膀胱尿道功能发育及尿失禁治疗的临床与基础研究
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摘要
背景和目的
下尿路障碍在成人和小儿均常见。全球超过2亿人因为下尿路功能障碍就医。其中下尿路功能障碍引起的尿失禁最常见。膀胱逼尿肌-外括约肌功能协同失调(Detrusor-Sphincter Dysfunction, DSD)是导致婴幼儿尿失禁,遗尿的常见原因。压力性尿失禁(Strss Urinary Incontinence, SUI)和膀胱过度活动症(Overactive Bladder, OAB)-急迫性尿失禁(Urge Urinary Incontinece, UUI)是成人尿失禁常见的类型其病理生理变化分别是尿道横纹肌括约肌缺损、盆底肌肉松弛和DSD。这些成人和小儿下尿路障碍疾病的病因绝大部分与下尿路肌肉病变有关,其中以下尿路横纹肌肉功能紊乱为主。为了更好地说明下尿路横纹肌对尿失禁为主的下尿路障碍的发病机制的作用,有必要知道下尿路横纹肌在新生儿的正常发育和功能发展过程。目前对新生儿排尿控尿模式的研究报道不多,很多基于4小时自由排尿观察。不完全排尿在新生儿排尿中比例很高,早产儿明显多于足月儿。代表生理性DSD间断排尿在新生儿中也较常见,但更多见于早产儿,这说明新生儿的尿道横纹括约肌控尿很不成熟。因此有必要对人体出生后早期阶段-新生儿期的排尿方式发展过程进行研究,从而为新生儿期排尿发育补充数据,也能更好追述成年后尿失禁发生的原因。
成人尿失禁主要有药品和手术治疗。OAB导致急迫性尿失禁患者目前主要是药物治疗,患者服用乙酰胆碱受体阻滞剂,如索利那新,托特罗定等。对于这类药物的疗效,有的报道服药后尿失禁症状有改善,有的报道患者无任何影响,有效与无效的比值,以及有效无效的标准,各个医疗中心报道不一致。并且这类药物对膀胱逼尿肌尿动力参数影响如何,国内少见报道。成人压力性尿失禁目前多采用手术治疗,如TVT/TVT-O手术。这个术后疗效如何,仍然是报道不一。因此我们对临床上OAB急迫性尿失禁患者服用索利那新12周的疗效和已行TVT/TVT-O手术的压力性尿失禁患者做了随访调查,发现M受体阻滞剂索利那新对大部分患者的OAB尿失禁状况有改善,但是仍然有部分患者无效。而压力性尿失禁的TVT/TVT-O手术治疗能缓解大部分患者的尿失禁,但仍然不能彻底解决尿失禁问题,并且很多患者自述有盆底慢性疼痛或者不适感,部分难治性尿失禁患者无任何治疗效果。还有其他研究人员报道了采用下尿路注射填充剂或者药物治疗压力性尿失禁,如尿道下牛胶原注射压力性尿失禁,A型肉毒毒素(Botulinum Toxin, BTX)治疗急迫性尿失禁等。这些治疗方法在短期的效果明显,但是长期效果差,并且有严重的并发症。目前,国际上热点的尿失禁的研究专注于再生修复受损尿横纹肌干细胞疗法或寻找细胞内新的药物分子靶点。
组胺是生物体合成的活性氨,是由组胺酸脱羧而形成的,主要在肥大细胞,嗜碱性细胞,肠道嗜铬细胞中合成,参与机体免疫,生化等功能。组胺到目前为止已经发现有4种受体(H1R, H2R, H3R, H4R)。国内外学者已经对组胺受体(Histamine Receptor) H1R和H2R研究多年,这两种受体是传统的组胺受体,它们对组胺的亲和力PK1分别为4.2和4.3。在平滑肌细胞,心肌细胞和骨骼肌组织中均发现这2种受体的表达,并检查出他们参与细胞的增殖和收缩。而本世纪初,研究者才开始关注到某些细胞浆中存在分子量为73kD的组胺前体存在。这种前体在某些细胞中的含量比传统的组胺合成细胞低100到1000倍。据推测这些细胞中存在某种正电荷转运蛋白(cation transporter protein, CTP)可以帮助某些能少量合成组胺及其前体的细胞淹着浓度梯度转运组胺或前体到细胞外。这些组胺的浓度很低,不可能去激活传统的组胺H1R, H2R受体。因此人们开始寻找组胺新的受体。近10年,一些研究细胞膜上G-蛋白偶联的跨膜蛋白受体的研究者发现了组胺新的受体,组胺H3R, H4R受体。这两种新型组胺受体对组胺亲和指数PK1值分别为8.0和8.2,对组胺的结合力相当于前2种传统受体的10000倍。进一步的研究,许多能少量合成组胺的非传统合成细胞被发现,比如树突细胞,淋巴细胞等。他们均存在新型的组胺受体。同时在中枢和周围神经细胞突出前膜发现了H3R广泛存在。肌肉细胞中也发现了传统和新型的组胺受体,如在支气管平滑肌细胞中发现了组胺H1R, H2R, H3R;在心肌细胞中发现了H1R, H2R, H3R;肠道平滑肌和膀胱逼尿肌细胞中H1R, H2R, H3R, H4R存在。国外许多研究者己大量研究了组胺传统和新型受体在细胞中的信号传导的报道。据研究发现,4种组胺受体均为G-蛋白偶联跨膜蛋白受体(G-coupled transmembrane receptor, GCTR),其中H1R和H2R与Gas亚基偶联,加强腺苷环化酶活性,增加细胞内第二信使环磷酸腺苷(Cyclic adenosine monophosphate, cAMP)的合成,增加PKA信号的传导和下游蛋白的磷酸化。H3R和H4R则与Gai亚基偶联,抑制腺苷环化酶(Adenlate cyclase,AC)的功能,降低细胞内第二信使cAMP的合成,抑制PKA信号的传导和下游蛋白的磷酸化。目前大量发现组胺新旧受体在其他器官的肌肉细胞中表达,我们开始研究组胺受体在成人尿道横纹肌括约肌和肌肉干细胞分化成横纹肌过程中的表达,进而探讨其在下尿路横纹肌中的功能和通路。
本研究目的在于首先在临床上调查出正常新生儿下尿道排尿控尿功能发育参数,然后检测了临床上药物治疗成人OAB-UUI及手术治疗SUI的大体疗效情况,再通过实验室测量组胺受体在成人下尿路肌肉组织及其肌肉干细胞分化过程中的表达,最后探讨H3R对收缩中肌肉细胞胞浆中钙离子浓度及其可能的细胞内信号通路,初步探讨出组胺受体在下尿路功能障碍疾病中的作用,从而为以后临床治疗下尿路障碍提供新的可能的细胞内药物靶位点或者组织工程学治疗方法。
第一部分新生儿控尿机制发育—新生儿期排尿功能发展研究材料和方法
选取21例,无病理疾病的单胎正常新生儿。足月儿10例,早产儿11例；每位新生儿均被观察其出生第1天,4天,7天,14天,28天12h连续自由排尿,记录排尿时间、每次排尿量,B超测量排尿后残余尿量,排尿时清醒睡眠状态。
结果
共记录排尿745次。足月儿和早产儿的排尿次数均在天龄第7天时明显多余第4天(P<0.05)。早产儿的排尿次数在第14天时开始下降,第28天次数明显低于第14天(P<0.05)。足月儿的排尿量在28天记录数据中,明显增加了两次,早产儿在这28天中增加了一次。足月儿的残余尿在28天内有波动。
足月儿在第14天和28天时,排尿次数明显少于早产儿(P<0.05)；但排尿量在第4,7,14,28天时,明显多于早产儿(P<0.05)；残余尿量在第4天,第28天时也明显多于早产儿(P<0.05)。不完全排空和间断排尿在早产儿中较足月儿多见。
第二部分控尿机制失调—成人尿失禁的药物、手术治疗效果评估
材料和方法
1.20例OAB患者服用膀胱逼尿肌M3受体阻滞剂索利那新治疗。男12例,女8例。年龄21-83岁,平均43岁。病程1-20年,平均8年。患者连续服用索利那新5mg/d12周。服药前后行尿动力学检查,观察膀胱逼尿肌功能变化、记录OABSS得分、感知膀胱症状量表(PPBC)评分,统计学比较治疗前后的差异。
2.选取已行TVT-O手术治疗0.5-3年的老年女性Ⅰ、Ⅱ型压力性尿失禁患者80例,术前年龄在60岁以上,采用ⅡQ-7生活质量和UDI-6症状量表进行电话问卷调查,比较患者术前术后日常生活与下尿路症状的差异。
结果
1.OAB患者治疗前后平均逼尿肌无抑制收缩波个数分别为2.3±2.4与0.6±1.3,差异有统计学意义(P<0.05)；其中6例患者服药后逼尿肌无抑制收缩完全消失。治疗前后膀胱初次排尿感容量(103士67ml与178±89m1)、膀胱容量(189士133ml与299士89m1)差异有统计学意义(P<0.01)；膀胱顺应性、最大尿流率时逼尿肌压力差异无统计学意义(P>0.05)。服药前后OABSS量表的尿急评分(5.0±0.0与2.8±2.0)、白天排尿评分(1.3±0.5与0.4±0.7)、夜尿评分(2.9±0.4与1.4±0.92)、尿失禁评分(3.3±2.1与1.6±2.1)、PPBC评分(5.5±0.5与2.9±1.6)差异均有统计学意义(P<0.05)。6例患者诉有口干现象。
