Preliminary verification of animal model of benign esophageal stricture caused by gastroesophageal reflux in rats_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 LI Zhitong ¹ , KONG Xianglin ² , LIU Bingrong ¹ , LIU Dan ¹ , WANG Meng ¹ , LI Deliang ¹

1. Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, R. P. China;
2. Experiment Center of Shandong University of Traditional Chinese Medicine, Jinan 250355, R. P. China;

Corresponding author：

LI Zhitong, Email: jylizhitong@163.com

Keywords：

gastroesophageal reflux; esophageal stricture; hydrochloric acid-pepsin; animal experimentation

DOI：

10.7507/1007-9424.202309076

Video：

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Objective To develop an experimental model of gastroesophageal reflux-induced esophageal stricture in rats and explore the mechanism of esophageal stricture. Methods A total of 30 male Sprague-Dawley (SD) rats by random number table method were randomly divided into three groups as follows: an operation+acid perfusion group, first the models of lower esophageal sphincter relaxation and hiatal hernia were made, and then the rats’ esophagus were perfused with hydrochloric acid-pepsin; acid perfusion group, the rats’ esophagus were directly perfused with hydrochloric acid-pepsin; and control group, rats’ esophagus were perfused with normal saline. After 4 weeks of continuous perfusion, the esophageal mucosal injury of SD rats in each group were observed, and the concentrations of inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-18] in esophageal tissues were detected by enzyme-linked immunosorbent assay. Results In the operation+acid perfusion group, esophageal stricture was formed in 2 SD rats, but no esophageal stenosis was found in the acid perfusion group and the control group. The body weight of rats in the operation+acid perfusion group and the acid perfusion group were lower than that in the control group (P<0.05). The esophageal mucosal injury scores of rats in the operation+acid perfusion group and the acid perfusion group were higher than that in the control group (P<0.001), and the operation+acid perfusion group was higher than that in the acid perfusion group (P=0.014). The concentrations of TNF-α, IL-1β and IL-18 in esophageal tissues were higher in the operation+acid perfusion group and the acid perfusion group than that in the control group (P<0.001), and the operation+acid perfusion group was higher than that in the acid perfusion group (P<0.001). Conclusions The anti-reflux barrier is an important part of preventing gastroesophageal reflux disease. The destruction of anti-reflux barrier, hydrochloric acid-pepsin perfusion and inflammatory cytokines jointly induced esophageal inflammation and injury, and even caused esophageal stricture.

