Información de la revista
Vol. 26. Núm. 7.
Páginas 437-446 (enero 2003)
Vol. 26. Núm. 7.
Páginas 437-446 (enero 2003)
Acceso a texto completo
Nuevos horizontes en los mecanismos de la lesión aguda y crónica del páncreas
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X. Molero
, E. Vaquero, J.A. Gómez, A. Alonso, L. Guarner
Autor para correspondencia
xmolero@hg.vhebron.es
Correspondencia: Dr. X. Molero. Servei d'Aparell Digestiu. Hospital Universitari Vall d'Hebron. Pg. Vall d'Hebron, 119-129. 08035 Barcelona. España.
Correspondencia: Dr. X. Molero. Servei d'Aparell Digestiu. Hospital Universitari Vall d'Hebron. Pg. Vall d'Hebron, 119-129. 08035 Barcelona. España.
Servei d'Aparell Digestiu. Hospital Universitari Vall d'Hebron. Barcelona. España
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Bibliografía
[1.]
A.J. Singer.
Clark RAF. Mechanisms of disease: cutaneous wound healing.
N Engl J Med, 341 (1999), pp. 738-746
[2.]
M.K. Winkler, J.L. Fowlkes.
Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?.
Am J Physiol Lung Cell Mol Physiol, 283 (2002), pp. 1L-11L
[3.]
Y. Yamaguchi, K. Matsuno, M. Goto, M. Ogawa.
In situ kinetics of acinar, duct and inflammatory cells in duct ligation-induced pancreatitis in rats.
Gastroenterology, 104 (1993), pp. 1498-1506
[4.]
E. Vaquero, X. Molero, X. Tian, A. Salas, J.R. Malagelada.
Myofibroblast proliferation, fibrosis and defective pancreatic repair induced by cyclosporin in rats.
Gut, 45 (1999), pp. 269-277
[5.]
S. Takano, T. Kimura, H. Yamaguchi, M. Linjo, H. Nawata.
Effects of stress on the development of chronic pancreatitis.
Pancreas, 7 (1992), pp. 548-555
[6.]
M. Inoue, Y. Ino, J. Gibo, T. Ito, T. Hisano, Y. Arita, et al.
The role of monocyte chemoattractant protein-1 in experimental chronic pancreatitis model induced by dibutyltin dichloride in rats.
Pancreas, 25 (2002), pp. 64E-70E
[7.]
D.C. Whitcomb.
Hereditary pancreatitis. New insights into acute and chronic pancreatitis.
Gut, 45 (1999), pp. 317-322
[8.]
B. Etemad, D.C. Whitcomb.
Chronic pancreatitis: diagnosis, classification, and new genetic developments.
Gastroenterology, 120 (2001), pp. 682-707
[9.]
P. Simon, F.U. Weiss, M. Sahin-Toth, M. Parry, O. Nayler, B. Lenfers, et al.
Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122 – > Cys) that alters autoactivation and autodegradation of cationic trypsinogen.
J Biol Chem, 277 (2002), pp. 5404-5410
[10.]
R. Pfutzer, E. Myers, S. Applebaum-Shapiro, R. Finch, I. Ellis, J. Neoptolemos, et al.
Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis.
Gut, 50 (2002), pp. 271-272
[11.]
N. Teich, N. Bauer, J. Mossner, V. Keim.
Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants.
Am J Gastroenterol, 97 (2002), pp. 341-346
[12.]
J.A. Cohn, K.J. Friedman, P.G. Noone, M.R. Knowles, L.M. Silverman, P.S. Jowell.
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.
N Engl J Med, 339 (1998), pp. 653-658
[13.]
P.G. Noone, Z. Zhou, L.M. Silverman, P.S. Jowell, M.R. Knowles, J.A. Cohn.
Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations.
Gastroenterology, 121 (2001), pp. 1310-1319
[14.]
R.H. Pfutzer, D.C. Whitcomb.
SPINK1 mutations are associated with multiple phenotypes.
