Preventing and Reversing Fibrosis in Autoimmune Hepatitis
Liver inflammation is probably an important driver of hepatic stellate cell activation in autoimmune hepatitis, and the transformation of quiescent hepatic stellate cells into myofibroblasts enhances the extracellular matrix by depositing collagen fibrils. The counterbalance between the fibrolytic metalloproteinases and their inhibitors determines the final status of the extracellular matrix, and as the collagen fibrils are cross-linked by lysyl oxidases, they become more resistant to dissolution. Prompt and complete suppression of inflammatory activity is a logical strategy to prevent progressive hepatic fibrosis, and it may be the principal anti-fibrotic action of the standard treatments (Figure 1).
(Enlarge Image)
Figure 1.
Feasible sites and types of intervention to prevent progressive hepatic fibrosis. Hepatic inflammation is a critical trigger for hepatic fibrosis, and it is targeted by current immunosuppressive and anti-inflammatory therapies. Budesonide, mycophenolate mofetil (mycophenolate) and the calcineurin inhibitors are anti-inflammatory and immunosuppressive agents whose anti-fibrotic effects in autoimmune hepatitis warrant further study. Kupffer cell activation promotes hepatocyte apoptosis by generating inducible nitric oxide synthase (iNOS), nitric oxide (NO) and the release of reactive oxygen species (ROS). Antioxidants, including N-acetylcysteine, S-adenosyl-l-methionine (SAMe) and vitamin E, may counter these actions. Activated hepatic stellate cells can transform into myofibroblasts, and this transformation can be enhanced by transforming growth factor-beta (TGFβ) and angiotensin II. Reactive oxygen species generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in myofibroblasts, macrophages and hepatocytes can activate more hepatic stellate cells and sustain fibrogenesis. Antioxidants, TGFβ antagonists (oltipraz) and angiotensin inhibitors (losartan) may disrupt this mechanism. The cannabinoid receptor CB1 on myofibroblasts stimulates production of extracellular matrix, and it can be blocked by a CB1 antagonist (rimonabant). The fibrotic process may also be dampened by interventions that promote myofibroblast apoptosis, such as angiotensin converting enzyme (ACE) inhibitors, interferon-gamma (IFNγ) therapy and natural killer (NK) cell activation. Interventions that enhance the activity of peroxisome proliferator-activated receptor-gamma (PPARγ) may dampen the activation of hepatic stellate cells, and therapies designed to enhance the activity of the metalloproteinses (MMP) or reduce the activity of their inhibitors (TIMP) may decrease the extracellular matrix. The interventions poised for investigation in autoimmune hepatitis are denoted by an asterisk and identified as most feasible.
Hepatic inflammation accompanies immune-mediated liver damage, and it can enhance the necrosis and apoptosis of hepatocytes. Apoptotic bodies released by dying hepatocytes can in turn activate quiescent hepatic stellate cells and transform them into myofibroblasts. Interventions that reduce immune-mediated liver damage and the inflammatory response can limit hepatocyte apoptosis and the release of apoptotic bodies. These actions can in turn blunt fibrogenesis. Prednisone, prednisolone, budesonide, mycophenolate mofetil and the calcineurin inhibitors are prime candidates to prevent progressive hepatic fibrosis through their immunosuppressive and anti-inflammatory actions which may in turn reduce hepatocyte apoptosis (Figure 1).
Reactive oxygen species released by myofibroblasts and by Kupffer cells activated by the ingestion of hepatocyte-derived apoptotic bodies can increase the oxidative stress on hepatocytes, promote their apoptosis, and further stimulate the activation of hepatic stellate cells. The production of reactive oxygen species is influenced by the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in hepatic stellate cells, macrophages and hepatocytes and by the production of nitric oxide (NO) via activation of inducible nitric acid synthase (iNOS) in Kupffer cells. Interventions that inhibit the production of reactive oxygen species may in turn limit hepatocyte apoptosis, the activation of hepatic stellate cells and the production of extracellular matrix. Drugs with anti-oxidant properties (N-acetylcysteine, S-adenosyl-l-methionine and vitamin E) may attenuate the pro-fibrotic effects of oxidative stress on the hepatocytes (Figure 1). Oxidative stress is not disease-specific, and its demonstration in animal models and humans with diverse liver diseases suggests that anti-oxidants may have a broad application.
