Cajal间质细胞与慢性假性结肠肠梗阻关系的研究进展

Cajal间质细胞(interstitial cells of cajal,ICC)主要分布在胃肠道平滑肌细胞与神经纤维之间,是一类特殊的间质细胞,它是胃肠运动的起搏细胞,具有产生、传导慢波,调节胃肠道平滑肌运动的功能。而慢性假性肠梗阻是由于胃肠神经抑制,毒素刺激或肠壁平滑肌本身病变,导致的肠壁肌肉运动功能减弱,临床上具有肠梗阻的症状和体征,但无肠内外机械性肠梗阻因素存在,故又称动力性肠梗阻,按病程有急性和慢性之分,麻痹性肠梗阻和痉挛性肠梗阻属于急性假性肠梗阻,深入研究Cajal间质细胞,对进一步认识胃肠运动的生理及胃肠动力疾病的发生机制有重要意义。     

膀胱ICC样细胞研究进展

Cajal间质细胞(ICC)是分布在消化道自主神经末梢和平滑肌之间的一类特殊细胞,是胃肠道慢波的起搏细胞,是胃肠运动的pacemaker,它推进电活动的传播以及介导神经信号传递,控制胃肠道自主神经运动功能.近年来在人和动物膀耽中已证实存在ICC样细胞,其功能研究是最近研究的热点.ICC样细胞证实具有和胃肠ICC一样的藕联及神经调节功能的结构基础和功能特点,其是否具有起搏特性值得期待.     

内脏平滑肌Cajal间质细胞起搏功能(英文)

胃肠道的大部分区域都存在着一种特殊的间质细胞——Cajal间质细胞(interstitial cells of Cajal,ICCs)。尽管在100多年前它们的存在就已被发现,但是直到最近几十年的研究才逐渐揭示了它们的功能。在胃肠道,ICCs被认为是平滑肌自发性节律性电活动,即"基本电节律"(又称"慢波")的起搏细胞,并介导神经至平滑肌的神经信号传递活动。除胃肠道外,ICC样细胞同样存在于其它内脏平滑肌,如泌尿、生殖系统以及血管平滑肌等。本文仅就这些内脏平滑肌ICCs的功能做一简单综述。     

Cajal间质细胞及其可塑性的研究进展

Cajal间质细胞(interstitial cells of Cajal,ICC)是一类主要分布于胃肠道的间质细胞,与平滑肌细胞以及肠神经细胞有着紧密的关系。ICC分布于整个胃肠道,是胃肠道起搏细胞,具有产生和传播慢波的功能,参与神经递质调节,在一些胃肠动力性疾病中表现为异常状态。近期,关于ICC的生理功能、损伤和恢复机制的研究取得了显著的进展。ICC网络存在动态平衡,为了维持ICC网络功能,ICC周期代谢需要被紧密的控制调节平衡ICC死亡和更替。研究表明,ICC具有高度的可塑性,在一些缺失ICC的疾病中ICC并不一定死亡,转分化、去分化和细胞凋亡可能是ICC丢失的机制。。本文主要对Cajal间质细胞及其可塑性的研究进展进行了综述。     

Cajal细胞与胃肠起搏

存在于胃肠平滑肌内的Cajal间质细胞（ＩＣＣ）与胃肠道运动的发生和控制密切相关。ＩＣＣ可自发激活并产生节律性去极化慢波（ＳＷ）,经由ＩＣＣ形成的网络传向平滑肌细胞,并向远端扩布。平滑肌细胞缺乏产生ＳＷ活动的必要离子基础,但对于由ＩＣＣ传来的ＳＷ产生反应,使ＳＷ增强或诱发动作电位和收缩活动。因此,ＩＣＣ不仅是胃肠ＳＷ活动的起搏者,也是ＳＷ的传播者,同时对神经递质等生物活性物质影响平滑肌收缩起着居间调制作用。     

