慢性前列腺炎病理生理模式图假说及血—前列腺屏障功能重建的大鼠实验研究
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摘要
前列腺炎是一个非常常见的疾病,困扰着2%～10%的男性。美国国立卫生研究院(NIH)Ⅰ型和Ⅱ型前列腺炎是由明确的前列腺感染造成,Ⅳ型前列腺炎是无症状型前列腺炎。有症状患者中绝大部分是Ⅲ型前列腺炎或称慢性前列腺炎/慢性盆腔疼痛综合征(CP/CPPS)。CP/CPPS的病因尚不清楚。前列腺液中的白细胞,作为传统意义上的炎症标志物,与盆腔痛这一主要症状并无相关性。就细胞因子而言,已发现了增多的促炎因子的和减少的抗炎因子间的不平衡,一些研究还发现这种不平衡与盆腔痛之间具有一定的相关性。在某些男性身上,这种细胞因子间的不平衡可能源于细胞因子基因位点的多态性。前列腺炎的发病机制可能包含了自身免疫反应过程,有实验证据表明这一过程受性激素影响。最近的研究提示雄激素受体可能存在缺陷。前列腺炎症状甚至可能并不是源自前列腺。盆腔痛还与神经生长因子存在相关性,而后者与神经源性炎症和中枢致敏有关。最后,精神压力可以造成相当程度的生化改变并影响其它病理生理过程。前列腺正常菌群在引发炎症反应过程中的作用受到了再次关注。大多数研究者相信,CP/CPPS症状可能源自精神因素、免疫机能障碍、神经和内分泌系统之间的相互作用。我们只知道感染或创伤触发了一个炎症过程,进而形成了一个不依赖于原发致病因子的一个炎症恶性循环。但至今为止,尚无研究者尝试建立一个完整的慢性前列腺炎病理生理模式图。这是前列腺炎研究的瓶颈。我们尝试建立了一个完整的慢性前列腺炎病理生理模式图。进而,我们又通过CAP大鼠模型验证了本模式图中的一个关键性步骤,并探索了一种重建CAP大鼠血-前列腺屏障功能的有效方法。研究内容如下:
目的:建立一个完整的慢性前列腺炎病理生理模式图;研究CAP大鼠前列腺中内膜屏障抗原(EBA,亦称血-脑屏障抗原)的分布特点和免疫抑制治疗前后的变化;研究美帕曲星联合非那雄胺在重建CAP大鼠模型血-前列腺屏障方面的疗效。
方法:生物医学专业文献之间存在着隐含联系,虽然它们之间并无直接的引用和被引用关系,但通过一些参数可以产生联系。这种参数组合起来可以产生新的推论,而后者是无法直接从上述个别的文献中直接得到的。SwansonDR教授描述了一种有助于确认(与某些文献)具有逻辑相关性的其它非相关文献的模型和在线搜索策略。利用这种方法,我们回顾分析了美国国立医学图书馆的PubMed数据库中2000年至2008年的文献。内膜屏障抗原(EBA)是由大鼠脑屏障血管内膜细胞特异性表达的一种蛋白。这一蛋白被认为是“屏障蛋白”并且被看作是血-脑屏障完整性的标志物。利用成年Sprague-Dawley大鼠,采用去势后苯甲酸雌二醇0.25mg/kg.d皮下注射4周的方法诱导成功CAP模型。利用免疫组织化学方法,我们研究了CAP大鼠前列腺中EBA的分布特点和免疫抑制治疗前后的变化。在另一个实验中,40只CAP模型大鼠被随机分为4组:空白对照组、吲哚美辛治疗组、美帕曲星联合非那雄胺治疗组和安慰剂组。药物干预时间为四周。治疗后,取前列腺组织进行常规病理学分析。
结果:我们在不同研究领域寻找关于血-前列腺屏障的理论及实验证据并提出了完整的血-前列腺屏障的概念。进而在“血-前列腺屏障”这一概念的基础上建立了完整的慢性前列腺炎病理生理模式图。我们发现EBA在大鼠睾丸网、前列腺背外侧叶腺管上皮的连续性强烈表达,在腹侧叶、精囊腺、凝集腺上皮细胞也有少量分布。在CAP大鼠模型中,EBA表达消失。然而在免疫抑制治疗后,前列腺腺管上皮细胞重新表达了EBA。在另外一个实验中,吲哚美辛显著减少了前列腺内炎细胞浸润。美帕曲星联合非那雄胺治疗未能对前列腺间质炎细胞浸润发挥作用,但是阻止了炎细胞向前列腺腺管内的渗透。
结论:我们相信,血一前列腺屏障是客观存在的,而且在前列腺炎的发病机制中扮演着关键性的角色。在血-前列腺屏障这一概念的基础上我们建立了完整的慢性前列腺炎病理生理模式图。基于第一个实验,我们可以知道自身免疫性前列腺炎可以破坏血-前列腺动态屏障,而且这种破坏是可逆性的。这个结果证实了我们的慢性前列腺炎病理生理模式图中的一个重要环节。第二个实验表明美帕曲星联合非那雄胺重建了CAP大鼠前列腺腺管上皮(血-前列腺屏障)的屏障功能,在治疗慢性前列腺炎方面具有令人感兴趣的应用前景。
Prostatitis is an extremely common syndrome that afflicts 2%-10% of men.National Institutes of Health categoriesⅠandⅡprostatitis result from identifiable prostatic infections,whereas patients with categoryⅣare asymptomatic.The majority of symptomatic cases are categoryⅢor chronic prostatitis (CP)/CPPS.The etiology of CP/CPPS is unknown.The traditional marker of inflammation,namely white blood cells in prostatic fluids,does not correlate with the predominant symptom of pelvic pain.An imbalance toward increased proinflammatory and decreased anti-inflammatory cytokines has been implicated and a few studies have shown some correlation of this with pelvic pain.The imbalance in some men may result from polymorphisms at the cytokine loci.An autoimmune process may be involved and experimental evidence indicates that this can be under hormonal influence.Recent findings include possible defects in the androgen receptor.The prostate may not even be the source of the symptoms.Pelvic pain also correlates with the neurotrophin nerve growth factor implicated in neurogenic inflammation and central sensitization.Finally,psychological stress may produce measurable biochemical changes and influence the other processes. The role of normal prostatic bacterial flora in inciting the inflammatory response has also been reconsidered.Most researchers believe that the symptoms of CP/CPPS appear to result from an interplay between psychological factors and dysfunction in the immune,neurological and endocrine systems.We only know that infecion or trauma triggers the inflammtory cascade and then a vicious cycle results in selfmaintenance of an inflammatory process,independent of the primary etiologic agent.But up to now, no researchers has try to establish a intact pathophysiological ideograph of chronic prostatitis.It is the bottleneck in studies of prostatitis.We try to establish a intact pathophysiological ideograph of chronic prostatitis.Furthermore,we proved a important step in this ideograph using CAP rat model and explore a validated method to restorate the blood-prostate barrier in CAP rat model.The studies are as follows:
