Enteric nerves and interstitial cells of Cajal are altered in patients with slow-transit constipation and megacolon

BACKGROUND & AIMS: A variety of gastrointestinal motility disorders have been attributed to alterations of interstitial cells of Cajal and malformations of the enteric nervous system. This study evaluates both the distribution of interstitial cells of Cajal and the pathohistology of the enteric nervous system in 2 severe human colorectal motility disorders. METHODS: Colonic specimens obtained from patients with slow-transit constipation (n = 11), patients with megacolon (n = 6), and a control group (n = 13, nonobstructing neoplasia) were stained with antibodies against c-kit (marker for interstitial cells of Cajal) and protein gene product 9.5 (neuronal marker). The morphometric analysis of interstitial cells of Cajal included the separate registration of the number and process length within the different regions of the muscularis propria. The structural architecture of the enteric nervous system was assessed on microdissected whole-mount preparations. RESULTS: In patients with slow-transit constipation, the number of interstitial cells of Cajal was significantly decreased in all layers except the outer longitudinal muscle layer. The myenteric plexus showed a reduced ganglionic density and size (moderate hypoganglionosis) compared with the control group. Patients with megacolon were characterized by a substantial decrease in both the number and the process length of interstitial cells of Cajal. The myenteric plexus exhibited either complete aganglionosis or severe hypoganglionosis. CONCLUSIONS: The enteric nervous system and interstitial cells of Cajal are altered concomitantly in slow-transit constipation and megacolon and may play a crucial role in the pathophysiology of colorectal motility disorders.     

Gastro-electric dysrhythm and lack of gastric interstitial cells of cajal

AIM: The pathophysiology underlying gastrointestinal complications of long-standing diabetes is poorly understood. Recent evidence suggests an important role of intestitial cells of cajal in controlling gastrointestinal motility. The aim of this study was to clarify the changes of ultrastructural characteristics of interstitial cells of cajal in stomach of diabetic gastro-electric dysrhythmic rats. METHODS: Rats were randomly divided into diabetic group and control group, the model of diabetic rats was established by peritoneally injection of streptozotocin. Electrogastrograms were recorded and intestitial cells of cajal in antrum were observed by electrictelescopy after diabetic model rat was established for 3 mo. RESULTS: In the rats of diabetic group, the gastro-electric dysrhythmia was increased compared with control group, the abnormal rhythm index and the cofficient of variation of slow wave frequency were significantly higher than those of normal rats. The number of the gap junctions of interstitial cells of cajal in antrum of diabetic rats was significantly decreased, and the remaining structures were damaged. The organelles were also damaged, and vacuoles were formed. CONCLUSION: It is possible that changes in ultrastructural characteristics of interstitial cells of cajal in stomach are one of the mechanisms underlying gastro-electric dysrhythm in diabetic rats.     

糖尿病大鼠肠道Cajal间质细胞结构变化的研究

目的：明确糖尿病时肠道Cajal间质细胞超微结构的变化。方法：对12周四氧嘧淀糖尿病大鼠模型的小肠、结肠组织进行透射电镜观察。结果：实验观察发现糖尿病时Cajal间质细胞与其他细胞间的缝隙连接显著减少、结构破坏、连接松散;线粒体肿胀、空泡样变、溶解;胞质广泛溶解,细胞器减少。结论：糖尿病时肠道Cajal间质细胞的超微结构发生了显著的变化,这些结构的改变与其功能的改变密切相关,Cajal间质细胞超微结构的变化很可能是糖尿病胃肠功能紊乱的病因之一。     

肠道炎症和恢复期Cajal间质细胞变化的相关机制

摘要炎症性肠病（IBD）患者常出现肠道动力紊乱，动力紊乱与肠道炎症密切相关。Cajal间质细胞（ICC）作为起搏细胞和肠道神经支配的调节者对控制胃肠道动力起关键作用。越来越多的证据显示在健康状态下或动力疾病中存在大量ICC的修复或再生。因此，明确ICC在肠道炎症中的病理生理机制，并阐明炎症恢复阶段促进ICC生长发育的因素具有重要意义。     

Decreased interstitial cell of cajal volume in patients with slow-transit constipation