2.73例压力性尿失禁患者随访成功,年龄(60-72)岁,平均(64±6.5)岁。术前患者做家务、活动、娱乐、外出、社交及情绪明显受到尿失禁症状影响,评分为(9-25)分,平均(17±6.7)分；下尿路症状尿急、尿频、运动、漏尿量、排尿困难及尿痛评分为(8～21)分,平均(14±4.7)分。轻度尿频8.2%(6/73).尿垫使用率为97.3%(71例)。11例患者诉排尿有耻骨上区不适。术后患者自评生活质量明显改善,日常生活评分(2～13)分,平均(6.4±3.2)分,下尿路症状评分(1～9)分,平均(5.4±3.2)分。轻度尿频1.4%(1/73)。39例(53.4%)患者尿失禁症状完全消失,尿垫使用率46.6%(34例)。18患者诉术后排尿有轻度耻骨上区不适。
第三部分组胺受体在尿道横纹肌和成肌分化过程中的表达
材料和方法
1.诱导横纹肌肉干细胞C2C12的成肌分化,标志物：早期标志物desmin,中期标志物myogenin,晚期标志物肌球蛋白重链；实时定量聚合酶链反应(PCR)测量分化标志物和组胺4种受体(H1R, H2R, H3R, H4R)的mRNA表达。免疫荧光染色各标志物和组胺H3受体(histamine H3receptor, H3R)
2.分化过程中,H3R拮抗剂Ciproxifan拮抗H3R受体6d,测量各标志物表达情况。
3.收集临床上因成年男性中段尿道横纹肌标本,选取尿道外括约肌(横纹肌)部分做石蜡包埋,石蜡切片,免疫组织化学染色组胺4种受体。
结果
1. H1R mRNA在未分化的C2C12干细胞中表达较高,但随着成肌分化,表达逐渐减低；H2R mRNA在肌源性干细胞及其分化中表达均较低,但比较稳定。H3R mRNA在肌源性干细胞中表达很低,但是随着成肌分化表达呈指数增加。免疫荧光染色发现H3R蛋白染色随着分化而荧光强度增加。H4R在肌源性干细胞及其成肌分化中均未检测出表达。
2.H3R阻滞剂Ciproxifan在分化过程中拮抗H3R,分化6天后,3种分化标志物表达与对照组相比,无差异(P>0.05)。
3.成人下尿路横纹肌的免疫组织化学染色发现HIR, H2R, H3R染色阳性,其中H1R阳性程度最强,H3R中度阳性,H2R弱阳性。
第四部分组胺H3R受体在横纹肌细胞收缩时对胞浆中钙离子的影响和可能的信号通路
材料和方法
1. Fluo-4标记的钙离子结合剂,测量双极交流电200mA刺激肌肉细胞时肌浆中钙离子的变化；H3R选择性激动剂a-甲基组胺(RMeHA)6种不同浓度(1nM,10nM,100nM,1uM,10uM,100uM)刺激在交流电下收缩的成熟肌肉细胞,测量收缩中钙离子浓度峰值的变化情况。
2.荧光标记H3R拮抗剂HT-1240追踪H3R在成熟横纹肌细胞的表达定位及该物质在细胞内运输过程
3.细胞环磷酸腺苷(cAMP)提升剂弗斯可林(forskolin)增加细胞内部cAMP表达；H3R激动剂RMeHA6种不同浓度(1nM,10nM,100nM,1uM,10uM,100uM)刺激成熟肌肉细胞,测量细胞表达cAMP的水平；
4.用H3R阻滞剂Ciproxifan预处理细胞,测量6种不同浓度的RMeHA刺激细胞后cAMP的表达情况。
结果
1. RMeHA浓度为10nM,100nM,1uM,10uM时,刺激5min,10min,20min均能明显降低胞浆中钙离子峰值(P<0.05),而浓度为100nM的RMeHA在10min,20min对电刺激细胞中Ca2+的抑制百分率最高。整体看来,同一浓度的RMeHA对Ca2+的抑制效果,在20min内,随着时间的增加而稍有增加,即在20min时所见到的抑制效果比在5min时有所增加低浓度H3R激动剂。RMeHA低浓度1nM,高浓度100uM,对收缩细胞胞浆中钙离子峰值均无明显影响(P>0.05)。
2. ST1240浓度越高,清洗细胞后,细胞内残存的荧光强度越高。
3.静息细胞的基础cAMP浓度很低,弗斯可林10uM可以明显提高细胞内cAMP的合成。RMeHA1nM时,对细胞内由FK提升的cAMP无影响。RMeHA浓度10nM,100nM,1uM时能降低由FK增加的cAMP合成(P<0.05),并随浓度增加,cAMP在细胞中浓度下降。RMeHA高浓度(10uM,100uM)时,RMeHA的抑制效果不明显,甚至有提升细胞cAMP的作用。
4.用CPF预处理细胞后,RMeHA在1nM时,对细胞内由FK提升的cAMP仍然无影响。但RMeHA浓度在10nM,100nM,1uM时候也能降低由FK增加的cAMP合成(P<0.05),并随RMeHA浓度增加,cAMP在细胞中浓度下降,与无处理组差别不大。RMeHA高浓度(10uM,100uM)时,RMeHA不出现抑制效果,而是有提升细胞cAMP的作用,并且比不处理组提高cAMP效果更明显(P<0.05)。
结论
1.新生儿期尿道横纹肌的发育主要表现在新生儿排尿模式的变化。间断排尿和不完全排空现象预示着膀胱-尿道括约肌(横纹肌)协同失调。在足月儿和早产儿中,可见间断排尿,而早产儿更常见。这预示着他们下尿路肌肉发育的成熟度很低导致排尿功能很不成熟,早产儿更显著。但是第28天时的新生儿的间断排尿明显少于出生后1天和4天的新生儿。总之,新生儿膀胱-尿道括约肌(横纹肌)协同失调的改善过程显示了尿道横纹肌在新生儿期逐渐发育的过程。
2.成人的尿道横纹肌功能紊乱导致的疾病主要是OAB引发的尿失禁和压力性尿失禁。膀胱逼尿肌M3受体阻滞剂索利那新药物治疗膀胱过度活动症在特发性OAB的病人有很大疗效,但是对一部分病人,比如膀胱-尿道括约肌协同失调的OAB-UUI患者病人效果不明显,甚至无效。TVT/TVT-O手术对因盆底肌肉松弛导致的压力性尿失禁有一定疗效,但是部分病人复发率和不适感明显。因此需要引入对尿失禁-下尿路障碍的新治疗理念,如组织工程学治疗或者新的药物细胞分子靶位点。
3.组胺受体在肌肉细胞的分化,成熟,功能,修复方面起到了十分重要的作用。在肌肉干细胞分化为横纹肌细胞过程中和成年男性尿道横纹肌中发现H1R, H2R和H3R。其中H1R受体可能参与细胞的增殖,H2R受体可能参与细胞胆碱能刺激后的松弛,H3R在成肌分化过程中没有发现参与分化功能,可能与成熟细胞的生理功能相关。
4.H1R和H2R这两个受体可能与G蛋白激动性亚基阿尔法相偶联,增加腺苷环化酶的活性。然而最重要的H3R可能与G蛋白抑制性亚基Gi/o相偶联,抑制腺苷环化酶,进而降低细胞内cAMP表达,抑制PKA通路,阻止肌膜上钙离子通道和肌浆网膜上钙离子通道磷酸化,从而阻止了钙离子从肌浆网中进入胞浆中,降低胞浆中的钙离子浓度,最终减低肌肉细胞的收缩作用,维持细胞的损伤修复,再生,抗疲劳等作用。
Background
Over200million adults worldwide are suffering from striated muscle dysfunction of lower urinary tract. The most common disease is urinary incontinence, to which in children, detrusor (smooth muscle)-sphincter (skeletal muscle) dyssynergia contributes most, while in adult, mainly two types, urgency urinary incontinence (SUI) or/and stress urinary incontinence (SUI) contribute absolutely most. UUI are common both in female and male patients suffered from detrusor (bladder smooth muslce) overactivity or overactive bladder (OAB); while the pathogenesis of SUI is the atrophy of pelvic muscles and/or midurethral sphincter (striated muscles) in female patients and the damage to midurethral sphincter (striated muscles) in male patients.