胃肠平滑肌运动单位SIP合胞体的生理与病理生理学意义

胃肠平滑肌层富有特殊分化的两种间质细胞,包括Cajal间质细胞(interstitial cells of Cajal,ICC)以及血小板衍生因子受体α阳性细胞(platelet-derived growth factor receptorα-positive cells,PDGFRα~+细胞)。ICC和PDGFRα~+细胞分别与平滑肌细胞(smooth muscle cells,SMC)形成缝隙连接调控平滑肌的收缩功能,因此,这三种细胞共同构成功能性的合胞体,称为SMC、ICC和PDGFRα~+细胞合胞体(SIP合胞体)。各种神经递质、体液因子、内源性生物活性分子以及药物等可以通过SIP合胞体影响胃肠运动。本文综述了SIP合胞体及其作用机制以及生理与病理生理学意义。     

胆囊收缩素参与胃肠运动功能调节

胰和胆囊是胆囊收缩素(CCK)在胃肠道中的主要靶器官。鉴于CCK受体存在于整个胃肠道,并且存在于胃、胆囊、小肠和结肠的平滑肌细胞上,因而有理由认为CCK不仅具有刺激胰、胆分泌的生理作用,而且亦可能调节胃肠运动。新近面世的CCK受体拮抗剂loxiglumide(Lox)系抗溃疡新药丙谷胺(proglumide)     

Ghrelin,CGRP,NT对胃肠作用的研究进展

胃肠道是人体内最大的激素分泌器官,是调节肽即胃肠激素最丰富的来源。胃肠激素与胃肠功能有很大关系,它们与神经系统一起,共同调节消化器官的运动、分泌和吸收及其他多种功能。促生长素(Ghrelin)、降钙素基因相关肽(CGRP)和神经降压素(NT)是近年来新发现的胃肠激素中的代表。Ghrelin主要由胃组织产生,可以促进胃肠蠕动,还可促进胃酸分泌,这些作用是由迷走神经所介导的,ghrelin还具有对消化道粘膜的保护作用,此作用受多种方式调控。CGRP广泛分布于中枢和外周神经系统,有调节胃肠血流、胃肠分泌及胃肠运动等多种功能,目前学者普遍认为CGRP这些生物学效应的发挥是通过一氧化氮(NO)及前列腺素(PG)介导的。NT广泛分布于脑和胃肠道及其它组织中,由肠道N细胞分泌,能够抑制胃肠运动,对胃肠黏膜细胞具有保护作用,这些作用是迷走神经、调节肽等多种途径介导的。随着对这三种胃肠激素的深入了解,人们将对人体胃肠道疾病产生更加深刻的认识。本文就近年来对Ghrelin、CGRP、NT对胃肠作用的研究作一综述。     

Cx43 在调节胃肠运动障碍机制中的研究进展

胃肠运动功能障碍是许多胃肠道疾病及其他疾病的重要临床表现,其发病率高达胃肠道疾病的70%以上。缝隙连接蛋白43(connexin 43,Cx43)是细胞间隙连接通讯中最重要的间隙连接蛋白,对胃肠道动力的形成和调节起着关键性作用。中西医治疗胃肠道疾病临床疗效显著,但其起效的分子机制尚未阐释清楚。本文从Cx43的细胞间隙连接通讯的角度,对Cx43在调节胃肠运动障碍机制中的研究进展作一综述,为进一步探究中西医调节胃肠运动障碍的机制研究奠定基础。     

肝细胞生长因子在损伤肾组织中的作用

肝细胞生长因子（hepatocyte growth factor．HGF）是一种多效性生长因子,主要由间质细胞产生,通过自分泌和旁分泌方式作用于上皮细胞、内皮细胞以及间质细胞本身,具有促有丝分裂、促细胞形态形成和调节细胞活动的功能,从而对损伤的器官和组织进行修复。许多新的研究显示,在急性肾损伤时给予外源性HGF可以保护肾小管上皮细胞、重建肾小管结构和维持肾功能完整性。此外,HGF还能有效地抑制与慢性肾脏疾病及慢性肾功能衰竭密切相关的肾间质纤维化的进展过程。     

Development of c‐kit immunopositive interstitial cells of Cajal in the human stomach

