多發性腎囊腫是一種因腎臟產生大量囊泡而導致腎臟衰竭的遺傳疾病。根據研究顯示，無論是在臨床上或囓齒類動物模式的多發性腎囊腫都發現c-myc在腎臟囊泡的上皮細胞內的表現量會增加。而且從過去的研究亦顯示c-myc會藉著結合前胸腺素基因啟動子上的E-box來調控前胸腺素基因的表現，因此我們希望透過前胸腺素基因轉殖小鼠的構築及臨床研究來探討前胸腺素基因過度表現是否參與在多發性腎囊腫的病發過程中。
　　異合型及同合型前胸腺素基因過度表現轉殖小鼠已完成構築。經過聚合酶鏈反應及南方墨點分析法的檢測發現，其中有兩個不同轉殖株的前胸腺素基因過度表現轉殖小鼠。經由解剖分析及組織分析發現，此兩個不同轉殖株的同合型轉殖小鼠的腎臟會病發多發性腎囊腫，其血液中具有極高含氮物質而且它們僅能存活十天左右。免疫生化分析亦發現前胸腺素會大量地表現在腎臟囊泡的上皮細胞內，無論是來自同合型轉殖小鼠的腎臟組織或來自臨床上自體顯性或隱性多發性腎囊腫患者的腎臟組織。此外，同合型轉殖小鼠的腎臟及尿液中前胸腺素的含量及其上皮細胞生長因子受體的mRNA表現量遠高於異合型轉殖小鼠及非轉殖小鼠。
　　從我們的研究結果顯示，前胸腺素過度表現可能是多發性腎囊腫的病發過程中的因子之一。因此，前胸腺素基因過度表現轉殖小鼠可作為一種新的多發性腎囊腫動物模式。

　Polycystic kidney disease (PKD) is a genetic disorder characterized by development of renal cysts and progressive renal dysfunction. Renal tissues from both PKD patients and rodent models of PKD show elevated c-myc expression. Prothymosin  (ProT) is positively regulated by c-Myc through binding to the E-box of its promoter. Through creating transgenic mice and clinical studies, we sought to investigate whether ProT overexpression contributes to PKD development.
　ProT heterozygous and homozygous transgenic mice were generated and characterized. Morphological, histological, immunohistochemical, and biochemical analyses of the transgenic mice were performed. Two transgenic lines that represented integration at two different loci of the chromosomes were generated. ProT overexpression in the kidneys of homozygous transgenic mice induced a PKD phenotype, which included polycystic kidneys, elevated blood urea nitrogen, and lethality at about 10 days of age. Similar overexpression pattern of ProT was noted in cystic kidneys of the transgenic mice as well as in human autosomal recessive PKD and autosomal dominant PKD kidneys. ProT protein levels in the kidneys and urine as well as renal mRNA level of epithelial growth factor receptor (EGFR) of homozygous ProT transgenic mice were significantly higher than heterozygous or non-transgenic littermates. Furthermore, the heterozygous transgenic mice at 17 months of age also developed mild cystic kidneys.
　Transgenic mice overexpressing ProT represent a novel model for PKD and may provide insights into PKD development. ProT, like c-myc and EGFR, may contribute to the development of renal cysts and may be a potential non-invasive diagnostic molecule of PKD.

