钙离子通道TRPV5在慢性前列腺炎患者及慢性前列腺炎小鼠前列腺组织中的表达及其意义
|
摘要
研究目的
探讨研究钙离子通道TRPV5在慢性前列腺炎患者及慢性前列腺炎小鼠前列腺组织中的表达及其意义
材料与方法
1．收集128例前列腺标本，其中我院2000年1月-2003年12月期间前列腺增生术后标本123例，年龄55-83岁；19岁和22岁男性尸体标本2例；48岁、49岁和51岁全膀胱术后标本3例；使用光学显微镜观察128例前列腺HE切片的组织学特点。选择良性前列腺增生术后标本73例，其中炎症组41例，非炎症组32例，然后调出相应的HE切片和包埋蜡块，病人年龄61-82岁，在光学显微镜下复查HE染色结果。应用SP法对其进行免疫组化染色，检测TRPV5在慢性前列腺炎患者前列腺上皮细胞中的表达。
2．根据国内外制作慢性免疫性非细菌性前列腺炎动物模型的经验，摸索优化造模方法，初步建立C57BL／6小鼠的慢性免疫性前列腺炎动物模型。验证造模成功后，应用SP法、Western blot及RT-PCR等方法检测TRPV5在慢性前列腺炎小鼠前列腺组织中的表达。
结果
1．128例前列腺标本67例腺体内局灶性炎症细胞浸润分布在外周区、移行区和尿道周围区，占52．3％；而中央区无明显的局灶性炎症细胞浸润。5例非前列腺增生组内，3例有局灶性炎症细胞浸润，2例无明显局灶性炎症细胞浸润。χ~2=8．795，P=0．122>0．05，两者间差别无统计学意义。41例炎症组前列腺标本中TRPV5强表达的有22例，中表达的10例，低表达的9例；32例非炎症前列腺标本中TRPV5强表达的有7例，中表达的9例，低表达的16例；χ~2=8．795，P=0．012<0．05，两组间差异有统计学意义。
2．造模8周后，C57BL／6小鼠前列腺呈现慢性炎症病理变化，与临床慢性前列腺炎病理变化相似。慢性前列腺炎小鼠前列腺组织TRPV5mRNA呈高表达((?)±s=0．587±0．080)，正常对照组呈低表达((?)±s=0．815±0．062)(P=0．004<0．05)。慢性前列腺炎小鼠前列腺组织中TRPV5蛋白呈高表达((?)±s=0．925±0．053)，正常对照组呈低表达((?)±s=0．733±0．097)(P=0．013<0．05)。
结论
1．前列腺腺体内的局灶性炎症细胞浸润大多集中于外周区、移行区和尿道周围区，而中央区均无明显的局灶性炎症细胞浸润，这可能与不同区域的腺泡大小、形态、腺管分布、排列和走行密切相关；前列腺腺体内有无炎症细胞浸润与良性前列腺增生也无明确相关性。TRPV5通道在慢性前列腺炎患者前列腺炎症组和非炎症组前列腺标本中前列腺上皮细胞中表达有明显差异，钙通道的改变可以影响细胞生物学行为，引起上皮细胞功能障碍。
2．应用免疫造模法建造小鼠慢性前列腺模型，其病理结果与临床慢性前列腺炎病理结果表现相近，为近一步研究慢性前列腺炎的发病机制及寻找有效治疗的新药提供了实验方法。TRPV5在慢性前列腺炎前列腺组织中高表达，提示TRPV5通道的改变可能是慢性前列腺炎的发病机制之一。
Objective
To investigate the function of TRPV5 channel in the pathogenesis of Chronic Prostatitis.
Methods
1. 128 prostate specimens were collected including 123 post-operation of human benign prostate hyperplasia which all came from our hospital during the time of 2000.1-2003.12,55-83 years old; 2 of corpse bodies for renal transplantation, 19 and 22 years old respectively. By using the light microscopy, the 128 hematoxylin-eosin stained slides were observed. Pick out pathological number of the 73 prostate specimens; then apply the methods of the SP immunohistochemisty to detect the expression of TRPV5 in human Prostatic epithelia.
2. To develop a mouse model of nonbacterial chronic prostatitis. Through adopting SP、Western blot and RT-PCR to examine the TRPV5 expression of the C57BL/6 mice contracting the experimental nonbacterial chronic prostatitis by comparison of the normal-functioning mice.
Results
1. Obvious nodular inflammatory cells infiltration in the peripheral zones, transitional zones and periureth gland regions but not in the central zones were observed in 67 among all the 128 prostate specimens, which accounting for the percentage of 52.2.For nodular inflammatory cells infiltration 3 were observed in the 5 non-hyperplasia of prostate, and 64 were observed in the 123 hyperplasia of prostate. There was no statistic difference between the two groups, x~2 =8.795, P =0.122>0.05.Of 41 inflammationgroup, according to TRPV5's degrees of expression,22 are designated as strong expression; 10 moderate; 9 low; of 32 noninflammation groups, 7 designated as strong;9 moderate; 16 low. There was statistic difference between the two groups (chi-squared, P<0.05).
