间质性膀胱炎--病因`病理和发病机理

1、间质性膀胱炎- 病因、病理和发病机理复旦大学附属华山医院方祖军间质性膀胱炎的病因病因不明目前研究说明主要有以下三种可能:尿路上皮功能异常肥大细胞激活神经生物学改变尿路上皮功能异常正常人膀胱有一天然屏障以阻止尿液及其溶质渗入膀胱粘膜下层这一屏障包括尿路上皮及其外表的粘液层UROLOGY 69(Supplement4A),April2007尿路上皮功能异常粘液层防渗透活性是由富含阴离子的多糖成份(如氨基葡 聚糖,GAG)发挥作用,后者多糖链中的硫酸盐局部具有极强的亲水性 GAG层的结构示意图电镜下的GAG层尿路上皮功能异常GAG层具有以下三重功能:阻止尿液及其溶质与尿路上皮接触防止渗入阻止细菌粘附

2、尿路上皮功能异常膀胱上皮外表的粘液层是膀胱阻止尿液中有害物质渗透的 重要调节因子,大多数IC患者中该结构存在缺陷 尿路上皮功能异常肝素结合表皮生长因子HB-EGF抗增殖因子APF上皮生长被抑制尿路上皮功能异常最近的研究说明,正常人的尿液中含有大量的带阳离子的低分子毒性因子，因而能与带阴离子的膀胱粘液层结合，改变粘液层亲水性，从而影响其抗渗透功能正常人尿液中富含的Tamm-Horsfall蛋白为阴离子蛋白，与肝素一样具有中和毒性因子的功能尿路上皮功能异常TH蛋白数量或其多糖局部缺陷,改变其电化学活性,从而影响其中和保护功能TH蛋白的异常很可能是IC患者最早出现的变化之一Stein P. Urol

3、ogy2005;66:903907.尿路上皮功能异常尿素吸收实验: 对照组 31例 4.3% IC组 40例 27% Hunner 34.5% Parsons CL. JUrol 1991;145:732735.尿路上皮功能异常正常人的尿液中存在高浓度的钾离子(24-133mEq/L)该浓度的钾离子不仅可使神经和肌肉去极化从而产生病症,并可引起组织损伤IC患者中膀胱上皮外表粘液层的损坏使尿液和膀胱粘膜直接接触从而引起病症,尤其尿路上皮也存在功能障碍时尿液中的溶质特别是钾离子极易渗入粘膜下尿路上皮功能异常Hohlbrugger对19例正常志愿者膀胱灌注钾离子溶液并保存20分钟结果仅少量钾离子被吸

4、收;用鱼精蛋白破坏粘液层后钾离子吸收量增加7倍;肝素灌注后恢复 尿 急 尿 痛 鱼精蛋白使用前 16%(3/19) 0 鱼精蛋白使用后 79%(15/19) 37%(7/19) 肝素使用后 42%(8/19) 11%(2/19)Hohlbrugger G.Eur Urol1985;11:127130.肥大细胞激活在有Hunner溃疡的IC患者中粘膜下和逼尿肌中肥大细胞及脱颗粒肥大细胞数量明显增加但在非溃疡型患者中报道有较大差异(存在亚型、标本固定和染色方法不同)TomaszewskiJE,et al. Urology2001;57(suppl6A):6781.ChristmasTJ. BrJU

5、rol1991;68:473478.肥大细胞激活但最近用纤溶蛋白酶细胞免疫组化技术揭示溃疡型IC患者中肥大细胞数量较对照组增加6-10倍；而非溃疡型患者中也增加2倍肥大细胞数量及尿液中组胺、纤溶酶等浓度与IC的严重程度和患者的病症成正比Peeker R,et al.J Urol.2000;163:10091015.肥大细胞激活电镜下观察发现IC患者80%肥大细胞被激活,而对照组为30%,移行上皮细胞癌患者为24%IC患者膀胱肥大细胞较对照组更易被激活(如IgE、Ach、抗原等)TheoharidesTC,et al.J Urol 1995;153:629636.肥大细胞激活IC的女性患者经期病

6、症加重与经期中高亲和力的雌激素受体表达增加、雌激素介导的肥大细胞浸润增加有关Pang X. Br J Urol 1995;75:154161.肥大细胞激活肥大细胞组胺细胞因子血管活性因子伤害因子多肽等ACHSP等神经炎症出现类似内脏痛病症膀胱粘膜下及肌层炎症神经生物学改变IC患者神经病理生理方面特征表现：膀胱粘膜下及逼尿肌中神经纤维密度增加；大量无髓鞘纤维A和C纤维出现；神经组织周围大量炎症细胞浸润神经生物学改变膀胱传入神经A和C纤维敏感性增加中枢神经元敏感性增加释放多肽如SP、CGRP神经生物学改变IC患者中P2X2和P2X3受体增加， P2X2和P2X3主要传递膀胱的机械感觉和痛觉阻断该受