Cytokines, including transforming growth factor-beta 1 (TGFβ1), platelet-derived growth factor (PDGF) and endothelial growth factor (EGF) induce the activated hepatic stellate cells to transform into myofibroblasts, and interventions that inhibit the production of these cytokines may limit this transformation and reduce collagen production. Similarly, angiotensin II is secreted by hepatic stellate cells, and it induces their proliferation and the production of extracellular matrix. These actions are in part counterbalanced by the production of peroxisome proliferator-activated receptor-gamma (PPARγ), which maintains the quiescence of hepatic stellate cells and dampens their transformation into myofibroblasts.
Myofibroblasts can also be targeted to limit their synthesis of collagen or induce their apoptosis and early demise. The cannabinoid receptor CB1 is upregulated in myofibroblasts, and it increases hepatic fibrosis. In contrast, the CB2 receptor on these cells is anti-fibrotic. Interventions that may interrupt these diverse pathways of fibrogenesis are antagonists to TGFβ activity (oltipraz), PPARγ agonists (thiazolidinediones such as rosiglitazone and pioglitazone), angiotensin inhibitors (losartin), cannabinoid receptor CB1 antagonists (rimonabant), and promoters of myofibroblast apoptosis (angiotensin inhibitors, interferon gamma and natural killer cells) (Figure 1). Pharmacological manipulations of the molecular receptors involved in the pathways of hepatic fibrosis are promising areas of investigation, but studies to date have demonstrated discrepancies between animal and human experiences and serious toxicities in some instances. These early experiences have indicated a need for safer interventions with more precise targeting, greater understanding of the alternative fibrotic pathways that may circumvent site-specific interventions and more insight into the disease specificity of each treatment.
The extracellular matrix is another therapeutic target, especially at early stages of formation before extensive cross-linkage of collagen fibrils. Metalloproteinases degrade the different types of collagen (collagens I and IV, procollagen III and elastin) that constitute the extracellular matrix, and tissue inhibitors of the metalloproteinases counter-regulate the degradation process and preserve hepatic stellate cell survival by expressing the anti-apoptotic protein, Bcl-2. Interventions that favour matrix degradation pathways over matrix preservation pathways are feasible strategies to prevent progressive hepatic fibrosis.
The activation of metalloproteinases, suppression of metalloproteinase inhibitors and inhibition of lysyl oxidase activity are actions that could counter matrix expansion. Restoration of metalloproteinase activity is possible by bone marrow transplantation, but this intervention is outside the immediate purview of therapies for autoimmune hepatitis. Polaprezinc, a chelated compound of zinc-carnosine, dampens the expression of tissue inhibitors of the metalloproteinases (TIMP) in a murine model of non-alcoholic steatohepatitis, but results are preliminary. The key sites that would enhance matrix degradation are identifiable, but the instruments by which to accomplish these objectives remain uncertain (Figure 1).
The incorporation of site-specific anti-fibrotic interventions in autoimmune hepatitis will require non-invasive methods of assessing hepatic fibrosis, the selection of interventions appropriate for autoimmune hepatitis and the performance of animal and human studies that fully define the efficacy and safety of these interventions. The fibrotic pathways may be similar in all chronic liver diseases, but the key fibrotic mechanism and the critical target of anti-fibrotic therapy may differ between diseases. Anti-fibrotic interventions may exhibit disease specificities, and this possibility compels the validation of any investigational anti-fibrotic intervention in the individual disease for which it is intended.
