慢传输型便秘发病机制的研究

慢传输型便秘（STC）是指由于结肠动力障碍,使内容物滞留在结肠及结肠运输缓慢所致的便秘。STC的病因复杂,确切的发病机制尚不完全清楚,症状顽固,治疗困难,主要与精神心理因素、肠神经系统（ENS）病理变化、Cajal间质细胞（ICC）的病理改变、平滑肌及肠神经递质变化等因素有关。此文就STC发病机制方面的研究进展作一综述,以期对临床治疗提供指导。     

Cajal间质细胞与慢传输型便秘研究的现状与趋势

Cajal间质细胞(ICC)是分布在胃肠道神经细胞与平滑肌之间的一种特殊细胞,具有起搏及协调胃肠道运动的功能。研究发现慢传输型便秘(STC)患者结肠组织中Cajal间质细胞数量减少,形态及其网状结构改变,因此ICC的异常可能是STC的重要发病机制。预防或干预ICC的病变,积极改善ICC的功能,协调肠道运动可能是潜在治疗STC的方向。     

Cajal间质细胞与慢传输型便秘

Cajal间质细胞是胃肠道神经系统(ENS)的一种非神经但又与神经密切相关的特殊间质细胞。近年的研究表明Cajal间质细胞(ICC)可能是肠道慢波的起搏者，并参与了NANC神经肌肉信息传递过程，有潜在的控制胃肠道动力的作用，而且与人类胃肠道运动性疾病以及胃肠道肿瘤的发病机制有关。慢传输型便秘(STC)就是胃肠运动性疾病中的一种，它是以结肠动     

Cajal间质细胞在消化系统动力性疾病发病中作用机制的研究进展

Cajal间质细胞(ICC)广泛分布于人类和哺乳动物的消化道平滑肌中,ICC具有胃肠道平滑肌动力起搏、消化道慢电波传播、介导和调节胃肠道神经递质等功能。此外,分布在消化系统中的ICC在多种消化系统动力性疾病的发病过程中可能具有重要的作用。该文就近年来ICC在消化系统中的分布和功能及其在相关消化系统动力性疾病发病中作用的研究进展作一综述。     

Cajal间质细胞与炎症性肠病关系的研究进展

Cajal间质细胞(ICC)主要分布在消化道平滑肌细胞与神经细胞之间,通常认为ICC是参与产生和传播消化道慢波的起搏细胞,并可通过传递和调节神经递质来调节胃肠道的活动,与肠道炎性反应的病理生理有关。炎症性肠病(IBD)是一种慢性非特异性炎性疾病,治疗困难,易复发,其病因和发病机制尚不明确。该文综述了ICC与IBD发生、发展的关系,旨在为探究IBD的发病机制及治疗方式提供新的思路。     

肠神经系统与慢传输型便秘

慢传输型便秘(STC)病因未明,多因素与其发病相关.肠神经系统(ENS)可独立调节肠道功能,其在慢传输型便秘中的改变具有重要意义.此文就此予以阐述,为STC临床治疗提供依据.     

针刺调节结肠慢传输便秘ICC相关机制的研究进展

针刺治疗结肠慢传输型便秘(slow transit constipation,STC)已得到临床上证实,应用也越来越广泛,针刺调节Cajal间质细胞(interstitial cells of Cajal,ICC)目前讨论的关键机制之一.针刺可以有效调节ICC的数量,改变其标志物C-kit蛋白的表达,有利于ICC-平滑肌细胞(smooth muscle cell,SMC)网络结构的恢复,使结肠功能得到恢复,这为临床上治疗结肠STC提供了有效的科学依据.本文对近几年针刺治疗结肠慢传输等相关结肠病变的机制进行梳理,以期为针灸治疗疾病提供科学化的依据提供参考资料,为临床制定治疗结肠STC的合理治疗方案做出参考.     