2. After 8 weeks, the prostates of model mice exhibited varying degree of inflammations, and were found to have lymphocytic infiltration of the storma and periglandluar region, which were similar to clinical nonbaterial chronic prostatitis. In opposition to the low expression of TPRV5 proteins and mRNA in NBCP-freemice, the high one has been found in the NBCP bears.
Conclusion
1. Almost all the obvious nodular inflammatory cells infiltration occur in the peripheral zones, transitional zones and periurethral gland regions but not in the central zones ,which may be closely correlated with the size,shape,distribution,arrange and track of the gland acini and ducts .Histopathologic finding of increased nodular inflammatory cells infiltration within the prostatitis parenchyma can not be recogised the diagnostic level of chronic prostatitis ,and there is no definite correlation between nodular inflammatory cells infiltration with benign prostatic hyperplasia .The expression of the TRPV5 channel was higher in prostatic epithelia cells from patients with chronic inflammation than from those without. The change of the calcium channel can conduce to genesis of Chronic Prostatitis.
2. Injection of immunizator ( antigen) and adjuvant can induce prostatic inflammation similar to clinical nonbatenal chronic prostatitis ,which may be an immune process. Itcould bring us a new way for studying pathogenesis of chronic prostatitis and drugtherapy.
探讨研究钙离子通道TRPV5在慢性前列腺炎患者及慢性前列腺炎小鼠前列腺组织中的表达及其意义
材料与方法
1．收集128例前列腺标本，其中我院2000年1月-2003年12月期间前列腺增生术后标本123例，年龄55-83岁；19岁和22岁男性尸体标本2例；48岁、49岁和51岁全膀胱术后标本3例；使用光学显微镜观察128例前列腺HE切片的组织学特点。选择良性前列腺增生术后标本73例，其中炎症组41例，非炎症组32例，然后调出相应的HE切片和包埋蜡块，病人年龄61-82岁，在光学显微镜下复查HE染色结果。应用SP法对其进行免疫组化染色，检测TRPV5在慢性前列腺炎患者前列腺上皮细胞中的表达。
2．根据国内外制作慢性免疫性非细菌性前列腺炎动物模型的经验，摸索优化造模方法，初步建立C57BL／6小鼠的慢性免疫性前列腺炎动物模型。验证造模成功后，应用SP法、Western blot及RT-PCR等方法检测TRPV5在慢性前列腺炎小鼠前列腺组织中的表达。
结果
1．128例前列腺标本67例腺体内局灶性炎症细胞浸润分布在外周区、移行区和尿道周围区，占52．3％；而中央区无明显的局灶性炎症细胞浸润。5例非前列腺增生组内，3例有局灶性炎症细胞浸润，2例无明显局灶性炎症细胞浸润。χ~2=8．795，P=0．122>0．05，两者间差别无统计学意义。41例炎症组前列腺标本中TRPV5强表达的有22例，中表达的10例，低表达的9例；32例非炎症前列腺标本中TRPV5强表达的有7例，中表达的9例，低表达的16例；χ~2=8．795，P=0．012<0．05，两组间差异有统计学意义。
2．造模8周后，C57BL／6小鼠前列腺呈现慢性炎症病理变化，与临床慢性前列腺炎病理变化相似。慢性前列腺炎小鼠前列腺组织TRPV5mRNA呈高表达((?)±s=0．587±0．080)，正常对照组呈低表达((?)±s=0．815±0．062)(P=0．004<0．05)。慢性前列腺炎小鼠前列腺组织中TRPV5蛋白呈高表达((?)±s=0．925±0．053)，正常对照组呈低表达((?)±s=0．733±0．097)(P=0．013<0．05)。
结论
1．前列腺腺体内的局灶性炎症细胞浸润大多集中于外周区、移行区和尿道周围区，而中央区均无明显的局灶性炎症细胞浸润，这可能与不同区域的腺泡大小、形态、腺管分布、排列和走行密切相关；前列腺腺体内有无炎症细胞浸润与良性前列腺增生也无明确相关性。TRPV5通道在慢性前列腺炎患者前列腺炎症组和非炎症组前列腺标本中前列腺上皮细胞中表达有明显差异，钙通道的改变可以影响细胞生物学行为，引起上皮细胞功能障碍。
2．应用免疫造模法建造小鼠慢性前列腺模型，其病理结果与临床慢性前列腺炎病理结果表现相近，为近一步研究慢性前列腺炎的发病机制及寻找有效治疗的新药提供了实验方法。TRPV5在慢性前列腺炎前列腺组织中高表达，提示TRPV5通道的改变可能是慢性前列腺炎的发病机制之一。
Objective
To investigate the function of TRPV5 channel in the pathogenesis of Chronic Prostatitis.
Methods
1. 128 prostate specimens were collected including 123 post-operation of human benign prostate hyperplasia which all came from our hospital during the time of 2000.1-2003.12,55-83 years old; 2 of corpse bodies for renal transplantation, 19 and 22 years old respectively. By using the light microscopy, the 128 hematoxylin-eosin stained slides were observed. Pick out pathological number of the 73 prostate specimens; then apply the methods of the SP immunohistochemisty to detect the expression of TRPV5 in human Prostatic epithelia.