To better understand the role of the developing striated muscle cells in urinary incontinence we studied a group of healthy full term and preterm newborns without any urinary pathogenesis findings. In newborns' urinary incontinence, detrusor (smooth muscle)-sphincter (striated muscle) dyssynergia contributes most to urinary incontinence and the frequent interrupted voiding which also suggests detrusor-sphincter dyssynergia is more common in preterms than full terms, which proved the less mature function of mid-urethral striated muscle cells in preterm. In all, the bladder-mid-urethral sphincter striated muscles dyssynergia contributes to urinary incontinence in normal newborns, which shows the maturation process of mid-urethral striated muscles during neonatal period.
Attempts to treat OAB with pharmaceuticals in adults, we have applied acetylcholine blockers Solifenancin, and short-term (12weeks) success has been achieved in most patients, but there were still a minority of patients without any effect. In addition, the long-term effects are unknown. We have also investigated the effects of TVT/TVT-O surgery to the patients, but it is invasive with unexpected post-operation adverse effects and some refractory incontinence without any effects. Other researchers found short-term success with injectable bulking agents such as bovine collagen to urethral treating SUI or/and injecting botulinum toxin A (BTX) to bladder treating UUI. However, long-term complications of these treatments are severe. Currently, the most promising incontinence research is being focused on regenerative repair of damaged urinary striated muscles with stem cell therapy or new molecular targets.
The myoblast is a type of progenitor cell that gives rise to muscle cells (myocytes). Myoblasts can be isolated from e.g. skeletal muscle tissues, the most common and numerous sources. And myoblasts originated from skeletal muscle tissues can be spontaneous differentiation into skeletal muscle cells (striated muscle cells), cardiac muscle cells (striated muscle cells), trans-differentiation into smooth muscle by inhibition of DNA methylation, and other mesenchymal cells (eg, bone cells, lipid cells) by their special differentiation cocktails. Treatment with differentiation cocktails can be performed in vitro or in situ, in vivo, if the molecular inducers are introduced locally e.g. in nanoparticles. Or, other new medicine molecular targets, such as receptors on the membrane or in the cells may be found during differentiation.
Histamine is a well-known biogenic, cationic amine synthesized, stored and released by professional histamine synthesizing cells. Mast cells, basophils and enterochromaffin cells contain an endoplasmic54kD histidine decarboxylase, which effectively converts L-histidine to histamine, which is released to and stored in storage granules, subjected to regulated release. Upon activation of the professional histamine producing cells, a burst release follows leading to a transient but very high histamine concentration in the extracellular space. These histamine concentrations are high enough to stimulate the conventional histamine receptors, histamine receptor type1(H1R, pKl for histamine is4.2) and histamine receptor type2(H2R, pKl for histamine is4.3). For example, smooth muscle cells, cardiomyocytes and skeletal muscle tissue have such conventional histamine receptors, which regulate the cellular proliferation and contraction state of the cells stimulated via the histamine/HIR or H2R axis.
Before the beginning of the millennium, it was noticed that the cytoplamic73kD "pro-form" of HDC produces histamine, albeit at a100-1,000-fold lower rate as the enzyme isoform typical for the professional histamine synthesizing cells. In the non-professional histamine producing cells histamine is released to the cellular cytoplasm. Therefore, it is not stored and not subjected to regulated burst release. Instead, such cells contain organic cation transporters, which are equilibrative uniporters, which transport the intracellularly synthesized histamine from the non-professional histamine synthesizing cells along the histamine concentration gradient, to the extracellular space. Histamine concentrations achieved in this way are all too low to stimulate the conventional histamine receptors, that it was first thought that this only represents perhaps an ancestral vestigium of a function that had become obsolete during phylogenesis. However studies in the last decade focusing on G-protein coupled receptors revealed, until then unknown, new members of the histamine receptor family. These novel histamine receptors, histamine receptor type3(H3R, pKi for histamine is8.0) and histamine receptor type4(H4R, pKi for histamine is8.2), have over10,000-fold higher affinity for histamine than the conventional receptors. It has become clear that the low basal levels of histamine, produced by various non-professional histamine producing cells, such as dendritic cells and lymphocytes, are enough to bind to and regulate cells equipped with the novel, high affinity histamine receptors. The role of high-dose histamine in the regulation of muscle cell tone was already mentioned. Findings using histamine receptor agonists and/or antagonists have suggested that also novel histamine receptors may be present and functional in at least the bronchial smooth muscle cells. In addition, histamine receptors (H1R, H2R, H3R and H4R) were also found in situ bladder tissue and in vitro cultured bladder smooth muscle cells. Histamine receptors have been found to contribute to the bladder smooth muscle dysfunction. However, what role the histamine receptors play in the urinary striated cells, hence how histamine receptors may influence the function of low urinary tract, there are no reports at present. Due to the presence and role of H1R, H2R and H3R for the function of other types of muscle cells, we aim to check the histamine receptors at different stages of striated myogenesis, and to test if H3R may couple to the Gi/o proteins, lead to inhibition of the formation of cyclic AMP and decrease of sarcoplasmic Ca2+, which help skeletal muscle relaxation and regeneration. Then we may get pilot comments about the probable role of histamine receptors may play at the low urinary striated muscle dysfunction diseases.
Our objective is to study the development of voiding function of the low urinary striated muscles in the newborns, the therapeutic efficacy of the current treatments for adult urinary incontinence in clinical practice, then to check expression, function and possible intracellular signal way of histamine receptors on striated myogenesis and the mature striated muscle cells in the bench, all of which may help us find pilot evidence for cellular therapies and/or new medical molecular-receptors targets for the treatment of urinary incontinence.
Part I:The development of voiding pattern in newborns less than4weeks of age
Methods:
Twenty-one healthy newborns aged from day1to28were included (10full-terms,11pre-terms). The12h free voiding parameters were recorded at day1,4,7,14and28after birth, respectively.