7、体可增加实验大鼠的膀胱容量、减少尿频、减少膀胱的收缩神经生物学改变动物实验说明：蛋白激酶受体、纤溶酶、-NGF、一氧化氮合酶、核转录因子-Kb，c-Fos、cAMP 依赖蛋白激酶等增量调节心脏休克因子(HSF-2)、IGF等下调环磷酰胺所致的化学性膀胱炎动物中脊髓神经元中Fos蛋白增量表达自体免疫机制大多IC患者血抗核抗体滴度增高，且与患者病症呈正相关很多IC患者伴有自体免疫性疾病如红斑狼疮等下丘脑垂体肾上腺轴异常IC患者晨尿中皮质醇浓度下降与炎症和刺激加重密切相关，表现为患者疼痛加重、尿频和夜尿增加LutgendorfSK,et al. JUrol2002;167:13381343;下丘脑垂

8、体肾上腺轴异常Iowa大学调查精神压力对IC患者的影响与对照组比，相同的压力下IC患者的生理反响更加强烈且压力解除后持续时间更长试验开始25分钟及结束后75分钟IC患者表现为尿频和疼痛加重，而对照组无反响精神压力的程度与IC患者尿频及膀胱疼痛的加重成正相关IC患者皮质醇昼夜曲线受到影响，且和患者病症密切相关Lutgendorf SK,et al.JUrol2002;167:13381343;Lutgendorf SK, etal.JUrol2004;172:227231.Rothrock NE,etal.Urology2001;57:422427.子宫内膜异位 IC与女性的慢性盆底疼痛综合症(

9、CPP)有很大局部重叠,认为子宫内膜异位是其共同病因但最近有作者认为膀胱是CPP的起因而且子宫内膜异位部位活检发现大量肥大细胞浸润 发病机理 尿路上皮异常通透性增加、神经多肽/神经递质释放肥大细胞激活C纤维传入神经增量上调脊髓及中枢神经兴奋增强内脏器官痛觉过敏泌尿系统胃肠道盆底妇科 有毒物质TH蛋白HB-EGFAPF病理大体重度中度轻度病理大体病理非特异性IC的早期，特征性的组织学表现为粘膜水肿和血管扩张，而肌肉往往正常Messing EM.Urology1978;12:381392.病理粘膜下和逼尿肌中肥大细胞及脱颗粒肥大细胞数量明显增加膀胱粘膜下及逼尿肌中神经纤维密度增加；大量无髓鞘纤维A

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25、0C4F7JaMdPhSkVnZq$u*x-A2D5G8KbNfQiTlXo#r%v(y+B3E6I9LcOgRjUmYp!t&w)z1C4F7JaMePhSkWnZq$u*x+A2D5H8KbNfQiUlXo#s%v(y0B3F6I9LdOgRjVmYq!t&w-z1C4G7JaMePhTkWnZr$u*x+A2E5H8KcNfQiUlXp#s%v)y0B3F6IaLdOgSjVmYq!t*w-z1D4G7JbMeQhTkWoZr$u(x+B2E5H9KcNfRiUmXp#s&v)y0C3F6IaLdPgSjVnYq!t*w-A1D4G8JbMeQhTlWoZr%u(x+B2E6H9KcOf

26、RiUmXp!s&v)z0C3F7IaMdPgSkVnYq$t*x-A1D5G8JbNeQhTlWo#r%u(y+B2E6H9LcOfRjUmXp!s&w)z0C4F7IaMdPhSkVnZq$t*x-A2D5G8KbNeQiTlXo#r%v(y+B3E6I9LcOgRjUmYp!s&w)z1C4F7JaMdPhSkWnZq$u*x-A2D5H8KbNfQiTlXo#s%v(y0B3E6I9LdOgRjVmYp!t&w-z1C4G7JaMePhTkWnZr$u*x+A2E5H8KcNfQiUlXo#s%v)y0B3F6I9LdOgSjVmYq!t&w-z1D4G7JbMePhTkWoZr$u(