2. To develop a mouse model of nonbacterial chronic prostatitis. Through adopting SP、Western blot and RT-PCR to examine the TRPV5 expression of the C57BL/6 mice contracting the experimental nonbacterial chronic prostatitis by comparison of the normal-functioning mice.
Results
1. Obvious nodular inflammatory cells infiltration in the peripheral zones, transitional zones and periureth gland regions but not in the central zones were observed in 67 among all the 128 prostate specimens, which accounting for the percentage of 52.2.For nodular inflammatory cells infiltration 3 were observed in the 5 non-hyperplasia of prostate, and 64 were observed in the 123 hyperplasia of prostate. There was no statistic difference between the two groups, x~2 =8.795, P =0.122>0.05.Of 41 inflammationgroup, according to TRPV5's degrees of expression,22 are designated as strong expression; 10 moderate; 9 low; of 32 noninflammation groups, 7 designated as strong;9 moderate; 16 low. There was statistic difference between the two groups (chi-squared, P<0.05).
2. After 8 weeks, the prostates of model mice exhibited varying degree of inflammations, and were found to have lymphocytic infiltration of the storma and periglandluar region, which were similar to clinical nonbaterial chronic prostatitis. In opposition to the low expression of TPRV5 proteins and mRNA in NBCP-freemice, the high one has been found in the NBCP bears.
Conclusion
1. Almost all the obvious nodular inflammatory cells infiltration occur in the peripheral zones, transitional zones and periurethral gland regions but not in the central zones ,which may be closely correlated with the size,shape,distribution,arrange and track of the gland acini and ducts .Histopathologic finding of increased nodular inflammatory cells infiltration within the prostatitis parenchyma can not be recogised the diagnostic level of chronic prostatitis ,and there is no definite correlation between nodular inflammatory cells infiltration with benign prostatic hyperplasia .The expression of the TRPV5 channel was higher in prostatic epithelia cells from patients with chronic inflammation than from those without. The change of the calcium channel can conduce to genesis of Chronic Prostatitis.
2. Injection of immunizator ( antigen) and adjuvant can induce prostatic inflammation similar to clinical nonbatenal chronic prostatitis ,which may be an immune process. Itcould bring us a new way for studying pathogenesis of chronic prostatitis and drugtherapy.
引文
1 McNaughton Collins M. The impact of chronic prostatitis/chronic pelvic pain syndrome on patients._World J Urol, 2003 , 21(2):86-89.
2 Krieger JN, Riley DE. Bacteria in the chronic prostatitis-chronic pelvic pain syndrome: molecular approaches to critical research questions.J Urol, 2002, 167(6):2574-2583.
3 梁朝朝，张学军，王克孝．前列腺炎病因学研究进展．中华泌尿外科杂志，2003，24(6)： 426-428
4 Schaeffer AJ, Landis JR, Knauss JS,etal. Demographic and clinical characteristics of men with chronic prostatitis: the national institutes of health chronic prostatitis cohort study.J Urol, 2002, 168(2):593-598.
5 Liang CZ, Zhang XJ, Hao ZY, etal. An epidemiological study of patients with chronic prostatitis.BJU Int, 2004,94(4):568-570.
6 范召应，钟红兴．慢性前列腺炎与男性不育研究进展．中华男科学杂志，2004，18(4)： 60-62．
7 Mehik A, Hellstrom P, Lukkarinen O, et al. Epidemiology of prostatitis in Finnish men: a population-based cross-sectional study. BJU Int, 2000,86: 443-448.
8 Parsons CL, Albo M. Intravesical potassium sensitivity in patients with prostatitis. J Urol, 2002,168(3):1054-1057.
9 Parsons CL, Zupkas P, Parsons JK. Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome.Urology, 2001, 57(3):428-432.
10 Eisenberg ER, Moldwin RM. Etiology: where does prostatitis stop and interstitial cystitis begin?World J Urol, 2003 ,21(2):64-69.
11 郝宗耀，梁朝朝，张学军，等．慢性前列腺炎患者前列腺液、尿液电解质测定及其相关性研究．中华泌尿外科杂志，2005，26(7)：456-468．
12 郭清奎，梁朝朝，张学军，等．慢性前列腺炎患者前列腺上皮钾通道的表达及其意义．中华泌尿外科杂志，2005,26(11)：782．
13 Nickel JC. Prostatitis and Related Conditions.In:Walsh PC,Retik AB,Vaughan ED,Jr.,etal,eds.Compbell's Urology,8~(th) edition,chapter 15,volume 1,section 4,2002:603-630.
14 Tuncel A,Uzun B,Eruyar T,et al. Do prostatic infarction, prostatic inflammation and prostate morphology play a role in actue urinary retention? European Urology, 2005,49(2)277-284.
15 武忠弼，杨光华主编．中华外科病理学．第一版.北京：人民卫生出版社，2002，1161-1162．
16 回允中 主译．诊断外科病理学．第一版,Stephens Stemberg．．Doagnotic SurgicalPathology,3th edition．北京：北京大学医学出版社，2003，1894-1896．
17 郭应禄，曾荔．临床泌尿外科病理学.北京：北京大学出版社，2004，223-252．
18 Shimizu M, Saitoh Y, Itoh H. Immunohistochemical staining of Ha-ras oncogene product in normal, benign, and malignant human pancreatic tissues. Hum Pathol,1990, 21(6):607-612.
