痛泻要方对D-IBS结肠黏膜5-HT及CGA相关离子通道转运机制的研究

【摘要】腹泻型肠易激综合征(diarrhea-predominant irritable bowel syndrome，D-IBS)是临床常见的功能性肠道疾病，给患者的生活和工作带来诸多不便。痛泻要方作为中医古代著名方剂，能够明显减轻D-IBS患者的腹痛、腹泻症状，提高其生活和工作质量，但其治疗的确切机制尚不明确，本文从5-羟色胺及嗜铬素A(chromogranin A，CGA)相关离子通道转运机制的角度出发，探讨痛泻要方对D-IBS结肠黏膜离子通道的影响，以期为后续的临床与基础研究提供可靠的依据。

［doi: 10．3969/j．issn．1006-7795．2015．04．026］·转化医学研究·

基金项目:国家自然科学基金(81473644)，北京市医院管理局临床医学发展专项经费资助(ZYLX201411)，北京市卫生系统高层次卫生技术人才培养计划(2011-2-13)。This study was supported by National Natural Science Foundation of China(81473644)，Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support(ZYLX201411)，Project of Health Technical Personnel of Beijing Health System(2011-2-13)．* Corresponding author，E-mail: zhss2000@ 163．com

网络出版时间: 2015－07－16 23∶15网络出版地址: http:∥www．cnki．net/kcms/detail/11．3662．r．20150716．2315．029．html

Effects of TongXie-YaoFang formula on serotonin and chromogranin a related transport mechanism of ion channels in colonic mucosa in diarrhea-predominant irritable bowel syndrome

Zhang Shengsheng *，Yang Cheng

(Center for Digestive Disease，Beijing Hospital of Traditional Chinese Medicine，Capital Medical University，Beijing 100010，China)

【Abstract】Diarrhea-predominant irritable bowel syndrome(D-IBS)is a clinically common functional intestinal disease and it brings inconvenience to patients＇live and work．TongXie-YaoFang(TXYF)formula，as a famous ancient prescription of Traditional Chinese Medicine，can significantly reduce the abdominal pain and diarrhea of D-IBS patients，thereby to improve the quality of their live and work．However，the exact mechanism is unclear．This article explores the influence of TXYF formula on ion channels of colon mucous membrane in D-IBS from the perspective of 5-HT and chromogranin A(CGA)related ion channel transport mechanism in order to provide reliable basis for subsequent clinical and basic research．

【Key words】　TongXie-YaoFang(TXYF)formula; diarrhea-predominant irritable bowel syndrome(D-IBS); serotonin(5-HT); chromogranin A; ion channels; colonic mucosa

Diarrhea-predominant irritable bowel syndrome(DIBS)is a chronic functional gastrointestinal disease and clinical manifestations are characterized by diarrhea，abdominal pain or discomfort with no organic gastrointestinal disorders．The diagnosis of D-IBS is based on symptom assessment and the Rome III criteria ［1］．It is believed that a combination of the Rome III criteria，blood tests，a physical examination，gastroscopy and colonoscopy with biopsies is considered necessary for diagnosis of D-IBS．In accordance with the epidemiologic data，DIBS mainly occurs in the young adults between 20 and 40 years of age and more often in women than in men ［2］．Currently，the pathogenesis of D-IBS has not been completely elucidated．With the“bio-psycho-social”medical model to be established，the pathogenesis of D-IBS seems to be multifactorial，with the following factors playing a central role in the pathogenesis of D-IBS: high visceral sensitivity，abnormal intestinal motility，brain-gut axis disorder，heritability and genetics，dietary/intestinal microbiota，low-grade inflammation，and disturbances in the neuroendocrine system(NES)of the gut ［3-4］．The usual treatment of Western medicine for the disease is symptomatic therapy which is not satisfactory to patients and increased use of health care resources simultaneously ［5-6］．However，alternative therapies，such as cognitive behavioural therapy and gut-directed hypnotherapy，have been used with good results ［7］．Traditional Chinese medicine(TCM)can significantly improve the patient＇s symptoms and the quality of life，more and more patients begin to seek treatment with TCM ［8-9］．