Objective:To establish a intact pathophysiological ideograph of chronic prostatitis;To study the distribution of endothelial barrier antigen(EBA,or blood-brain barrier antigen) in prostate of chronic abacterial prostatitis(CAP) rat model and its changes after immunosuppressive therapy;To study synergistic effect of mepartricin combined with finasteride in reestablishment of blood-prostate barrier in chronic abacterial prostatitis rat model.
Method:Specialized biomedical literatures have been found that are implicitly linked by arguments that they respectively contain, but which nonetheless do not cite or refer to each other.The combined arguments lead to new inferences and conclusions that cannot be drawn from the separate literatures.Swanson DR describ a model and an online search strategy to aid in identifying other logically related noninteractive literatures.Based on this method,a literature review for the years 2000 to 2008 was performed using the PubMed database of the United States National Library of Medicine.The endothelial barrier antigen(EBA) is a protein expressed specifically by the endothelial cells of the rat brain barrier vessels.This antigen has been described as a 'barrier protein' and is used as a marker for the competent blood-brain barrier.An experimental CAP model was induced in adult male Sprague-Dawley rats by injection of Estradiol Benzoate subcutaneously(0.25mg/kg.d) for four weeks after castration.Using immunohistochemistry method,we studied the distribution of EBA in the prostate of CAP rat model and its changes after immunosuppressive therapy.In another experiment,40 CAP rats were randomly divided into four groups:control,indomethacin, mepartricin combined with finasteride and placebo groups.All drug treatments were conducted over a period of 4 weeks.After treatment,the results were analyzed with histological findings of the prostate to compare each group.
Results:We found the theoretical and experimental proof of blood-prostate barrier in various research field and posed the intact concept of blood-prostate barrier.We further establish a intact pathophysiological ideograph of chronic prostatitis based on the concept of blood-prostate barrier.We found that EBA was strongly and consistently detected in epithelial cells of the rete testis and dorsolateral prostate gland,and in a few epithelial cells of the ventral prostate gland,the seminal vesicle and the coagulating gland.In CAP rat model,EBA could not be detected. However,after immunosuppressive therapy,the epithelial cells of prostate express EBA again.In another experiment,we found Indomethacin reduce the infiltration of inflammatory cells markedly.Mepartricin combined with Finasteride showed no effect on leukocyte infiltration in the inflamed prostatic interstitium, but penetration of inflammatory cell into the ductal lumen was restricted significantly.
Conclusions:We believe that the blood-prostate barrier is existing indeed and play a key role in the pathogenesy of chronic prostatitis.Based on the concept of blood-prostate barrier,we established a intact pathophysiological ideograph of chronic prostatitis.Based on the first experiment,we can concluded that the dynamic blood-prostate bariier can be destroyed by autoimmune prostatitis and the destroy is reversible.The result proved a important step in our pathophysiological ideograph of chronic prostatitis.The second experiment indicated that mepartricin combined with finasteride reestablished the barrier function of prostate duct epithelium(blood-prostate barrier) in CAP rat model, thus showed the interesting therapeutic perspective in CAP.