27、x+A2E5H9KcNfRiUlXp#s&v)y0C3F6IaLdPgSjVnYq!t*w-z1D4G8JbMeQhTkWoZr%u(x+B2E5H9KcOfRiUmXp#s&v)z0C3F7IaLdPgSkVnYq$t*w-A1D5G8JbNeQhTlWlWo#r%u(y+B2E6H9LcOfRjUmXp!s&w)z0C4F7IaMdPgSkVnZq$t*x-A1D5G8KbNeQiTlWo#r%v(y+B3E6H9LcOgRjUmYp!s&w)z1C4F7JaMdPhSkWnZq$u*x-A2D5H8KbNfQiTlXo#r%v(y0B3E6I9LcOgRjVmYp!t&w)z1C4G7J

28、aMePhSkWnZr$u*x+A2D5H8KcNfQiUlXo#s%v)y0B3F6I9LdOgSjVmYq!t&w-z1D4G7JbMePhTkWnZr$u(x+A2E5H8KcNfRiUlXp#s%v)y0C3F6IaLdOgSjVnYq!t*w-z1D4G8JbMeQhTkWoZr%u(x+B2E5H9KcOfRiUmXp#s&v)y0C3F7IaLdPgSjVnYq$t*w-A1D4G8JbNeQhTlWoZr%u(y+B2E6H9KcOfRjUmXp!s&v)z0C4F7IaMdPgSkVnZq$t*x-A1D5G8JbNeQiTlWo#r%u(y+B3E6H9LcOfRjUmYp

29、!s&w)z0C4F7JaMdPhSkVnZq$u*x-A2D5G8KbNfQiTlXo#r%v(y0B3E6I9LcOgRjVmYp!t&w)z1C4F7JaMePhSkWnZq$u*x+A2D5H8KbNfQiUlXo#s%v(y0B3F6I9LdOgRjVmYq!t&w-z1C4G7JbMePhTkWnZr$u(x+A2E5H8KcNfQiUlXp#s%v)y0B3F6IaLdOgSjVmYq!t*w-z1D4G7JbMeQhTkWoZr$u(x+B2E5H9KcNfRiUmXp#s&v)y0C3F7IaLdPgSjVnYq$t*w-A1D4G8JbMeQhTlWoZr%u(x+B2E6

30、H9KcOfRiUmXp!s&v)z0C3F7IaMdPgSkVnYq$t*x-A1D5G8JbNeQiTlWo#r%u(y+B3E6H9LcOfRjUmXp!s&w)z0C4F7IaMdPhSkVnZq$t*x-A2D5G8KbNeQiTlXo#r%v(y+B3E6I9LcOgRjUmYp!t&w)z1C4F7JaMePhPhSkWnZq$u*x+A2D5H8KbNfQiUlXo#s%v(y0B3E6I9LdOgRjVmYp!t&w-z1C4G7JaMePhTkWnZr$u*x+A2E5H8KcNfQiUlXp#s%v)y0B3F6IaLdOgSjVmYq!t*w-z1D4G7JbMePhT

31、kWoZr$u(x+A2E5H9KcNfRiUlXp#s&v)y0C3F6IaLdPgSjVnYq!t*w-A1D4G8JbMeQhTlWoZr%u(x+B2E6H9KcOfRiUmXp#s&v)z0C3F7IaLdPgSkVnYq$t*w-A1D5G8JbNeQhTlWo#r%u(y+B2E6H9LcOfRjUmXp!s&w)z0C4F7IaMdPhSkVnZq$t*x-A2D5G8KbNeQiTlWo#r%v(y+B3E6H9LcOgRjUmYp!s&w)z1C4F7JaMdPhSkWnZq$u*x-A2D5H8KbNfQiTlXo#s%v(y0B3E6I9LdOgRjVmYp!t&w)z

32、1C4G7JaMePhSkWnZr$u*x+A2D5H8KcNfQiUlXo#s%v)y0B3F6I9LdOgSjVmYq!t&w-z1D4G7JbMePhTkWoZr$u(x+A2E5H9KcNfRiUlXp#s%v)y0C3F6IaLdOgSjVnYq!t*w-z1D4G8JbMeQhTkWoZr%u(x+B2E5H9KcOfRiUmXp#s&v)z0C3F7IaLdPgSkVnYq$t*w-A1D4G8JbNeQhTlWoZr%u(y+B2E6H9KcOfRjUmXp!s&v)z0C4F7IaMdPgSkVnZq$t*x-A1D5G8KbNeQiTlWo#r%v(y+B3E6H9LcOf

