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      Xiaozhang Tie Improves Intestinal Motility in Rats With Cirrhotic Ascites by Regulating the Stem Cell Factor/c-kit Pathway in Interstitial Cells of Cajal

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          We previously discovered that Xiaozhang Tie (XZT) was helpful for cirrhotic ascites, with obvious abdominal distention relief, suggesting that it may improve gastrointestinal (GI) motility. However, the underlying mechanisms of GI motility in cirrhotic ascites are unclear. Here, we aimed to discover explored the effect of XZT on GI motility in animal cirrhotic ascites and probed the action mechanism affecting GI motility by regulating the stem cell factor (SCF)/c-kit pathway in interstitial cells of Cajal (ICCs) and GI hormones. First, rat models of cirrhotic ascites were developed and then divided randomly into the following three subgroups: model control, XZT group, and mosapride group. The efficacy of XZT on treating cirrhotic ascites was evaluated on the basis of ascites weight and volume, 24 h urine volume, and feces water content. GI motility of the cirrhotic model, intestine propulsion, and gastric residue were detected using the migration distance of ink in vivo, and the frequency of contraction and tension of isolated gastric and jejunal muscle strips were measured after incubation with XZT extracts. Serum GI hormone content, including motilin (MTL), substance P (SP), somatostatin (SS), and vasoactive intestinal polypeptide were assayed. Subsequently, ICCs were isolated from jejunum, and primarily cultured ICCs were incubated with and without XZT and SCF. The cell vitality of the ICCs was measured. A whole-cell patch recording technique was used to record the current of K + and Na + channels in the ICC membrane. Expressions of c-kit/p-c-kit, p-Akt, p-STAT3, and p-Erk1/2 were detected in vivo and in vitro. The results revealed that XZT significantly reduced ascites weight and increased urine volume and fecal water content in model rats. XZT promoted intestinal motility and increased MTL level but reduced SP and SS levels. It enhanced the current of Na + and K + in ICCs and improved c-kit expression and signaling mediator phosphorylation in SCF/c-kit, which was inhibited by imatinib in vitro and downregulated in model rats in vivo. Our study concluded that XZT reduced the amount of ascites and improved intestinal motility in cirrhotic rats, which may be associated with its effect on ascites and was involved in the mechanisms regulating the SCF/c-kit signaling pathway in ICCs and improving gastrointestinal hormone secretion.

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          Most cited references 13

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          Management of adult patients with ascites due to cirrhosis: an update.

           ,  Justin Runyon (2009)
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            Natural history of patients hospitalized for management of cirrhotic ascites.

            Since the International Ascites Club published the diagnostic criteria of refractory ascites (RA) and hepatorenal syndrome (HRS), there have been few studies assessing the natural history of ascites. The aims of this study were to define the natural history of cirrhotic ascites and to identify prognostic factors for dilutional hyponatremia (DH), RA, HRS, and survival. Two hundred sixty-three consecutive cirrhotic patients were followed for 40.9 +/- 2.6 months after their first significant ascites. During follow-up 74 (28.1%) patients developed DH, 30 (11.4%) RA (diuretic-resistant in 2 cases and diuretic-intractable because of the development of diuretic-induced complications in 28 cases), and 20 (7.6%) HRS (type 1, 7; type 2, 13). The 5-year probability of DH, RA, and HRS development was 37.1%, 11.4%, and 11.4%, respectively. The probability of survival at 1 and 5 years was 85% and 56.5%, respectively. The independent predictors for survival were baseline age, baseline Child-Pugh score, and DH development. The 1-year probability of survival after developing DH, RA, and type 2 HRS was 25.6%, 31.6%, and 38.5%, respectively. In contrast, the mean survival was only 7 +/- 2 days in those patients developing type 1 HRS. (1) The survival of cirrhotic patients with first episode of ascites is relatively high, and it is mainly influenced by age and Child-Pugh score at the time of ascites decompensation, as well as by DH development. (2) The probability of RA and HRS development is relatively low, but they are associated with a poor prognosis.
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              Gut transit is associated with gastrointestinal symptoms and gut hormone profile in patients with cirrhosis.

              Liver cirrhosis is associated with increased prevalence of gastrointestinal symptoms, insulin resistance, and altered gut transit. We aimed to assess the prevalence of gut transit abnormalities in patients with cirrhosis, compared with healthy controls, and to evaluate the relation of gut transit with gastrointestinal symptoms and postprandial glucose and hormone profiles. Half gastric emptying, small bowel residence, and colonic filling times were measured with a validated radiologic procedure in 42 consecutive patients with cirrhosis. In a subgroup of 25 patients, gastrointestinal symptoms were evaluated by using a validated questionnaire and a caloric satiation test. Postprandial glucose, insulin, leptin, ghrelin, glucagon-like peptide 1, and PYY responses were also studied. Eighty-three healthy subjects served as controls for the transit studies and 10 for the hormone analyses. Of patients with cirrhosis, 24% had delayed gastric emptying and 38% had prolonged small bowel transit (P < .05 compared with controls). Delayed gastric emptying was related to postprandial fullness and prolonged small bowel transit to diarrhea and abdominal pain (P < .05 for all). The patients with cirrhosis had increased postprandial glucose, insulin, and glucagon-like peptide 1 responses and reduced postprandial ghrelin. Delayed gastric emptying was related to increased postprandial glucose and reduced postprandial ghrelin. Prolonged small bowel transit was related to increased postprandial glucose and insulin and reduced postprandial ghrelin. A high proportion of patients with cirrhosis exhibit delayed gastric emptying or small bowel transit, which is related to gastrointestinal symptoms. Postprandial hyperglycemia, hyperinsulinemia, and hypoghrelinemia might be linked to delayed gut transit in cirrhosis.

                Author and article information

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                04 February 2020
                : 11
                1 Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, China
                2 Shanghai Key Laboratory of Traditional Chinese Clinical Medicine , Shanghai, China
                3 Department of Pharmaceutical Sciences, School of Pharmacy, Shanghai University of Traditional Chinese Medicine , Shanghai, China
                4 Key Laboratory of Liver and Kidney Diseases, Ministry of Education , Shanghai, China
                5 Shanghai Innovation Center of TCM Health Service , Shanghai, China
                Author notes

                Edited by: Yibin Feng, The University of Hong Kong, Hong Kong

                Reviewed by: Feng Mei, Army Medical University, China; Wen-xie Xu, Shanghai Jiao Tong University, China

                *Correspondence: Chenghai Liu, chenghailiu@ 123456hotmail.com ; Nianping Feng, npfeng@ 123456hotmail.com

                †These authors have contributed equally to this work and share first authorship

                ‡Present address: Qiang Zhao, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China

                This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

                Copyright © 2020 Zhao, Xing, Tao, Liu, Huang, Peng, Feng and Liu

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 13, Pages: 10, Words: 5981
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81473479
                Original Research


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