目的:建立一个完整的慢性前列腺炎病理生理模式图;研究CAP大鼠前列腺中内膜屏障抗原(EBA,亦称血-脑屏障抗原)的分布特点和免疫抑制治疗前后的变化;研究美帕曲星联合非那雄胺在重建CAP大鼠模型血-前列腺屏障方面的疗效。
方法:生物医学专业文献之间存在着隐含联系,虽然它们之间并无直接的引用和被引用关系,但通过一些参数可以产生联系。这种参数组合起来可以产生新的推论,而后者是无法直接从上述个别的文献中直接得到的。SwansonDR教授描述了一种有助于确认(与某些文献)具有逻辑相关性的其它非相关文献的模型和在线搜索策略。利用这种方法,我们回顾分析了美国国立医学图书馆的PubMed数据库中2000年至2008年的文献。内膜屏障抗原(EBA)是由大鼠脑屏障血管内膜细胞特异性表达的一种蛋白。这一蛋白被认为是“屏障蛋白”并且被看作是血-脑屏障完整性的标志物。利用成年Sprague-Dawley大鼠,采用去势后苯甲酸雌二醇0.25mg/kg.d皮下注射4周的方法诱导成功CAP模型。利用免疫组织化学方法,我们研究了CAP大鼠前列腺中EBA的分布特点和免疫抑制治疗前后的变化。在另一个实验中,40只CAP模型大鼠被随机分为4组:空白对照组、吲哚美辛治疗组、美帕曲星联合非那雄胺治疗组和安慰剂组。药物干预时间为四周。治疗后,取前列腺组织进行常规病理学分析。
结果:我们在不同研究领域寻找关于血-前列腺屏障的理论及实验证据并提出了完整的血-前列腺屏障的概念。进而在“血-前列腺屏障”这一概念的基础上建立了完整的慢性前列腺炎病理生理模式图。我们发现EBA在大鼠睾丸网、前列腺背外侧叶腺管上皮的连续性强烈表达,在腹侧叶、精囊腺、凝集腺上皮细胞也有少量分布。在CAP大鼠模型中,EBA表达消失。然而在免疫抑制治疗后,前列腺腺管上皮细胞重新表达了EBA。在另外一个实验中,吲哚美辛显著减少了前列腺内炎细胞浸润。美帕曲星联合非那雄胺治疗未能对前列腺间质炎细胞浸润发挥作用,但是阻止了炎细胞向前列腺腺管内的渗透。
结论:我们相信,血一前列腺屏障是客观存在的,而且在前列腺炎的发病机制中扮演着关键性的角色。在血-前列腺屏障这一概念的基础上我们建立了完整的慢性前列腺炎病理生理模式图。基于第一个实验,我们可以知道自身免疫性前列腺炎可以破坏血-前列腺动态屏障,而且这种破坏是可逆性的。这个结果证实了我们的慢性前列腺炎病理生理模式图中的一个重要环节。第二个实验表明美帕曲星联合非那雄胺重建了CAP大鼠前列腺腺管上皮(血-前列腺屏障)的屏障功能,在治疗慢性前列腺炎方面具有令人感兴趣的应用前景。
Prostatitis is an extremely common syndrome that afflicts 2%-10% of men.National Institutes of Health categoriesⅠandⅡprostatitis result from identifiable prostatic infections,whereas patients with categoryⅣare asymptomatic.The majority of symptomatic cases are categoryⅢor chronic prostatitis (CP)/CPPS.The etiology of CP/CPPS is unknown.The traditional marker of inflammation,namely white blood cells in prostatic fluids,does not correlate with the predominant symptom of pelvic pain.An imbalance toward increased proinflammatory and decreased anti-inflammatory cytokines has been implicated and a few studies have shown some correlation of this with pelvic pain.The imbalance in some men may result from polymorphisms at the cytokine loci.An autoimmune process may be involved and experimental evidence indicates that this can be under hormonal influence.Recent findings include possible defects in the androgen receptor.The prostate may not even be the source of the symptoms.Pelvic pain also correlates with the neurotrophin nerve growth factor implicated in neurogenic inflammation and central sensitization.Finally,psychological stress may produce measurable biochemical changes and influence the other processes. The role of normal prostatic bacterial flora in inciting the inflammatory response has also been reconsidered.Most researchers believe that the symptoms of CP/CPPS appear to result from an interplay between psychological factors and dysfunction in the immune,neurological and endocrine systems.We only know that infecion or trauma triggers the inflammtory cascade and then a vicious cycle results in selfmaintenance of an inflammatory process,independent of the primary etiologic agent.But up to now, no researchers has try to establish a intact pathophysiological ideograph of chronic prostatitis.It is the bottleneck in studies of prostatitis.We try to establish a intact pathophysiological ideograph of chronic prostatitis.Furthermore,we proved a important step in this ideograph using CAP rat model and explore a validated method to restorate the blood-prostate barrier in CAP rat model.The studies are as follows:
Objective:To establish a intact pathophysiological ideograph of chronic prostatitis;To study the distribution of endothelial barrier antigen(EBA,or blood-brain barrier antigen) in prostate of chronic abacterial prostatitis(CAP) rat model and its changes after immunosuppressive therapy;To study synergistic effect of mepartricin combined with finasteride in reestablishment of blood-prostate barrier in chronic abacterial prostatitis rat model.
