Targeting hepatic stellate cells for cell-specific treatment of liver fibrosis.

Since hepatic stellate cells (HSC) play a crucial role in the development of liver fibrosis, this cell is the major target for anti-fibrotic drugs. Most of the experimental drugs that influenced the HSC activity showed however low efficacy in vivo. Either a low uptake of the compounds in the cells that cause disease might account for this lack of effect, or side-effects in other cells may limit the dosage of the drugs. These side-effects may even counteract the beneficial effects. Therefore a selective delivery of drugs to the HSC may comprise a promising new way to improve liver fibrosis. The targeting to HSC has become a feasible option, because albumin-based carriers have been developed that preferentially distribute to HSC in fibrotic rat livers. In addition to the targeting of drugs, also the selective delivery of genes to HSC in fibrotic livers is of interest for therapeutic purposes and a start is made in this respect. The present review discusses the drugs to be targeted to HSC and summarizes some of the problems encountered during this novel strategy in the treatment of liver fibrosis.

[1]  J. Maher Interactions between Hepatic Stellate Cells and the Immune System , 2001, Seminars in liver disease.

[2]  R. DePinho,et al.  Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. , 2000, Science.

[3]  D. Rockey,et al.  Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. , 1996, The Journal of clinical investigation.

[4]  J. Iredale,et al.  Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. , 1998, The Journal of clinical investigation.

[5]  Anping Chen,et al.  E-box-binding Repressor Is Down-regulated in Hepatic Stellate Cells during Up-regulation of Mannose 6-Phosphate/Insulin-like Growth Factor-II Receptor Expression in Early Hepatic Fibrogenesis* , 1998, The Journal of Biological Chemistry.

[6]  D. Sohn,et al.  Antifibrotic effects of a polysaccharide extracted from Ganoderma lucidum, glycyrrhizin, and pentoxifylline in rats with cirrhosis induced by biliary obstruction. , 1997, Biological & pharmaceutical bulletin.

[7]  M. Zern,et al.  Hepatic stellate cells: a target for the treatment of liver fibrosis , 2000, Journal of Gastroenterology.

[8]  A. Rolland From genes to gene medicines: recent advances in nonviral gene delivery. , 1998, Critical reviews in therapeutic drug carrier systems.

[9]  A. Burt,et al.  Macrophage and hepatic stellate cell responses during experimental hepatocarcinogenesis , 1998, Journal of gastroenterology and hepatology.

[10]  O. Chazouilleres,et al.  Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: Clinical features and response to therapy , 1998, Hepatology.

[11]  T. Willson,et al.  Peroxisome Proliferator-activated Receptors and Hepatic Stellate Cell Activation* , 2000, The Journal of Biological Chemistry.

[12]  M. Arthur,et al.  Extracellular Matrix Degradation and the Role of Hepatic Stellate Cells , 2001, Seminars in liver disease.

[13]  E. De Clercq,et al.  Charge modification of plasma and milk proteins results in antiviral active compounds , 1999, Journal of peptide science : an official publication of the European Peptide Society.

[14]  V. Carloni,et al.  Signal transduction in hepatic stellate cells. , 2008, Liver.

[15]  M. Kaplan The Use of Methotrexate, Colchicine, and Other Immunomodulatory Drugs in the Treatment of Primary Biliary Cirrhosis , 1997, Seminars in liver disease.

[16]  D. Rockey,et al.  Gene transfer of the neuronal NO synthase isoform to cirrhotic rat liver ameliorates portal hypertension. , 2000, The Journal of clinical investigation.

[17]  J. Iredale,et al.  Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. , 2001, Gastroenterology.

[18]  W. Meyers,et al.  V-PYRRO/NO: AN HEPATO-SELECTIVE NITRIC OXIDE DONOR IMPROVES PORCINE LIVER HEMODYNAMICS AND FUNCTION AFTER ISCHEMIA REPERFUSION1 , 2001, Transplantation.

[19]  V. Sandig,et al.  Liver-directed gene transfer and application to therapy , 1996, Journal of Molecular Medicine.

[20]  W. Border,et al.  Targeting TGF-beta overexpression in renal disease: maximizing the antifibrotic action of angiotensin II blockade. , 1998, Kidney international.