1.Hooper JA, McDaniel MC, Thurman GB, et al: Purification and properties of bovine thymosin. Ann NY Acad Sci 249:125–144, 1975
2.Low TLK, Thurman GB, McAdoo M, et al: The chemistry and biology of thymosin. I. Isolation, characterization and biological activities of thymosin alpha 1 and polypeptide beta 1 from calf thymus. J Biol Chem 254:981– 986, 1979
3.Caldarella J, Goodall GJ, Felix AM, et al: T11: a peptide related to T1 isolated from calf thymus fraction V. Proc Natl Acad Sci USA 80:7424 –7427, 1983
4.Haritos AA, Goodall GJ, Horecker BL: Prothymosin alpha: isolation and properties of the major immunoreactive form of thymosin alpha1 in rat thymus. Proc Natl Acad Sci USA 81:1008 –1011, 1984
5.Pan LX, Haritos AA, Widemann J, et al: Human prothymosin alpha: amino acid sequence and immunologic properties. Arch Biochem Biophys 250:197–201, 1986
6.Salvin SB, Horecker BL, Pan LX, Rabin BS: The effect of dietary zinc and prothymosin alpha on cellular immune responses of RF/J mice. Clin Immunol Immunopathol 43:281– 288, 1987
7.Maric D, Jankovic BD, Veljic J: Immunostimulatory activity of prothymosin- in senescence. Ann NY Acad Sci 621:148 –158, 1991
8.Maric D, Veljic J, Ranin J, Jankovic BD: In vivo effect of prothymosin-1 on humoral and cell-mediated immune responses in the young rat. Int J Neurosci 59:135–142, 1991
9.Baxevanis CN, Gritzapis AD, Dedoussis GVZ, et al: Induction of lymphokine-activated killer activity in mice by prothymosin alpha. Cancer Immunol Immunother 38:281– 286, 1994
10.Baxevanis CN, Gritzapis AD, Spanakos G, et al: Induction of tumor-specific T lymphocyte responses in vivo by prothymosin alpha. Cancer Immunol Immunother 40:410–418, 1995
11.Papanastasiou M, Baxevanis CN, Papamichail M: Promotion of murine antitumor activity by prothymosin alpha treatment: I. Introduction of tumoricidal peritoneal cells producing high levels of TNF. Cancer Immunol Immunother 35:145–150, 1992
12.Reclos GC, Baxevanis CN, Sfagos C, et al: Multiple sclerosis: II. Effects of prothymosin alpha on the autologous and allogeneic MLR in patients with multiple sclerosis. Clin Exp Immunol 70:336–344, 1987
13.Baxevanis CN, Reclos GJ, Papamichail M, Tsokos GC: Prothymosin alpha restores the depressed autologous and allogeneic mixed lymphocyte responses in patients with systemic lupus erythematosus. Immunopharmacol Immunotoxicol 9:429–440, 1987
14.Baxevanis CN, Reclos GJ, Economou M, et al: Mechanism of action of prothymosin alpha in the human autologous mixed lymphocyte response. Immunopharmacol Immunotoxicol 10:443–461, 1988
15.Baxevanis CN, Reclos GJ, Paneerselvam M, Papamichail M: Enhancement of human T lymphocyte functions by prothymosin alpha 1. Augmentation of mixed lymphocyte culture reactions and soluble protein-induced proliferative responses. Immunopharmacology 15:73– 84, 1988
16.Baxevanis CN, Anastasopoulos E, Reclos GJ, Papamichail M: Prothymosin- enhances HLA-DR antigen expression on monocytes from patients with multiple sclerosis. J Neuroimmunol 27:141–148, 1990
17.Baxevanis CN, Frillingos S, Reclos GJ, et al: Enhancement of human T lymphocyte function by prothymosin alpha: increased production of IL-2 and expression of IL-2 receptors on normal human peripheral blood T lymphocytes. Immunopharmacol Immunotoxicol 12:595– 617, 1990
18.Cordero OJ, Sarandeses CS, Lopez JL, et al: Prothymosin alpha enhances IL-2 receptor expression in normal human T-lymphocytes. Int J Immunopharmacol 13:1059–1065, 1991
19.Cordero OJ, Sarandeses CS, Nogueira M: Phytohemagglutin-stimulated human T cell: prothymosin alpha as an accessory signal. J Biol Regul Homeost Agents 4:7–12, 1990
20.Baxevanis CN, Thanos D, Reclos GJ, et al: Prothymosin alpha enhances human and murine MHC class II surface antigen expression and messenger RNA accumulation. J Immunol 148:1979–1984, 1992
21.Vlachoyiannopoulos PG, Frillingos S, Tzioulas AG, et al: Circulating antibodies to prothymosin alpha in systemic lupus erythematosus. Clin Immunol Immunopathol 53:151–160, 1989
22.Baxevanis CN, Reclos GJ, Papamichail M: Prothymosin alpha restores depressed allogeneic cell-mediated lympholysis and naturalkiller-cell activity in patients with cancer. Int J Cancer 53:264–268, 1993