Method:Specialized biomedical literatures have been found that are implicitly linked by arguments that they respectively contain, but which nonetheless do not cite or refer to each other.The combined arguments lead to new inferences and conclusions that cannot be drawn from the separate literatures.Swanson DR describ a model and an online search strategy to aid in identifying other logically related noninteractive literatures.Based on this method,a literature review for the years 2000 to 2008 was performed using the PubMed database of the United States National Library of Medicine.The endothelial barrier antigen(EBA) is a protein expressed specifically by the endothelial cells of the rat brain barrier vessels.This antigen has been described as a 'barrier protein' and is used as a marker for the competent blood-brain barrier.An experimental CAP model was induced in adult male Sprague-Dawley rats by injection of Estradiol Benzoate subcutaneously(0.25mg/kg.d) for four weeks after castration.Using immunohistochemistry method,we studied the distribution of EBA in the prostate of CAP rat model and its changes after immunosuppressive therapy.In another experiment,40 CAP rats were randomly divided into four groups:control,indomethacin, mepartricin combined with finasteride and placebo groups.All drug treatments were conducted over a period of 4 weeks.After treatment,the results were analyzed with histological findings of the prostate to compare each group.
Results:We found the theoretical and experimental proof of blood-prostate barrier in various research field and posed the intact concept of blood-prostate barrier.We further establish a intact pathophysiological ideograph of chronic prostatitis based on the concept of blood-prostate barrier.We found that EBA was strongly and consistently detected in epithelial cells of the rete testis and dorsolateral prostate gland,and in a few epithelial cells of the ventral prostate gland,the seminal vesicle and the coagulating gland.In CAP rat model,EBA could not be detected. However,after immunosuppressive therapy,the epithelial cells of prostate express EBA again.In another experiment,we found Indomethacin reduce the infiltration of inflammatory cells markedly.Mepartricin combined with Finasteride showed no effect on leukocyte infiltration in the inflamed prostatic interstitium, but penetration of inflammatory cell into the ductal lumen was restricted significantly.
Conclusions:We believe that the blood-prostate barrier is existing indeed and play a key role in the pathogenesy of chronic prostatitis.Based on the concept of blood-prostate barrier,we established a intact pathophysiological ideograph of chronic prostatitis.Based on the first experiment,we can concluded that the dynamic blood-prostate bariier can be destroyed by autoimmune prostatitis and the destroy is reversible.The result proved a important step in our pathophysiological ideograph of chronic prostatitis.The second experiment indicated that mepartricin combined with finasteride reestablished the barrier function of prostate duct epithelium(blood-prostate barrier) in CAP rat model, thus showed the interesting therapeutic perspective in CAP.
引文
1 Habermacher GM,Chason JT,Schaeffer AJ.Prostatitis/chronic pelvic pain syndrome.Annu Rev Med,2006,57:195-206.
2 郭应禄,李宏军.前列腺炎.第2版.北京:人民军医出版社,2007.59-122.
3 Swanson DR.Medical literature as a potential source of new knowledge.Bull Med Libr Assoc,1990,78:29-37.
4 董风华,兰小筠.基于文献的科学假说.医学与哲学,2004,25:57-58.
5 Schaeffer AJ.Clinical practice.Chronic prostatitis and the chronic pelvic pain syndrome.N Engl J Med,2006,355:1690-8.
6 Nickel JC.A new era in prostatitis research begins.Rev Urol,2000,2:16-8.
7 True LD,Berger RE,Rothman I,et al.Prostate histopathology and the chronic prostatitis/chronic pelvic pain syndrome:a prospective biopsy study.J Urol,1999,162:2014-8.
8 Nickel JC,Moon T.Chronic bacterial prostatitis:an evolving clinical enigma.Urology,2005,66:2-8.
9 Hua VN,Williams DH,Schaeffer AJ.Role of bacteria in chronic prostatitis/chronic pelvic pain syndrome.Curt Urol Rep,2005,6:300-6.
10 Lee JC,Muller CH,Rothman I,et al.Prostate biopsy culture findings of men with chronic pelvic pain syndrome do not differ from those of healthy controls.J Urol,2003,169:584-7;discussion 587-8.
11 Pontari MA,Ruggieri MR.Mechanisms in prostatitis/chronic pelvic pain syndrome.J Urol,2004,172:839-45.
12 Ludwig M,Steltz C,Huwe P,et al.Immunocytological analysis of leukocyte subpopulations in urine specimens before and after prostatic massage.Eur Urol,2001,39:277-82.
13 John H,Barghorn A,Funko G,et al.Noninflammatory chronic pelvic pain syndrome:immunological study in blood,ejaculate and prostate tissue.Eur Urol,2001,39:72-8.
14 Batstone GR,Doblo A,Gaston JS.Autoimmune T cell responses to seminal plasma in chronic pelvic pain syndrome(CPPS).Clin Exp Immunol,2002,128:302-7.
15 Hruz P,Danuser H,Studer UE,et al.Non-inflammatory chronic pelvic pain syndrome can be caused by bladder neck hypertrophy.Eur Urol,2003,44:106-10;discussion 110.
16 Nickel JC,Downey J,Pontari MA,et al.A randomized placebocontrolled multicentre study to evaluate the safety and efficacy of finasteride for male chronic pelvic pain syndrome (category IIIA chronic nonbacterial prostatitis).BJU Int,2004,93:991-5.