[21]  Wu,et al.  Pre-clinical trials using hepatic gene delivery. , 1998, Advanced drug delivery reviews.

[22]  K. Okita,et al.  Prolyl 4-hydroxylase inhibitor (HOE 077) prevents TIMP-1 gene expression in rat liver fibrosis , 1999, Journal of Gastroenterology.

[23]  M. Zern,et al.  Targeting of therapeutics to the liver: liposomes and viral vectors. , 1999, Alcoholism, clinical and experimental research.

[24]  W. Brown,et al.  Abnormal surface distribution of the human asialoglycoprotein receptor in cirrhosis , 1992, Hepatology.

[25]  G. Nemerow Cell receptors involved in adenovirus entry. , 2000, Virology.

[26]  D. Meijer,et al.  Hepatic and intrahepatic targeting of an anti-inflammatory agent with human serum albumin and neoglycoproteins as carrier molecules. , 1993, Biochemical pharmacology.

[27]  R. Kok,et al.  Development of Proteinaceous Drug Targeting Constructs Using Chemical and Recombinant DNA Approaches , 2001 .

[28]  A. Desmoulière,et al.  Effect of pentoxifylline on early proliferation and phenotypic modulation of fibrogenic cells in two rat models of liver fibrosis and on cultured hepatic stellate cells. , 1999, Journal of hepatology.

[29]  T. C. Peterson Pentoxifylline prevents fibrosis in an animal model and inhibits platelet‐derived growth factor–driven proliferation of fibroblasts , 1993, Hepatology.

[30]  R. Bataller,et al.  Angiotensin II induces contraction and proliferation of human hepatic stellate cells. , 2000, Gastroenterology.

[31]  M. Pinzani,et al.  Biology of Hepatic Stellate Cells and Their Possible Relevance in the Pathogenesis of Portal Hypertension in Cirrhosis , 1999, Seminars in liver disease.

[32]  P. Calès Apoptosis and liver fibrosis: antifibrotic strategies. , 1998, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[33]  A. Ooshima,et al.  Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[34]  A. Gressner,et al.  Comparative evaluation of gene delivery devices in primary cultures of rat hepatic stellate cells and rat myofibroblasts , 2000, BMC Cell Biology.

[35]  M. Newman,et al.  Reduction of the cardiotoxicity of doxorubicin in rabbits and dogs by encapsulation in long-circulating, pegylated liposomes. , 1999, The Journal of pharmacology and experimental therapeutics.

[36]  E. Ruoslahti,et al.  Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease , 1992, Nature.

[37]  P. Olinga,et al.  Dexamethasone coupled to albumin is selectively taken up by rat nonparenchymal liver cells and attenuates LPS-induced activation of hepatic cells. , 2000, Journal of hepatology.

[38]  R. Caporale,et al.  Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. , 2000, Gastroenterology.

[39]  E. Hanisch,et al.  Endothelin-Induced Contraction of the Portal Vein in Cirrhosis , 1999, European Surgical Research.

[40]  D. Rockey,et al.  Hepatic Blood Flow Regulation by Stellate Cells in Normal and Injured Liver , 2001, Seminars in liver disease.

[41]  D. Schuppan,et al.  Matrix as a modulator of hepatic fibrogenesis. , 2001, Seminars in liver disease.

[42]  V. Carloni,et al.  Effect of pentoxifylline on the degradation of procollagen type I produced by human hepatic stellate cells in response to transforming growth factor‐β1 , 1997, British journal of pharmacology.

[43]  D. Crabb,et al.  The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and disease. , 2000, Liver.

[44]  D. Curiel,et al.  Insertion of an RGD motif into the HI loop of adenovirus fiber protein alters the distribution of transgene expression of the systemically administered vector , 1999, Gene Therapy.

[45]  A. Gressner The cell biology of liver fibrogenesis – an imbalance of proliferation, growth arrest and apoptosis of myofibroblasts , 1998, Cell and Tissue Research.

[46]  A. de Gottardi,et al.  Overexpression of endothelin-1 in bile duct ligated rats: correlation with activation of hepatic stellate cells and portal pressure. , 2001, Journal of hepatology.

[47]  A. Mallat,et al.  Pentoxifylline inhibits growth and collagen synthesis of cultured human hepatic myofibroblast‐like cells , 1997, Hepatology.