19 Volm M, Koomagi R, Mattera J. Prognostic value of vascular endothelial growth factor and its receptor Flt-1 in squamous cell lung cancer. Int J Cancer, 1997, 74(1):64-68.
20 McNeal JE. The prostate and prostatic urethra: a morphologic synthesis. J Urol, 1972,107(6): 1008-1016.
21 Hruz P, Danuser H, Studer UE, et al. Non-Inflammatory Chronic Pelvic Pain Syndrome Can Be Caused by Bladder Neck Hypertrophy. Eur Urol, 2003, 44:106-110.
22张小马，梁朝朝，付圣权，等．犬正常前列腺导管系统形态的初步研究．中华泌尿外科杂志，2006，27(12)：843-846．
23杨宝峰 主编．离子通道药理学[M]．第一版．北京：人民卫生出版社，2005，155-163, 164-182．
24 McHale N, Hollywood M, Sergeant G, etal.Origin of spontaneous rhythmicity in smooth muscle [J]. J Physiol, 2006, 570(Pt l):23-28.
25 Kerfoot WW, Park HY, Schwartz LB,etal. Characterization of calcium channel blocker induced smooth muscle relaxation using a model of isolated corpus cavernosum [J].JUrol, 1993,150(l):249-52.
26 Perez-Reyes E. Three for T: molecular analysis of the low voltage-activated calcium channel family[J]. Cell Mol Life Sci, 1999, 56(7-8): 660-669
27 Hardie RC, Minke B.Phosphoinositide-mediated phototransduction in Drosophila photoreceptors: the role of Ca2+ and trp. Cell Calcium,1995,18(4): 256-274.
28 Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, Birnbaumer L. trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell, 1996, 85(5): 661-671.
29 Corey D P. New TRP channels in hearing and mechanosenation.Neuron, 2003; 39:585-588.
30 Zufall F, Ukhanov K, Lucas P, et al. Neurobiology of TRPC2: from gene to behavior[J]. Pflugers Arch, 2005,451(1):61-71.
31 West RJ, Sun AY, Church DL, et al. The C. elegans gon-2 gene encodes a putative TRP cation channel protein required for mitotic cell cycle progression [J]. Gene,2001, 266(1-2):103-110.
32 Xu XZ, Steinberg PW. A C. elegans sperm TRP protein required for sperm-egg interactions during fertilization[J]. Cell, 2003,114(3):285-297.
33 TsavalerL, Shapero MH, Morkowski S, et al., Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins [J]. Cancer Res, 2001, 61(9):3760-3769.
34 王怀鹏，杨晓茹，王行环等．Trp-p8在前列腺组织中的表达及其意义[J]．中华医学杂志，2005，85(22)：1571-1572．
35 Zhang L, Barritt GJ. Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer Cells [J]. Cancer Res, 2004, 64(22):8365-8373.
36 Fixemer T, Wissenbach U, Flockerzi V,et al. Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression [J]. Oncogene, 2003,22(49):7858-7861.
37 Wissenbach U, Niemeyer BA, Fixemer T, et al. Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer [J]. J Biol Chem, 2001,276(22):19461-19468.
38 Niemeyer BA, Bergs C, Wissenbach U, et al. Competitive regulation of CaT-like-mediated Ca2+entry by protein kinase C and calmodulin [J]. Proc Natl Acad Sci USA,2001,98 (6): 3600 - 3605.
39 夏同礼 主编．前列腺癌的基础与临床[M]．北京：科学出版社，2000，142-147．
40 Montell C. Physiology, phylogeny, and functions of the TRP superfamily of cation channels [J].Sci STKE, 2001,2001(90):RE1.
41 史娟，李继硕．TRP离子通道[J]．神经解剖杂志，2004，20(2)：197-204．
42 Ghobish AA. Quantitative and qualitative assessment of flowmetrograms in patients with prostatodynia [J]. Eur Urol, 2000, 38(5):576-583
43 Wesselmann U.Neurogenic inflammation and chronic pelvic pain [J].World J Urol, 2001,19(3): 180-185.
44 Richardson JD, Vasko MR. Cellular mechanisms of neurogenic inflammation [J].J Pharmacol Exp Ther, 2002, 302(3):839-845.
45 Obata K, Katsura H, Mizushima T, et al. TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury [J]. J Clin Invest, 2005,115(9):2393-2401.
46 Kavanagh JP. Sodium, potassium, calcium, magnesium, zinc, citrate and chloride content of human prostatic and seminal fluid [J]. J Reprod??Fertil, 1985,75(1 ):35-41.
47 Peng JB, Brown EM, Hediger MA. Epithelial Ca~(2+) entry channels: transcellular Ca~(2+) transport and beyond [J]. J Physiol ,2003,551 (Pt 3):729 - 740.
48 Grafton G, Thwaite L. Calcium channels in lymphocytes [J]. Immunology, 2001,104 (2):119-126.
49 Li SW, Westwick J, Poll CT. Receptor-operated Ca~(2+) influx channels in leukocytes: a therapeutic target? [J]. Trends Pharmacol Sci, 2002, 23(2):63-70.