17 Vykhovanets EV,Resnick MI,Maclennan GT,et al.Experimental rodent models of prostatitis:limitations and potential.Prostate Cancer Prostatic Dis,2007,10:15-29.
18 Riley DE,Krieger JN.X Chromosomal short tandem repeat polymorphisms near the phosphoglycerate kinase gene in men with chronic prostatitis,giochim giophys Acta,2002,1586:99-107.
19 Edorh AP,Tachev K,Hadou T,et al.Magnesium content in seminal fluid as an indicator of chronic prostatitis.Cell Mol giol(Noisy-le-grand),2003,49 Online Pub:OL419-23.
20 郝宗耀[1],梁朝朝[1],张学军[2],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,2004,25:465-468.
21 Parsons CL,Greenberger M,Gabal L,et al.The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis.J Urol,1998,159:1862-6;discussion 1866-7.
22 Parsons CL,Albo M.Intravesical potassium sensitivity in patients with prostatitis. J Urol, 2002,168:1054-7.
23 Parsons CL, Forrest J, Nickel JC, et al. Effect of pentosan polysulfate therapy on intravesical potassium sensitivity. Urology, 2002,59:329-33.
24 Nickel JC, Forrest JB, Tomera K, et al. Pentosan polysulfate sodium therapy for men with chronic pelvic pain syndrome: a multicenter, randomized, placebo controlled study. J Urol, 2005, 173:1252-5.
25 Parsons CL. Prostatitis, interstitial cystitis, chronic pelvic pain, and urethral syndrome share a common pathophysiology: lower urinary dysfunctional epithelium and potassium recycling. Urology, 2003,62:976-82.
26 Fulmer BR, Turner TT. A blood-prostate barrier restricts cell and molecular movement across the rat ventral prostate epithelium. J Urol, 2000,163:1591-4.
27 Motrich RD, Maccioni M, Molina R, et al. Reduced semen quality in chronic prostatitis patients that have cellular autoimmune response to prostate antigens. Hum Reprod, 2005,20:2567-72.
28 Motrich RD, Maccioni M, Molina R, et al. Presence of INFgamma- secreting lymphocytes specific to prostate antigens in a group of chronic prostatitis patients. Clin Immunol, 2005,116:149-57.
29 Motrich RD, Maccioni M, Ponce AA, et al. Pathogenic Consequences in Semen Quality of an Autoimmune Response against the Prostate Gland: From Animal Models to Human Disease. J Immunol, 2006,177:957-67.
30 Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol, 2005,2:416-22.
31 Nickel JC, Barkin J, Forrest J, et al. Randomized, double- blind,dose-ranging study of pentosan polysulfate sodium for interstitial cystitis.Urology,2005,65:654-8.
32 Lang MD,Nickel JC,Olson ME,et al.Rat model of experimentally induced abacterial prostatitis.Prostate,2000,45:201-6.
33 Ghabriel MN,Lu JJ,Hermanis G,et al.Expression of a bloodbrain barrier-specific antigen in the reproductive tract of the male rat.Reproduction,2002,123:389-97.
34 Lawrenson JG,Ghabriel MN,Reid AR,et al.Distribution of a putative endothelial barrier antigen in the ocular and orbital tissues of the rat.Br J Ophthalmol,1995,79:462-6.
35 El-Alfy M,Pelletier G,Hermo LS,et al.Unique features of the basal cells of human prostate epithelium.Microsc Res Tech,2000,51:436-46.
36 Chen J,Zhao HF,Xu ZS.The Prostate has Secretory Dysfunction for Category IIIA and IIIB Prostatitis.J Urol,2007,177:2166-2169.
37 Hayward SW,Del guono R,Deshpande N,et al.A functional model of adult human prostate epithelium.The role of androgens and stroma in architectural organisation and the maintenance of differentiated secretory function.J Cell Sci,1992,102(Pt 2):361-72.
38 Lai CH,Kuo KH,Leo JM.Critical role of actin in modulating BBB permeability.Brain Res Brain Res Roy,2005,50:7-13.
39 Murakoshi M,Inada R,Tagawa M,et al.Immunohistochemical localization of tubulin and actin in rat prostate.Tokai J Exp Clin Med,1993,18:5-10.
40 袁小丽,白汝岚,刘姗姗,等.血睾屏障开放调节机制研究进展.动物医学进展,2006,27:31-34.
41 张志琳,鲍欢.血脑屏障紧密连接的分子基础及信号调节.国外医学: 生理病理科学与临床分册, 2003,23:165-167.
42 Musch MW, Walsh-Reitz MM, Chang EB. Roles of ZO-1, occludin, and actin in oxidant-induced barrier disruption. Am J Physiol Gastrointest Liver Physiol, 2006, 290:G222-31.
43 Pasqualotto FF, Sharma RK, Potts JM, et al. Seminal oxidative stress in patients with chronic prostatitis. Urology, 2000,55:881-5.
44 Anderson RU. Traditional therapy for chronic pelvic pain does not work: what do we do now?. Nat Clin Pract Urol, 2006,3:145- 56.
45 Leibovitz A, Baumoehl Y, Segal R. Increased incidence of pathological and clinical prostate cancer with age: age related alterations of local immune surveillance. J Urol, 2004, 172:435-7.
