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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Kangfuxin solution alleviates esophageal stenosis after endoscopic submucosal dissection: A natural ingredient strategy
Xin Zhou, Dan Ma, Yi-Xiang He, Jing Jin, Hong-Lian Wang, Yun-Feng Wang, Fan Yang, Jian-Qin Liu, Jie Chen, Zhi Li
Xin Zhou, Yi-Xiang He, Zhi Li, Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China
Xin Zhou, Yi-Xiang He, Jian-Qin Liu, Zhi Li, The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, The Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China
Dan Ma, Jing Jin, Yun-Feng Wang, Fan Yang, Jie Chen, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 20082, China
Hong-Lian Wang, Jian-Qin Liu, Research Center of Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China
Zhi Li, School of Integrated Traditional Chinese and Western Clinical Medicine, North Sichuan Medical College, Nanchong, 637100, Sichuan Province, China
Co-first authors: Xin Zhou and Dan Ma.
Co-corresponding authors: Jie Chen and Zhi Li.
Author contributions: Zhou X and Ma D designed the research study; Zhou X, Ma D, and Chen J conducted the animal experiments; Zhou X, He YX, and Liu JQ conducted the in vitro experiments; Jin J, Wang YF, and Yang F was performed data analysis; Zhou X and Ma D were responsible for the visualization of the data; Zhou X wrote the manuscript; Wang HL and Li Z edited the manuscript; Ma D, Chen J, and Li Z provided foundational support for the study. Zhou X and Ma D contributed equally to this work as co-first authors. We propose Chen J and Li Z as co-corresponding authors due to their equal contributions in experimental design, research execution, and funding support. Our rationale is as follows: (1) Experimental design: Li Z conducted thorough literature research and preliminary experiments to assess the potential of Kangfuxin solution for esophageal stenosis following endoscopic submucosal dissection. Simultaneously, Chen J, leveraging his clinical experience, emphasized the use of a full circumferential endoscopic submucosal dissection (ESD) model to enhance the clinical relevance of our findings; (2) Research procedure: This complex procedure required high clinical proficiency. Professors Chen J and Li Z jointly performed all ESD operations with a strict adherence to animal welfare regulations, both taking on critical regulatory roles throughout the study; and (3) Funding support: This research was funded by Chen J (No. 2020YFS0376) and Li Z (No. 2022-CXTD-01), which was essential for procuring experimental animals and reagents. In conclusion, this study merges traditional Chinese and Western medicine approaches to address esophageal stenosis post-ESD. The diverse expertise of Chen J and Li Z enriches our research, and the authors unanimously support their designation as co-corresponding authors.
Supported by Science and Technology Department of Sichuan Province, No. 2020YFS0376; National Natural Science Foundation of China, No. 81900599; and Science and Technology Program of Hospital of TCM, Southwest Medical University, No. 2022-CXTD-01.
Institutional animal care and use committee statement: All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee of the Animal Ethics Committee of Southwest Medical University [SWMU20210381].
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Zhi Li, MD, PhD, Professor, Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, No. 1 Xianglin Road, Longmatan District, Luzhou 646000, Sichuan Province, China.
lizhi_swmu@126.com
Received: June 29, 2024
Revised: October 8, 2024
Accepted: October 25, 2024
Published online: January 7, 2025
Processing time: 163 Days and 3.7 Hours
BACKGROUND
Esophageal stricture ranks among the most significant complications following endoscopic submucosal dissection (ESD). Excessive fibrotic repair is a typical pathological feature leading to stenosis after ESD.
AIM
To examine the effectiveness and underlying mechanism of Kangfuxin solution (KFX) in mitigating excessive fibrotic repair of the esophagus post-ESD.
METHODS
Pigs received KFX at 0.74 mL/kg/d for 21 days after esophageal full circumferential ESD. Endoscopic examinations occurred on days 7 and 21 post-ESD. In vitro, recombinant transforming growth factor (TGF)-β1 (5 ng/mL) induced a fibrotic microenvironment in primary esophageal fibroblasts (pEsF). After 24 hours of KFX treatment (at 1.5%, 1%, and 0.5%), expression of α-smooth muscle actin-2 (ACTA2), fibronectin (FN), and type collagen I was assessed. Profibrotic signaling was analyzed, including TGF-β1, Smad2/3, and phosphor-smad2/3 (p-Smad2/3).
RESULTS
Compared to the Control group, the groups treated with KFX and prednisolone exhibited reduced esophageal stenosis, lower weight loss rates, and improved food tolerance 21 d after ESD. After treatment, Masson staining revealed thinner and less dense collagen fibers in the submucosal layer. Additionally, the expression of fibrotic effector molecules was notably inhibited. Mechanistically, KFX downregulated the transduction levels of fibrotic functional molecules such as TGF-β1, Smad2/3, and p-Smad2/3. In vitro, pEsF exposed to TGF-β1-induced fibrotic microenvironment displayed increased fibrotic activity, which was reversed by KFX treatment, leading to reduced activation of ACTA2, FN, and collagen I. The 1.5% KFX treatment group showed decreased expression of p-Smad 2/3 in TGF-β1-activated pEsF.
CONCLUSION
KFX showed promise as a therapeutic option for post-full circumferential esophageal ESD strictures, potentially by suppressing fibroblast fibrotic activity through modulation of the TGF-β1/Smads signaling pathway.
Core Tip: This study investigated the therapeutic effects and mechanisms of Kangfuxin solution (KFX) on esophageal stenosis following endoscopic submucosal dissection (ESD). Pigs underwent full circumferential ESD and received KFX treatment for 21 days. Endoscopic examinations assessed esophageal repair, while the expression of α-smooth muscle actin-2, fibronectin, and collagen I was evaluated. Profibrotic signaling was analyzed, including transforming growth factor (TGF)-β1, Smad2/3, and phosphor-smad2/3. In vitro, TGF-β1 induced a fibrotic microenvironment in primary esophageal fibroblasts, and KFX treatment reduced the expression of fibrotic markers in these cells.