50 Lowell PC. Prostatitis, interstitial cystitis, chronic pelvic pain and urethral syndrome share a common pathophyiology: lower urinary dysfunctional epithelium and potassium recycling. Urol 2003,62 (6 ):976 - 982.
51 叶伟成，薛慈民，徐兆东，等．免疫佐剂法制作慢性非细菌性前列腺炎小鼠模型的方法[J]．中国男科学杂志，2001，15(1)：29-31．
52 魏武然，张唯力，戴君勇．大鼠慢性非细菌性前列腺炎模型的建立．中国男科学杂志[J]．2006，20(1)：22-24．
53 Keetch DW, Humphrey P, Ratliff TL. Development of a mouse model for nonbacterial prostatitis. J Urol, 1994, 152 (l):247-520.
54 Hoenderop JG, van Leeuwen JP, van der Eerden BC, et al. Renal Ca2+ Wasting, Hyperabsorption, and Reduced Bone Thickness in Mice Lacking TRPV5.J Clin Invest 2003 ,112(12):1906-1914.
55 Ben-Sreti MM, Gonzalez JP, Sewell RD. Effects of elevated calcium and calcium antagonists on 6, 7-benzomorphan-induced analgesia. Eur J Pharmacol, 1983 , 90(4):385-390.
56 Nadler RB, Koch AE, Calhoun EA. et al. IL-1beta and TNF-alpha in prostatitis secretions are men with chronic prostatitis. [J]. J Urol ,2000,164(1):214-218.
1 史娟，李继硕．TRP离子通道[J]．神经解剖杂志，2004，20(2)：197-204．
2 杨宝峰 主编．离子通道药理学 [M]．北京：人民卫生出版社2005．157-158，165-168，175-182．
3 Montell C, Birnbaumer L, Flockerzi V, et al. A unified nomenclature for the superfamily of TRP cation channels [J]. Mol Cell, 2002, 9(2):229-231.
4 Montell C. Physiology, phylogeny, and functions of the TRP superfamily of cation channels [J].Sci STKE, 2001, 2001(90):REl.
5 Zufall F, Ukhanov K, Lucas P, et al. Neurobiology of TRPC2: from gene to behavior[J]. Pflugers Arch, 2005,451(1):61-71.
6 West RJ, Sun AY, Church DL, et al. The C. elegans gon-2 gene encodes a putative TRP cation channel protein required for mitotic cell cycle progression [J]. Gene,2001, 266(1-2):103-110.
7 Xu XZ, Sternberg PW. A C. elegans sperm TRP protein required for sperm-egg interactions during fertilization [J]. Cell,2003 ,114(3):285-297.
8刑俊平，崔险峰，邱曙东．离子通道在阴茎海绵体平滑肌紧张性调节中的作用[J]．中华男科学，2004，10(12)：941-943．
9刘继红，陈俊．离子通道与阴茎勃起[J]．中华男科学，2004，10(6)：403-410．
10 Patapoutian A, Peier AM, Story GM, et al. ThermoTRP channels and beyond: mechanisms of temperature sensation [J].Nat Rev Neurosci, 2003, 4(7):529-539.
11 Gunthorpe MJ, Benham CD, Randall A,et al. The diversity in the vanilloid (TRPV) receptor family of ion channels[J]. Trends Pharmacol Sci, 2002 ,23(4): 183-191.
12 Birder LA, Nakamura Y, Kiss S, et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1 [J]. Nat Neurosci, 2002 ,5(9):856-860.
13 Tsavaler L, Shapero MH, Morkowski S, et al., Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high??homology with transient receptor potential calcium channel proteins[J]. Cancer Res, 2001, 61(9):3760-3769
14王怀鹏，杨晓茹，王行环等．Trp-p8在前列腺组织中的表达及其意义[J]．中华医学杂志，2005，85(22)：1571-1572．
15 Zhang L, Barritt GJ. Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer Cells[J] . Cancer Res, 2004, 64(22):8365-8373.
16 Fixemer T, Wissenbach U, Flockerzi V,et al. Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression[J]. Oncogene, 2003,22(49):7858-7861.
17 Wissenbach U, Niemeyer BA, Fixemer T, et al. Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer [J]. J Biol Chem, 2001,276(22):19461-19468.
18 Niemeyer BA, Bergs C, Wissenbach U, et al. Competitive regulation of CaT-like-mediated Ca2+entry by protein kinase C and calmodulin [J]. Proc Natl Acad Sci USA,2001,98 (6): 3600-3605.
19夏同礼 主编．前列腺癌的基础与临床[M]．北京：科学出版社，2000，142-147．
20 Ghobish AA. Quantitative and qualitative assessment of flowmetrograms in patients with prostatodynia [J]. Eur Urol, 2000, 38(5):576-583.
21 Wesselmann U.Neurogenic inflammation and chronic pelvic pain [J].World J Urol, 2001,19(3):180-185.
22 Richardson JD, Vasko MR. Cellular mechanisms of neurogenic inflammation [J].J Pharmacol Exp Ther, 2002, 302(3):839-845.
23 Obata K, Katsura H, Mizushima T, et al. TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury [J]. J Clin Invest, 2005,115(9):2393-2401.