46 Wiygul RD. Prostatitis: epidemiology of inflammation. Curr Urol Rep, 2005,6:282-9.
47 Schaeffer AJ, Knauss JS, Landis JR, et al. Leukocyte and bacterial counts do not correlate with severity of symptoms in men with chronic prostatitis: the National Institutes of Health Chronic Prostatitis Cohort Study. J Urol, 2002,168:1048-53.
48 Nickel JC, Alexander RB, Schaeffer AJ, et al. Leukocytes and bacteria in men with chronic prostatitis/chronic pelvic pain syndrome compared to asymptomatic controls. J Urol, 2003, 170:818-22.
49 Potts JM. Chronic pelvic pain syndrome: a non-prostatocentric perspective. World J Urol, 2003,21:54-6.
50 Pontari MA. Chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: are they related?. Curr Urol Rep, 2006,7:329-34.
51 Parsons CL.Interstitial cystitis and lower urinary tract symptoms in males and females-the combined role of potassium and epithelial dysfunction.Rev Urol,2002,4 Suppl 1:S49-55.
52 Schaeffer AJ.Etiology and management of chronic pelvic pain syndrome in men.Urology,2004,63:75-84.
53 马文强,王养民,李卫平.血-前列腺屏障的假说及其对前列腺炎研究的意义.医学与哲学(临床决策版),2007,28:32-34.
54 Potts JM.Therapeutic options for chronic prostatitis/chronic pelvic pain syndrome.Curt Wrol Rep,2005,6:313-7.
55 Armitage J,Emberton M.Is it time to reconsider the role of prostatic inflammation in the pathogenesis of lower urinary tract symptoms?.BJU Int,2005,96:745-6.
56 Lauren Sompayrac.免疫学概览.2nd版.北京:化学工业出版社,2005.158-161.
57 Mehik A,Leskinen MJ,Hellstrom P.Mechanisms of pain in chronic pelvic pain syndrome:influence of prostatic inflammation.World J Urol,2003,21:90-4.
58 Chuang YC,Yoshimura N,Wu M,et al.Intraprostatic capsaicin injection as a novel model for nonbacterial prostatitis and effects of botulinum toxin A.Eur Urol,2007,51:1119-27.
59 Nickel JC.Alpha-Blockers for the Treatment of Prostatitis-Like Syndromes.Rev Urol,2006,8:S26-S34.
60 Nickel JC,Berger R,Pontari M.Changing paradigms for chronic pelvic pain:a report from the chronic pelvic pain/chronic prostatitis scientific workshop,october 19-21,2005,Baltimore,MD.Rev Urol,2006,8:28-35.
61 Anderson RU,Orenberg EK,than CA,et al.Psychometric Profiles and Hypothalamic-Pituitary-Adrenal Axis Function in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome.J Urol,2008.
62 Hochreiter WW,Z'Brun S.Chronic pelvic pain syndrome and voiding dysfunction.Curt Urol Rep,2004,5:300-4.
63 Gonzalez RR,Te AE.Is there a role for urodynamics in chronic nonbacterial prostatitis?.Curt Urol Rep,2006,7:335-8.
64 Dellabella M,Milanese G,Muzzonigro G.Correlation between ultrasound alterations of the preprostatic sphincter and symptoms in patients with chronic prostatitis-chronic pelvic pain syndrome.J Urol,2006,176:112-8.
65 Seethalakshmi L,gala RS,Malhotra RK,et al.17 betaestradiol induced prostatitis in the rat is an autoimmune disease.J Urol,1996,156:1838-42.
66 Bernoulli J,Yatkin E,Talvitie EM,et al.Urodynamic changes in a noble rat model for nonbacterial prostatic inflammation.Prostate,2007,67:888-99.
67 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,2006,20:22-24.
68 the YH,Lee SJ,Lee JY,et al.Antibacterial effect of intraprostatic zinc injection in a rat model of chronic bacterial prostatitis.Int J Antimicrob Agents,2002,19:576-82.
2 郭应禄,李宏军.前列腺炎.第2版.北京:人民军医出版社,2007.59-122.
3 Swanson DR.Medical literature as a potential source of new knowledge.Bull Med Libr Assoc,1990,78:29-37.
4 董风华,兰小筠.基于文献的科学假说.医学与哲学,2004,25:57-58.
5 Schaeffer AJ.Clinical practice.Chronic prostatitis and the chronic pelvic pain syndrome.N Engl J Med,2006,355:1690-8.
6 Nickel JC.A new era in prostatitis research begins.Rev Urol,2000,2:16-8.
7 True LD,Berger RE,Rothman I,et al.Prostate histopathology and the chronic prostatitis/chronic pelvic pain syndrome:a prospective biopsy study.J Urol,1999,162:2014-8.
8 Nickel JC,Moon T.Chronic bacterial prostatitis:an evolving clinical enigma.Urology,2005,66:2-8.
9 Hua VN,Williams DH,Schaeffer AJ.Role of bacteria in chronic prostatitis/chronic pelvic pain syndrome.Curt Urol Rep,2005,6:300-6.
10 Lee JC,Muller CH,Rothman I,et al.Prostate biopsy culture findings of men with chronic pelvic pain syndrome do not differ from those of healthy controls.J Urol,2003,169:584-7;discussion 587-8.