Pancreatology, 1 (2001), pp. 457-460
[15.]
N. Sharer, M. Schwarz, G. Malone, A. Howarth, J. Painter, M. Super, et al.
Mutations of the cystic fibrosis gene in patients with chronic pancreatitis.
N Engl J Med, 339 (1998), pp. 645-652
[16.]
H. Witt, W. Luck, H.C. Hennies, M. Classen, A. Kage, U. Lass, et al.
Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis.
Nat Genet, 25 (2000), pp. 213-216
[17.]
A. Schneider, A. Suman, L. Rossi, M.M. Barmada, C. Beglinger, S. Parvin, et al.
SPINK1/PSTI mutations are associated with tropical pancreatitis and type II diabetes mellitus in Bangladesh.
Gastroenterology, 123 (2002), pp. 1026-1030
[18.]
E. Bhatia, G. Choudhuri, S.S. Sikora, O. Landt, A. Kage, M. Becker, et al.
Tropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations.
Gastroenterology, 123 (2002), pp. 1020-1025
[19.]
K. Truninger, H. Witt, J. Kock, A. Kage, B. Seifert, R.W. Ammann, et al.
Mutations of the serine protease inhibitor, Kazal type 1 gene, in patients with idiopathic chronic pancreatitis.
Am J Gastroenterol, 97 (2002), pp. 1133-1137
[20.]
L. Guarner, X. Molero, N. Malats, N. Nogués, L. Subirana, A. Alonso, et al.
Study of genetic mutations associated with chronic pancreatitis in our population.
Pancreatology, 2 (2002), pp. 181
[21.]
P.G. Noone, M.R. Knowles.
'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations.
Resp Res, 2 (2001), pp. 328-332
[22.]
A.K. Saluja, E.A. Donovan, K. Yamanaka, Y. Yamaguchi, B. Hofbauer, M.L. Steer.
Cerulein-induced in vitro activation of trypsinogen in rat pancreatic acini is mediated by cathepsin B.
Gastroenterology, 113 (1997), pp. 304-310
[23.]
G.J. Van Acker, A.K. Saluja, L. Bhagat, V.P. Singh, A.M. Song, M.L. Steer.
Cathepsin B inhibition prevents trypsinogen activation and reduces pancreatitis severity.
Am J Physiol Gastrointest Liver Physiol, 283 (2002), pp. 794G-800G
[24.]
M.M. Lerch, F.S. Gorelich.
Early trypsinogen activation in acute pancreatitis.
Med Clin North Am, 84 (2000), pp. 549-563
[25.]
T. Grady, M. Mah'Moud, T. Otani, S. Rhee, M.M. Lerch, F.S. Gorelick.
Zymogen proteolysis within the pancreatic acinar cell is associated with cellular injury.
Am J Physiol, 275 (1998), pp. 1010G-1017G
[26.]
D.C. Whitcomb.
Early trypsinogen activation in acute pancreatitis.
Gastroenterology, 116 (1999), pp. 770-772
[27.]
M. Ruthenburger, B. Kruger, W. Halangk, M.M. Lerch.
Intracellular pro-elastase but not trypsinogen activation is associated with acinar cell injury.
Int J Pancreatol, 28 (2000), pp. 148
[28.]
B. Brandt-Nedelev, C. Peters, W. Halangk, M.M. Lerch.
Trypsinogen activation and severity of CDE diet-induced pancreatitis in cathepsin B deficient mice [abstract].
Gastroenterology, 122 (2002), pp. 284A
[29.]
T. Imamura, M. Asada, S.K. Vogt, D.A. Rudnick, M.E. Lowe, L.J. Muglia.
Protection from pancreatitis by the zymogen granule membrane protein integral membrane-associated protein-1 [en prensa].
J Biol Chem, (2002),
[30.]
J.R. Hoidal.
Reactive oxygen species and cell signaling.
Am J Respir Cell Mol Biol, 25 (2001), pp. 661-663
[31.]
