Información del artículo
La fibrosis hepática es un proceso dinámico y regulado que se desencadena en respuesta a la lesión hepatocelular crónica provocada por diversas causas. La fuente principal de ese tejido fibroso son las células mesenquimales estrelladas del hígado (CEH), que se ubican en el espacio perisinusoidal de Disse entre los hepatocitos y las células endoteliales.
En condiciones fisiológicas, las CEH quiescentes desempeñan un papel fundamental al regular la homeostasis de los retinoides y la remodelación de la matriz extracelular (MEC) tanto por medio de su capacidad de sintetizar los componentes de ésta, como por su habilidad para producir diferentes metaloproteinasas degradantes de la MEC y sus inhibidores. Sin embargo, durante la fibrogénesis hepática, las CEH se activan diferenciándose en células parecidas a los miofibroblastos con capacidad proliferativa, fibrogénica y contráctil para desempeñar un papel primordial en la configuración de la fibrosis hepática y en el control del flujo sanguíneo del hígado.
En esta revisión se comentarán la morfología básica y las funciones de las CEH en condiciones normales y durante su activación en la fibrosis.
Hepatic fibrosis is a dynamic and sophisticatedly regulated wound healing response to chronic hepatocellular injury. This fibrotic process results from the accumulation of extracellular matrix (ECM) including collagen, proteoglycan, and adhesive glycoproteins which are principally produced by hepatic stellate cells (HSC), a mesenchymal cell type located between parenchymal cell plates and sinusoidal endothelial cells in the space of Disse.
In physiological conditions, quiescent HSCs play important roles in the regulation of retinoid homeostasis and ECM remodeling by producing ECM components as well as metalloproteases and its inhibitor.
However during hepatic fibrogenesis, HSCs are known to be activated or «transdifferentiated» to myofibroblast-like cells which play a pivotal role in ECM remodeling and hepatic blood flow regulation. Activation of HSC is now well established as the key process involved in the development of hepatic fibrosis.
Both basic morphology and functions of HSCs in normal conditions and its role in pathological fibrosis will be discussed in this review.
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Bibliograf¿a
[1]
Karl Wilhelm Kupffer and his contributions to modern hepatology comparative. Hepatology. 2004; 3(Suppl 1):2.
[2]
The stellate cell (Ito-cell, fat-storing cell, lipocyte, perisinusoidal cell) of the liver. New insights into pathophysiology of an intriguing cell. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991; 61:147-58.
[3]
Hepatic ultrastructural specialization in Antarctic fishes. Cell Tissue Res. 1981; 219:489-96.
[4]
Hígado y vías biliares. En: Cotran R.S., Kumar V., Robbins S.L., editors. Patología estructural y functional. 5.ª ed. Madrid: McGraw-Hill Interamericana de España S.A.; 1995. 919-91.
[5]
Collagen type I and III occur together in hybrid fibrils in the space of Disse of normal rat liver. Hepatology. 1990; 12:233-41.
[6]
Nerves and perisinusoidal cells in human liver. J Hepatol. 1990; 10:105-12.
[7]
Basement membrane proteins in the space of Disse: a reappraisal. J Clin Pathol. 1991; 44:646-8.
[8]
Structure and function of hepatic stellate cells. Med Electron Microsc. 2004; 37:3-15.
[9]
Hepatic fibrosis-role of hepatic stellate cell activation. Med Gen Med. 2002; 4:27.
[10]
History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis. 2001; 21:311-35.
[11]
Professor Toshio Ito: a clairvoyant in pericyte biology. Keio J Med. 2001; 50:66-71.
[12]
Hepatic retinol metabolism. Distribution of retinoids, enzymes, and binding proteins in isolated rat liver cells. J Biol Chem. 1985; 260:13560-5.
[13]
Biochemical characteristics of isolated rat liver stellate cells. Hepatology. 1987; 7:1224-9.
[14]
Storage of vitamin A in extrahepatic stellate cells in normal rats. J Lipid Res. 1997; 38:645-58.
[15]
Hepatic stellate cell: unique characteristics in cell biology and phenotype. Cell Struct Funct. 2003; 28:105-12.