1.	Stein HJ, Barlow AP, DeMeester TR, et al. Complications of gastroesophageal reflux disease. Role of the lower esophageal sphincter, esophageal acid and acid/alkaline exposure, and duodenogastric reflux. Ann Surg, 1992, 216(1): 35-43.
2.	Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol, 2013, 108(3): 308-328.
3.	李治仝, 季锋, 韩新巍, 等. 胃食管反流致食管良性狭窄的诊治. 中华普通外科杂志, 2018, 33(1): 77-78.
4.	White RJ, Morris GP, Cooke K, et al. Morphology and glycoconjugate content of opossum esophageal epithelium and glands: regional heterogeneity and effects of acid-induced mucosal injury and recovery. Dig Dis Sci, 2005, 50(9): 1591-1604.
5.	Amir I, Konikoff FM, Oppenheim M, et al. Gastric microbiota is altered in oesophagitis and Barrett’s oesophagus and further modified by proton pump inhibitors. Environ Microbiol, 2014, 16(9): 2905-2914.
6.	van Boeckel PG, Siersema PD. Refractory esophageal strictures: what to do when dilation fails. Curr Treat Options Gastroenterol, 2015, 13(1): 47-58.
7.	Li ZT, Kong XL, Zhang R, et al. Laparoscopic antireflux surgery or PPIs in the management of reflux-related esophageal stricture. Surg Endosc, 2023, 37(2): 1077-1085.
8.	Elton C, Uppal R, Moore D, et al. Partial cardiomyectomy—an animal model of gastro-oesophageal reflux. Int J Surg Investig, 1999, 1(1): 81-5.
9.	Wang RH. From reflux esophagitis to Barrett's esophagus and esophageal adenocarcinoma. World J Gastroenterol, 2015, 21(17): 5210-5219.
10.	Huo X, Zhang X, Yu C, et al. In oesophageal squamous cells exposed to acidic bile salt medium, omeprazole inhibits IL-8 expression through effects on nuclear factor-κB and activator protein-1. Gut, 2014, 63(7): 1042-1052.
11.	Chaudhuri V, Zhou L, Karasek M. Inflammatory cytokines induce the transformation of human dermal microvascular endothelial cells into myofibroblasts: a potential role in skin fibrogenesis. J Cutan Pathol, 2007, 34(2): 146-153.
12.	Platis A, Yu Q, Moore D, et al. The effect of daily administration of IL-18 on cardiac structure and function. Perfusion, 2008, 23(4): 237-242.
13.	Adams J, Heintz P, Gross N, et al. Acid/pepsin promotion of carcinogenesis in the hamster cheek pouch. Arch Otolaryngol Head Neck Surg, 2000, 126(3): 405-409.
14.	Zijlstra FG, Hynna-Liepert TT, Dinda PK, et al. Microvascular permeability increases early in the course of acid-induced esophageal injury. Gastroenterology, 1991, 101(2): 295-302.
15.	Naya MJ, Pereboom D, Ortego J, et al. Superoxide anions produced by inflammatory cells play an important part in the pathogenesis of acid and pepsin induced oesophagitis in rabbits. Gut, 1997, 40(2): 175-181.
16.	McMahon RL, Ali A, Chekan EG, et al. A canine model of gastroesophageal reflux disease (GERD). Surg Endosc, 2002, 16(1): 67-74.
17.	Wang RH. From reflux esophagitis to Barrett’s esophagus and esophageal adenocarcinoma. World J Gastroenterol, 2015, 21(17): 5210-5219.
18.	Li Y, Wo JM, Su RR, et al. Esophageal injury with external esophageal perfusion. J Surg Res, 2005, 129(1): 107-113.
19.	Li Y, Wo JM, Ellis S, et al. A novel external esophageal perfusion model for reflux esophageal injury. Dig Dis Sci, 2006, 51(3): 527-532.
20.	Li Y, Wo JM, Su RR, et al. Loss of manganese superoxide dismutase expression and activity in rat esophagus with external esophageal perfusion. Surgery, 2007, 141(3): 359-367.
21.	Ruigómez A, García Rodríguez LA, Wallander MA, et al. Esophageal stricture: incidence, treatment patterns, and recurrence rate. Am J Gastroenterol, 2006, 101(12): 2685-2692.
22.	Gaia Filho EV, Goldenberg A, Costa HO. Experimental model of gastroesophageal reflux in rats. Acta Cir Bras, 2005, 20(6): 437-444.
23.	Li Q, Kong L, Zhang S, et al. A novel external esophageal perfusion model for reflux-associated respiratory symptoms. Pathobiology, 2010, 77(3): 163-168.
24.	Ergün P, Capanoglu D, Kipcak S, et al. Response of esophageal epithelium to acute and chronic stress in rabbits. Bull Exp Biol Med, 2021, 171(5): 582-587.
25.	Rogler G, Andus T. Cytokines in inflammatory bowel disease. World J Surg, 1998, 22(4): 382-389.
26.	Rieder F, Biancani P, Harnett K, et al. Inflammatory mediators in gastroesophageal reflux disease: impact on esophageal motility, fibrosis, and carcinogenesis. Am J Physiol Gastrointest Liver Physiol, 2010, 298(5): G571-G581.
27.	Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliott M, et al. Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants. Gut, 2002, 50(4): 451-459.
28.	Zhao L, Xie P, Geng B, et al. Destruction of the dorsal motor nucleus of the vagus aggravates inflammation and injury from acid-induced acute esophagitis in a rat model. Anal Cell Pathol (Amst), 2019, 2019: 8243813.
29.	李兆申, 宛新建, 许国铭. 食管支架术后再狭窄的病理学分析. 中华消化内镜杂志, 2000, 17(4): 217.