1　Traditional Chinese medicine TongX-ie-Yaofang formula

Tongxie Yaofang formula(TXYF)was created by Zhudanxi who was a famous Chinese medical scientist of the Yuan dynasty．TXYF is composed of Radix paeoniae alba，dried Tangerine Peel，Radix sileris and Atractylodes ovata．In recent years，there are more and more clinical studies and animal experiments about TXYF ［10-12］．However，the exact mechanism of the treatment of D-IBS is unclear．The authors will further explore the mechanism of TXYF’treatment for D-IBS on the basis of previous animal experiments ［13］．Recent studies have preliminarily showed that the mechanism of TXYF’treatment for D-IBS is via adjusting the colonic mucosa ion channels，changing the dynamics of the colon，and further affects the secretion and absorption of colonic mucosa．

2　Serotonin(5　-hydroxytryptamine，5　-HT)

5-HT is an important monoamine neurotransmitter in the hypothalamic-pituitary-adrenal(HPA)axis and plays significant physiopathological role in the secretion and absorption of colonic mucosa as well as in the contraction and relaxation of smooth muscle ［14］．According to the authoritative researches ［15-17］，5-HT3 receptors are widely distributed in the neurons of the gastrointestinal tract accounted for about 95%，as well as in the spinal cord and brain accounted for about 5%．The 5-HT3 receptor is a unique one which is a ligand-gated cation channel that belongs to the nicotine/γ-aminobutyric acid-receptor superfamily among the seven major subtypes，termed 5-HT1 to 5-HT7，while all the others are part of the family of G-protein-coupled receptors ［17］．The activation of gastrointestinal 5-HT3 receptors can lead to secretion and absorption of intestinal tract as well as peristaltic activity by stimulating the release of various neurotransmitters such as acetylcholine ［18-19］．Furthermore，it has been reported that selective 5-HT3-receptor antagonists，such as ramosetron，can effectively alleviate abdominal pain which is resulted from colonic distension，so that to illustrate that 5-HT3 receptors are involved in visceral nociceptive transmission ［20］．

3　Chromogranin A(CGA)

CGA，as a member of the nerve peptide family，is distributed within the chromaffin granules of neuroendocrine cells as well as in all neuroendocrine intracellular vesicles which can secrete catecholamine．At the same time，CGA is distributed in the intestinal endocrine tissues and participates in metabolism of the Ca 2+and catecholamine ［3］．It has been reported that the density of CGA-containing cells are lower in the duodenum of IBS patients ［21］while the sensitivity and specificity at the cutoff＜31 cells/mm 2in the duodenum are 91% and 89%，respectively ［3］．However，the density of CGA and CGA-containing cells in the colon tissues are unclear．An ongoing research shows that CGA is implicated as a potential mechanism of D-IBS and the density of CGA and CGA-containing cells in the colon tissues are lower in DIBS rats．CGA cell density may become a promising biomarker for the diagnosis of IBS．

4　Hypothalamic-pituitary-adrenal(HPA)axis

Recently，greater attention has been paid to the topic of dysregulation in HPA axis because of its importance in pathogenesis of D-IBS ［22-23］．According to a research conducted by Videlock et al． ［23］，HPA axis hyperresponsiveness to a visceral stressor which is correlative to a history of early adverse life events is more than to the existence of IBS．On the other hand，HPA axis reactivityhas a moderate effect on IBS symptoms．CGA and 5-hydroxytryptamine，as the regulatory factors of bowel function activity，play significant physiopathological roles in the secretion and absorption of colonic mucosa as well as in the motor and sensation of smooth muscle ［14］．Meanwhile，all of them play important roles in the HPA

axis ［2］．

5　Summary

CGA and 5-hydroxytryptamine play significant physiopathological roles in the pathogenesis of D-IBS．The author have preliminarily reviewed the literature and explored that the interaction of CGA and 5-hydroxytryptamine maybe an important potential pathogenesis of D-IBS．However，it still need further research and further work to elucidate D-IBS mechanisms will focus on understanding how they interact．Although the details of TXYF’therapeutic mechanism of action remain to be clarified，TXYF has clear prospect for D-IBS therapy and may completely replace current treatments such as ramosetron．

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(收稿日期: 2012-02-11)

编辑慕萌