L. Parcker, S.U. Weber, G. Rimbach.
Molecular aspects of -tocotrienol antioxidant action and cell signaling.
J Nutr, 131 (2001), pp. 369S-373S
[32.]
D.B. Gough, B. Boyle, W.P. Joyce, C.P. Delaney, K.F. McGeeney, T.F. Gorey, et al.
Free radical inhibition and serial chemiluminiscence in evolving experimental pancreatitis.
Br J Surg, 77 (1990), pp. 1256-1259
[33.]
B. Rau, B. Poch, F. Gansauge, A. Bauer, A.K. Nussler, T. Nevalainen, et al.
Pathophysiological role of oxygen free radicals in acute pancreatitis: initiating event or mediator of tissue damage?.
Ann Surg, 231 (2000), pp. 352-360
[34.]
K. Fu, M.P. Sarras Jr, R.C. De Lisle, G.K. Andrews.
Expression of oxidative stress-responsive genes and cytokine genes during caerulein-induced acute pancreatitis.
Am J Physiol, 273 (1997), pp. 696G-705G
[35.]
H. Sato, R.C. Siow, S. Bartlett, S. Taketani, T. Ishii, S. Bannai, et al.
Expression of stress proteins heme oxygenase-1 and -2 in acute pancreatitis and pancreatic islet betaTC3 and acinar AR42J cells.
FEBS Lett, 405 (1997), pp. 219-223
[36.]
R.T. Ethridge, R.A. Ehlers, M.R. Hellmich, S. Rajaraman, B.M. Evers.
Acute pancreatitis results in induction of heat shock proteins 70 and 27 and heat shock factor-1.
Pancreas, 21 (2000), pp. 248-256
[37.]
E.S. Christians, L.J. Yan, I.J. Benjamin.
Heat shock factor 1 and heat shock proteins: critical partners in protection against acute cell injury.
Crit Care Med, 30 (2002), pp. 43S-50S
[38.]
E.M. Ortiz, N.J. Dusetti, S. Vasseur, D. Malka, H. Bodeker, J.C. Dagorn, et al.
The pancreatitis-associated protein is induced by free radicals in AR 4-2 J cells and confers cell resistance to apoptosis.
Gastroenterology, 114 (1998), pp. 808-816
[39.]
R. Graf, M. Schiesser, G.A. Scheele, K. Marquardt, T.W. Frick, R.W. Ammann, et al.
A family of 16-kDa pancreatic secretory stress proteins form highly organized fibrillar structures upon tryptic activation.
J Biol Chem, 276 (2001), pp. 21028-21038
[40.]
M.V. Apte, P.A. Phillips, R.G. Fahmy, S.J. Darby, S.C. Rodgers, G.W. McCaughan, et al.
Does alcohol directly stimulate pancreatic fibrogenesis?.
Studies with rat pancreatic stellate cells. Gastroenterology, 118 (2000), pp. 780-794
[41.]
D.W. Powell, R.C. Mifflin, J.D. Valentich, S.E. Crowe, J.I. Saada, A.B. West.
Myofibroblasts (I). Paracrine cells important in health and disease.
Am J Physiol, 277 (1999), pp. 1C-9C
[42.]
H. Lum, K.A. Roebuck.
Oxidant stress and endothelial cell dysfunction.
Am J Physiol Cell Physiol, 280 (2001), pp. 719C-741C
[43.]
J.A. Lawson, J. Rokach, G.A. FitzGerald.
Isoprostanes: formation, analysis and use as indices of lipid peroxidation in vivo.
J Biol Chem, 274 (1999), pp. 24441-24444
[44.]
L.J. Roberts 2nd, C.J. Brame, Y. Chen, J.D. Morrow.
Novel eicosanoids. Isoprostanes and related compounds.
Methods Mol Biol, 120 (1999), pp. 257-285
[45.]