[48]  J. Armendáriz-Borunda,et al.  Liver cirrhosis is reverted by urokinase-type plasminogen activator gene therapy. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[49]  V. Koteliansky,et al.  In vivo inhibition of rat stellate cell activation by soluble transforming growth factor beta type II receptor: a potential new therapy for hepatic fibrosis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[50]  D. Schuppan,et al.  Fibrosis of liver, pancreas and intestine: common mechanisms and clear targets? , 2000, Acta gastro-enterologica Belgica.

[51]  C. Gandhi,et al.  Enhanced synthesis and reduced metabolism of endothelin-1 (ET-1) by hepatocytes--an important mechanism of increased endogenous levels of ET-1 in liver cirrhosis. , 2000, Journal of hepatology.

[52]  D. Roulot,et al.  Transforming growth factor β and the liver , 2001 .

[53]  G. Batist,et al.  Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  P. Olinga,et al.  Albumin modified with mannose 6‐phosphate: A potential carrier for selective delivery of antifibrotic drugs to rat and human hepatic stellate cells , 1999, Hepatology.

[55]  Y. Kamegaya,et al.  Enhanced expression of endothelin receptor subtypes in cirrhotic rat liver. , 2001, Liver.

[56]  E. Wisse,et al.  Insulinlike growth factor—ii/mannose 6‐phosphate receptor is expressed on ccl4‐exposed rat fat‐storing cells and facilitates activation of latent transforming growth factor‐β in cocultures with sinusoidal endothelial cells , 1995 .

[57]  A. Gerbes,et al.  The effect of endothelin and its antagonist Bosentan on hemodynamics and microvascular exchange in cirrhotic rat liver. , 1998, Journal of hepatology.

[58]  G. Wu,et al.  Hepatocyte-directed Gene Delivery by Receptor-mediated Endocytosis , 1999, Seminars in liver disease.

[59]  L. Ferrell,et al.  Low proliferative activity in macroregenerative nodules: evidence for an alternate hypothesis concerning human hepatocarcinogenesis. , 2008, Liver.

[60]  A. Gressner,et al.  Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis. , 1997, General pharmacology.

[61]  H. Yoshiji,et al.  Angiotensin‐II type 1 receptor interaction is a major regulator for liver fibrosis development in rats , 2001, Hepatology.

[62]  S. Friedman Cytokines and Fibrogenesis , 1999, Seminars in liver disease.

[63]  D. Zeeuw,et al.  (Glyco)-protein drug carriers with an intrinsic therapeutic activity : The concept of dual targeting , 1996 .

[64]  M. Rugge,et al.  Liver stellate cells in chronic viral hepatitis: the effect of interferon therapy. , 1996, Journal of hepatology.

[65]  J. Henriksen,et al.  Splanchnic and systemic hemodynamic derangement in decompensated cirrhosis. , 2001, Canadian journal of gastroenterology = Journal canadien de gastroenterologie.

[66]  S. Thung,et al.  Hepatic stellate cell activation in dysplastic nodules: evidence for an alternate hypothesis concerning human hepatocarcinogenesis. , 2008, Liver.

[67]  P. Waring,et al.  Gliotoxin and related epipolythiodioxopiperazines. , 1996, General pharmacology.

[68]  P. Olinga,et al.  Characteristics of the hepatic stellate cell-selective carrier mannose 6-phosphate modified albumin (M6P(28)-HSA). , 2001, Liver.

[69]  G. Feldmann,et al.  Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation. , 1997, Journal of hepatology.

[70]  D. de Zeeuw,et al.  Specific delivery of captopril to the kidney with the prodrug captopril-lysozyme. , 1999, The Journal of pharmacology and experimental therapeutics.

[71]  D. Meijer,et al.  Drug targeting to the kidney with low-molecular-weight proteins , 1994 .

[72]  D. Schuppan,et al.  Successful Targeting to Rat Hepatic Stellate Cells Using Albumin Modified with Cyclic Peptides That Recognize the Collagen Type VI Receptor* , 2000, The Journal of Biological Chemistry.

[73]  F. Marra,et al.  Cytokine Receptors and Signaling in Hepatic Stellate Cells , 2001, Seminars in liver disease.