Fibrogenic Mechanisms and Feasible Sites of Intervention
Liver inflammation is probably an important driver of hepatic stellate cell activation in autoimmune hepatitis, and the transformation of quiescent hepatic stellate cells into myofibroblasts enhances the extracellular matrix by depositing collagen fibrils. The counterbalance between the fibrolytic metalloproteinases and their inhibitors determines the final status of the extracellular matrix, and as the collagen fibrils are cross-linked by lysyl oxidases, they become more resistant to dissolution. Prompt and complete suppression of inflammatory activity is a logical strategy to prevent progressive hepatic fibrosis, and it may be the principal anti-fibrotic action of the standard treatments (Figure 1).
(Enlarge Image)
Figure 1.
Feasible sites and types of intervention to prevent progressive hepatic fibrosis. Hepatic inflammation is a critical trigger for hepatic fibrosis, and it is targeted by current immunosuppressive and anti-inflammatory therapies. Budesonide, mycophenolate mofetil (mycophenolate) and the calcineurin inhibitors are anti-inflammatory and immunosuppressive agents whose anti-fibrotic effects in autoimmune hepatitis warrant further study. Kupffer cell activation promotes hepatocyte apoptosis by generating inducible nitric oxide synthase (iNOS), nitric oxide (NO) and the release of reactive oxygen species (ROS). Antioxidants, including N-acetylcysteine, S-adenosyl-l-methionine (SAMe) and vitamin E, may counter these actions. Activated hepatic stellate cells can transform into myofibroblasts, and this transformation can be enhanced by transforming growth factor-beta (TGFβ) and angiotensin II. Reactive oxygen species generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in myofibroblasts, macrophages and hepatocytes can activate more hepatic stellate cells and sustain fibrogenesis. Antioxidants, TGFβ antagonists (oltipraz) and angiotensin inhibitors (losartan) may disrupt this mechanism. The cannabinoid receptor CB1 on myofibroblasts stimulates production of extracellular matrix, and it can be blocked by a CB1 antagonist (rimonabant). The fibrotic process may also be dampened by interventions that promote myofibroblast apoptosis, such as angiotensin converting enzyme (ACE) inhibitors, interferon-gamma (IFNγ) therapy and natural killer (NK) cell activation. Interventions that enhance the activity of peroxisome proliferator-activated receptor-gamma (PPARγ) may dampen the activation of hepatic stellate cells, and therapies designed to enhance the activity of the metalloproteinses (MMP) or reduce the activity of their inhibitors (TIMP) may decrease the extracellular matrix. The interventions poised for investigation in autoimmune hepatitis are denoted by an asterisk and identified as most feasible.
Hepatic inflammation accompanies immune-mediated liver damage, and it can enhance the necrosis and apoptosis of hepatocytes. Apoptotic bodies released by dying hepatocytes can in turn activate quiescent hepatic stellate cells and transform them into myofibroblasts. Interventions that reduce immune-mediated liver damage and the inflammatory response can limit hepatocyte apoptosis and the release of apoptotic bodies. These actions can in turn blunt fibrogenesis. Prednisone, prednisolone, budesonide, mycophenolate mofetil and the calcineurin inhibitors are prime candidates to prevent progressive hepatic fibrosis through their immunosuppressive and anti-inflammatory actions which may in turn reduce hepatocyte apoptosis (Figure 1).
Reactive oxygen species released by myofibroblasts and by Kupffer cells activated by the ingestion of hepatocyte-derived apoptotic bodies can increase the oxidative stress on hepatocytes, promote their apoptosis, and further stimulate the activation of hepatic stellate cells. The production of reactive oxygen species is influenced by the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in hepatic stellate cells, macrophages and hepatocytes and by the production of nitric oxide (NO) via activation of inducible nitric acid synthase (iNOS) in Kupffer cells. Interventions that inhibit the production of reactive oxygen species may in turn limit hepatocyte apoptosis, the activation of hepatic stellate cells and the production of extracellular matrix. Drugs with anti-oxidant properties (N-acetylcysteine, S-adenosyl-l-methionine and vitamin E) may attenuate the pro-fibrotic effects of oxidative stress on the hepatocytes (Figure 1). Oxidative stress is not disease-specific, and its demonstration in animal models and humans with diverse liver diseases suggests that anti-oxidants may have a broad application.