E. Folch, A. Salas, J. Panes, E. Gelpi, J. Roselló-Catafau, D.C. Anderson, et al.
Role of P-selectin and ICAM-1 in pancreatitis-induced lung inflammation in rats: significance of oxidative stress.
Ann Surg, 230 (1999), pp. 792-799
[46.]
A. Colell, C. García-Ruiz, M. Miranda, E. Ardite, M. Mari, A. Morales, et al.
Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor.
Gastroenterology, 115 (1998), pp. 1541-1551
[47.]
I.D. Norton, M.V. Apte, P.S. Haber, G.W. McCaughan, R.C. Pirola, J.S. Wilson.
Cytochrome P4502E1 is present in rat pancreas and is induced by chronic ethanol administration.
Gut, 42 (1998), pp. 426-430
[48.]
M. Matsumura, K. Ochi, M. Ichimura, T. Mizushima, H. Harada, M. Harada.
Study on free radicals and pancreatic fibrosis-pancreatic fibrosis induced by repeated injections of superoxide dismutase inhibitor.
Pancreas, 22 (2001), pp. 53-57
[49.]
P. Mathew, R. Wyllie, F. Van Lente, R.M. Steffen, M.H. Kay.
Antioxidants in hereditary pancreatitis.
Am J Gastroenterol, 9 (1996), pp. 1558-1562
[50.]
A. Van Gossum, P. Closset, E. Noel, M. Cremer, J. Neve.
Deficiency in antioxidant factors in patients with alcohol-relat e d chronic pancreatitis.
Dig Dis Sci, 41 (1996), pp. 1225-1231
[51.]
A. Szuster-Ciesielska, J. Daniluk, M. Kandefer-Szerszen.
Oxidative stress in blood of patients with alcohol-related pancreatitis.
Pancreas, 22 (2001), pp. 261-266
[52.]
K. Tsai, S.S. Wang, T.S. Chen, C.W. Kong, F.Y. Chang, S.D. Lee, et al.
Oxidative stress: an important phenomenon with pathogenetic significance in the progression of acute pancreatitis.
Gut, 42 (1998), pp. 850-855
[53.]
M. Tashiro, C. Schafer, H. Yao, S.A. Ernst, J.A. Williams.
Arginine induced acute pancreatitis alters the actin cytoskeleton and increases heat shock protein expression in rat pancreatic acinar cells.
Gut, 49 (2001), pp. 241-250
[54.]
G.E. Groblewski, T. Grady, N. Mehta, H. Lambert, C.D. Logsdon, J. Landry, et al.
Cholecystokinin stimulates heat shock protein 27 phosphorylation in rat pancreas both in vivo and in vitro.
Gastroenterology, 112 (1997), pp. 1354-1361
[55.]
J.L. Frossard, L. Bhagat, H.S. Lee, A.J. Hietaranta, V.P. Singh, A.M. Song, et al.
Both thermal and non-thermal stress protect against caerulein induced pancreatitis and prevent trypsinogen activation in the pancreas.
Gut, 50 (2002), pp. 78-83
[56.]
H.S. Lee, L. Bhagat, J.L. Frossard, A. Hietaranta, V.P. Singh, M.L. Steer, et al.
Water immersion stress induces heat shock protein 60 expression and protects against pancreatitis in rats.
Gastroenterology, 119 (2000), pp. 220-229
[57.]
K. Grise, F. Kim, D. McFadden.
Hyperthermia induces heatshock protein expression, reduces pancreatic injury, and improves survival in necrotizing pancreatitis.
Pancreas, 21 (2000), pp. 120-125
[58.]
A.G. Pockley.
Heat shock proteins, inflammation, and cardiovascular disease.
Circulation, 105 (2002), pp. 1012-1017
[59.]
V. Malhotra, H.R. Wong.
Interactions between the heat shock response and the nuclear factor-KB signaling pathway.
Crit Care Med, 30 (2002), pp. 89S-95S
[60.]
B. Kruger, E. Albrecht, M.M. Lerch.
The role of intracellular calcium signaling in premature protease activation and the onset of pancreatitis.