Results:
Altogether778voidings were recorded. Voiding frequency (VF) increased in both the full-term and pre-term newborns between day4and7, and decreased in pre-terms between day14and28. Voiding volume (W) increased twice in full-terms and once in pre-terms. Post-voiding residual volumes (PRV) fluctuated in the full-terms. VF in the full-terms was lower at day14and28compared to the pre-terms. W was higher in the full-terms than the pre-terms at days4,7,14, and28. PRV was also higher at day4and28. Interrupted voiding was more seen in the pre-terms.
Part II The treatment effcacy of adult urinary incontinence Patients and methods
1. A total of20OAB out-patients with1-30(mean8.5±9.96) years medical history,12males and8females, aged21-83(mean42.9±20.38) were included in this study. They were given5mg solifenacin orally once daily for12weeks. Before and after treatment, overactive bladder symptom score (OABSS), patient perception of bladder condition symptoms rating scale (PPBC), filling cystometry obout detrusor and adverse events were evaluated.
2. Select80cases of elderly female patients with I, II-type stress urinary incontinence, who had TVT-O surgical treatment0.5-3years before investigation, and age over60years before TVT-O. Compare daily life and lower urinary tract symptoms difference before and after surgery in patients by IIQ-7and UDI-6through telephone survey.
Result
1. Before and after solifenacin medication, significant changes are found in the detrusor overactivity waves were (2.29±2.35)VS(0.64±1.33)(P<0.05); detrusor overactivity (DO) disappeared in six patients (15VS9). Bladder capacities at first desire to void and maximum bladder capacity were significantly increased (P<0.01).Bladder compliance and detrusor pressure when maximum urine flow had no statistical difference (P>0.05). All patients had significant improvements of OAB symptoms in OABSS and PPBC (P<0.05). Six patients had mild side effect of dry mouth and could overcome by drinking more.
2.73patients were followed up successfully, aged60to72years old, mean64±4.5years. Preoperatively patients' daily life quality as making household chores, activities, entertainment, meals, social and emotional has obviously been affected as the scores from9to25by their own scoring, mean17±6.7;and Lower urinary tract symptoms of urgency, frequent urination, movement, leakage of urine volume, voiding difficulty and dysuria scores are from8to21, mean14±4.7. Mild urinary frequency was8.2%(6/73). Urinal pad usage was71(97.3%). After TVT-O, patients felt improved by their own scoring. The daily life quality scores were ranging from2to13, mean6.4±3.2, and lower urinary tract symptoms from1to9, mean5.4±3.2. Mild urinary frequency after surgery was1.4%(1/73).39cases were completely dry (53.4%); urinal pad usage was34(46.6%).11cases occasionally had voiding suprapubic area pain or discomfort postoperatively.
Part III The expression of Histamine receptors during striated myogenesis and adult mid-urethral striated muscles
Methods
1. Myogenesis of C2C12skeletal myoblasts was followed using desmin, myogenin and myosin heavy chain (MHC) as early, intermediate and late differentiation markers, respectively. Quantitative real time-polymerase chain reaction was used to measure HR-subtype-mRNA with markers. H3R-protein was immunostained with markers.
2. One group of myoblasts was under incubation by H3R antagonist Ciproxifan10uM during differentiaton for6days to check if H3R was functional during differentiation.
3. Mid-urethral striated muscle samples from five adults, who bear the resection of prostate, are immunostained with HR-subtype-protein.
Results
1. H1R-mRNA was high in myoblasts, but then decreased, H2R remained rather constant and H3R-mRNA increased28-,103-and198-fold at days2,4and6, respectively. MHC increased7,718-,94,487-and286,288-fold over the baseline day0values. H3R-protein was weakly stained at day2but strongly stained in day4-6cells.
2. Myoblasts under Ciproxifan incubation for6days has no influence on the striated myogenesis markers.
3. In the adult mid-urethral striated muscle samples, H1R was found very strong staining, H3R is moderate strong staining and H2R is stained weak.
Part V The function of H3R in mature muscle cells and its possible subcellular signal way
Methods
1. Cultured and differentiated C2C12myoblasts on the18mm round glass coverslips for6days. Loaded cells with4μmol/L Fluo-4calcium indicator dye and transferred to recording chamber with electrodes for field stimulation and maintained at+37℃while imaging. Ca2+imaging was conducted and recorded at50frames per second by camera. The samples were electrically paced at a frequency of0.5Hz with10ms bipolar pulses (200mA). Record the basal cytoplasma calcium and the calcium under the electrical stimulation, then check the calcium changes under the stimulation of6different concentration (1nM,10nM,100nM,1uM,10uM,100uM) of H3R agonist, R-a-methylhistamine (RMeHA)with time under electrically paced.
2. Check how the cells internalized the H3R modulators and where H3R was on the cells by fluorescence labled H3R antagonist ST-1240with different concentration.
3. Load differentiated cells with2.5μCi/ml3H-adenine to check the cAMP while under the stimulation of Forskolin alone. Check cAMP under the stimulation of Forskolin plus6different concentration (1nM,10nM,100nM,1uM,10uM,100uM) of RMeHA.
4. Pretreated cells with H3R antagonist, Ciproxifan, then repeat to check cAMP by Forskolin plus6different concentration (1nM,10nM,100nM,1uM,10uM,100uM) of RMeHA.
Results
1. In C2C12mytubes, H3R agonist, RMeHA can diminished cytoplasma calcium peak when cells are electrically paced.
2. H3R gathered on the surface of myotubes and the cells can internalize H3R antagonist, Ciproxifan into cells.
3. RMeHA was not strict selective H3R agonist, and its low concentration can stimulate H3R to diminished cAMP gently and higher concentration (over1uM) can stimulate H1R or H2R to increase cAMP in the cells.
4. When the myotubes were pretreated by H3R antagonist, Ciproxifan, low concentration of H3R (0,1,1and10nM) can also diminished cAMP and higher concentration (over1uM) can greatly stimulate H1R or H2R to increase cAMP.
Conclusion
1. The development of voiding patterns in newborns suggests the mature process of urethral striated muscle in neonatal period. Voiding pattern in newborns has shown very common unconscious voidings in the very beginning of life, which more like'normal neonate incontience'. In newborns'unconscious voidings, detrusor (smooth muscle)-sphincter (striated muscle) dyssynergia, which represented by the frequent interrupted voidings both in preterms and full terms, contributes most to this type of normal urinary incontinence, which proved the weak mature function of mid-urethral striated muscle cells in newborns. In all, the bladder-mid-urethral sphincter striated muscles dyssynergia contributes to'urinary incontinence' in normal newborns, which shows the maturation process of mid-urethral striated muscles during neonatal period.
2. The dysfunction of urethral striated muscles in adults is presented by adult OAB and stress incontinence. In clinical practice at present, Solifenacin urodynamically decreases the overactivity of detrusor, increases bladder capacity and improves life quality in parts of symptomatic OAB patients. Some patients without improvement may seak other methods. TVT/TVT-O surgery is effective to some patients suffered from SUI resulting from the prolapse of pelvic striated muscles within five years. But some SUI patients is still high relapse and obvious discomfort, and the long-term effects is still unclear. So it is necessity to seek new therapy or new medical molecular targets
3. Histamine subtypes, such as H1R, H2R, and H3R are found during striated myogenesis and also the adult urethral striated cells. And H3R antagonist, Ciproxifan has no influence on the myogenic differentiation. This and earlier findings suggest a role for H1R in the regulation of progenitor cell mitogenesis, H2R in the relaxation of acetylcholine-stimulated contraction of the muscle cells, when professional histamine producing cells, e.g. mast cells, are activated.
4. H1R and H2R may be coupled with Ga protein and increase the adenylyl cyclase (AC) activiry. In contrast, H3R may be coupled with Gi/o protein in skeletal muscle cells that it may inhibit adenylyl cyclase, decrease cAMP, inhibit PKA signal way, calcium channels on the membrane of sarcoplasmic reticulum (SR), decrease cytoplasmic Ca2+, hence, H3R would seems to participate in the regulation of specialized myocyte functions, perhaps the maintenance of its relaxed state under the influence of constitutive H3R activity and low histamine concentrations locally produced/released by non-professional histamine producing cells.
