate cells in culture and in vivo, leading to reduced fibrosis.[90] Apoptosis can also be provoked by disruption of integrin-mediated adhesion.[91] Stellate cells contain several families of apoptotic mediators, including Fas/FasL, TNF receptors (including those for nerve growth factor), and Bcl/Bax, so that additional targets to promote apoptosis will likely be exploited in the future.[92]

F. Increase the degradation of scar matrix. This component of treatment is very important, because antifibrotic therapy in human liver disease will need to provoke resorption of existing matrix in addition to preventing deposition of new scar. As noted above, TGF-beta antagonists have the advantage of stimulating matrix degradation by downregulating TIMPs and increasing net activity of interstitial collagenase (see [93] for review). Direct administration of matrix-degrading enzymes in animal models of hepatic fibrosis has begun to confirm the fact that, in principle, matrix can be resorbed[94]; however, it is not yet certain whether this represents a practical approach in patients.

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