24 Kavanagh JP. Sodium, potassium, calcium, magnesium, zinc, citrate??and chloride content of human prostatic and seminal fluid [J]. J Reprod Fertil, 1985,75(1):35-41.
25郝宗耀，梁朝朝，张学军等．慢性前列腺炎患者前列腺液、尿液电解质测定及其相关性研究[J]．中华泌尿外科杂志,2005,4(7)：456-468．
26 Liang CZ, Guo QK, Hao ZY , et al. K channel expression in prostate epithelium and its implications in men with chronic prostatitis [J]. BJU Int, 2006, 97(1): 190-192.
27 Peng JB, Brown EM, Hediger MA. Epithelial Ca~(2+) entry channels: transcellular Ca~(2+) transport and beyond [J]. J Physiol ,2003,551 (Pt 3):729-740.
28 Grafton G, Thwaite L. Calcium channels in lymphocytes [J]. Immunology, 2001,104 (2):119-126.
29 Li SW, Westwick J , Poll CT. Receptor-operated Ca~(2+) influx channels in leukocytes : a therapeutic target ? [J]. Trends Pharmacol Sci,2002,23(2):63-70.
2 Krieger JN, Riley DE. Bacteria in the chronic prostatitis-chronic pelvic pain syndrome: molecular approaches to critical research questions.J Urol, 2002, 167(6):2574-2583.
3 梁朝朝，张学军，王克孝．前列腺炎病因学研究进展．中华泌尿外科杂志，2003，24(6)： 426-428
4 Schaeffer AJ, Landis JR, Knauss JS,etal. Demographic and clinical characteristics of men with chronic prostatitis: the national institutes of health chronic prostatitis cohort study.J Urol, 2002, 168(2):593-598.
5 Liang CZ, Zhang XJ, Hao ZY, etal. An epidemiological study of patients with chronic prostatitis.BJU Int, 2004,94(4):568-570.
6 范召应，钟红兴．慢性前列腺炎与男性不育研究进展．中华男科学杂志，2004，18(4)： 60-62．
7 Mehik A, Hellstrom P, Lukkarinen O, et al. Epidemiology of prostatitis in Finnish men: a population-based cross-sectional study. BJU Int, 2000,86: 443-448.
8 Parsons CL, Albo M. Intravesical potassium sensitivity in patients with prostatitis. J Urol, 2002,168(3):1054-1057.
9 Parsons CL, Zupkas P, Parsons JK. Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome.Urology, 2001, 57(3):428-432.
10 Eisenberg ER, Moldwin RM. Etiology: where does prostatitis stop and interstitial cystitis begin?World J Urol, 2003 ,21(2):64-69.
11 郝宗耀，梁朝朝，张学军，等．慢性前列腺炎患者前列腺液、尿液电解质测定及其相关性研究．中华泌尿外科杂志，2005，26(7)：456-468．
12 郭清奎，梁朝朝，张学军，等．慢性前列腺炎患者前列腺上皮钾通道的表达及其意义．中华泌尿外科杂志，2005,26(11)：782．
13 Nickel JC. Prostatitis and Related Conditions.In:Walsh PC,Retik AB,Vaughan ED,Jr.,etal,eds.Compbell's Urology,8~(th) edition,chapter 15,volume 1,section 4,2002:603-630.
14 Tuncel A,Uzun B,Eruyar T,et al. Do prostatic infarction, prostatic inflammation and prostate morphology play a role in actue urinary retention? European Urology, 2005,49(2)277-284.
15 武忠弼，杨光华主编．中华外科病理学．第一版.北京：人民卫生出版社，2002，1161-1162．
16 回允中 主译．诊断外科病理学．第一版,Stephens Stemberg．．Doagnotic SurgicalPathology,3th edition．北京：北京大学医学出版社，2003，1894-1896．
17 郭应禄，曾荔．临床泌尿外科病理学.北京：北京大学出版社，2004，223-252．
18 Shimizu M, Saitoh Y, Itoh H. Immunohistochemical staining of Ha-ras oncogene product in normal, benign, and malignant human pancreatic tissues. Hum Pathol,1990, 21(6):607-612.
19 Volm M, Koomagi R, Mattera J. Prognostic value of vascular endothelial growth factor and its receptor Flt-1 in squamous cell lung cancer. Int J Cancer, 1997, 74(1):64-68.
20 McNeal JE. The prostate and prostatic urethra: a morphologic synthesis. J Urol, 1972,107(6): 1008-1016.
21 Hruz P, Danuser H, Studer UE, et al. Non-Inflammatory Chronic Pelvic Pain Syndrome Can Be Caused by Bladder Neck Hypertrophy. Eur Urol, 2003, 44:106-110.
22张小马，梁朝朝，付圣权，等．犬正常前列腺导管系统形态的初步研究．中华泌尿外科杂志，2006，27(12)：843-846．
23杨宝峰 主编．离子通道药理学[M]．第一版．北京：人民卫生出版社，2005，155-163, 164-182．
24 McHale N, Hollywood M, Sergeant G, etal.Origin of spontaneous rhythmicity in smooth muscle [J]. J Physiol, 2006, 570(Pt l):23-28.