Cytokines, including transforming growth factor-beta 1 (TGFβ1), platelet-derived growth factor (PDGF) and endothelial growth factor (EGF) induce the activated hepatic stellate cells to transform into myofibroblasts, and interventions that inhibit the production of these cytokines may limit this transformation and reduce collagen production. Similarly, angiotensin II is secreted by hepatic stellate cells, and it induces their proliferation and the production of extracellular matrix. These actions are in part counterbalanced by the production of peroxisome proliferator-activated receptor-gamma (PPARγ), which maintains the quiescence of hepatic stellate cells and dampens their transformation into myofibroblasts.
Myofibroblasts can also be targeted to limit their synthesis of collagen or induce their apoptosis and early demise. The cannabinoid receptor CB1 is upregulated in myofibroblasts, and it increases hepatic fibrosis. In contrast, the CB2 receptor on these cells is anti-fibrotic. Interventions that may interrupt these diverse pathways of fibrogenesis are antagonists to TGFβ activity (oltipraz), PPARγ agonists (thiazolidinediones such as rosiglitazone and pioglitazone), angiotensin inhibitors (losartin), cannabinoid receptor CB1 antagonists (rimonabant), and promoters of myofibroblast apoptosis (angiotensin inhibitors, interferon gamma and natural killer cells) (Figure 1). Pharmacological manipulations of the molecular receptors involved in the pathways of hepatic fibrosis are promising areas of investigation, but studies to date have demonstrated discrepancies between animal and human experiences and serious toxicities in some instances. These early experiences have indicated a need for safer interventions with more precise targeting, greater understanding of the alternative fibrotic pathways that may circumvent site-specific interventions and more insight into the disease specificity of each treatment.
The extracellular matrix is another therapeutic target, especially at early stages of formation before extensive cross-linkage of collagen fibrils. Metalloproteinases degrade the different types of collagen (collagens I and IV, procollagen III and elastin) that constitute the extracellular matrix, and tissue inhibitors of the metalloproteinases counter-regulate the degradation process and preserve hepatic stellate cell survival by expressing the anti-apoptotic protein, Bcl-2. Interventions that favour matrix degradation pathways over matrix preservation pathways are feasible strategies to prevent progressive hepatic fibrosis.
The activation of metalloproteinases, suppression of metalloproteinase inhibitors and inhibition of lysyl oxidase activity are actions that could counter matrix expansion. Restoration of metalloproteinase activity is possible by bone marrow transplantation, but this intervention is outside the immediate purview of therapies for autoimmune hepatitis. Polaprezinc, a chelated compound of zinc-carnosine, dampens the expression of tissue inhibitors of the metalloproteinases (TIMP) in a murine model of non-alcoholic steatohepatitis, but results are preliminary. The key sites that would enhance matrix degradation are identifiable, but the instruments by which to accomplish these objectives remain uncertain (Figure 1).
The incorporation of site-specific anti-fibrotic interventions in autoimmune hepatitis will require non-invasive methods of assessing hepatic fibrosis, the selection of interventions appropriate for autoimmune hepatitis and the performance of animal and human studies that fully define the efficacy and safety of these interventions. The fibrotic pathways may be similar in all chronic liver diseases, but the key fibrotic mechanism and the critical target of anti-fibrotic therapy may differ between diseases. Anti-fibrotic interventions may exhibit disease specificities, and this possibility compels the validation of any investigational anti-fibrotic intervention in the individual disease for which it is intended.
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