下尿路障碍在成人和小儿均常见。全球超过2亿人因为下尿路功能障碍就医。其中下尿路功能障碍引起的尿失禁最常见。膀胱逼尿肌-外括约肌功能协同失调(Detrusor-Sphincter Dysfunction, DSD)是导致婴幼儿尿失禁,遗尿的常见原因。压力性尿失禁(Strss Urinary Incontinence, SUI)和膀胱过度活动症(Overactive Bladder, OAB)-急迫性尿失禁(Urge Urinary Incontinece, UUI)是成人尿失禁常见的类型其病理生理变化分别是尿道横纹肌括约肌缺损、盆底肌肉松弛和DSD。这些成人和小儿下尿路障碍疾病的病因绝大部分与下尿路肌肉病变有关,其中以下尿路横纹肌肉功能紊乱为主。为了更好地说明下尿路横纹肌对尿失禁为主的下尿路障碍的发病机制的作用,有必要知道下尿路横纹肌在新生儿的正常发育和功能发展过程。目前对新生儿排尿控尿模式的研究报道不多,很多基于4小时自由排尿观察。不完全排尿在新生儿排尿中比例很高,早产儿明显多于足月儿。代表生理性DSD间断排尿在新生儿中也较常见,但更多见于早产儿,这说明新生儿的尿道横纹括约肌控尿很不成熟。因此有必要对人体出生后早期阶段-新生儿期的排尿方式发展过程进行研究,从而为新生儿期排尿发育补充数据,也能更好追述成年后尿失禁发生的原因。
成人尿失禁主要有药品和手术治疗。OAB导致急迫性尿失禁患者目前主要是药物治疗,患者服用乙酰胆碱受体阻滞剂,如索利那新,托特罗定等。对于这类药物的疗效,有的报道服药后尿失禁症状有改善,有的报道患者无任何影响,有效与无效的比值,以及有效无效的标准,各个医疗中心报道不一致。并且这类药物对膀胱逼尿肌尿动力参数影响如何,国内少见报道。成人压力性尿失禁目前多采用手术治疗,如TVT/TVT-O手术。这个术后疗效如何,仍然是报道不一。因此我们对临床上OAB急迫性尿失禁患者服用索利那新12周的疗效和已行TVT/TVT-O手术的压力性尿失禁患者做了随访调查,发现M受体阻滞剂索利那新对大部分患者的OAB尿失禁状况有改善,但是仍然有部分患者无效。而压力性尿失禁的TVT/TVT-O手术治疗能缓解大部分患者的尿失禁,但仍然不能彻底解决尿失禁问题,并且很多患者自述有盆底慢性疼痛或者不适感,部分难治性尿失禁患者无任何治疗效果。还有其他研究人员报道了采用下尿路注射填充剂或者药物治疗压力性尿失禁,如尿道下牛胶原注射压力性尿失禁,A型肉毒毒素(Botulinum Toxin, BTX)治疗急迫性尿失禁等。这些治疗方法在短期的效果明显,但是长期效果差,并且有严重的并发症。目前,国际上热点的尿失禁的研究专注于再生修复受损尿横纹肌干细胞疗法或寻找细胞内新的药物分子靶点。
组胺是生物体合成的活性氨,是由组胺酸脱羧而形成的,主要在肥大细胞,嗜碱性细胞,肠道嗜铬细胞中合成,参与机体免疫,生化等功能。组胺到目前为止已经发现有4种受体(H1R, H2R, H3R, H4R)。国内外学者已经对组胺受体(Histamine Receptor) H1R和H2R研究多年,这两种受体是传统的组胺受体,它们对组胺的亲和力PK1分别为4.2和4.3。在平滑肌细胞,心肌细胞和骨骼肌组织中均发现这2种受体的表达,并检查出他们参与细胞的增殖和收缩。而本世纪初,研究者才开始关注到某些细胞浆中存在分子量为73kD的组胺前体存在。这种前体在某些细胞中的含量比传统的组胺合成细胞低100到1000倍。据推测这些细胞中存在某种正电荷转运蛋白(cation transporter protein, CTP)可以帮助某些能少量合成组胺及其前体的细胞淹着浓度梯度转运组胺或前体到细胞外。这些组胺的浓度很低,不可能去激活传统的组胺H1R, H2R受体。因此人们开始寻找组胺新的受体。近10年,一些研究细胞膜上G-蛋白偶联的跨膜蛋白受体的研究者发现了组胺新的受体,组胺H3R, H4R受体。这两种新型组胺受体对组胺亲和指数PK1值分别为8.0和8.2,对组胺的结合力相当于前2种传统受体的10000倍。进一步的研究,许多能少量合成组胺的非传统合成细胞被发现,比如树突细胞,淋巴细胞等。他们均存在新型的组胺受体。同时在中枢和周围神经细胞突出前膜发现了H3R广泛存在。肌肉细胞中也发现了传统和新型的组胺受体,如在支气管平滑肌细胞中发现了组胺H1R, H2R, H3R;在心肌细胞中发现了H1R, H2R, H3R;肠道平滑肌和膀胱逼尿肌细胞中H1R, H2R, H3R, H4R存在。国外许多研究者己大量研究了组胺传统和新型受体在细胞中的信号传导的报道。据研究发现,4种组胺受体均为G-蛋白偶联跨膜蛋白受体(G-coupled transmembrane receptor, GCTR),其中H1R和H2R与Gas亚基偶联,加强腺苷环化酶活性,增加细胞内第二信使环磷酸腺苷(Cyclic adenosine monophosphate, cAMP)的合成,增加PKA信号的传导和下游蛋白的磷酸化。H3R和H4R则与Gai亚基偶联,抑制腺苷环化酶(Adenlate cyclase,AC)的功能,降低细胞内第二信使cAMP的合成,抑制PKA信号的传导和下游蛋白的磷酸化。目前大量发现组胺新旧受体在其他器官的肌肉细胞中表达,我们开始研究组胺受体在成人尿道横纹肌括约肌和肌肉干细胞分化成横纹肌过程中的表达,进而探讨其在下尿路横纹肌中的功能和通路。
本研究目的在于首先在临床上调查出正常新生儿下尿道排尿控尿功能发育参数,然后检测了临床上药物治疗成人OAB-UUI及手术治疗SUI的大体疗效情况,再通过实验室测量组胺受体在成人下尿路肌肉组织及其肌肉干细胞分化过程中的表达,最后探讨H3R对收缩中肌肉细胞胞浆中钙离子浓度及其可能的细胞内信号通路,初步探讨出组胺受体在下尿路功能障碍疾病中的作用,从而为以后临床治疗下尿路障碍提供新的可能的细胞内药物靶位点或者组织工程学治疗方法。
第一部分新生儿控尿机制发育—新生儿期排尿功能发展研究材料和方法
选取21例,无病理疾病的单胎正常新生儿。足月儿10例,早产儿11例；每位新生儿均被观察其出生第1天,4天,7天,14天,28天12h连续自由排尿,记录排尿时间、每次排尿量,B超测量排尿后残余尿量,排尿时清醒睡眠状态。
结果
共记录排尿745次。足月儿和早产儿的排尿次数均在天龄第7天时明显多余第4天(P<0.05)。早产儿的排尿次数在第14天时开始下降,第28天次数明显低于第14天(P<0.05)。足月儿的排尿量在28天记录数据中,明显增加了两次,早产儿在这28天中增加了一次。足月儿的残余尿在28天内有波动。
足月儿在第14天和28天时,排尿次数明显少于早产儿(P<0.05)；但排尿量在第4,7,14,28天时,明显多于早产儿(P<0.05)；残余尿量在第4天,第28天时也明显多于早产儿(P<0.05)。不完全排空和间断排尿在早产儿中较足月儿多见。
第二部分控尿机制失调—成人尿失禁的药物、手术治疗效果评估
材料和方法
1.20例OAB患者服用膀胱逼尿肌M3受体阻滞剂索利那新治疗。男12例,女8例。年龄21-83岁,平均43岁。病程1-20年,平均8年。患者连续服用索利那新5mg/d12周。服药前后行尿动力学检查,观察膀胱逼尿肌功能变化、记录OABSS得分、感知膀胱症状量表(PPBC)评分,统计学比较治疗前后的差异。
2.选取已行TVT-O手术治疗0.5-3年的老年女性Ⅰ、Ⅱ型压力性尿失禁患者80例,术前年龄在60岁以上,采用ⅡQ-7生活质量和UDI-6症状量表进行电话问卷调查,比较患者术前术后日常生活与下尿路症状的差异。
结果
1.OAB患者治疗前后平均逼尿肌无抑制收缩波个数分别为2.3±2.4与0.6±1.3,差异有统计学意义(P<0.05)；其中6例患者服药后逼尿肌无抑制收缩完全消失。治疗前后膀胱初次排尿感容量(103士67ml与178±89m1)、膀胱容量(189士133ml与299士89m1)差异有统计学意义(P<0.01)；膀胱顺应性、最大尿流率时逼尿肌压力差异无统计学意义(P>0.05)。服药前后OABSS量表的尿急评分(5.0±0.0与2.8±2.0)、白天排尿评分(1.3±0.5与0.4±0.7)、夜尿评分(2.9±0.4与1.4±0.92)、尿失禁评分(3.3±2.1与1.6±2.1)、PPBC评分(5.5±0.5与2.9±1.6)差异均有统计学意义(P<0.05)。6例患者诉有口干现象。