Am J Pathol, 157 (2000), pp. 43-50
[61.]
M. Raraty, J. Ward, G. Erdemli, C. Vaillant, J.P. Neoptolemos, R. Sutton, et al.
Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells.
Proc Natl Acad Sci USA, 97 (2000), pp. 13126-13131
[62.]
M.M. Lerch, M.P. Lutz, H. Weidenbach, F. Muller-Pillasch, T.M. Gress, J. Leser, et al.
Dissociation and reassembly of adherens junctions during experimental acute pancreatitis.
Gastroenterology, 113 (1997), pp. 1355-1366
[63.]
J. Leser, M.F. Beil, O.A. Musa, G. Adler, M.P. Lutz.
Regulation of adherens junction protein p120(ctn) by 10 nM CCK precedes actin breakdown in rat pancreatic acini.
Am J Physiol Gastrointest Liver Physiol, 278 (2000), pp. 486G-491G
[64.]
E. Riesle, H. Friess, L. Zhao, M. Wagner, W. Uhl, K. Baczako, et al.
Increased expression of transforming growth factor beta after acute oedematous pancreatitis in rats suggests a role in pancreatic repair.
Gut, 40 (1997), pp. 73-79
[65.]
J.L. Van Laethem, P. Robberecht, A. Resibois, J. Deviere.
Transforming growth factor beta promotes development of fibrosis after repeated courses of acute pancreatitis in mice.
Gastroenterology, 110 (1996), pp. 576-582
[66.]
K.B. Hahm, Y.H. Im, C. Lee, W.T. Parks, Y.J. Bang, J.E. Green, et al.
Loss of TGF-beta signaling contributes to autoimmune pancreatitis.
J Clin Invest, 105 (2000), pp. 1057-1065
[67.]
A. Demols, J.L. Van Laethem, E. Quertinmont, C. Degraef, M. Delhaye, A. Geerts, et al.
Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis.
Am J Physiol Gastrointest Liver Physiol, 282 (2002), pp. 1105G-1112G
[68.]
R.M. Rai, F.Y. Lee, A. Rosen, S.Q. Yang, H.Z. Lin, A. Koteish, et al.
Impaired liver regeneration in inducible nitric oxide synthasedeficient mice.
Proc Natl Acad Sci USA, 95 (1998), pp. 13829-13834
[69.]
M.V. Apte, P.S. Haber, T.L. Applegate, I.D. Norton, G.W. McCaughan, M.A. Korsten, et al.
Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture.
Gut, 43 (1998), pp. 128-133
[70.]
M.G. Bachem, E. Schneider, H. Gross, H. Weidenbach, R.M. Schmid, A. Menke, et al.
Identification, culture, and characterization of pancreatic stellate cells in rats and humans.
Gastroenterology, 115 (1998), pp. 421-432
[71.]
E.H. Sage.
Regulation of interactions between cells and extracellular matrix: a command performance on several stages.
J Clin Invest, 107 (2001), pp. 781-783
[72.]
F. Demayo, P. Minoo, C.G. Plopper, L. Schuger, J. Shannon, J.S. Torday.
Mesenchymal-epithelial interactions in lung development and repair: are modeling and remodeling the same process?.
Am J Physiol Lung Cell Mol Physiol, 283 (2002), pp. L510L-517L
[73.]
M.V. Apte, P.S. Haber, S.J. Darby, S.C. Rodgers, G.W. McCaughan, M.A. Korsten, et al.
Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis.
Gut, 44 (1999), pp. 534-541
[74.]
F.W. Shek, R.C. Benyon, F.M. Walker, P.R. McCrudden, S.L. Pender, E.J. Williams, et al.
Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis.
Am J Pathol, 160 (2002), pp. 1787-1798
[75.]
S.L. Friedman.
Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.
J Biol Chem, 275 (2000), pp. 2247-2250
[76.]
