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Tojapride Reverses Esophageal Epithelial Inflammatory Responses on Reflux Esophagitis Model Rats

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Abstract

Objective

To investigate the mechanism of Tojapride, a Chinese herbal formula extract, on strengthening the barrier function of esophageal epithelium in rats with reflux esophagitis (RE).

Methods

Ten out of 85 SD rats were randomly selected as the sham group (n10), and 75 rats were developed a reflux esophagitis model (RE) by the esophageal and duodenal side-to-side anastomosis. Fifty successful modeling rats were divided into different medicated groups through a random number table including the model, low-, medium-, and high-dose of Tojapride as well as omeprazole groups (n10). Three doses of Tojapride [5.73, 11.46, 22.92 g/(kg•d)] and omeprazole [4.17 mg/(kg•d)] were administrated intragastrically twice daily for 3 weeks. And the rats in the sham and model groups were administered 10 mL/kg distilled water. Gastric fluid was collected and the supernatant was kept to measure for volume, pH value and acidity. Esophageal tissues were isolated to monitor the morphological changes through hematoxylin-eosin (HE) staining, and esophageal epithelial ultrastructure was observed by transmission electron microscopy. The expressions of nuclear factor kappa-light-chain-enhancer of activated B cells p65 (NF-KBp65), κB kinase beta (IKKß), occludin, and zonula occludens-1 (ZO-1) in the esophageal tissues were measured by immunohistochemistry and Western blot, respectively.

Results

The gastric pH value in the model group was significantly lower than the sham group (P<0.05). Compared with the model group, gastric pH value in the omeprazole and medium-dose of Tojapride groups were significantly higher (P<0.05). A large area of ulceration was found on the esophageal mucosa from the model rats, while varying degrees of congestion and partially visible erosion was observed in the remaining groups. Remarkable increase in cell gap width and decrease in desmosome count was seen in RE rats and the effect was reversed by Tojapride treatment. Compared with the sham group, the IKKß levels were significantly higher in the model group (P<0.05). However, the IKKß levels were down-regulated after treatment by all doses of Tojapride (P<0.01 or P<0.05). The occluding and ZO-1 levels decreased in the model group compared with the sham group (Ps0.01 or Ps0.05), while both indices were significantly up-regulated in the Tojapride-treated groups (P<0.01 or P<0.05).

Conclusions

Tojapride could improve the pathological conditions of esophageal epithelium in RE rats. The underlying mechanisms may involve in down-regulating the IKKß expression and elevating ZO-1 and occludin expression, thereby alleviating the inflammation of the esophagus and strengthening the barrier function of the esophageal epithelium.

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Authors and Affiliations

  1. Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China

    Xiao-lan Yin, Xiao-shuang Shi, Jiao Zhang, Zheng-yi Chen, Hui Che, Xiang-xue Ma, Ya-xin Tian, Yuan-zhi Duan, Lin Lu, Hai-jie Ji, Xu-dong Tang & Feng-yun Wang

  2. School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region, Kowloon, China

    Linda Zhong & Cheng-yuan Lin

  3. Department of Gastroenterology, Changping Hospital of Traditional Chinese Medicine, Beijing, 102200, China

    Jiao Zhang

  4. Department of Traditional Chinese Medicine, Dongfeng General Hospital, Shiyan, Hubei Province, 442000, China

    Zheng-yi Chen

  5. Center of Clinical Pharmacology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China

    Ying-pan Zhao

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  1. Xiao-lan Yin
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Corresponding author

Correspondence to Feng-yun Wang.

Additional information

Author Contributions|Tang XD and Wang FY designed the study; Yin XL and Zhong L participated in the paper design and preparation; Zhang J, Chen ZY, Duan YZ, JI HJ and Shi XS mainly performed the experiments; Che H, and Tian YX carried out the animal study

Ma XX and Lu L participated in the experimental design and data analysis; Lin CY and Zhao YP were involved in discussion of experiment and preparing the manuscript. All authors read and approved the final manuscript for publication.

Supported by Natural Science Foundation of China (No.81503560), “Ten Diseases and Ten Drugs” Program and the Cultivation Research of Biological Medicine and Life Science Innovation of Beijing Municipal Science and Technology Commission (No. Z141100002214012, Z161100000116046)

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Yin, Xl., Zhong, L., Lin, Cy. et al. Tojapride Reverses Esophageal Epithelial Inflammatory Responses on Reflux Esophagitis Model Rats. Chin. J. Integr. Med. 27, 604–612 (2021). https://doi.org/10.1007/s11655-019-3027-5

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