2.73例压力性尿失禁患者随访成功,年龄(60-72)岁,平均(64±6.5)岁。术前患者做家务、活动、娱乐、外出、社交及情绪明显受到尿失禁症状影响,评分为(9-25)分,平均(17±6.7)分；下尿路症状尿急、尿频、运动、漏尿量、排尿困难及尿痛评分为(8～21)分,平均(14±4.7)分。轻度尿频8.2%(6/73).尿垫使用率为97.3%(71例)。11例患者诉排尿有耻骨上区不适。术后患者自评生活质量明显改善,日常生活评分(2～13)分,平均(6.4±3.2)分,下尿路症状评分(1～9)分,平均(5.4±3.2)分。轻度尿频1.4%(1/73)。39例(53.4%)患者尿失禁症状完全消失,尿垫使用率46.6%(34例)。18患者诉术后排尿有轻度耻骨上区不适。
第三部分组胺受体在尿道横纹肌和成肌分化过程中的表达
材料和方法
1.诱导横纹肌肉干细胞C2C12的成肌分化,标志物：早期标志物desmin,中期标志物myogenin,晚期标志物肌球蛋白重链；实时定量聚合酶链反应(PCR)测量分化标志物和组胺4种受体(H1R, H2R, H3R, H4R)的mRNA表达。免疫荧光染色各标志物和组胺H3受体(histamine H3receptor, H3R)
2.分化过程中,H3R拮抗剂Ciproxifan拮抗H3R受体6d,测量各标志物表达情况。
3.收集临床上因成年男性中段尿道横纹肌标本,选取尿道外括约肌(横纹肌)部分做石蜡包埋,石蜡切片,免疫组织化学染色组胺4种受体。
结果
1. H1R mRNA在未分化的C2C12干细胞中表达较高,但随着成肌分化,表达逐渐减低；H2R mRNA在肌源性干细胞及其分化中表达均较低,但比较稳定。H3R mRNA在肌源性干细胞中表达很低,但是随着成肌分化表达呈指数增加。免疫荧光染色发现H3R蛋白染色随着分化而荧光强度增加。H4R在肌源性干细胞及其成肌分化中均未检测出表达。
2.H3R阻滞剂Ciproxifan在分化过程中拮抗H3R,分化6天后,3种分化标志物表达与对照组相比,无差异(P>0.05)。
3.成人下尿路横纹肌的免疫组织化学染色发现HIR, H2R, H3R染色阳性,其中H1R阳性程度最强,H3R中度阳性,H2R弱阳性。
第四部分组胺H3R受体在横纹肌细胞收缩时对胞浆中钙离子的影响和可能的信号通路
材料和方法
1. Fluo-4标记的钙离子结合剂,测量双极交流电200mA刺激肌肉细胞时肌浆中钙离子的变化；H3R选择性激动剂a-甲基组胺(RMeHA)6种不同浓度(1nM,10nM,100nM,1uM,10uM,100uM)刺激在交流电下收缩的成熟肌肉细胞,测量收缩中钙离子浓度峰值的变化情况。
2.荧光标记H3R拮抗剂HT-1240追踪H3R在成熟横纹肌细胞的表达定位及该物质在细胞内运输过程
3.细胞环磷酸腺苷(cAMP)提升剂弗斯可林(forskolin)增加细胞内部cAMP表达；H3R激动剂RMeHA6种不同浓度(1nM,10nM,100nM,1uM,10uM,100uM)刺激成熟肌肉细胞,测量细胞表达cAMP的水平；
4.用H3R阻滞剂Ciproxifan预处理细胞,测量6种不同浓度的RMeHA刺激细胞后cAMP的表达情况。
结果
1. RMeHA浓度为10nM,100nM,1uM,10uM时,刺激5min,10min,20min均能明显降低胞浆中钙离子峰值(P<0.05),而浓度为100nM的RMeHA在10min,20min对电刺激细胞中Ca2+的抑制百分率最高。整体看来,同一浓度的RMeHA对Ca2+的抑制效果,在20min内,随着时间的增加而稍有增加,即在20min时所见到的抑制效果比在5min时有所增加低浓度H3R激动剂。RMeHA低浓度1nM,高浓度100uM,对收缩细胞胞浆中钙离子峰值均无明显影响(P>0.05)。
2. ST1240浓度越高,清洗细胞后,细胞内残存的荧光强度越高。
3.静息细胞的基础cAMP浓度很低,弗斯可林10uM可以明显提高细胞内cAMP的合成。RMeHA1nM时,对细胞内由FK提升的cAMP无影响。RMeHA浓度10nM,100nM,1uM时能降低由FK增加的cAMP合成(P<0.05),并随浓度增加,cAMP在细胞中浓度下降。RMeHA高浓度(10uM,100uM)时,RMeHA的抑制效果不明显,甚至有提升细胞cAMP的作用。
4.用CPF预处理细胞后,RMeHA在1nM时,对细胞内由FK提升的cAMP仍然无影响。但RMeHA浓度在10nM,100nM,1uM时候也能降低由FK增加的cAMP合成(P<0.05),并随RMeHA浓度增加,cAMP在细胞中浓度下降,与无处理组差别不大。RMeHA高浓度(10uM,100uM)时,RMeHA不出现抑制效果,而是有提升细胞cAMP的作用,并且比不处理组提高cAMP效果更明显(P<0.05)。
结论
1.新生儿期尿道横纹肌的发育主要表现在新生儿排尿模式的变化。间断排尿和不完全排空现象预示着膀胱-尿道括约肌(横纹肌)协同失调。在足月儿和早产儿中,可见间断排尿,而早产儿更常见。这预示着他们下尿路肌肉发育的成熟度很低导致排尿功能很不成熟,早产儿更显著。但是第28天时的新生儿的间断排尿明显少于出生后1天和4天的新生儿。总之,新生儿膀胱-尿道括约肌(横纹肌)协同失调的改善过程显示了尿道横纹肌在新生儿期逐渐发育的过程。
2.成人的尿道横纹肌功能紊乱导致的疾病主要是OAB引发的尿失禁和压力性尿失禁。膀胱逼尿肌M3受体阻滞剂索利那新药物治疗膀胱过度活动症在特发性OAB的病人有很大疗效,但是对一部分病人,比如膀胱-尿道括约肌协同失调的OAB-UUI患者病人效果不明显,甚至无效。TVT/TVT-O手术对因盆底肌肉松弛导致的压力性尿失禁有一定疗效,但是部分病人复发率和不适感明显。因此需要引入对尿失禁-下尿路障碍的新治疗理念,如组织工程学治疗或者新的药物细胞分子靶位点。
3.组胺受体在肌肉细胞的分化,成熟,功能,修复方面起到了十分重要的作用。在肌肉干细胞分化为横纹肌细胞过程中和成年男性尿道横纹肌中发现H1R, H2R和H3R。其中H1R受体可能参与细胞的增殖,H2R受体可能参与细胞胆碱能刺激后的松弛,H3R在成肌分化过程中没有发现参与分化功能,可能与成熟细胞的生理功能相关。
4.H1R和H2R这两个受体可能与G蛋白激动性亚基阿尔法相偶联,增加腺苷环化酶的活性。然而最重要的H3R可能与G蛋白抑制性亚基Gi/o相偶联,抑制腺苷环化酶,进而降低细胞内cAMP表达,抑制PKA通路,阻止肌膜上钙离子通道和肌浆网膜上钙离子通道磷酸化,从而阻止了钙离子从肌浆网中进入胞浆中,降低胞浆中的钙离子浓度,最终减低肌肉细胞的收缩作用,维持细胞的损伤修复,再生,抗疲劳等作用。
Background
Over200million adults worldwide are suffering from striated muscle dysfunction of lower urinary tract. The most common disease is urinary incontinence, to which in children, detrusor (smooth muscle)-sphincter (skeletal muscle) dyssynergia contributes most, while in adult, mainly two types, urgency urinary incontinence (SUI) or/and stress urinary incontinence (SUI) contribute absolutely most. UUI are common both in female and male patients suffered from detrusor (bladder smooth muslce) overactivity or overactive bladder (OAB); while the pathogenesis of SUI is the atrophy of pelvic muscles and/or midurethral sphincter (striated muscles) in female patients and the damage to midurethral sphincter (striated muscles) in male patients.