23.Cordero OJ, Sarandeses CS, Lopez JL, Nogueira M: Prothymosin alpha enhances human natural killer cell cytotoxicity: role in mediating signals for NK activity. Lymphokine Cytokine Res 11:277–285, 1992
24.Baxevanis CN, Spanakos G, Voutsas IF, et al: Increased generation of autologous tumor-reactive lymphocytes by anti-CD3 monoclonal antibody and prothymosin alpha. Cancer Immunol Immunother 48:71–84, 1999
25.Eckert K, Garbin F, Maurer HR, et al: Prothymosin -1 modulates lymphokine-activated killer cell activity and IL-2 production by peripheral blood lymphocytes from melanoma patients in vitro. Int J Immunopharmacol 17:555–561, 1995
26.Eckert K, Grunberg E, Immenschuh P, et al: IL-2 activated killer cell activity in colorectal tumor patients: evaluation of in vitro effects by prothymosin alpha 1. J Cancer Res Clin Oncol 123:420–428, 1997
27.Eckert K, Grunberg E, Garbin F, Maurer HR: Preclinical studies with prothymosin alpha 1 on mononuclear cells from tumor patients. Int J Immunopharmacol 19:493–500, 1997
28.Garbin F, Eckert K, Buettner P, et al: Prothymosin alpha augments deficient antitumor activity of monocytes from melanoma patients in vitro. Anticancer Res 14:2405–2411, 1994
29.Garbin F, Eckert K, Immenschuh P, et al: Prothymosin alpha 1 effects, in vitro, on the antitumor activity and cytokine production of blood monocytes from colorectal tumor patients. Int J Immunopharmacol 19:323–332, 1997
30.Pineiro A, Begona Bugia M, Pilar Arias M, et al: Identification of receptors for prothymosin alpha on human lymphocytes. Biol Chem 382:1473-1482, 2001
31.Haritos AA, Blacher R, Stein S, et al: Primary structure of rat thymus prothymosin alpha. Proc Natl Acad Sci USA 82:343– 346, 1985
32.Clinton M, Frangou-Lazaridis M, Panneerselvam C, Horecker BL: Prothymosin alpha and parathymosin: mRNA and polypeptide levels in rodent tissues. Arch Biochem Biophys 269:256–263, 1989
33.Eschenfeldt WH, Berger SL: The human prothymosin alpha gene is polymorphic and induced upon growth simulation: evidence using a cloned cDNA. Proc Natl Acad Sci USA 83:9403–9407, 1986
34.Gomez-Marquez J, Segade F, Dosil M, et al: The expression of prothymosin  gene in T lymphocytes and leukemic lymphoid cells is tied to lymphocyte proliferation. J Biol Chem 264:84518454, 1989
35.Sburlati AR, Manrow RE, Berger SL: Prothymosin  antisense oligomers inhibit myeloma cell division. Proc Natl Acad Sci USA 88:253257, 1991
36.Wu CL, Shiau AL, Lin CC: Prothymosin alpha promotes cell proliferation in NIH3T3 cells. Life Sci 61:2091–2101, 1997
37.Pavlov N, Evstafieva A, Rubtsov Y, Vartapetian A: Human prothymosin alpha inhibits division of yeast Saccharomyces cerevisiae cells, while its mutant lacking nuclear localization signal does not. FEBS Lett 366:43–45, 1995
38.Rubtsov YP, Zolotukhin AS, Vorobjev IA, et al: Mutational analysis of human prothymosin alpha reveals a bipartite nuclear localization signal. FEBS Lett 413:135–141, 1997
39.Papamarcaki T, Tsolas O: Prothymosin alpha binds to histone H1 in vitro. FEBS Lett 345:71–75, 1994
40.Gomez-Marquez J, Rodriguez P: Prothymosin alpha is a chromatinremodelling protein in mammalian cells. Biochem J 333:1–3, 1998
41.Karetsou Z, Sandaltzopoulos R, Frangou-Lazaridis M, et al: Prothymosin alpha modulates the interaction of histone H1 with chromatin. Nucleic Acids Res 26:3111–311 8, 1998
42.Eilers M, Schirm S, Bishop JM: The MYC protein activates transcription of the -prothymosin gene. EMBO J 10:133–142, 1991
43.Gaubatz S, Meichle A, Eilers M: An E-box element localized in the first intron mediates regulation of the prothymosin alpha gene by c-myc. Mol Cell Biol 14:3853–3862, 1994
44.Desbarats L, Gaubatz S, Eilers M: Discrimination between different E-box-binding proteins at an endogenous target gene of c-myc. Genes & Dev 10:447-460, 1996
45.Moll J, Schimd P, Sansig G, Van-Der-Putten H: The pattern of prothymosin alpha gene expression coincides with that of myc proto-oncogenes during mouse embryogenesis. Histochem J 28:45–52, 1996