BACKGROUND & AIMS: The cause of slow-transit constipation is incompletely understood. Recent observations suggest a central role for interstitial cells of Cajal in the control of intestinal motility. The aim of this study was to determine the volume of interstitial cells of Cajal in the normal sigmoid colon and in the sigmoid colon from patients with slow transit constipation. METHODS: Sigmoid colonic samples were stained with antibodies to protein gene product 9.5, c-Kit, and alpha-smooth muscle actin. Three-dimensional reconstruction of regions of interest was performed using consecutive images collected on a laser scanning confocal microscope and ANALYZE software. RESULTS: Volume of interstitial cells of Cajal was significantly decreased in all layers of sigmoid colonic specimens from patients with slow-transit constipation compared with normal controls. Neuronal structures within the colonic circular smooth muscle layer were also decreased. CONCLUSIONS: A decrease in the volume of interstitial cells of Cajal may play an important role in the pathophysiology of slow-transit constipation.     

Advances in diabetic gastroparesis

This review addresses the advances in our understanding of the epidemiology and mechanisms in diabetic gastroparesis and dyspepsia. The mechanisms discussed include: blood glucose levels at the time of presentation, "autovagotomy," and the intrinsic innervation (particularly the interstitial cells of Cajal and nitrergic nerves). In animal models of diabetic gastroparesis, there is evidence that homeostatic mechanisms are activated in the enteric nervous system to compensate for the loss of extrinsic innervation. Understanding these advances is key to the development of novel therapeutic strategies and for making rational choices in the management of diabetic gastroparesis and dyspepsia.     

Evolving concepts in the cellular control of gastrointestinal motility: neurogastroenterology and enteric sciences

The enteric nervous system is an independent nervous system with a complexity comparable with the central nervous system. This complex system is integrated into several other complex systems, such as interstitial cells of Cajal networks and immune cells. The result of these interactions is effective coordination of motility, secretion, and blood flow in the gastrointestinal tract. Loss of subsets of enteric nerves, of interstitial cells of Cajal, malfunction of smooth muscle, and alteration in immune cells have been identified as the basis of many motility disorders. The initial factors triggering these changes and how to intervene to prevent, halt, and reverse them needs to be understood.     

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。     

胰岛素、干细胞因子和Cajal间质细胞在糖尿病胃轻瘫中的作用

糖尿病胃轻瘫是糖尿病的常见并发症，严重影响患者的生活质量和血糖控制。胃肠道Cajal间质细胞在维持胃肠功能中发挥重要作用，糖尿病智组织中存在Cajal间质细胞数量和结构的异常改变，从而影响胃动力。胰岛素、干细胞因子对糖尿病胃肠道Cajal间质细胞的病变具有重要调控作用。本文就胰岛素、干细胞因子和Cajal间质细胞在糖尿病胃轻瘫中的作用作一综述。     

Therapy Insight: gastrointestinal complications of diabetes--pathophysiology and management

Patients with diabetes often have gastrointestinal symptoms, but the extent and severity of this problem and the specificity of the symptoms are not nearly as well defined as frequently assumed. Any part of the gastrointestinal tract can be affected, and the presenting symptoms depend on the composite of dysfunctional elements. Gastroesophageal reflux, Candida esophagitis, gastroparesis, diarrhea and constipation are among the many common gastrointestinal complications of diabetes. No specific risk factor for the development of these complications has been identified and their etiology is most likely to be multifactorial, involving both reversible and irreversible processes. Treatment should be directed at tighter glycemic and symptom control, which can bring about clinical improvement for many patients. For other patients, however, effective clinical management is problematic because no therapies are available to prevent or correct the underlying disease mechanisms. Studies now suggest that reduced levels of key trophic factors cause transdifferentiation of pacemaker interstitial cells of Cajal into a smooth-muscle-like phenotype. If this really is the case, therapies directed at restoring the normal milieu of trophic signals could correct the dysfunction of the interstitial cells of Cajal and resolve many gastrointestinal complications. Advances in stem cell technology also hold promise to provide a cure for diabetes and to correct abnormalities in gastrointestinal pathology.     

Key elements determining the intestinal region-specific environment of enteric neurons in type 1 diabetes

Diabetes,as a metabolic disorder,is accompanied with several gastrointestinal(GI) symptoms,like abdominal pain,gastroparesis,diarrhoea or constipation.Serious and complex enteric nervous system damage is confirmed in the background of these diabetic motility complaints.The anatomical length of the GI tract,as well as genetic,developmental,structural and functional differences between its segments contribute to the distinct,intestinal region-specific effects of hyperglycemia.These observations su...     