[16]
The hepatic perisinusoidal stellate cell. Histol Histpathol. 1997; 12:1069-80.
[17]
Quantitation of rat hepatic stellate cell contraction: stellate cells’ contribution to sinusoidal resistance. Am J Physiol. 1999; 277:G137-43.
[18]
Factores involucrados en la fibrogénesis hepática. Gastroenterol Hepatol. 2000; 26:186-99.
[19]
Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis. 2001; 21:397-416.
[20]
Fibrogénesis y trasplante hepático. Gastroenterol Hepatol. 2003; 26:381-95.
[21]
Cellular sources of noncollagenous matrix proteins: role of fat-storing cells in fibrogenesis. Semin Liver Dis. 1990; 10:30-46.
[22]
The hepatic stellate (Ito) cell: its role in human liver disease. Virchows Arch. 1997; 430:195-207.
[23]
Is liver fibrosis reversible?. N Engl J Med. 2001; 344:452-4.
[24]
Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000; 275:2247-50.
[25]
Tissue inhibitors of metalloproteinases in liver fibrosis. Int J Biochem Cell Biol. 1997; 29:43-54.
[26]
Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis. J Gastroenterol Hepatol. 1998; 13(Supl):33-8.
[27]
Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis. Kidney Int Suppl. 1996; 54:S39-45.
[28]
Perisinusoidal stellate cells or Ito cells and their role in hepatic fibrosis. Pathologica. 1994; 86:467-99.
[29]
La progresión de la fibrosis hepática en la hepatitis C crónica. Gastroenterol Hepatol. 2000; 23:1-6.
[30]
Recent studies on Ito cells with molecular biology. Nippon Rinsho. 1993; 51:472-81.
[31]
Los mediadores de la inflamación y la hepatitis crónica. Gastroenterol Hepatol. 1995; 18:42-54.
[32]
Signal transduction in hepatic stellate cells. Liver. 1998; 18:2-13.
[33]
Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy. J Gastroenterol Hepatol. 1999; 14:618-33.
[34]
Roles of TGF-beta in hepatic fibrosis. Front Biosci. 2002; 7:793-807.
[35]
Regulation of extracellular matrix synthesis by transforming growth factor beta 1 in human fat-storing cells. Gastroenterology. 1993; 105:245-53.
[36]
The role of TGFbeta1 in initiating hepatic stellate cell activation in vivo. J Hepatol. 1999; 30:77-87.
[37]
Transforming growth factor b in tissue fibrosis. N Engl J Med. 1994; 331:1286-92.
[38]
Fibrogenesis V. TGF-ß signaling pathways. Am J Physiol Gastrointest Liver Physiol. 2000; 279:G845-50.
[39]
Controlling TGF-beta signaling. Genes Dev. 2000; 14:627-44.
[40]
Activation of rat liver perisinusoidal lipocytes by transforming growth factors derived from myofibroblastlike cells. A potential mechanism of self perpetuation in liver fibrogenesis. J Clin Invest. 1992; 89:19-27.
[41]
Tumor necrosis factor alpha (TNF alpha) and transforming growth factor beta 1 (TGF beta 1) stimulate fibronectin synthesis and the transdifferentiation of fat-storing cells in the rat liver into myofibroblasts. Virchows Arch B Cell Pathol Incl Mol Pathol. 1993; 63:123-30.
[42]
The role of TGFbeta1 in initiating hepatic stellate cell activation in vivo. J Hepatol. 1999; 30:77-87.
[43]
TGF-beta1 induces aberrant laminin chain and collagen type IV isotype expression in the glomerular basement membrane. Nephron Exp Nephrol. 2003; 94:e123-36.
[44]
Transforming growth factor-beta1 stimulates the synthesis of basement membrane proteins laminin, collagen type IV and entactin in rat liver sinusoidal endothelial cells. J Hepatol. 1999; 31:692-702.
[45]
TGF-beta in liver fibrosis? an inducible transgenic mouse model to study liver fibrogenesis. Am J Physiol. 1999; 276:G1059-68.
[46]
Neutralizing antibody to TGFbeta modulates stromal fibrosis but not regression of photoablative effect following PRK. Curr Eye Res. 1998; 17:736-47.