46.Mori M, Barnard GF, Staniunas RJ, et al: Prothymosin alpha mRNA expression correlates with that of c-myc in human colon cancer. Oncogene 8:2821– 2826, 1993
47.Shibuta K, Mori M, Mimori K, et al: Expression of prothymosin alpha and c-myc mRNA in human gastric cancer. Int J Oncol 9:247–251, 1996
48.Vareli K, Frangou-Lazaridis M, Tsolas O: Prothymosin alpha mRNA levels vary with c-myc expression during tissues proliferation, viral infection and heat shock. FEBS Lett 371:337– 340, 1995
49.Wu CG, Boers W, Reitsma PR, et al: Overexpression of prothymosin alpha, concomitant with c-myc, during rat hepatic carcinogenesis. Biochem Biophys Res Commun 232:817–21, 1997
50.Ben-yosef T, Yanuka O, Halle D, Benvenisty N: Involvement of Myc targets in c-myc and N-myc induced human tumors. Oncogene 17:165-171, 1998
51.Martini PG, Delage-Mourroux R, Kraichely DM, Katzenellenbogen BS: Prothymosin alpha selectively enhances estrogen receptor transcriptional activity by interacting with a repressor of estrogen receptor activity. Mol Cell Biol 20:6224-6232, 2000
52.Martini PG, Katzenellenbogen BS: Regulation of prothymosin alpha gene expression by estrogen in estrogen receptor-containing breast cancer cells via upstream half-palindromic estrogen response element motifs. Endocrinology 142:3493-3501, 2001
53.Bianco NR, Montano MM: Regulation of prothymosin alpha by estrogen receptor alpha: molecular mechanisms and relevance in estrogen-mediated breast cell growth. Oncogene 21:5233-5244, 2002
54.Karetsou Z, Kretsovali A, Murphy C, et al: Prothymosin alpha interacts with the CREB-binding protein and potentiates transcription.
EMBO Rep 3:361-366, 2002
55.Yang CH, Murti A, Baker SJ, et al: Interferon induces the interaction of prothymosin-alpha with STAT3 and results in the nuclear translocation of the complex. Exp Cell Res 298:197-206, 2004
56.Kubota S, Adachi Y, Copeland TD, Oroszlan S: Binding of human prothymosin alpha to the leucine-motif/activation domains of HTLV-I Rex and HIV-1 Rev. Eur J Biochem 233:48 –54, 1995
57.Vartapetian AB, Makarova TN, Koonin EV, et al: Small cytoplasmic RNA from mouse cells covalently linked to a protein. FEBS Lett 232:35–38, 1988
58.Makarova T, Grebenshikov N, Egorov E, et al: Prothymosin alpha is an evolutionary conserved protein covalently linked to a small RNA. FEBS Lett 257:247–250, 1989
59.Rodriguez P, Vinuela JE, Alvarez-Fernandez L, Gomez-Marquez J: Prothymosin alpha antisense oligonucleotides induce apoptosis in HL-60 cells. Cell Death Differ 6:3-5, 1999
60.Enkemann SA, Wang RH, Trumbore MW, Berger SL: Functional discontinuities in prothymosin alpha caused by caspase cleavage in apoptotic cells. J Cell Physiol 182:256-68, 2000
61.Jiang X, Kim HE, Shu H, et al:Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science 299:223-226, 2003
62.Welling LW, Grantham JJ: Cystic and developmental disease of the kidney, in The Kidney, 5th ed, edited by Brenner BM, Philadelphia, Saunders Co., 1996, pp 1828-1863
63.Mcdonald RA, Watkins SL, Avner ED: Polycystic kidney disease, in Pediatric Nephrology, 4th ed, edited by Barratt TM, Avner ED, Harmon WE, Baltimore, Lippincott Williams & Wilkins, 1999, pp 459-474
64.The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77:881-894, 1994
65.Mochizuki T, Wu G, Hayashi T, et al: PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272:1339-1342, 1996
66.Ward CJ, Hogan MC, Rossetti S, et al: The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 30:259-269, 2002
67.Onuchic LF, Furu L, Nagasawa Y, et al: PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet 70:1305-1317, 2002
68.Harris PC: Autosomal dominant polycystic kidney disease: clues to pathogenesis. Hum Mol Genet 8:1861-1866, 1999
69.Pei Y, He N, Wang K, et al: A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds. J Am Soc Nephrol 9:1853-1860, 1998
70.Cowley BD Jr, Smardo FL Jr, Grantham JJ, Calvet JP: Elevated c-myc protooncogene expression in autosomal recessive polycystic kidney disease. Proc Natl Acad Sci USA 84:8394-8398, 1987
71.Cowley BD Jr, Chadwick LJ, Grantham JJ, Calvet JP: Elevated protooncogene expression in polycystic kidneys of the C57BL/6J(cpk) mouse. J Am Soc Nephrol 1:1048-1053, 1991