Paraneoplastic dysmotility: loss of interstitial cells of Cajal

Autoimmune impairment and destruction of the enteric nervous plexus are thought to play a central role in the pathogenesis of paraneoplastic motility disorders. We present a case of a small-cell lung carcinoma-related paraneoplastic motility disorder associated with abnormal interstitial cells of Cajal networks. Antibodies against c-Kit and protein gene product 9.5 were used to selectively stain interstitial cells of Cajal and the enteric nervous plexus, respectively. A 68-yr-old man presented with anorexia, early satiety, nausea, and weight loss. Investigations revealed gastroparesis, delayed small intestinal transit, and mediastinal lymphadenopathy. The patient was seropositive for type 1 antineuronal nuclear autoantibody and P/Q-type calcium channel antibody. Biopsy of mediastinal lymph nodes revealed metastatic small-cell carcinoma cells that were immunoreactive for c-Kit. Immunohistochemical staining of a full-thickness small intestinal biopsy revealed a relatively intact myenteric plexus but a sparse and disorganized interstitial cells of Cajal network. The histopathology of this case suggests that interstitial cells of Cajal may be a target in the pathogenesis of paraneoplastic motility disorders.     

Changes in the gastric enteric nervous system and muscle: A case report on two patients with diabetic gastroparesis

Background  

The pathophysiological basis of diabetic gastroparesis is poorly understood, in large part due to the almost complete lack of data on neuropathological and molecular changes in the stomachs of patients. Experimental models indicate various lesions affecting the vagus, muscle, enteric neurons, interstitial cells of Cajal (ICC) or other cellular components. The aim of this study was to use modern analytical methods to determine morphological and molecular changes in the gastric wall in patients with diabetic gastroparesis.     

实验性脂肪肝大鼠肠道Cajal间质细胞的研究

背景：随着社会经济的飞速发展，脂肪肝的发病率呈逐年增高的趋势。目前关于脂肪肝对胃肠动力影响的研究仍较少，尤其是对并发症的影响因素及其相关机制。目的：观察实验性脂肪肝大鼠空肠Cajal间质细胞数量的变化，探讨其与胃肠动力的相关性。方法：35只Sprague—Dawley（SD）大鼠分为脂肪肝模型组和对照组，其中脂肪肝模型组25只，对照组10只。以高脂饲料喂养大鼠制备脂肪肝模型。造模12周后，以蓝色葡聚糖-2000灌胃，通过检测大鼠小肠推进率评估肠道动力。免疫组化染色检测空肠c—kit阳性Cajal间质细胞的变化。结果：脂肪肝模型制备成功。与对照组相比。脂肪肝模型组肠道动力显著减弱（P〈0．05）。空肠c—kit阳性Cajal间质细胞显著减少（P〈0．05）。结论：脂肪肝大鼠肠道动力减弱可能与空肠CaM间质细胞减少有关。     

Isolated symptomatic peripheral neuropathy in type 1 insulin-dependent diabetes mellitus

Diabetic neuropathy is probably the most frequent of the chronic complications of diabetes, and is usually found in association with diabetic retinopathy and/or nephropathy. We report seven patients with long-standing insulin-dependent diabetes mellitus in whom symptomatic peripheral neuropathy was the first and only documented complication. The diagnosis of peripheral symmetrical neuropathy was based on the presence of symptoms and abnormal physical findings, confirmed with abnormal electrophysiological and/or vibratory and thermal threshold measurements. Diabetic retinopathy and nephropathy were absent. We conclude that in some type 1 insulin-dependent diabetic patients, similar to what has been reported in type 2 non-insulin-dependent diabetes, peripheral neuropathy may be the first chronic complication to become manifest. This observation provides additional evidence to suggest that each of the diabetic complications may have a different pathogenic mechanism.     