慢传输型便秘发病机制的研究进展

慢传输型便秘（slow transit constipation，STC）是一种涉及全胃肠道动力紊乱，尤其是结肠传输减慢而导致的便秘。其主要特征是无便意、大便次数减少、坚硬、排便费力、排便不尽感、用手帮助排便等。随着人们生活水平的提高，工作节奏的加快，STC的发病率逐年上升。由于临床上对STC患者难以进行前瞻性研究．因而目前对该病的病因、发病机制和病理生理的改变缺乏深入了解。多数研究认为STC是一个全身性、涉及多系统、多器官的综合征，如结肠传输减慢可涉及整个胃肠道动力变化，还伴有胆囊、膀胱的动力改变；神经系统包括植物神经系统、肠神经系统（ENS）的改变也参与了STC的发病。STC的发病机制很复杂，可能为一种病因产生多种机制，也可由多种因素协同所致，本文就STC的研究进展作一简要综述。     

Cajal间质细胞在胃肠运动中的作用

Cajal间质细胞(ICC)是肠神经系统中的一种与肠运动神经元及平滑肌密切相关的间质细胞，基于其形态学和组织学上与平滑肌和神经元的相互关系，ICC具有某些功能：起搏胃肠平滑肌运动并传导肌电信号，调节神经递质。ICC生物学特征是表达c-kit基因产物(编码酪氨酸激酶受体的原癌基因Kit)。平滑肌、肠神经系统和ICC共同形成复杂的胃肠运动控制系统；ICC缺失可能导致某些胃肠功能丧失，与一些胃肠疾病有关。     

酚酞对大鼠结肠动力及肠神经系统的影响研究

目的 探讨长期应用酚酞对结肠肌电及肠神经系统(ENS)的影响。方法 建立大鼠“泻剂结肠”模型，应用电生理、组化及免疫组化技术研究酚酞对大鼠结肠动力、ENS多种神经递质及Cajal间质细胞(ICC)的影响。结果 大鼠饲以酚酞3个月后，结肠慢波频率减慢，结肠肌间丛还原型烟酰胺腺嘌呤二核苷磷酸黄递酶阳性神经细胞数目增多，乙酰胆碱酯酶阳性神经细胞数目减少，一氧化氮合酶免疫反应性增强，生长抑素免疫反应性减弱，肌间丛ICC分布不均匀，突起连接杂乱。结论 长期应用酚酞对结肠动力和ENS有损害作用，在临床治疗顽固性便秘时应避免长期应用酚酞等刺激性泻剂。     

Intestinale Innervationsstörungen: Anatomische Grundlagen und Diagnostik

Histopathological insights into intestinal innervation disorders require the knowledge of the anatomical topography and structure of the enteric nervous system (ENS). The ENS of the human colon is composed of intramural nerve meshes located in different layers of the intestinal wall (plexus musculares, plexus myentericus, plexus submucosi, plexus mucosi). A differentiated visualization of the components of the ENS is achieved-by enzyme- and immunohistochemical methods. In comparison to cross-sections, wholemount preparations of the intestinal wall allow a two dimensional demonstration of the network-character of the nerve plexus and preserve the anatomical in-situ conditions. A complete histopathological diagnosis of the ENS requires full-thickness biopsies or resected specimens, as an assessment of the entire plexus layers is achieved only by this procedure. The establishment of reference values by means of morphometrical studies of ENS contributes to an objective and standardized histopathological diagnosis. Aganglionosis, hypoganglionosis, intestinal neuronal dysplasia and heterotopias are considered to be the most acknowledged forms of intestinal innervation disorders. In addition, degenerative changes of enteric nerve plexus, visceral neuropathies and a disturbed homeostasis of enteric neurotransmitters are described. Recently, a pathogenetical significance for functional intestinal motility disorders has been attributed to interstitial cells of Cajal (ICC). The ENS and ICC play a major role in mediating and coordinating gastrointestinal motility and therefore shoud be taken into account in clinical disorders of the intestinal motor function.     