J.P. Iredale, R.C. Benyon, J. Pickering, M. McCullen, M. Northrop, S. Pawley, et al.
Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.
J Clin Invest, 102 (1998), pp. 538-549
[77.]
J.P. Iredale.
Hepatic stellate cell behavior during resolution of liver injury.
Semin Liver Dis, 21 (2001), pp. 427-436
[78.]
A.M. Gressner.
The cell biology of liver fibrogenesis. An imbalance of proliferation, growth arrest and apoptosis of myofibroblasts.
Cell Tissue Res, 292 (1998), pp. 447-452
[79.]
M.C. Wright, R. Issa, D.E. Smart, N. Trim, G.I. Murray, J.N. Primrose, et al.
Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats.
Gastroenterology, 121 (2001), pp. 685-698
[80.]
M.A. Padilla, X. Molero, A. Skoudy, T. Adell, E. Vaquero, J.A. Gómez-Valero, et al.
The exocrine pancreas-specific factor p48: role in experimental pancreatitis [abstract].
Pancreatology, 1 (2001), pp. 144
[81.]
S.J. Leibovich, R. Ross.
The role of macrophage in wound repair: a study with hydrocortisone and antimacrophage serum.
Am J Pathol, 78 (1975), pp. 71-100
[82.]
S.E. Mutsaers, D. Whitaker, J.M. Papadimitriou.
Stimulation of mesothelial cell proliferation by exudate macrophages enhances serosal wound healing in a murine model.
Am J Pathol, 160 (2002), pp. 681-692
[83.]
K. Okazaki, K. Uchida, M. Ohana, H. Nakase, S. Uose, M. Inai, et al.
Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response.
Gastroenterology, 118 (2000), pp. 573-581
[84.]
M.P. Ebert, K. Ademmer, F. Muller-Ostermeyer, H. Friess, M.W. Buchler, W. Schubert, et al.
CD8+ CD103+ T cells analogous to intestinal intraepithelial lymphocytes infiltrate the pancreas in chronic pancreatitis.
Am J Gastroenterol, 93 (1998), pp. 2141-2147
[85.]
G.P. Aithal, N.P. Breslin, B. Gumustop.
High serum IgG4 concentrations in patients with sclerosing pancreatitis.
N Engl J Med, 345 (2001), pp. 147-148
[86.]
S. Tanaka, T. Kobayashi, K. Nakanishi, M. Okubo, T. Murase, M. Hashimoto, et al.
Evidence of primary beta-cell destruction by T-cells and beta-cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis.
Diabetes Care, 24 (2001), pp. 1661-1667
[87.]
M. Artuc, B. Hermes, U.M. Steckelings, A. Grutzkau, B.M. Henz.
Mast cells and their mediators in cutaneous wound healing–active participants or innocent bystanders?.
Exp Dermatol, 8 (1999), pp. 1-16
[88.]
A.M. Gressner, M.G. Bachem.
Molecular mechanims of liver fibrogenesis –a homage to the role of activated fat-storing cells.
Digestion, 56 (1995), pp. 335-346
[89.]
C. Wu, S. Dedhar.
Integrin-linked kinase (ILK) and its interactors: a new paradigm for the coupling of extracellular matrix to actin cytoskeleton and signaling complexes.
J Cell Biol, 155 (2001), pp. 505-510
[90.]
P. Bornstein.
Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1.
J Cell Biol, 130 (1995), pp. 503-506
[91.]
S.E. Crawford, V. Stellmach, J.E. Murphy-Ullrich, S.M. Ribeiro, J. Lawler, RO. B Hynes, et al.
Thrombospondin-1 is a major activator of TGF-beta1 in vivo.
Cell, 93 (1998), pp. 1159-1170
[92.]
A. Francki, A.D. Bradshaw, J.A. Bassuk, C.C. Howe, W.G. Couser, E.H. Sage.
SPARC regulates the expression of collagen type I and transforming growth factor-beta1 in mesangial cells.
J Cell Biol, 274 (1999), pp. 32145-32152
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