Autonome Neuropathie und mehr

In patients with diabetes almost all relevant regulatory systems and effector organs which are of importance for physiological functioning of gastrointestinal motility, secretion and sensitivity may be altered. Possible disturbances with negative effects on the gastrointestinal tract include autonomic neuropathy, enteric neuropathy with alterations of the myenteric and submucosal plexus, loss of interstitial cells of Cajal (ICC), altered secretion of insulin and other regulatory peptide hormones and diabetic myopathy of smooth muscles of the gastrointestinal canal. Moreover, almost all gastrointestinal functions are also impaired by hyperglycemia. In individual patients with gastrointestinal functional disturbances and corresponding complaints it is usually impossible to clarify the exact role of these mechanisms for the pathogenesis of symptoms; however, there is preliminary evidence that improved understanding may lead to new therapeutic options.     

Gastrointestinale Probleme bei Diabetes

The prevalence of gastrointestinal symptoms in diabetic subjects is higher than in the general population and any segment of the gastrointestinal tract can be affected. Gastroesophageal reflux and symptoms of gastropathy, such as nausea, sensation of fullness, constipation and diarrhea are the most common. A single specific risk factor to enhance the development of gastrointestinal symptoms in diabetics has not been identified. Neither the duration of diabetes nor the presence of secondary diabetic lesions correlates with the complaints described. Only the degree of hyperglycemic decompensation seems to be associated with gastrointestinal symptoms. Functional damage to the gastrointestinal afferent and efferent fibers of the sympathetic and parasympathetic nervous systems appears to be predominantly involved within the context of autonomic neuropathy and possibly also loss of so-called interstitial pacemaker cells (Cajal cells) aside from other reversible and irreversible processes which have so far not clearly been defined. Structural, infectious and immunological causes should be diagnostically excluded as would be done in metabolically healthy patients and a supplemental scan to assess gastric emptying may be useful. In terms of treatment, stabilization of the diabetic metabolism is of foremost importance as hypoglycemia and, even more so, hyperglycemia result in reversible gastrointestinal dysfunction. The risk of colorectal cancer is higher in patients with type 2 diabetes because of as yet unknown reasons.     

内源性一氧化碳和Cajal间质细胞在糖尿病结肠功能紊乱中的作用

糖尿病胃肠功能紊乱是糖尿病常见的并发症,严重影响患者的生活质量和血糖的控制。胃肠道一氧化碳和Cajal间质细胞在维持胃肠功能中发挥重要作用,两者在糖尿病结肠组织中均有异常改变,影响糖尿病结肠运动。本文就其在糖尿病结肠功能紊乱中的作用作一综述。     

糖尿病大鼠胃肠功能紊乱时结肠组织中Cajal间质细胞的表达

目的观察糖尿病大鼠胃肠功能紊乱时结肠组织内Cajal间质细胞的分布及表达变化,探讨Cajal间质细胞在糖尿病胃肠功能紊乱发病机制中的作用。方法30只SD大鼠随机分为两组,糖尿病组20只,正常对照组10只。糖尿病组大鼠用链脲佐菌素单剂量腹腔注射建立糖尿病模型,对照组注射等量枸橼酸缓冲液。两组大鼠饲养6周后处死,计算胃肠推进率并且收集结肠组织标本。用免疫组化方法观察Cajal间质细胞在两组大鼠结肠组织内的分布和表达,用W estern b lot方法检测c-k it蛋白在两组大鼠结肠内的表达。结果糖尿病组大鼠胃肠推进率较对照组明显降低（P〈0.05）。免疫组化和W estern b lot检测都显示糖尿病大鼠结肠组织内Cajal间质细胞的表达较正常大鼠明显减少（P均〈0.05）。结论糖尿病大鼠结肠组织内Cajal间质细胞表达减少,推测与糖尿病大鼠胃肠功能紊乱有一定相关性。     

Brainstem auditory and visual evoked potentials in Type 1 (insulin-dependent) diabetic patients

Summary Brainstem auditory evoked potentials and pattern shift visual evoked potentials were measured in 34 Type 1 (insulin-dependent) diabetic patients with long-standing disease and in 43 control subjects. Thirty-two percent of diabetic patients had abnormal brainstem auditory evoked potentials and 15% had abnormal visual evoked potentials. These abnormalities were not related to duration of diabetes, diabetic control or individual diabetic complications (retinopathy, nephropathy, peripheral or autonomic neuropathy). The aetiology of the abnormalities must remain a subject for speculation. The findings of this study are consistent with a central diabetic neuropathy involving the brainstem in long-standing diabetic patients.