Decreased interstitial cells of Cajal in the sigmoid colon of patients with slow transit constipation

Background and aims Slow transit constipation (STC) is a colonic motor disorder that is characterized by measurably delayed movement of materials through the colon. Although abnormalities in the neuronal networks of the colon have been demonstrated in patients with STC, the etiology of STC remains unclear. Interstitial cells of Cajal (ICC) have been shown to be the pacemaker cells of the intestine and have been implied in the pathogenesis of a number of gastrointestinal motility dysfunctions, including idiopathic STC. This study aimed to determine the normal distribution of ICC within the colon of the Chinese and also to determine if ICC are decreased in Chinese STC patients.Patients and methods Twelve patients with STC and eight age-matched normal controls were studied. Specimens of sigmoid colon were obtained immediately after resection. ICC were identified with a monoclonal antibody to c-kit by an indirect immunofluorescence method. Immunostained tissues were examined with a laser scanning confocal microscope and the area occupied by ICC was calculated with an image analysis system.Results ICC were located in the external muscle layers including myenteric plexus (MP) and submucosal border (SMB). Two types of Kit-positive ICC were observed: bipolar cells characterized by one or two long processes and multipolar cells characterized by long stellate processes extending in various directions. A higher percentage of ICC was present in the MP regions and circular muscle (CM) layers compared with the SMB and longitudinal muscle (LM) layers. Tissues from STC patients showed a considerable decrease in the number of ICC located in the four regions (ICC-LM, ICC-MP, ICC-CM, ICC-SMB), especially the ICC-SMB, in which ICC almost completely disappeared.Conclusions Similar distribution of ICC was observed in the normal sigmoid colon of the Chinese. Decreased area of c-kit+ ICC may play an important role in the pathophysiology of STC. It remains to be determined whether the loss of ICC is primary or secondary to another lesion.     

Role of Tenascin-X in regulating TGF-β/Smad signaling pathway in pathogenesis of slow transit constipation

BACKGROUND Chronic constipation is a gastrointestinal functional disease that seriously harms physical and mental health and impacts the quality of life of patients.Its incidence rate is 2%-27%.Slow transit constipation(STC)is a common type of chronic functional constipation,accounting for 10.3%-45.5%of such cases.Scholars have performed many studies on the pathogenesis of STC.These studies have indicated that the occurrence of STC may be related to multiple factors,such as dysfunction of the enteric nervous system,interstitial cells of Cajal(ICC)damage,and changes in neurotransmitters regulating intestinal peristalsis.AIM To investigate the role of Tenascin-X(TNX)in regulating the TGF-β/Smad signaling pathway in the pathogenesis of STC.METHODS This study included an experimental group and a control group.The experimental group included 28 patients with severe colonic STC,and the control group included 18 patients with normal colon tissues.Immunohistochemistry(IHC)was used to detect c-Kit,a specific marker of the ICC.Western blot,immunofluorescence,and IHC were used to detect the localization and expression of TNX and TGF-β/Smad.RESULTS IHC showed that the number of ICC with positive c-Kit expression was significantly reduced in the colon of STC patients(22.17±3.28 vs 28.69±3.53,P<0.05)and that the distribution was abnormal.Western blot results showed that c-Kit and Smad7 levels were significantly decreased in the colon of STC patients(c-kit:0.462±0.099 vs 0.783±0.178,P<0.01;Smad7:0.626±0.058 vs 0.799±0.03,P<0.01)and that TNX and Smad2/3 levels were higher in the STC group(TNX:0.868±0.028 vs 0.482±0.032,P<0.01).There was no significant difference in TGF-βbetween the two groups(0.476±0.028 vs 0.511±0.044,P=0.272).Pearson correlation analysis showed that the TNX protein exhibited a strong correlation with Smad2/3 and Smad7(P<0.05,|R|>0.8)and TGF-β(P<0.05,|R|=0.7).CONCLUSION The extracellular matrix protein TNX may activate the TGF-β/Smad signaling pathway by upregulating the Smad 2/3 signaling protein and thereby induce slight or complete epithelial stromal cell transformation,leading to an abnormal distribution and dysfunction of ICC in the diseased colon,which promotes the occurrence and development of STC.     