72.Trudel M, D’Agati V, Costantini F: C-myc as an inducer of polycystic kidney disease in transgenic mice. Kidney Int 39:665-671, 1991
73.Trudel M, Barisoni L, Lanoix J, et al: Polycystic kidney disease in SBM transgenic mice: Role of c-myc in disease induction and progression. Am J Pathol 152:219-229, 1998
74.Lanoix J, D’agatI V, Szabolcs M, Trudel M: Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD). Oncogene 13:1153-1160, 1996
75.Du J, Wilson PD: Abnormal polarization of EGF receptors and autocrine stimulation of cyst epithelial growth in human ADPKD. Am J Physiol 269:C487-C495, 1995
76.Orellana SA, Sweeney WE, Neff CD, Avner ED: Epidermal growth factor receptor expression is abnormal in murine polycystic kidney. Kidney Int 47:490-499, 1995
77.Sweeney WE Jr, Avner ED: Functional activity of epidermal growth factor receptors in autosomal recessive polycystic kidney disease. Am J Physiol 275:F387-F394, 1998
78.Woo D: Apoptosis and loss of renal tissue in polycystic kidney diseases. N Engl J Med 333:18-25, 1995
79.Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ: Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75:229-240, 1993
80.Moser M, Pscherer A, Roth C, et al: Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta. Genes Dev 11:1938-1948, 1997
81.Nadasdy T, Laszik Z, Lajoie G, et al: Proliferative activity of cyst epithelium in human renal cystic diseases. J Am Soc Nephrol 5:1462-1468, 1995
82.MacKay K, Striker LJ, Pinkert CA, et al: Glomerulosclerosis and renal cysts in mice transgenic for the early region of SV40. Kidney Int 32:827-837, 1987
83.Schaffner DL, Barrios R, Massey C, et al: Targeting of the rasT24 oncogene to the proximal convoluted tubules in transgenic mice results in hyperplasia and polycystic kidneys. Am J Pathol 142:1051-1060, 1993
84.Metcalf D, Mifsud S, Di Rago L, et al: Nicola NA, Hilton DJ, Alexander WS. Polycystic kidneys and chronic inflammatory lesions are the delayed consequences of loss of the suppressor of cytokine signaling-1 (SOCS-1). Proc Natl Acad Sci USA 99:943-948, 2002
85.Du J, Wilson PD: Abnormal polarization of EGF receptors and autocrine stimulation of cyst epithelial growth in human ADPKD. Am J Physiol 269:C487-C495, 1995
86.Richards WG, Sweeney WE, Yoder BK, et al: Epidermal growth factor receptor activity mediates renal cyst formation in polycystic kidney disease. J Clin Invest 101:935-939, 1998
87.Sweeney WE, Chen Y, Nakanishi K, et al: Frost P, Avner ED. Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int 57:33-40, 2000
88.Burrow CR, Wilson SJ, Wilson PD: Developmental regulation of Erb-b2 in human kidney organogenesis with persistent expression in autosomal dominant polycystic kidney disease. Mol Biol Cell 8:Suppl: 441a. abstract, 1997
89.Stocklin E, Botteri F, Groner: An activated allele of the c-erbB-2 oncogene impairs kidney and lung function and causes early death of transgenic mice. J Cell Biol 122:199-208, 1993
90.Grantham JJ, Ye M, Davidow C, et al: Holub BJ, Sharma M. Evidence for a potent lipid secretagogue in the cyst fluids of patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol 6:1242-1249, 1995
91.Chatterjee S, Shi WY, Wilson P, Mazumdar A: Role of lactosylceramide and MAP kinase in the proliferation of proximal tubular cells in human polycystic kidney disease. J Lipid Res 37:1334-1344, 1996
92.Bhunia AK, Piontek K, Boletta A, et al: PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAKSTAT signaling pathway in a process requiring PKD2. Cell 109:157-168, 2002
93.Hanaoka K, Guggino W: cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells. J Am Soc Nephrol 11:1179-1187, 2000
94.Burrow CR, Devuyst O, Li X, et al: Expression of the beta2-subunit and apical localization of Na+-K+-ATPase in metanephric kidney. Am J Physiol 277: F391-F403, 1999
95.Wilson PD, Geng L, Li X, Burrow CR: The PKD1 gene product, “polycystin-1,” is a tyrosine-phosphorylated protein that colocalizes with alpha2beta1-integrin in focal clusters in adherent renal epithelia. Lab Invest 79:1311-1323, 1999
96.Hyink DP, Burrow CR, Bloswick B, Wilson PD: Reversal of the ADPKD epithelial cell decreased motility phenotype by lithium. J Am Soc Nephrol 11:392A. abstract, 2000