[47]
Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2000; 279:G245-9.
[48]
Extracellular matrix degradation and the role of stellate cells. Semin Liver Dis. 2001; 21:373-84.
[49]
Expression patterns of matrix metalloproteinases and theirinhibitors in parenchymal and non parenchymal cell of rat liver. Regulation by TNF-α and TGF-β1. J Hepatol. 1999; 30:48-60.
[50]
Liver fibrosis, the hepatic stellate cell and tissue inhibitors of metalloproteinases. Histol Histopathol. 2000; 15:1159-68.
[51]
Herbal medicine Sho-saiko-to (TJ-9) increases expression matrix metalloproteinases (MMPs) with reduced expression of tissue inhibitor of metalloproteinases (TIMPs) in rat stellate cell. Life Sci. 2004; 74:2251-63.
[52]
Tissue inhibitor of metalloproteinases-1 and 2 RNA expression in rats and human liver fibrosis. Am J Pathol. 1997; 150:1647-59.
[53]
Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinases- 1. Implications for regulation of matrix degradation in liver. J Clin Invest. 1992; 90:282-7.
[54]
Tissue inhibitor of metalloproteinase-1 and interstitial collagenase expression in autoimmune chronic active hepatitis and activated human hepatic lipocytes. Clin Sci (Lond). 1995; 89:75-81.
[55]
Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis. Hepatology. 1996; 24:176-84.
[56]
Expression of tissue inhibitor of metalloproteinases-1 and -2 is increased in fibrotic human liver. Gastroenterology. 1996; 110:821-31.
[57]
Hepatic circulation in cirrhosis. Clin Gastroenterol. 1985; 14:155-68.
[58]
Basement membrane proteins in the space of Disse: a reappraisal. J Clin Pathol. 1991; 44:646-8.
[59]
The role of capillarization in hepatic failure: studies in carbon tetrachloride-induced cirrhosis. Hepatology. 1991; 14:864-74.
[60]
Myofibroblasts in the cirrhotic rat liver reflect hepatic remodeling and correlate with fibrosis and sinusoidal capillarization. J Hepatol. 1999; 30:646-52.
[61]
Liver fibrosis and altered matrix synthesis. Can J Gastroenterol. 2001; 15:187-93.
[62]
The coordinated expression of laminin and its integrin receptor in hepatic sinusoidal capillarization. Zhonghua Nei Ke Za Zhi. 2001; 40:618-20.
[63]
Studies on capillarization of the hepatic sinusoids in alcoholic liver disease. Alcohol Alcohol Suppl. 1993; 1B:77-84.
[64]
Capillarization and venularization of hepatic sinusoids in porcine serum-induced rat liver fibrosis: a mechanism to maintain liver blood flow. Hepatology. 1993; 18:1450-8.
[65]
The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin, and nitric oxide. Hepatology. 1997; 25:2-5.
[66]
Microvascular pericyte contractility in vitro: comparison with other cells of the vascular wall. J Cell Biol. 1987; 104:483-90.
[67]
Hepatic blood flow regulation by stellate cells in normal and injured liver. Semin Liver Dis. 2001; 21:337-49.
[68]
Endothelin-1 induces direct constriction of hepatic sinusoids. Am J Physiol. 1994; 266(4 Pt 1):G624-32.
[69]
Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension. Gut. 2002; 50:571-81.
[70]
Morphological mechanisms for regulating blood flow through hepatic sinusoids. Liver. 2000; 20:3-7.
[71]
Regulation of sinusoidal perfusion: in vivo methodology and control by endothelins. Semin Liver Dis. 1999; 19:383-96.
[72]
The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances. Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. Eur J Biochem. 1993; 213:815-23.
[73]
Expression of the gene of a-smooth muscle actin isoform in rat liver and in rat fat-storing (ITO) cells. Virchows Arch B Cell Pathol Incl Mol Pathol. 1990; 59:349-57.
[74]
Modulation of alpha smooth muscle actin and desmin expression in perisinusoidal cells of normal and diseased human livers. Am J Pathol. 1991; 138:1233-42.
[75]
Expression and function of integrin receptors for collagen and laminin in cultured human hepatic stellate cells. Gastroenterology. 1996; 110:1127-36.