To better understand the role of the developing striated muscle cells in urinary incontinence we studied a group of healthy full term and preterm newborns without any urinary pathogenesis findings. In newborns' urinary incontinence, detrusor (smooth muscle)-sphincter (striated muscle) dyssynergia contributes most to urinary incontinence and the frequent interrupted voiding which also suggests detrusor-sphincter dyssynergia is more common in preterms than full terms, which proved the less mature function of mid-urethral striated muscle cells in preterm. In all, the bladder-mid-urethral sphincter striated muscles dyssynergia contributes to urinary incontinence in normal newborns, which shows the maturation process of mid-urethral striated muscles during neonatal period.
Attempts to treat OAB with pharmaceuticals in adults, we have applied acetylcholine blockers Solifenancin, and short-term (12weeks) success has been achieved in most patients, but there were still a minority of patients without any effect. In addition, the long-term effects are unknown. We have also investigated the effects of TVT/TVT-O surgery to the patients, but it is invasive with unexpected post-operation adverse effects and some refractory incontinence without any effects. Other researchers found short-term success with injectable bulking agents such as bovine collagen to urethral treating SUI or/and injecting botulinum toxin A (BTX) to bladder treating UUI. However, long-term complications of these treatments are severe. Currently, the most promising incontinence research is being focused on regenerative repair of damaged urinary striated muscles with stem cell therapy or new molecular targets.
The myoblast is a type of progenitor cell that gives rise to muscle cells (myocytes). Myoblasts can be isolated from e.g. skeletal muscle tissues, the most common and numerous sources. And myoblasts originated from skeletal muscle tissues can be spontaneous differentiation into skeletal muscle cells (striated muscle cells), cardiac muscle cells (striated muscle cells), trans-differentiation into smooth muscle by inhibition of DNA methylation, and other mesenchymal cells (eg, bone cells, lipid cells) by their special differentiation cocktails. Treatment with differentiation cocktails can be performed in vitro or in situ, in vivo, if the molecular inducers are introduced locally e.g. in nanoparticles. Or, other new medicine molecular targets, such as receptors on the membrane or in the cells may be found during differentiation.
Histamine is a well-known biogenic, cationic amine synthesized, stored and released by professional histamine synthesizing cells. Mast cells, basophils and enterochromaffin cells contain an endoplasmic54kD histidine decarboxylase, which effectively converts L-histidine to histamine, which is released to and stored in storage granules, subjected to regulated release. Upon activation of the professional histamine producing cells, a burst release follows leading to a transient but very high histamine concentration in the extracellular space. These histamine concentrations are high enough to stimulate the conventional histamine receptors, histamine receptor type1(H1R, pKl for histamine is4.2) and histamine receptor type2(H2R, pKl for histamine is4.3). For example, smooth muscle cells, cardiomyocytes and skeletal muscle tissue have such conventional histamine receptors, which regulate the cellular proliferation and contraction state of the cells stimulated via the histamine/HIR or H2R axis.
Before the beginning of the millennium, it was noticed that the cytoplamic73kD "pro-form" of HDC produces histamine, albeit at a100-1,000-fold lower rate as the enzyme isoform typical for the professional histamine synthesizing cells. In the non-professional histamine producing cells histamine is released to the cellular cytoplasm. Therefore, it is not stored and not subjected to regulated burst release. Instead, such cells contain organic cation transporters, which are equilibrative uniporters, which transport the intracellularly synthesized histamine from the non-professional histamine synthesizing cells along the histamine concentration gradient, to the extracellular space. Histamine concentrations achieved in this way are all too low to stimulate the conventional histamine receptors, that it was first thought that this only represents perhaps an ancestral vestigium of a function that had become obsolete during phylogenesis. However studies in the last decade focusing on G-protein coupled receptors revealed, until then unknown, new members of the histamine receptor family. These novel histamine receptors, histamine receptor type3(H3R, pKi for histamine is8.0) and histamine receptor type4(H4R, pKi for histamine is8.2), have over10,000-fold higher affinity for histamine than the conventional receptors. It has become clear that the low basal levels of histamine, produced by various non-professional histamine producing cells, such as dendritic cells and lymphocytes, are enough to bind to and regulate cells equipped with the novel, high affinity histamine receptors. The role of high-dose histamine in the regulation of muscle cell tone was already mentioned. Findings using histamine receptor agonists and/or antagonists have suggested that also novel histamine receptors may be present and functional in at least the bronchial smooth muscle cells. In addition, histamine receptors (H1R, H2R, H3R and H4R) were also found in situ bladder tissue and in vitro cultured bladder smooth muscle cells. Histamine receptors have been found to contribute to the bladder smooth muscle dysfunction. However, what role the histamine receptors play in the urinary striated cells, hence how histamine receptors may influence the function of low urinary tract, there are no reports at present. Due to the presence and role of H1R, H2R and H3R for the function of other types of muscle cells, we aim to check the histamine receptors at different stages of striated myogenesis, and to test if H3R may couple to the Gi/o proteins, lead to inhibition of the formation of cyclic AMP and decrease of sarcoplasmic Ca2+, which help skeletal muscle relaxation and regeneration. Then we may get pilot comments about the probable role of histamine receptors may play at the low urinary striated muscle dysfunction diseases.
Our objective is to study the development of voiding function of the low urinary striated muscles in the newborns, the therapeutic efficacy of the current treatments for adult urinary incontinence in clinical practice, then to check expression, function and possible intracellular signal way of histamine receptors on striated myogenesis and the mature striated muscle cells in the bench, all of which may help us find pilot evidence for cellular therapies and/or new medical molecular-receptors targets for the treatment of urinary incontinence.
Part I:The development of voiding pattern in newborns less than4weeks of age
Methods:
Twenty-one healthy newborns aged from day1to28were included (10full-terms,11pre-terms). The12h free voiding parameters were recorded at day1,4,7,14and28after birth, respectively.