97.Kreidberg JA, Donovan MJ, Goldstein SL, et al: Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development 122:3537-3547, 1996
98.Lo SH, Yu QC, Degenstein L, et al: Progressive kidney degeneration in mice lacking tensin. J Cell Biol 136:1349-1361, 1997
99.Hildebrandt F, Otto E, Rensing C, et al: A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 17:149-153, 1997
100.Lu W, Peissel B, Babakhanlou H, et al: Perinatal lethality with kidney and pancreas defects in mice with a targetted Pkd1 mutation. Nat Genet 17:179-181, 1997
101.Pritchard L, Sloane-Stanley JA, Sharpe JA, et al: A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Hum Mol Genet 9:2617-2627, 2000
102.Saadi-Kheddouci S, Berrebi D, Romagnolo B, et al: Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 20:5972-5981, 2001
103.Wilson PD, Sherwood AC, Palla K, et al: Reversed polarity of Na(+)-K(+)-ATPase: mislocation to apical plasma membranes in polycystic kidney disease epithelia. Am J Physiol 260:F420-F430, 1991
104.Lebeau C, Hanaoka K, Moore-Hoon ML, et al: BSC2 is the basolateral chloride transporter in a subset of cysts in autosomal dominant polycystic kidney disease (ADPKD). J Am Soc Nephrol 10:36A. abstract, 1999
105.Wilson PD, Devuyst O, Li X, et al: Apical plasma membrane mispolarization of NaKATPase in polycystic kidney disease epithelia is associated with aberrant expression of the beta2 isoform. Am J Pathol 156: 253-268, 2000
106.Wilson PD: Pathogenesis of polycystic kidney disease: altered cellular function. In: Watson ML, Torres VE, eds. Polycystic kidney diseases. Oxford, England: Oxford University Press, 1996:125-163.
107.Charron AJ, Nakamura S, Bacallao R, Wandinger-Ness A: Compromised cytoarchitecture and polarized trafficking in autosomal dominant polycystic kidney disease cells. J Cell Biol 149:111-124, 2000
108.Wilson PD: Epithelial cell polarity and disease. Am J Physiol 272:F434-F442, 1997
109.Hou X, Mrug M, Yoder BK, et al: Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease. J Clin Invest 109:533-540, 2002
110.Omran H, Haffner K, Burth S, et al: Human adolescent nephronophthisis: gene locus synteny with polycystic kidney disease in pcy mice. J Am Soc Nephrol 12:107-113, 2001
111.Wilson PD: In vitro methods in renal research: Avner ED, Harmon WE, Niaudet P, eds. Pediatric nephrology. 5th ed. Baltimore: Lippincott Williams & Wilkins, 2003:269-281.
112.Sweeney WE, Chen Y, Nakanishi K, et al: Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int 57:33-40, 2000
113.Torres VE, SweeneY WE Jr, Wang X, et al: EGF receptor tyrosine kinase inhibition attenuates the development of PKD in Han:SPRD rats. Kidney Int 64:1573-1579, 2003
114.Teresa D: Macrophages and the Pathogenesis of COPD. Chest 121:156S-159S, 2002
115.Snider GL. Emphysema: the first two centuries; part II. Am Rev Respir Dis 146:1615–1622, 1992
116.MacNee W: Neutrophil traffic and COPD. Eur Respir Rev 7:43:124–127, 1997
117.Shapiro SD: The Macrophage in Chronic Obstructive Pulmonary Disease. Am J Resp Crit Care Med 160:S29-S31, 1999
118.Keatings VM, Collins PD, Scott DM, Barnes PJ: Differences in interleukin- 8 and tumor necrosis factor- in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Resp Crit Care Med 153:530–534, 1996
119.De Godoy I, Donahoe M, Calhoun WJ, et al: Elevated TNF- production by peripheral blood monocytes of weightlosing COPD patients. Am J Resp Crit Care Med 153:633–637, 1996
120.Langen RC, Schols AM, Kelders MC, et al: Inflammatory cytokines inhibit myogenic differentiation through activation of nuclear factor–B. FASEB J 15:1169–1180, 2001
121.Barnes PJ: Cytokine modulators as novel therapies for airway disease. Eur Resp J 18:67S–77S, 2001
122.Liu H, Sidiropoulos P, Song G, et al: TNF-a Gene Expression in Macrophages: Regulation by NF-kB Is Independent of c-Jun or C/EBPb J Immuno 4277-4285, 2000
123.Fujita M, Shannon JM, Irvin CG, et al: Overexpression of tumor necrosis factor-a produces an increase in lung volumes and pulmonary hypertension Am J Physiol Lung Cell Mol Physiol 280: L39–L49, 2001.