33、RjUmYp!s&w)z0C4F7JaMdPhSkVnZq$u*x-A2D5G8KbNfQiTlXo#r%v(y0B3E6I9LcOgRjVmYp!t&w)z1C4G7JaMePhSkWnZr$u*u*x+A2D5H8KcNfQiUlXo#s%v(y0B3F6I9LdOgRjVmYq!t&w-z1C4G7JbMePhTkWnZr$u(x+A2E5H8KcNfRiUlXp#s%v)y0C3F6IaLdOgSjVnYq!t*w-z1D4G7JbMeQhTkWoZr$u(x+B2E5H9KcNfRiUmXp#s&v)y0C3F7IaLdPgSjVnYq$t*w-A1D4G8JbNeQhTlWoZr%

34、u(y+B2E6H9KcOfRjUmXp!s&v)z0C3F7IaMdPgSkVnYq$t*x-A1D5G8JbNeQiTlWo#r%u(y+B3E6H9LcOfRjUmYp!s&w)z0C4F7JaMdPhSkVnZq$u*x-A2D5G8KbNeQiTlXo#r%v(y+B3E6I9LcOgRjUmYp!t&w)z1C4F7JaMePhSkWnZq$u*x+A2D5H8KbNfQiUlXo#s%v(y0B3F6I9LdOgRjVmYq!t&w-z1C4G7JaMePhTkWnZr$u*x+A2E5H8KcNfQiUlXp#s%v)y0B3F6IaLdOgSjVmYq!t*w-z1D4G7J

35、bMeQhTkWoZr$u(x+B2E5H9KcNfRiUlXp#s&v)y0C3F6IaLdPgSjVnYq!t*w-A1D4G8JbMeQhTlWoZr%u(x+B2E6H9KcOfRiUmXp!s&v)z0C3F7IaMdPgSkVnYq$t*w-A1D5G8JbNeQhTlWo#r%u(y+B2E6H9LcOfRjUmXp!s&w)z0C4F7IaMdPhSkVnZq$t*x-A2D5G8KbNeQiTlXo#r%v(y+B3E6I9LcOgRjUmYp!s&w)z1C4F7JaMdPhSkWnZq$u*x-A2D5H8KbNfQiTlXo#s%v(y0B3E6I9LdOgRjVmYp

36、!t&w-z1C4G7JaMePhThTkWnZr$u*x+A2E5H8KcNfQiUlXp#s%v)y0B3F6I9LdOgSjVmYq!t&w-z1D4G7JbMePhTkWoZr$u(x+A2E5H9KcNfRiUlXp#s&v)y0C3F6IaLdPgSjVnYq!t*w-A1D4G8JbMeQhTkWoZr%u(x+B2E5H9KcOfRiUmXp#s&v)z0C3F7IaLdPgSkVnYq$t*w-A1D5G8JbNeQhTlWo#r%u(y+B2E6H9LcOfRjUmXp!s&v)z0C4F7IaMdPgSkVnZq$t*x-A1D5G8KbNeQiTlWo#r%v(y+B3

37、E6H9LcOgRjUmYp!s&w)z1C4F7JaMdPhSkWnZq$u*x-A2D5H8KbNfQiTlXo#r%v(y0B3E6I9LcOgRjVmYp!t&w)z1C4G7JaMePhSkWnZr$u*x+A2D5H8KcNfQiUlXo#s%v)y0B3F6I9LdOgSjVmYq!t&w-z1C4G7JbMePhTkWnZr$u(x+A2E5H8KcNfRiUlXp#s%v)y0C3F6IaLdOgSjVnYq!t*w-z1D4G8JbMeQhTkWoZr%u(x+B2E5H9KcNfRiRiUmXp#s&v)z0C3F7IaLdPgSjVnYq$t*w-A1D4G8JbNeQ

38、hTlWoZr%u(y+B2E6H9KcOfRjUmXp!s&v)z0C4F7IaMdPgSkVnZq$t*x-A1D5G8KbNeQiTlWo#r%u(y+B3E6H9LcOfRjUmYp!s&w)z0C4F7JaMdPhSkVnZq$u*x-A2D5G8KbNfQiTlXo#r%v(y0B3E6I9LcOgRjVmYp!t&w)z1C4G7JaMePhSkWnZq$u*x+A2D5H8KbNfQiUlXo#s%v(y0B3F6I9LdOgRjVmYq!t&w-z1C4G7JbMePhTkWnZr$u(x+A2E5H8KcNfRiUlXp#s%v)y0B3F6IaLdOgSjVmYq!t*w-z1D4G7JbMeQhTkWoZr$u(x+B2E5H9KcNfRiUmXp#s&v)y0C3F7IaLdP