Results:
Altogether778voidings were recorded. Voiding frequency (VF) increased in both the full-term and pre-term newborns between day4and7, and decreased in pre-terms between day14and28. Voiding volume (W) increased twice in full-terms and once in pre-terms. Post-voiding residual volumes (PRV) fluctuated in the full-terms. VF in the full-terms was lower at day14and28compared to the pre-terms. W was higher in the full-terms than the pre-terms at days4,7,14, and28. PRV was also higher at day4and28. Interrupted voiding was more seen in the pre-terms.
Part II The treatment effcacy of adult urinary incontinence Patients and methods
1. A total of20OAB out-patients with1-30(mean8.5±9.96) years medical history,12males and8females, aged21-83(mean42.9±20.38) were included in this study. They were given5mg solifenacin orally once daily for12weeks. Before and after treatment, overactive bladder symptom score (OABSS), patient perception of bladder condition symptoms rating scale (PPBC), filling cystometry obout detrusor and adverse events were evaluated.
2. Select80cases of elderly female patients with I, II-type stress urinary incontinence, who had TVT-O surgical treatment0.5-3years before investigation, and age over60years before TVT-O. Compare daily life and lower urinary tract symptoms difference before and after surgery in patients by IIQ-7and UDI-6through telephone survey.
Result
1. Before and after solifenacin medication, significant changes are found in the detrusor overactivity waves were (2.29±2.35)VS(0.64±1.33)(P<0.05); detrusor overactivity (DO) disappeared in six patients (15VS9). Bladder capacities at first desire to void and maximum bladder capacity were significantly increased (P<0.01).Bladder compliance and detrusor pressure when maximum urine flow had no statistical difference (P>0.05). All patients had significant improvements of OAB symptoms in OABSS and PPBC (P<0.05). Six patients had mild side effect of dry mouth and could overcome by drinking more.
2.73patients were followed up successfully, aged60to72years old, mean64±4.5years. Preoperatively patients' daily life quality as making household chores, activities, entertainment, meals, social and emotional has obviously been affected as the scores from9to25by their own scoring, mean17±6.7;and Lower urinary tract symptoms of urgency, frequent urination, movement, leakage of urine volume, voiding difficulty and dysuria scores are from8to21, mean14±4.7. Mild urinary frequency was8.2%(6/73). Urinal pad usage was71(97.3%). After TVT-O, patients felt improved by their own scoring. The daily life quality scores were ranging from2to13, mean6.4±3.2, and lower urinary tract symptoms from1to9, mean5.4±3.2. Mild urinary frequency after surgery was1.4%(1/73).39cases were completely dry (53.4%); urinal pad usage was34(46.6%).11cases occasionally had voiding suprapubic area pain or discomfort postoperatively.
Part III The expression of Histamine receptors during striated myogenesis and adult mid-urethral striated muscles
Methods
1. Myogenesis of C2C12skeletal myoblasts was followed using desmin, myogenin and myosin heavy chain (MHC) as early, intermediate and late differentiation markers, respectively. Quantitative real time-polymerase chain reaction was used to measure HR-subtype-mRNA with markers. H3R-protein was immunostained with markers.
2. One group of myoblasts was under incubation by H3R antagonist Ciproxifan10uM during differentiaton for6days to check if H3R was functional during differentiation.
3. Mid-urethral striated muscle samples from five adults, who bear the resection of prostate, are immunostained with HR-subtype-protein.
Results
1. H1R-mRNA was high in myoblasts, but then decreased, H2R remained rather constant and H3R-mRNA increased28-,103-and198-fold at days2,4and6, respectively. MHC increased7,718-,94,487-and286,288-fold over the baseline day0values. H3R-protein was weakly stained at day2but strongly stained in day4-6cells.
2. Myoblasts under Ciproxifan incubation for6days has no influence on the striated myogenesis markers.
3. In the adult mid-urethral striated muscle samples, H1R was found very strong staining, H3R is moderate strong staining and H2R is stained weak.
Part V The function of H3R in mature muscle cells and its possible subcellular signal way
Methods
1. Cultured and differentiated C2C12myoblasts on the18mm round glass coverslips for6days. Loaded cells with4μmol/L Fluo-4calcium indicator dye and transferred to recording chamber with electrodes for field stimulation and maintained at+37℃while imaging. Ca2+imaging was conducted and recorded at50frames per second by camera. The samples were electrically paced at a frequency of0.5Hz with10ms bipolar pulses (200mA). Record the basal cytoplasma calcium and the calcium under the electrical stimulation, then check the calcium changes under the stimulation of6different concentration (1nM,10nM,100nM,1uM,10uM,100uM) of H3R agonist, R-a-methylhistamine (RMeHA)with time under electrically paced.
2. Check how the cells internalized the H3R modulators and where H3R was on the cells by fluorescence labled H3R antagonist ST-1240with different concentration.
3. Load differentiated cells with2.5μCi/ml3H-adenine to check the cAMP while under the stimulation of Forskolin alone. Check cAMP under the stimulation of Forskolin plus6different concentration (1nM,10nM,100nM,1uM,10uM,100uM) of RMeHA.
4. Pretreated cells with H3R antagonist, Ciproxifan, then repeat to check cAMP by Forskolin plus6different concentration (1nM,10nM,100nM,1uM,10uM,100uM) of RMeHA.
Results
1. In C2C12mytubes, H3R agonist, RMeHA can diminished cytoplasma calcium peak when cells are electrically paced.
2. H3R gathered on the surface of myotubes and the cells can internalize H3R antagonist, Ciproxifan into cells.
3. RMeHA was not strict selective H3R agonist, and its low concentration can stimulate H3R to diminished cAMP gently and higher concentration (over1uM) can stimulate H1R or H2R to increase cAMP in the cells.
4. When the myotubes were pretreated by H3R antagonist, Ciproxifan, low concentration of H3R (0,1,1and10nM) can also diminished cAMP and higher concentration (over1uM) can greatly stimulate H1R or H2R to increase cAMP.
Conclusion
1. The development of voiding patterns in newborns suggests the mature process of urethral striated muscle in neonatal period. Voiding pattern in newborns has shown very common unconscious voidings in the very beginning of life, which more like'normal neonate incontience'. In newborns'unconscious voidings, detrusor (smooth muscle)-sphincter (striated muscle) dyssynergia, which represented by the frequent interrupted voidings both in preterms and full terms, contributes most to this type of normal urinary incontinence, which proved the weak mature function of mid-urethral striated muscle cells in newborns. In all, the bladder-mid-urethral sphincter striated muscles dyssynergia contributes to'urinary incontinence' in normal newborns, which shows the maturation process of mid-urethral striated muscles during neonatal period.
2. The dysfunction of urethral striated muscles in adults is presented by adult OAB and stress incontinence. In clinical practice at present, Solifenacin urodynamically decreases the overactivity of detrusor, increases bladder capacity and improves life quality in parts of symptomatic OAB patients. Some patients without improvement may seak other methods. TVT/TVT-O surgery is effective to some patients suffered from SUI resulting from the prolapse of pelvic striated muscles within five years. But some SUI patients is still high relapse and obvious discomfort, and the long-term effects is still unclear. So it is necessity to seek new therapy or new medical molecular targets
3. Histamine subtypes, such as H1R, H2R, and H3R are found during striated myogenesis and also the adult urethral striated cells. And H3R antagonist, Ciproxifan has no influence on the myogenic differentiation. This and earlier findings suggest a role for H1R in the regulation of progenitor cell mitogenesis, H2R in the relaxation of acetylcholine-stimulated contraction of the muscle cells, when professional histamine producing cells, e.g. mast cells, are activated.
4. H1R and H2R may be coupled with Ga protein and increase the adenylyl cyclase (AC) activiry. In contrast, H3R may be coupled with Gi/o protein in skeletal muscle cells that it may inhibit adenylyl cyclase, decrease cAMP, inhibit PKA signal way, calcium channels on the membrane of sarcoplasmic reticulum (SR), decrease cytoplasmic Ca2+, hence, H3R would seems to participate in the regulation of specialized myocyte functions, perhaps the maintenance of its relaxed state under the influence of constitutive H3R activity and low histamine concentrations locally produced/released by non-professional histamine producing cells.
引文
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