25 Kerfoot WW, Park HY, Schwartz LB,etal. Characterization of calcium channel blocker induced smooth muscle relaxation using a model of isolated corpus cavernosum [J].JUrol, 1993,150(l):249-52.
26 Perez-Reyes E. Three for T: molecular analysis of the low voltage-activated calcium channel family[J]. Cell Mol Life Sci, 1999, 56(7-8): 660-669
27 Hardie RC, Minke B.Phosphoinositide-mediated phototransduction in Drosophila photoreceptors: the role of Ca2+ and trp. Cell Calcium,1995,18(4): 256-274.
28 Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, Birnbaumer L. trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell, 1996, 85(5): 661-671.
29 Corey D P. New TRP channels in hearing and mechanosenation.Neuron, 2003; 39:585-588.
30 Zufall F, Ukhanov K, Lucas P, et al. Neurobiology of TRPC2: from gene to behavior[J]. Pflugers Arch, 2005,451(1):61-71.
31 West RJ, Sun AY, Church DL, et al. The C. elegans gon-2 gene encodes a putative TRP cation channel protein required for mitotic cell cycle progression [J]. Gene,2001, 266(1-2):103-110.
32 Xu XZ, Steinberg PW. A C. elegans sperm TRP protein required for sperm-egg interactions during fertilization[J]. Cell, 2003,114(3):285-297.
33 TsavalerL, Shapero MH, Morkowski S, et al., Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins [J]. Cancer Res, 2001, 61(9):3760-3769.
34 王怀鹏，杨晓茹，王行环等．Trp-p8在前列腺组织中的表达及其意义[J]．中华医学杂志，2005，85(22)：1571-1572．
35 Zhang L, Barritt GJ. Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer Cells [J]. Cancer Res, 2004, 64(22):8365-8373.
36 Fixemer T, Wissenbach U, Flockerzi V,et al. Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression [J]. Oncogene, 2003,22(49):7858-7861.
37 Wissenbach U, Niemeyer BA, Fixemer T, et al. Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer [J]. J Biol Chem, 2001,276(22):19461-19468.
38 Niemeyer BA, Bergs C, Wissenbach U, et al. Competitive regulation of CaT-like-mediated Ca2+entry by protein kinase C and calmodulin [J]. Proc Natl Acad Sci USA,2001,98 (6): 3600 - 3605.
39 夏同礼 主编．前列腺癌的基础与临床[M]．北京：科学出版社，2000，142-147．
40 Montell C. Physiology, phylogeny, and functions of the TRP superfamily of cation channels [J].Sci STKE, 2001,2001(90):RE1.
41 史娟，李继硕．TRP离子通道[J]．神经解剖杂志，2004，20(2)：197-204．
42 Ghobish AA. Quantitative and qualitative assessment of flowmetrograms in patients with prostatodynia [J]. Eur Urol, 2000, 38(5):576-583
43 Wesselmann U.Neurogenic inflammation and chronic pelvic pain [J].World J Urol, 2001,19(3): 180-185.
44 Richardson JD, Vasko MR. Cellular mechanisms of neurogenic inflammation [J].J Pharmacol Exp Ther, 2002, 302(3):839-845.
45 Obata K, Katsura H, Mizushima T, et al. TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury [J]. J Clin Invest, 2005,115(9):2393-2401.
46 Kavanagh JP. Sodium, potassium, calcium, magnesium, zinc, citrate and chloride content of human prostatic and seminal fluid [J]. J Reprod??Fertil, 1985,75(1 ):35-41.
47 Peng JB, Brown EM, Hediger MA. Epithelial Ca~(2+) entry channels: transcellular Ca~(2+) transport and beyond [J]. J Physiol ,2003,551 (Pt 3):729 - 740.
48 Grafton G, Thwaite L. Calcium channels in lymphocytes [J]. Immunology, 2001,104 (2):119-126.
49 Li SW, Westwick J, Poll CT. Receptor-operated Ca~(2+) influx channels in leukocytes: a therapeutic target? [J]. Trends Pharmacol Sci, 2002, 23(2):63-70.
50 Lowell PC. Prostatitis, interstitial cystitis, chronic pelvic pain and urethral syndrome share a common pathophyiology: lower urinary dysfunctional epithelium and potassium recycling. Urol 2003,62 (6 ):976 - 982.
51 叶伟成，薛慈民，徐兆东，等．免疫佐剂法制作慢性非细菌性前列腺炎小鼠模型的方法[J]．中国男科学杂志，2001，15(1)：29-31．
52 魏武然，张唯力，戴君勇．大鼠慢性非细菌性前列腺炎模型的建立．中国男科学杂志[J]．2006，20(1)：22-24．
53 Keetch DW, Humphrey P, Ratliff TL. Development of a mouse model for nonbacterial prostatitis. J Urol, 1994, 152 (l):247-520.
54 Hoenderop JG, van Leeuwen JP, van der Eerden BC, et al. Renal Ca2+ Wasting, Hyperabsorption, and Reduced Bone Thickness in Mice Lacking TRPV5.J Clin Invest 2003 ,112(12):1906-1914.