Cajal beyond the gut: interstitial cells in the urinary system--towards general regulatory mechanisms of smooth muscle contractility?

Interstitial cells of Cajal (ICC), similar to GI pacemakers have been identified throughout the urinary system. Although each part of the system serves a different function, ranging from peristalsis of the ureters, storage of urine by the bladder, and a sphincteric action by the urethra, they share a common mechanism in being able to generate phasic myogenic contractions. Even the urethra, often considered to be a 'tonic' smooth muscle, achieves an apparently sustained contraction by averaging numerous small asynchronous 'phasic' contractions. This activity can occur in the absence of any neural input, implying the presence of an intrinsic pacemaker. Intracellular microelectrode recordings from urethral muscle strips reveal electrical slow waves similar to those of the GI tract. To study this further, we isolated single cells from rabbit urethra and found not only smooth muscle cells (SMC), but a second cell type comprising -10% of the total. The latter cells were branched and non-contractile and closely resembled intestinal ICC. Electrophyiological studies revealed that, while the isolated smooth muscle cells were electrically quiescent, the 'ICC' fired electrical slow waves similar to those observed in the whole tissue. The basis of this difference was the presence of a large pacemaker current involving the activation of calcium-activated Cl channels by spontaneous intracellular Ca2+ waves. These, in turn, have been shown to be modulated by neurotransmitters such as nitric oxide, noradrenaline and ATP, thus providing a possible mechanism whereby neural regulation of the urethra, as well as spontaneous tone, may be mediated via ICC.     

Ultrastructure of interstitial cells of Cajal at the colonic submuscular border in patients with ulcerative colitis

BACKGROUND & AIMS: Submuscular interstitial cells of Cajal (ICC) are putative pacemaker cells of the colonic external muscle. Although motility disturbances and smooth muscle dysfunction are prevalent in patients with ulcerative colitis (UC), ICC have never been studied in this disease. The aim of this study was to examine the ultrastructure of submuscular ICC in UC. METHODS: Transmission electron microscopy of the colonic submuscular region was performed using specimens from 4 adult patients who had undergone resection for severe UC. The specimens were compared with similarly processed control samples. RESULTS: ICC often showed multiple secondary lysosomes, large confluent lipid bodies, and disrupted aggregates of vacuolated glycogen clusters. Intermediate filaments showed margination and clumping. Intramuscular and submucosal nerve terminals were often swollen. Macrophages were frequent, often close to nerves and ICC. Muscle cells of the innermost circular layer, fibroblast-like cells, and glial cells appeared undisturbed. Other inflammatory cells were inconspicuous. CONCLUSIONS: Alterations of ICC ultrastructure are present in the submuscular pacemaker region of the colon in patients with severe UC. The changes in ICC may result from primary damage or changes secondary to defective muscular function, or they may reflect neuroimmune-mediated metabolic responses. It is suggested that ICC are actively involved in the pathogenesis of motility disturbances in UC. (Gastroenterology 1996 Dec;111(6):1447-55)     

Decreased density of interstitial cells of Cajal and neuronal cells in patients with slow-transit constipation and acquired megacolon

BACKGROUND: The pathophysiology of constipation is not clearly identified as yet, and the interstital cells of Cajal (ICC), known to generate the slow wave activity and to be involved in intestinal neurotransmission and the enteric nervous system (ENS), are suspected to play an important role. The aims of the present study were to assess the distribution of ICC and neuronal cells of ENS in patients with slow-transit constipation and acquired megacolon. METHODS: Sigmoid colon specimens were obtained from patients who underwent colectomy due to slow-transit constipation (n = 10), acquired megacolon (n = 9) and non-obstructive colon cancer (n = 10) as a control group. The ICC were visualized by c-Kit immunohistochemistry and neuronal cells of the ENS were demonstrated by protein gene product (PGP) 9.5. Density of cells stained by c-Kit and PGP 9.5 was calculated as percent area (area stained/area of X-Y plane) x 100, when images were collected at a magnification of x40 objective, with maximum area examined in the horizontal X-Y plane of 400 microm x 400 microm using an image analyzer. RESULTS: The densities of ICC and PGP 9.5 reactive neuronal structures were significantly decreased in all layers of sigmoid colon specimens in patients with slow-transit constipation and acquired megacolon, compared with that of the control group. However, there was no statistically significant difference in either the density of ICC or that of neuronal structures between the patients with slow-transit constipation and acquired megacolon. CONCLUSIONS: Slow-transit constipation and acquired megacolon were associated with alteration of ICC and neuronal cells of ENS in the sigmoid colon.     