124.Yamamoto C, Yoneda T, Yoshikawa M, et al: Airway inflammation in COPD assessed by sputum levels of interleukin-8. Chest 112:505–510, 1997
125.Pesci A, Balbi B, Majori M, et al: Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Resp J 12:380–386, 1998
126.Hill AT, Bayley D, Stockley RA: The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am J Resp Crit Care Med 160:893–898, 1999
127.Dekhuijzen PNR, Aben KHH, Dekker I, et al: Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am J Resp Crit Care Med 154:813–816, 1996
128.Montuschi P, Collins JV, Ciabattoni G, et al: Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Resp Crit Care Med 162:1175–1177, 2000
129.Paredi P, Kharitonov SA, Leak D, et al: Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am J Resp Crit Care Med 162:369–373, 2000
130.Finkelstein R, Fraser RS, Ghezzo H, Cosio MG: Alveolar inflammation and its relation to emphysema in smokers. Am J Resp Crit Care Med 152:1666–1672, 1995
131.Meshi B, Vitalis TZ, Ionescu D, et al: Emphysematous lung destruction by cigarette smoke. The effects of latent adenoviral infection on the lung inflammatory response. Am J Resp Cell Mol Biol 26:52–57, 2002
132.Di Stefano A, Capelli A, Lusuardi M, et al: Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Resp Crit Care Med 158:1277–1285, 1998
133.Russell REK, Thorley A, Culpitt SV, et al: Alveolar macrophage mediated elastolysis: roles of matrix metalloproteinases, cysteine and serine proteases. Am J Physiol Lung Cell Mol Physiol 283:L867–L73, 2002
134.Tomita K, Caramori G, Lim S, et al: Increased p21CIP and Bcl-xL expression and reduced apoptosis in alveolar macrophages from smokers. Am J Resp Crit Care Med 166:724–731, 2002
135.Lacoste JY, Bousquet J, Chanez P: Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis and chronic obstructive pulmonary disease. J Allergy Clin Immunol 92:537–548, 1993
136.Di Stefano A, Maestrelli P, Roggeri A, et al: Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am J Resp Crit Care Med 149:803–810, 1994
137.Hashimoto S, Kobayashi A, Kooguchi K, et al: Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome. Am J Resp Crit Care Med 161:237–243, 2000
138.Majo J, Ghezzo H, Cosio MG: Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur Resp J 17:946–953, 2001
139.Takizawa H, Tanaka M, Takami K, et al: Increased expression of transforming growth factor–1 in small airway epithelium from tobacco smokers and patients with COPD. Am J Resp Crit Care Med 163:1476–1483, 2001
140.Kasahara Y, Tuder RM, Taraseviciene-Stewart L, et al: Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 106:1311–1319,2000
141.Gottlieb DJ, Stone PJ, Sparrow D, et al: Urinary desmosine excretion in smokers with and without rapid decline of lung function. Am J Resp Crit Care Med 154:1290–1295, 1996
142.Stockley RA: Neutrophils and protease/antiprotease imbalance. Am J Resp Crit Care Med 160:S49–S52, 1999
143.Shapiro SD, Senior RM: Matrix metalloproteinases. Matrix degradation and more. Am J Resp Cell Mol Biol 20:1100–1102, 1999
144.Finlay GA, O’Driscoll LR, Russell KJ, et al: Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Resp Crit Care Med 156:240–247, 1997
145.Culpitt SV, Nightingale JA, Barnes PJ: Effect of high dose inhaled steroid on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Resp Crit Care Med 160:1635–1639, 1999
146.Betsuyaku T, Nishimura M, Takeyabu K, et al: Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema. Am J Resp Crit Care Med 159:1985–1991, 1999