[74]  G. Molema,et al.  Targeting of sugar- and charge-modified albumins to fibrotic rat livers: the accessibility of hepatic cells after chronic bile duct ligation. , 1998, Journal of hepatology.

[75]  W. Klepetko,et al.  Decreased hepatic function in patients with hepatoma or liver metastasis monitored by a hepatocyte specific galactosylated radioligand. , 1990, British Journal of Cancer.

[76]  A. Gentilini,et al.  Inhibition by pentoxifylline of extracellular signal‐regulated kinase activation by platelet‐derived growth factor in hepatic stellate cells , 1996, British journal of pharmacology.

[77]  S. Friedman,et al.  Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinases-1. Implications for regulation of matrix degradation in liver. , 1992, The Journal of clinical investigation.

[78]  P. Olinga,et al.  Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats , 2001, Hepatology.

[79]  D. Webb,et al.  Altered peripheral vascular responses to exogenous and endogenous endothelin‐1 in patients with well‐compensated cirrhosis , 2001, Hepatology.

[80]  S. Friedman,et al.  Fibrogenesis I. New insights into hepatic stellate cell activation: the simple becomes complex. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[81]  A. Gressner,et al.  LIM-domain protein cysteine- and glycine-rich protein 2 (CRP2) is a novel marker of hepatic stellate cells and binding partner of the protein inhibitor of activated STAT1. , 2001, The Biochemical journal.

[82]  C. O’Riordan,et al.  Strategies to adapt adenoviral vectors for targeted delivery. , 2003, Methods in molecular medicine.

[83]  P. Stewart,et al.  Role of alpha(v) integrins in adenovirus cell entry and gene delivery. , 1999, Microbiology and molecular biology reviews : MMBR.

[84]  W. Jiménez,et al.  Chronic blockade of endothelin receptors in cirrhotic rats: hepatic and hemodynamic effects. , 1999, Gastroenterology.

[85]  R. Groszmann,et al.  The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough , 2002, Hepatology.

[86]  P. Angelberger,et al.  Functional liver imaging with 99 Tcm-galactosyl‐neoglycoalbumin (NGA) in alcoholic liver cirrhosis and liver fibrosis , 1991, Nuclear medicine communications.

[87]  A. Panduro,et al.  Treatment with anti-transforming growth factor beta antibodies influences an altered pattern of cytokines gene expression in injured rat liver. , 1998, Biochimica et biophysica acta.

[88]  D. Schuppan,et al.  Regulation of the Hepatic Endothelin System in Advanced Biliary Fibrosis in Rats , 2000, Clinical chemistry and laboratory medicine.

[89]  E. Schacht,et al.  The crucial role of spacer groups in macromolecular prodrug design , 1996 .

[90]  G. Hofstede,et al.  Liposomal doxorubicin‐induced toxicity: Depletion and impairment of phagocytic activity of liver macrophages , 1995, International journal of cancer.

[91]  D. Schuppan,et al.  An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. , 2000, Gastroenterology.

[92]  Y Ando,et al.  Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. , 2001, Gastroenterology.

[93]  M. Ahmad,et al.  Induction of stromelysin gene expression by tumor necrosis factor alpha is inhibited by dexamethasone, salicylate, and N-acetylcysteine in synovial fibroblasts. , 1999, The Journal of pharmacology and experimental therapeutics.

[94]  F. Sánchez‐Madrid,et al.  Cell adhesion molecules: selectins and integrins. , 1999, Critical reviews in immunology.

[95]  D. Rockey,et al.  Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance , 1996, Hepatology.

[96]  G. Abrams,et al.  Endothelin-1 stimulation of endothelial nitric oxide synthase in the pathogenesis of hepatopulmonary syndrome. , 1999, The American journal of physiology.

[97]  G. Molema,et al.  Targeting of Drugs to the Liver , 1995, Seminars in liver disease.

[98]  G. Zimmerman,et al.  Endothelial cell interactions with granulocytes: tethering and signaling molecules. , 1992, Immunology today.

[99]  G. Groothuis,et al.  Oxford Textbook of Clinical Hepatology , 1999 .

[100]  A. Morelli,et al.  NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[101]  R. Farzaneh-Far,et al.  Nitric oxide and the liver. , 2001, Liver.