11 Pontari MA,Ruggieri MR.Mechanisms in prostatitis/chronic pelvic pain syndrome.J Urol,2004,172:839-45.
12 Ludwig M,Steltz C,Huwe P,et al.Immunocytological analysis of leukocyte subpopulations in urine specimens before and after prostatic massage.Eur Urol,2001,39:277-82.
13 John H,Barghorn A,Funko G,et al.Noninflammatory chronic pelvic pain syndrome:immunological study in blood,ejaculate and prostate tissue.Eur Urol,2001,39:72-8.
14 Batstone GR,Doblo A,Gaston JS.Autoimmune T cell responses to seminal plasma in chronic pelvic pain syndrome(CPPS).Clin Exp Immunol,2002,128:302-7.
15 Hruz P,Danuser H,Studer UE,et al.Non-inflammatory chronic pelvic pain syndrome can be caused by bladder neck hypertrophy.Eur Urol,2003,44:106-10;discussion 110.
16 Nickel JC,Downey J,Pontari MA,et al.A randomized placebocontrolled multicentre study to evaluate the safety and efficacy of finasteride for male chronic pelvic pain syndrome (category IIIA chronic nonbacterial prostatitis).BJU Int,2004,93:991-5.
17 Vykhovanets EV,Resnick MI,Maclennan GT,et al.Experimental rodent models of prostatitis:limitations and potential.Prostate Cancer Prostatic Dis,2007,10:15-29.
18 Riley DE,Krieger JN.X Chromosomal short tandem repeat polymorphisms near the phosphoglycerate kinase gene in men with chronic prostatitis,giochim giophys Acta,2002,1586:99-107.
19 Edorh AP,Tachev K,Hadou T,et al.Magnesium content in seminal fluid as an indicator of chronic prostatitis.Cell Mol giol(Noisy-le-grand),2003,49 Online Pub:OL419-23.
20 郝宗耀[1],梁朝朝[1],张学军[2],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,2004,25:465-468.
21 Parsons CL,Greenberger M,Gabal L,et al.The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis.J Urol,1998,159:1862-6;discussion 1866-7.
22 Parsons CL,Albo M.Intravesical potassium sensitivity in patients with prostatitis. J Urol, 2002,168:1054-7.
23 Parsons CL, Forrest J, Nickel JC, et al. Effect of pentosan polysulfate therapy on intravesical potassium sensitivity. Urology, 2002,59:329-33.
24 Nickel JC, Forrest JB, Tomera K, et al. Pentosan polysulfate sodium therapy for men with chronic pelvic pain syndrome: a multicenter, randomized, placebo controlled study. J Urol, 2005, 173:1252-5.
25 Parsons CL. Prostatitis, interstitial cystitis, chronic pelvic pain, and urethral syndrome share a common pathophysiology: lower urinary dysfunctional epithelium and potassium recycling. Urology, 2003,62:976-82.
26 Fulmer BR, Turner TT. A blood-prostate barrier restricts cell and molecular movement across the rat ventral prostate epithelium. J Urol, 2000,163:1591-4.
27 Motrich RD, Maccioni M, Molina R, et al. Reduced semen quality in chronic prostatitis patients that have cellular autoimmune response to prostate antigens. Hum Reprod, 2005,20:2567-72.
28 Motrich RD, Maccioni M, Molina R, et al. Presence of INFgamma- secreting lymphocytes specific to prostate antigens in a group of chronic prostatitis patients. Clin Immunol, 2005,116:149-57.
29 Motrich RD, Maccioni M, Ponce AA, et al. Pathogenic Consequences in Semen Quality of an Autoimmune Response against the Prostate Gland: From Animal Models to Human Disease. J Immunol, 2006,177:957-67.
30 Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol, 2005,2:416-22.
31 Nickel JC, Barkin J, Forrest J, et al. Randomized, double- blind,dose-ranging study of pentosan polysulfate sodium for interstitial cystitis.Urology,2005,65:654-8.
32 Lang MD,Nickel JC,Olson ME,et al.Rat model of experimentally induced abacterial prostatitis.Prostate,2000,45:201-6.
33 Ghabriel MN,Lu JJ,Hermanis G,et al.Expression of a bloodbrain barrier-specific antigen in the reproductive tract of the male rat.Reproduction,2002,123:389-97.
34 Lawrenson JG,Ghabriel MN,Reid AR,et al.Distribution of a putative endothelial barrier antigen in the ocular and orbital tissues of the rat.Br J Ophthalmol,1995,79:462-6.
35 El-Alfy M,Pelletier G,Hermo LS,et al.Unique features of the basal cells of human prostate epithelium.Microsc Res Tech,2000,51:436-46.
36 Chen J,Zhao HF,Xu ZS.The Prostate has Secretory Dysfunction for Category IIIA and IIIB Prostatitis.J Urol,2007,177:2166-2169.
37 Hayward SW,Del guono R,Deshpande N,et al.A functional model of adult human prostate epithelium.The role of androgens and stroma in architectural organisation and the maintenance of differentiated secretory function.J Cell Sci,1992,102(Pt 2):361-72.