胰岛素样生长因子-1对糖尿病大鼠结肠平滑肌细胞表达干细胞因子的影响

背景：糖尿病胃肠动力障碍与Cajal间质细胞（ICC）数量和超微结构异常有关。前期实验发现胰岛素样生长因子-1（IGF-1）可诱导正常大鼠胃肠平滑肌细胞（SMC）表达干细胞因子（SCF）,从而有利于ICC的生存。目的：探讨IGF-1对糖尿病大鼠结肠SMC表达SCF的影响及其信号转导通路。方法：以链脲霉素建立糖尿病大鼠模型。分离、培养正常和糖尿病大鼠结肠SMC,设不同浓度（0、50、100、150μg/L）、不同时间（0、8、16、24、48h）IGF-1十预组和MEK抑制剂PD98059＋IGF-1、P13K抑制剂LY294002＋IGF-1干预组．以RT—PCR和蛋白质印迹法检测SMC中的SCF表达。结果：糖尿病大鼠结肠SMC的生长速度较正常大鼠减慢。无血清培养条件下．正常和糖尿病结肠SMC中SCFmRNA和蛋白表达较低,IGF-1可诱导SCF表达增加,最大有效浓度为100μg／L,诱导高峰时间正常对照组为16h,糖尿病组为24h。经PD98059预处理的SMC,IGF-1诱导的SCF表达部分受抑．IN294002预处理对IGF-1的作用无明显影响。结论：0～100μg／L IGF-1在24h内能以剂量和时间依赖性方式诱导糖尿病大鼠结肠SMC表达SCF．但效应弱于其对正常大鼠结肠SMC的作用,该作用的发挥可能部分依赖于ERKMAPK信号通路。     

斯钙素-1在慢性阻塞性肺疾病平滑肌增殖中的作用研究

目的探讨斯钙素-1(Stanniocalcin-1, STC1)对慢性阻塞性肺疾病(COPD)平滑肌增殖的影响及STC1在COPD气道重塑中的作用。 方法采用臭氧暴露法构建COPD小鼠模型,选取BALB/c雌性小鼠24只,将小鼠随机分为4组：1周空气对照组(简称1周空气组)、1周臭氧暴露组(简称1周臭氧组)、3周空气对照组(简称3周空气组)、3周臭氧暴露组(简称3周臭氧组),每组6只。HE染色观察肺部炎症、肺泡间距及基底膜厚度。采用免疫组织化学法(简称免疫组化)检测小鼠肺组织α-平滑肌动蛋白(α-SMA)及STC1表达。采用2%及10%胎牛血清刺激人原代平滑肌细胞增殖,外源加入重组STC1(rhSTC1)处理平滑肌细胞,EdU染色检测平滑肌细胞增殖。 结果臭氧暴露诱导小鼠肺部炎症、肺气肿及气道重塑发生(肺组织基底膜增厚及平滑肌细胞标志物α-SMA表达增加)。STC1主要表达在支气管上皮顶端膜,且在COPD小鼠中表达升高(P<0.05),但随着臭氧暴露3周,肺组织STC1较α-SMA表达下降(P<0.05)。外源加入rhSTC1抑制了平滑肌细胞增殖(P<0.01)。 结论支气管上皮表达的STC1能够抑制平滑肌细胞增殖,外源给予足量的STC1可能延缓COPD气道重塑的发生。