55 Ben-Sreti MM, Gonzalez JP, Sewell RD. Effects of elevated calcium and calcium antagonists on 6, 7-benzomorphan-induced analgesia. Eur J Pharmacol, 1983 , 90(4):385-390.
56 Nadler RB, Koch AE, Calhoun EA. et al. IL-1beta and TNF-alpha in prostatitis secretions are men with chronic prostatitis. [J]. J Urol ,2000,164(1):214-218.
1 史娟，李继硕．TRP离子通道[J]．神经解剖杂志，2004，20(2)：197-204．
2 杨宝峰 主编．离子通道药理学 [M]．北京：人民卫生出版社2005．157-158，165-168，175-182．
3 Montell C, Birnbaumer L, Flockerzi V, et al. A unified nomenclature for the superfamily of TRP cation channels [J]. Mol Cell, 2002, 9(2):229-231.
4 Montell C. Physiology, phylogeny, and functions of the TRP superfamily of cation channels [J].Sci STKE, 2001, 2001(90):REl.
5 Zufall F, Ukhanov K, Lucas P, et al. Neurobiology of TRPC2: from gene to behavior[J]. Pflugers Arch, 2005,451(1):61-71.
6 West RJ, Sun AY, Church DL, et al. The C. elegans gon-2 gene encodes a putative TRP cation channel protein required for mitotic cell cycle progression [J]. Gene,2001, 266(1-2):103-110.
7 Xu XZ, Sternberg PW. A C. elegans sperm TRP protein required for sperm-egg interactions during fertilization [J]. Cell,2003 ,114(3):285-297.
8刑俊平，崔险峰，邱曙东．离子通道在阴茎海绵体平滑肌紧张性调节中的作用[J]．中华男科学，2004，10(12)：941-943．
9刘继红，陈俊．离子通道与阴茎勃起[J]．中华男科学，2004，10(6)：403-410．
10 Patapoutian A, Peier AM, Story GM, et al. ThermoTRP channels and beyond: mechanisms of temperature sensation [J].Nat Rev Neurosci, 2003, 4(7):529-539.
11 Gunthorpe MJ, Benham CD, Randall A,et al. The diversity in the vanilloid (TRPV) receptor family of ion channels[J]. Trends Pharmacol Sci, 2002 ,23(4): 183-191.
12 Birder LA, Nakamura Y, Kiss S, et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1 [J]. Nat Neurosci, 2002 ,5(9):856-860.
13 Tsavaler L, Shapero MH, Morkowski S, et al., Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high??homology with transient receptor potential calcium channel proteins[J]. Cancer Res, 2001, 61(9):3760-3769
14王怀鹏，杨晓茹，王行环等．Trp-p8在前列腺组织中的表达及其意义[J]．中华医学杂志，2005，85(22)：1571-1572．
15 Zhang L, Barritt GJ. Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer Cells[J] . Cancer Res, 2004, 64(22):8365-8373.
16 Fixemer T, Wissenbach U, Flockerzi V,et al. Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression[J]. Oncogene, 2003,22(49):7858-7861.
17 Wissenbach U, Niemeyer BA, Fixemer T, et al. Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer [J]. J Biol Chem, 2001,276(22):19461-19468.
18 Niemeyer BA, Bergs C, Wissenbach U, et al. Competitive regulation of CaT-like-mediated Ca2+entry by protein kinase C and calmodulin [J]. Proc Natl Acad Sci USA,2001,98 (6): 3600-3605.
19夏同礼 主编．前列腺癌的基础与临床[M]．北京：科学出版社，2000，142-147．
20 Ghobish AA. Quantitative and qualitative assessment of flowmetrograms in patients with prostatodynia [J]. Eur Urol, 2000, 38(5):576-583.
21 Wesselmann U.Neurogenic inflammation and chronic pelvic pain [J].World J Urol, 2001,19(3):180-185.
22 Richardson JD, Vasko MR. Cellular mechanisms of neurogenic inflammation [J].J Pharmacol Exp Ther, 2002, 302(3):839-845.
23 Obata K, Katsura H, Mizushima T, et al. TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury [J]. J Clin Invest, 2005,115(9):2393-2401.
24 Kavanagh JP. Sodium, potassium, calcium, magnesium, zinc, citrate??and chloride content of human prostatic and seminal fluid [J]. J Reprod Fertil, 1985,75(1):35-41.
25郝宗耀，梁朝朝，张学军等．慢性前列腺炎患者前列腺液、尿液电解质测定及其相关性研究[J]．中华泌尿外科杂志,2005,4(7)：456-468．
26 Liang CZ, Guo QK, Hao ZY , et al. K channel expression in prostate epithelium and its implications in men with chronic prostatitis [J]. BJU Int, 2006, 97(1): 190-192.
27 Peng JB, Brown EM, Hediger MA. Epithelial Ca~(2+) entry channels: transcellular Ca~(2+) transport and beyond [J]. J Physiol ,2003,551 (Pt 3):729-740.
28 Grafton G, Thwaite L. Calcium channels in lymphocytes [J]. Immunology, 2001,104 (2):119-126.
29 Li SW, Westwick J , Poll CT. Receptor-operated Ca~(2+) influx channels in leukocytes : a therapeutic target ? [J]. Trends Pharmacol Sci,2002,23(2):63-70.