Interstitial cells of Cajal (ICC) include several types of specialized cells within the musculature of the gastrointestinal tract (GIT). Some types of ICC act as pacemakers in the GIT musculature, whereas others are implicated in the modulation of enteric neurotransmission. Kit immunohistochemistry reliably identifies the location of these cells and provides information on changes in ICC distribution and density. Human stomach specimens were obtained from 7 embryos and 28 foetuses without gastrointestinal disorders. The specimens were 7–27 weeks of gestational age, and both sexes are represented in the sample. The specimens were exposed to anti‐c‐kit antibodies to investigate ICC differentiation. Enteric plexuses were immunohistochemically examined by using anti‐neuron specific enolase and the differentiation of smooth muscle cells (SMC) was studied with anti‐α smooth muscle actin and anti‐desmin antibodies. By week 7, c‐kit‐immunopositive precursors formed a layer in the outer stomach wall around myenteric plexus elements. Between 9 and 11 weeks some of these precursors differentiated into ICC. ICC at the myenteric plexus level differentiated first, followed by those within the muscle layer: between SMC, at the circular and longitudinal layers, and within connective tissue septa enveloping muscle bundles. In the fourth month, all subtypes of c‐kit‐immunoreactivity ICC which are necessary for the generation of slow waves and their transfer to SMC have been developed. These results may help elucidate the origin of ICC and the aetiology and pathogenesis of stomach motility disorders in neonates and young children that are associated with absence or decreased number of these cells.     

Deficiency of intramuscular ICC increases fundic muscle excitability but does not impede nitrergic innervation

The motility of the gastrointestinal tract is generated by smooth muscle cells and is controlled to a large extent by an intrinsic neural network. A gap of approximately 200 nm usually separates nerve varicosities from smooth muscle cells, which suggests that direct innervation of the smooth muscle by synapses does not occur. Enteric nerves do make synapse-like contact with proposed regulatory cells, the interstitial cells of Cajal (ICC), which in turn may be in gap junction contact with smooth muscle cells. The role played by ICC in enteric innervation is controversial. Experimental evidence has been presented in vitro for the hypothesis that nitrergic inhibitory innervation is strongly reduced in the absence of ICC. However, in vivo data appear to dispute that. The present report provides evidence that explains the discrepancy between in vivo and in vitro data and provides evidence that inhibitory neurotransmitters can reach smooth muscle cells without hindrance when ICC are absent. The fundic musculature shows increased responses to substance P-mediated innervation and shows marked spontaneous activity, which is consistent with increased muscle excitability.     

Enteric motor neurons form synaptic-like junctions with interstitial cells of Cajal in the canine gastric antrum

Morphological studies have shown synaptic-like structures between enteric nerve terminals and interstitial cells of Cajal (ICC) in mouse and guinea pig gastrointestinal tracts. Functional studies of mice lacking certain classes of ICC have also suggested that ICC mediate enteric motor neurotransmission. We have performed morphological experiments to determine the relationship between enteric nerves and ICC in the canine gastric antrum with the hypothesis that conservation of morphological features may indicate similar functional roles for ICC in mice and thicker-walled gastrointestinal organs of larger mammals. Four classes of ICC were identified based on anatomical location within the tunica muscularis. ICC in the myenteric plexus region (IC-MY) formed a network of cells that were interconnected to each other and to smooth muscle cells by gap junctions. Intramuscular interstitial cells (IC-IM) were found in muscle bundles of the circular and longitudinal layers. ICC were located along septa (IC-SEP) that separated the circular muscle into bundles and were also located along the submucosal surface of the circular muscle layer (IC-SM). Immunohistochemistry revealed close physical associations between excitatory and inhibitory nerve fibers and ICC. These contacts were synaptic-like with pre- and postjunctional electron-dense regions. Synaptic-like contacts between enteric neurons and smooth muscle cells were never observed. Innervated ICC formed gap junctions with neighboring smooth muscle cells. These data show that ICC in the canine stomach are innervated by enteric neurons and express similar structural features to innervated ICC in the murine GI tract. This morphology implies similar functional roles for ICC in this species.     

