Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2017; 23(40): 7242-7252
Published online Oct 28, 2017. doi: 10.3748/wjg.v23.i40.7242
Dachaihu decoction ameliorates pancreatic fibrosis by inhibiting macrophage infiltration in chronic pancreatitis
Li-Fang Duan, Xiao-Fan Xu, Lin-Jia Zhu, Fang Liu, Xiao-Qin Zhang, Nan Wu, Jian-Wei Fan, Jia-Qi Xin, Hong Zhang
Li-Fang Duan, Lin-Jia Zhu, Fang Liu, Xiao-Qin Zhang, Nan Wu, Jian-Wei Fan, Jia-Qi Xin, Hong Zhang, Department of Pathophysiology, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
Xiao-Fan Xu, Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
Author contributions: Zhang H designed the research; Duan LF and Xu XF contributed equally to the work, and both performed most of the experiments and wrote the paper; Zhu LJ, Wu N, Fan JW and Xin JQ performed the experiments; Zhang XQ and Liu F analyzed the data.
Supported by the National Natural Science Foundation of China, No. 81673816; the Key Basic Research Project of Shaanxi Province, No. 2017ZDJC-14; and the Key Research Program of Natural Science of Shaanxi Education Department, No. 15JS027.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of the Shaanxi University of Chinese Medicine, Xianyang, China.
Informed consent statement: All study participants provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest related to this study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Hong Zhang, MD, PhD, Professor, Department of Pathophysiology, Shaanxi University of Chinese Medicine, Shiji Avenue, Xianyang 712046, Shaanxi Province, China. zhangh1227@163.com
Telephone: +86-29-38183453 Fax: +86-29-38183453
Received: July 31, 2017
Peer-review started: August 19, 2017
First decision: September 6, 2017
Revised: September 22, 2017
Accepted: September 29, 2017
Article in press: September 26, 2017
Published online: October 28, 2017
Processing time: 71 Days and 4.2 Hours
ARTICLE HIGHLIGHTS
Research background

Pancreatic fibrosis is a common pathological feature characteristic of chronic pancreatitis (CP). As the necrosis-fibrosis sequence plays an important role in the underlying pathogenesis of CP, pancreatic fibrosis commonly develops after repeated inflammation. Macrophages are important inflammatory cells that can also promote fibrogenesis by interfering with the synthesis and degradation of the extracellular matrix. This has been confirmed in models of liver fibrosis and renal fibrosis, but any role of macrophages in pancreatic fibrosis has remained unclear. A traditional Chinese medicinal formula, Dachaihu decoction (DCHD), has been widely used in the clinical treatment of AP, and recently, DCHD was used to treat CP, which significantly improved the patient’s clinical symptoms, but, again, the underlying mechanism has been unclear.

Research motivation

CP is a progressive inflammatory disease characterized by irreversible injury to the pancreas leading to endocrine and exocrine dysfunctions that pose serious threats to human health, because the pathogenesis is unclear, and few treatments are available. Recent studies suggested that DCHD can significantly improve the clinical symptoms of CP patients, such as abdominal pain, abdominal distension, loss of appetite and others. However, DCHD cannot be widely used clinically because the therapeutic mechanism of action remains unclear.

Research objectives

The aim was to explore the role played by macrophages in the pathogenesis of CP to further elucidate the mechanisms of CP. In addition, they assessed the efficacy of DCHD in treating CP in animal experiments to determine the mechanism involved, providing an experimental basis for promoting the use of DCHD in clinical practice.

Research methods

KunMing mice were randomly divided into a control group, CP group, and DCHD group. In the CP and DCHD groups, mice were intraperitoneally injected with 20% L-arginine (3 g/kg twice a day, 1 d a week). Mice in the DCHD group were given DCHD (14 g/kg per day) intragastrically for 1 wk after CP induction. The animals were anesthetized and sacrificed at 2 wk, 4 wk and 6 wk after study commencement. Pancreatic morphology and the extent of fibrosis were assessed using hematoxylin and eosin and Masson staining. Serum interleukin-6 (IL-6) levels were assessed by enzyme-linked immunosorbent assay. Double immunofluorescence staining was performed to assess the co-expression of F4/80 and IL-6 in the pancreas. The mRNA levels of inflammatory factors including monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α) and IL-6 were determined by real time-polymerase chain reaction. Western blotting was used to measure fibronectin (FN) levels in the pancreas.

Research results

We found that macrophage infiltration was significantly increased in the CP group, and the IL-6 levels in serum and IL-6 mRNA levels in the pancreas were also increased in the CP group. Further, immunofluorescent double-staining of F4/80 and IL-6 revealed that macrophages were the main source of the IL-6. In addition, DCHD ameliorated pancreatic fibrosis, inhibited the pancreatic infiltration of macrophages in the CP group, and reduced the release of cytokines IL-6, MCP-1 and MIP-1α mRNA, and FN levels. However, our work had certain limitations. We confirmed that the effect of macrophages on CP is related to IL-6, but the detailed mechanism of IL-6 on CP progression was not further explored. In addition, DCHD is effective in CP treatment, but its in-depth mechanism was not studied further.

Research conclusions

The authors confirmed that macrophages are involved in the development of pancreatic fibrosis and may constitute a new therapeutic target. In addition, DCHD can ameliorate pancreatic fibrosis by inhibiting macrophage infiltration and inflammatory factor secretion in the pancreas.