147.Ohnishi K, Takagi M, Kurokawa Y, et al: Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab Invest 78:1077–87, 1998
148.Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD: Requirement for macrophage metalloelastase for cigarette smoke–induced emphysema in mice. Science 277:2002–2004, 1997
149.Fry JL Jr, Koch WE, Jennette JC, et al: A genetically determined murine model of infantile polycystic kidney disease. J Urol 134:828-833, 1985
150.Gattone II VH, Calvet JP, Cowley BD Jr, et al: Autosomal recessive polycystic kidney disease in a murine model. A gross and microscopic description. Lab Invest 59:231-238, 1988
151.Gattone II VH, Macnaughton KA, Kraybill AL: Murine autosomal recessive polycystic kidney disease with multiorgan involvement induced by the cpk gene. Anat Rec 245:488-499, 1996
152.Nauta J, ozawa Y, Sweeney WE Jr, et al: Renal and biliary abnormalities in a new murine model of autosomal recessive polycystic kidney disease. Pediatr Nephrol 7:163-172, 1993
153.Ricker JL, Gattone II VH, Calvet JP, Rankin CA: Development of autosomal recessive polycystic kidney disease in BALB/c-cpk/cpk mice. J Am Soc Nephrol 11:1837-1847, 2000
154.Cowley BD Jr, Gudapaty S, Kraybill AL, et al: Autosomal-dominant polycystic kidney disease in the rat. Kidney Int 43:522-534, 1993
155.Ray P, Higgins KM, Tan JC, et al: Ectopic expression of a c-kitW42 minigene in transgenic mice: recapitulation of W phenotypes and evidence for c-kit function in melanoblast progenitors. Genes & Dev 5:2265-2273, 1991
156.Klebig ML, Wilkinson JE, Geisler JG, Woychik RP: Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur. Proc Natl Acad Sci USA 92:4728-4732, 1995
157.Avner ED, Sweeney WE Jr: Polypeptide growth factors in metanephric growth and segmental nephron differentiation. Pediatr Nephrol 4:372-377, 1990
158.Bachmann S, Metzger R, Bunnemann B: Tamm-Horsfall protein-mRNA synthesis is localized to the thick ascending limb of Henle's loop in rat kidney. Histochemistry 94:517-523, 1990
159.Mason DY, Taylor CR: The distribution of muramidase (lysozyme) in human tissues. J Clin Pathol 28:124-132, 1975
160.Norman JT, Bohman RE, Fischmann G, et al: Patterns of mRNA expression during early cell growth differ in kidney epithelial cells destined to undergo compensatory hypertrophy versus regenerative hyperplasia. Proc Natl Acad Sci USA 85:6768-6772, 1988
161.Nakanishi K, Sweeney W Jr, Avner ED: Segment-specific c-ErbB2 expression in human autosomal recessive polycystic kidney disease. J Am Soc Nephrol 12:379-384, 2001
162.Liu JY, Brass DM, Hoyle GW, Brody AR: TNF receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers. Am J Pathol 153:1839–1847, 1998
163.Gearing AJH, Beckett P, Christodoulou M, et al: Processing of tumor necrosis factor- precursor by metalloproteinases. Nature 370:555–557, 1994
164.Watanbe N, Nakada K, Kobayashi Y: Processing and release of tumor necrosis factor-. Eur J Biochem 253:576–582, 1998
165.Newton RC, Solomon KA, Conginton MB, et al: Biology of TACE inhibition. Ann Rheum Dis 2001;60:25–32, 2001
166.Garbin F, Eckert K, Immenschuh P, et al: Prothymosin alpha 1 effects, in vitro, on the antitumor activity and cytokine production of blood monocytes from colorectal tumor patients. Int J Immunopharmacol 19:323-332, 1997
167.Eckert K, Grunberg E, Garbin F, et al: Preclinical studies with prothymosin alpha1 on mononuclear cells from tumor patients. Int J Immunopharmacol 19:493-500, 1997
168.Qiu L, Guo BY, Miao H, et al: Effect of recombinant prothymosin alpha on secretion of IFN-gamma, IFN-alpha and TNF-alpha in vitro. Yao Xue Xue Bao 37:326-328, 2002