Appearance of interstitial cells of Cajal in the human midgut

Several subtypes of the interstitial cells of Cajal (ICC) form networks that play a role in gastrointestinal motor control. ICC express c-kit and depend on signaling via Kit receptors for development and phenotype maintenance. At 7-8 weeks of development, c-kit-immunoreactive (c-kit-IR) cells are present in the human oesophagus, stomach and proximal duodenum wall. In the remaining small and large bowel, c-kit-IR cells appear later. The object of the present study is to determine the timing of the appearance of c-kit-IR ICC in the parts of the digestive tube originating from the midgut (distal duodenum, jejunum, ileum and proximal colon). Specimens were obtained from eight human embryos and 11 fetuses at 7-12 weeks of gestational age. The specimens were exposed to anti-c-kit antibodies to investigate ICC differentiation. The differentiation of enteric neurons and smooth muscle cells was immunohistochemically examined by using anti-PGP9,5 and anti-desmin antibodies, respectively. In the distal duodenum, jejunum and ileum, c-kit-IR cells emerged at week 9 at the level of the myenteric plexus in the form of a thin row of cells encircling the inception of the ganglia. These cells were multipolar or spindle-shaped with two long processes and corresponded to the ICC of the myenteric plexus. In the proximal colon, c-kit-IR cells emerged at week 9-10 in the form of two parallel belts of cells extending at the submucosal plexus and the myenteric plexus levels. We conclude that ICC develop following two different patterns in the human midgut.     

Two patterns of development of interstitial cells of Cajal in the human duodenum

At the end of the embryonic period of human development, c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal (ICC) are present in the oesophagus and stomach wall. In the small and large bowel, c-kit-IR cells appear later (in the small bowel at 9 weeks, and in the colon at 10-12 weeks), also in the MP region. The object of this study was to determine the timing of appearance and distribution of c-kit IR cells in the human embryonic and foetal duodenum. I used immunohistochemistry to examine the embryonic and foetal duodenum for cells expressing CD117 (Kit), expressed by mature ICC and ICC progenitor cells and CD34 to identify presumed ICC progenitors. Enteric plexuses were examined by way of antineuron-specific enolase and the differentiation of smooth muscle cells was studied using antidesmin antibodies. At the end of the embryonic period of development, c-kit IR cells were solely present in the proximal duodenum in the form of a wide belt of densely packed cells around the inception of the myenteric plexus (MP) ganglia. In the distal duodenum, c-kit IR cells emerged at the beginning of the foetal period in the form of thin rows of pleomorphic cells at the level of the MP. From the beginning of the fourth month, the differences in the distribution of ICC in the different portions of the duodenum were established, and this relationship was still present in later developmental stages. In fact, in the proximal duodenum, ICC of the MP (ICC-MP), ICC of the circular muscle (ICC-CM) and ICC of the septa (ICC-SEP) were present, and in the distal duodenum ICC-MP and ICC-SEP only. In conclusion, in the humans there is a difference in the timing and patterns of development of ICC in the proximal duodenum compared to the distal duodenum.     

Pathophysiology of motility dysfunction in bowel obstruction: role of stretch-induced COX-2