[76]
The role of alpha1beta1 integrin in wound contraction. A quantitative analysis of liver myofibroblasts in vivo and in primary culture. J Biol Chem. 1997; 272:30911-7.
[77]
Contraction of human hepatic stellate cells activated in culture: a role for voltage-operated calcium channels. J Hepatol. 1998; 29:398-408.
[78]
In vitro and in vivo activation of rat hepatic stellate cells results in de novo expression of L-type voltageoperated calcium channels. Hepatology. 2001; 33:956-62.
[79]
A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988; 332:411-5.
[80]
Physiology and pharmacology of endothelins. Med Res Rev. 1992; 12:391-421.
[81]
Hepatic effects of endothelin. Receptor characterization and endothelin-induced signal transduction in hepatocytes. Biochem J. 1992; 287:897-904.
[82]
Endothelin receptors in rat liver: lipocytes as a contractile target for endothelin 1. Proc Natl Acad Sci U S A. 1993; 90:9266-70.
[83]
Regulation of endothelin-1 action on the perfused rat liver. FEBS Lett. 1993; 318:353-7.
[84]
Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Hepatology. 1996; 24:233-40.
[85]
The effect of endothelin and its antagonist Bosentan on hemodynamics and microvascular exchange in cirrhotic rat liver. J Hepatol. 1998; 28:1020-30.
[86]
Mediadores celulares III. En: Flórez J., Armijo J.A., Mediavilla A., editors. Farmacología humana. 3.ª ed. Barcelona: Editorial Masson S.A.; 1997. 343-53.
[87]
The expression of AT1 receptor on hepatic stellate cells in rat fibrosis induced by CCl4. Chin Med J (Engl). 2001; 114:583-7.
[88]
Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology. 2000; 118:1149-56.
[89]
Expression of angiotensin II type 1 receptor in rat hepatic stellate cells and its effects on cell growth and collagen production. Horm Res. 2003; 60:105-10.
[90]
Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 2001; 34:745-50.
[91]
An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells. Br J Pharmacol. 2003; 139:1085-94.
[92]
Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology. 2003; 125:117-25.
[93]
Inhibitory effect of angiotensin II receptor antagonist on the contraction and growth of hepatic stellate cells. Korean J Gastroenterol. 2003; 42:134-41.
[94]
Arginine vasopressin induces contraction and stimulates growth of cultured human hepatic stellate cells. Gastroenterology. 1997; 113:615-24.
[95]
Selective alteration of agonist-mediated contraction in hepatic arteries isolated from patients with cirrhosis. Gastroenterology. 2000; 118:765-71.
[96]
The response of liver macrophages to inflammatory stimulation. Keio J Med. 1998; 47:1-9.
[97]
Nitric oxide a physiologic messenger molecule. Annu Rev Biochem. 1994; 63:175-95.
[98]
Nitric oxide synthase structure and mechanism. J Biol Chem. 1993; 268:12231-4.
[99]
Nitric oxide in the pathogenesis of vascular disease. J Pathol. 2000; 190:244-54.
[100]
Nitric oxide a physiologic messenger. Ann Intern Med. 1994; 120:227-37.
[101]
Nitric oxide modulates hepatic vascular tone in normal rat liver. Am J Physiol. 1994; 267:G416-22.
[102]
Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. 1998; 28:926-31.
[103]
Treatment of hepatic fibrosis. Almost there. Curr Gastroenterol Rep. 2003; 5:48-56.
[104]
Liver fibrosis-from bench to bedside. J Hepatol. 2003; 38:38-53.
[105]
Gliotoxin and related epipolythiodioxopiperazines. Gen Pharmacol. 1996; 27:1311-6.
[106]
Transforming growth factor beta-1: structure, function, and regulation mechanisms in cancer. Salud Publica Mex. 2001; 43:340-51.
[107]
The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in autoimmune diseases. J Autoimmun. 2000; 14:23-42.
[108]
The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and disease. Liver. 2000; 20:191-9.
[109]
Targeting hepatic stellate cells for cell-specific treatment of liver fibrosis. Front Biosci. 2002; 7:e214-22.