38 Lai CH,Kuo KH,Leo JM.Critical role of actin in modulating BBB permeability.Brain Res Brain Res Roy,2005,50:7-13.
39 Murakoshi M,Inada R,Tagawa M,et al.Immunohistochemical localization of tubulin and actin in rat prostate.Tokai J Exp Clin Med,1993,18:5-10.
40 袁小丽,白汝岚,刘姗姗,等.血睾屏障开放调节机制研究进展.动物医学进展,2006,27:31-34.
41 张志琳,鲍欢.血脑屏障紧密连接的分子基础及信号调节.国外医学: 生理病理科学与临床分册, 2003,23:165-167.
42 Musch MW, Walsh-Reitz MM, Chang EB. Roles of ZO-1, occludin, and actin in oxidant-induced barrier disruption. Am J Physiol Gastrointest Liver Physiol, 2006, 290:G222-31.
43 Pasqualotto FF, Sharma RK, Potts JM, et al. Seminal oxidative stress in patients with chronic prostatitis. Urology, 2000,55:881-5.
44 Anderson RU. Traditional therapy for chronic pelvic pain does not work: what do we do now?. Nat Clin Pract Urol, 2006,3:145- 56.
45 Leibovitz A, Baumoehl Y, Segal R. Increased incidence of pathological and clinical prostate cancer with age: age related alterations of local immune surveillance. J Urol, 2004, 172:435-7.
46 Wiygul RD. Prostatitis: epidemiology of inflammation. Curr Urol Rep, 2005,6:282-9.
47 Schaeffer AJ, Knauss JS, Landis JR, et al. Leukocyte and bacterial counts do not correlate with severity of symptoms in men with chronic prostatitis: the National Institutes of Health Chronic Prostatitis Cohort Study. J Urol, 2002,168:1048-53.
48 Nickel JC, Alexander RB, Schaeffer AJ, et al. Leukocytes and bacteria in men with chronic prostatitis/chronic pelvic pain syndrome compared to asymptomatic controls. J Urol, 2003, 170:818-22.
49 Potts JM. Chronic pelvic pain syndrome: a non-prostatocentric perspective. World J Urol, 2003,21:54-6.
50 Pontari MA. Chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: are they related?. Curr Urol Rep, 2006,7:329-34.
51 Parsons CL.Interstitial cystitis and lower urinary tract symptoms in males and females-the combined role of potassium and epithelial dysfunction.Rev Urol,2002,4 Suppl 1:S49-55.
52 Schaeffer AJ.Etiology and management of chronic pelvic pain syndrome in men.Urology,2004,63:75-84.
53 马文强,王养民,李卫平.血-前列腺屏障的假说及其对前列腺炎研究的意义.医学与哲学(临床决策版),2007,28:32-34.
54 Potts JM.Therapeutic options for chronic prostatitis/chronic pelvic pain syndrome.Curt Wrol Rep,2005,6:313-7.
55 Armitage J,Emberton M.Is it time to reconsider the role of prostatic inflammation in the pathogenesis of lower urinary tract symptoms?.BJU Int,2005,96:745-6.
56 Lauren Sompayrac.免疫学概览.2nd版.北京:化学工业出版社,2005.158-161.
57 Mehik A,Leskinen MJ,Hellstrom P.Mechanisms of pain in chronic pelvic pain syndrome:influence of prostatic inflammation.World J Urol,2003,21:90-4.
58 Chuang YC,Yoshimura N,Wu M,et al.Intraprostatic capsaicin injection as a novel model for nonbacterial prostatitis and effects of botulinum toxin A.Eur Urol,2007,51:1119-27.
59 Nickel JC.Alpha-Blockers for the Treatment of Prostatitis-Like Syndromes.Rev Urol,2006,8:S26-S34.
60 Nickel JC,Berger R,Pontari M.Changing paradigms for chronic pelvic pain:a report from the chronic pelvic pain/chronic prostatitis scientific workshop,october 19-21,2005,Baltimore,MD.Rev Urol,2006,8:28-35.
61 Anderson RU,Orenberg EK,than CA,et al.Psychometric Profiles and Hypothalamic-Pituitary-Adrenal Axis Function in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome.J Urol,2008.
62 Hochreiter WW,Z'Brun S.Chronic pelvic pain syndrome and voiding dysfunction.Curt Urol Rep,2004,5:300-4.
63 Gonzalez RR,Te AE.Is there a role for urodynamics in chronic nonbacterial prostatitis?.Curt Urol Rep,2006,7:335-8.
64 Dellabella M,Milanese G,Muzzonigro G.Correlation between ultrasound alterations of the preprostatic sphincter and symptoms in patients with chronic prostatitis-chronic pelvic pain syndrome.J Urol,2006,176:112-8.
65 Seethalakshmi L,gala RS,Malhotra RK,et al.17 betaestradiol induced prostatitis in the rat is an autoimmune disease.J Urol,1996,156:1838-42.
66 Bernoulli J,Yatkin E,Talvitie EM,et al.Urodynamic changes in a noble rat model for nonbacterial prostatic inflammation.Prostate,2007,67:888-99.
67 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,2006,20:22-24.
68 the YH,Lee SJ,Lee JY,et al.Antibacterial effect of intraprostatic zinc injection in a rat model of chronic bacterial prostatitis.Int J Antimicrob Agents,2002,19:576-82.