In gastrointestinal conditions such as bowel obstruction, pseudo-obstruction, and idiopathic megacolon, the lumen of affected bowel segments is distended and its motility function impaired. Our hypothesis is that mechanical stretch of the distended segments alters gene expression of cyclooxygenase-2 (COX-2), which impairs motility function. Partial obstruction was induced with a silicon band in the distal colon of rats for up to 7 days, and wild-type and COX-2 gene-deficient mice for 4 days. Mechanical stretch was mimicked in vitro in colonic circular muscle strips and in primary culture of colonic circular smooth muscle cells (SMC) with a Flexercell system. The rat colonic circular muscle contractility was significantly decreased in the distended segment oral to obstruction, but not in the aboral segment. This change started as early as day 1 and persisted for at least 7 days after obstruction. The expression of COX-2 mRNA and protein increased dramatically also in the oral, but not aboral, segment. The upregulation of COX-2 expression started at 12 h and the effect persisted for 7 days. At 24 h after obstruction, the COX-2 mRNA level in the oral segment increased 26-fold compared with controls. This was not accompanied by any significant increase of myeloperoxidase or inflammatory cytokines. Immunohistochemical studies showed that COX-2 was selectively induced in the colonic SMC. In vitro stretch of colonic muscle strips or cultured SMC drastically induced COX-2 expression. Incubation of circular muscle strips from obstructed segment with COX-2 inhibitor NS-398 restored the contractility. The impairment of muscle contractility in obstructed colon was attenuated in the COX-2 gene-deficient mice. In conclusion, mechanical stretch in obstruction induces marked expression of COX-2 in the colonic SMC, and stretch-induced COX-2 plays a critical role in the suppression of smooth muscle contractility in bowel obstruction.     

Physiology and pathophysiology of the interstitial cells of Cajal: from bench to bedside. IV. Genetic and animal models of GI motility disorders caused by loss of interstitial cells of Cajal

Several human motility disorders have been shown to be associated with loss or defects in interstitial cells of Cajal (ICC) networks. Because tissue samples for these studies were taken from patients with well-advanced motility problems, it is difficult to determine whether the loss of ICC is a cause or a consequence of the disease process. To establish the cause-and-effect relationship of ICC loss in motility disorders, it may be feasible to use animal models in which ICC are lost as motility dysfunction develops. Several models with defects in ICC networks have been developed, and these include animals with defects in the Kit signaling pathway (e.g., white-spotting mutants that have defects in Kit receptors; steel mutants that have mutations in stem cell factor, the ligand for Kit; and animals that are chronically treated with reagents that block Kit or downstream signaling proteins). ICC do not die when Kit signaling is blocked, rather, they redifferentiate into a smooth muscle-like phenotype. Diabetic animals (NOD/LtJ mice), animals with chronic bowel obstruction, and inflammatory bowel models also have defects in ICC networks that have been associated with motility disorders. By studying these models with molecular and genomic techniques it may be possible to determine the signals that cause loss of ICC and find ways of restoring ICC to dysfunctional tissues. This article discusses recent progress in the utilization of animal models to study the consequences of losing ICC on the development of motility disorders.     

Modulation of electrical activity in gastrointestinal smooth muscle by peptides.

A rise in intracellular calcium is the predominant signal that leads to the activation of the contractile machinery in gastrointestinal smooth muscle. The primary sources of activating calcium are illustrated in Fig. 2. Voltage- and peptide-mediated release of intracellular calcium contribute to activation of some gastrointestinal smooth muscles. However, the primary source of activating calcium appears to be an influx of calcium across the plasma membrane. The degree of modulation of electrical activity by peptides varies depending upon the region of the gastrointestinal tract studied. Second messenger systems are undoubtly involved in the transduction pathway for receptor-mediated changes in ion channel activity in gastrointestinal smooth muscle. However, in comparison to other excitable cell types, little is known about the coupling mechanisms whereby peptide-receptor binding alters ion channel activity in gastrointestinal smooth muscle. This represents one of the challenging areas to be studied in the field of gastrointestinal smooth muscle. One disease in which a better appreciation of the regulation of ion channel activity could lead to therapeutic benefit is irritable bowel syndrome. A coupling of smooth muscle electrical activity to hypermotility in irritable bowel syndrome has been reported. CCK increases the level of spike activity which triggers hypermotility [40]. It would follow that inhibition of calcium influx should reduce spiking and, therefore, hypermotility. In fact, the calcium channel blockers nifedipine and nicardipine have been shown to decrease colonic motility in irritable bowel syndrome patients [62-64]. As our understanding of gastrointestinal smooth muscle ion channels expands, development of a gastrointestinal selective calcium channel blocker may be possible. This class of agents would be effective in the treatment of irritable bowel syndrome and potentially other peptide-related spastic smooth muscle disorders.