1. Stein HJ, Barlow AP, DeMeester TR, et al. Complications of gastroesophageal reflux disease. Role of the lower esophageal sphincter, esophageal acid and acid/alkaline exposure, and duodenogastric reflux. Ann Surg, 1992, 216(1): 35-43.
2. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol, 2013, 108(3): 308-328.
3. 李治仝, 季锋, 韩新巍, 等. 胃食管反流致食管良性狭窄的诊治. 中华普通外科杂志, 2018, 33(1): 77-78.
4. White RJ, Morris GP, Cooke K, et al. Morphology and glycoconjugate content of opossum esophageal epithelium and glands: regional heterogeneity and effects of acid-induced mucosal injury and recovery. Dig Dis Sci, 2005, 50(9): 1591-1604.
5. Amir I, Konikoff FM, Oppenheim M, et al. Gastric microbiota is altered in oesophagitis and Barrett’s oesophagus and further modified by proton pump inhibitors. Environ Microbiol, 2014, 16(9): 2905-2914.
6. van Boeckel PG, Siersema PD. Refractory esophageal strictures: what to do when dilation fails. Curr Treat Options Gastroenterol, 2015, 13(1): 47-58.
7. Li ZT, Kong XL, Zhang R, et al. Laparoscopic antireflux surgery or PPIs in the management of reflux-related esophageal stricture. Surg Endosc, 2023, 37(2): 1077-1085.
8. Elton C, Uppal R, Moore D, et al. Partial cardiomyectomy—an animal model of gastro-oesophageal reflux. Int J Surg Investig, 1999, 1(1): 81-5.
9. Wang RH. From reflux esophagitis to Barrett's esophagus and esophageal adenocarcinoma. World J Gastroenterol, 2015, 21(17): 5210-5219.
10. Huo X, Zhang X, Yu C, et al. In oesophageal squamous cells exposed to acidic bile salt medium, omeprazole inhibits IL-8 expression through effects on nuclear factor-κB and activator protein-1. Gut, 2014, 63(7): 1042-1052.
11. Chaudhuri V, Zhou L, Karasek M. Inflammatory cytokines induce the transformation of human dermal microvascular endothelial cells into myofibroblasts: a potential role in skin fibrogenesis. J Cutan Pathol, 2007, 34(2): 146-153.
12. Platis A, Yu Q, Moore D, et al. The effect of daily administration of IL-18 on cardiac structure and function. Perfusion, 2008, 23(4): 237-242.
13. Adams J, Heintz P, Gross N, et al. Acid/pepsin promotion of carcinogenesis in the hamster cheek pouch. Arch Otolaryngol Head Neck Surg, 2000, 126(3): 405-409.
14. Zijlstra FG, Hynna-Liepert TT, Dinda PK, et al. Microvascular permeability increases early in the course of acid-induced esophageal injury. Gastroenterology, 1991, 101(2): 295-302.
15. Naya MJ, Pereboom D, Ortego J, et al. Superoxide anions produced by inflammatory cells play an important part in the pathogenesis of acid and pepsin induced oesophagitis in rabbits. Gut, 1997, 40(2): 175-181.
16. McMahon RL, Ali A, Chekan EG, et al. A canine model of gastroesophageal reflux disease (GERD). Surg Endosc, 2002, 16(1): 67-74.
17. Wang RH. From reflux esophagitis to Barrett’s esophagus and esophageal adenocarcinoma. World J Gastroenterol, 2015, 21(17): 5210-5219.
18. Li Y, Wo JM, Su RR, et al. Esophageal injury with external esophageal perfusion. J Surg Res, 2005, 129(1): 107-113.
19. Li Y, Wo JM, Ellis S, et al. A novel external esophageal perfusion model for reflux esophageal injury. Dig Dis Sci, 2006, 51(3): 527-532.
20. Li Y, Wo JM, Su RR, et al. Loss of manganese superoxide dismutase expression and activity in rat esophagus with external esophageal perfusion. Surgery, 2007, 141(3): 359-367.
21. Ruigómez A, García Rodríguez LA, Wallander MA, et al. Esophageal stricture: incidence, treatment patterns, and recurrence rate. Am J Gastroenterol, 2006, 101(12): 2685-2692.
22. Gaia Filho EV, Goldenberg A, Costa HO. Experimental model of gastroesophageal reflux in rats. Acta Cir Bras, 2005, 20(6): 437-444.
23. Li Q, Kong L, Zhang S, et al. A novel external esophageal perfusion model for reflux-associated respiratory symptoms. Pathobiology, 2010, 77(3): 163-168.
24. Ergün P, Capanoglu D, Kipcak S, et al. Response of esophageal epithelium to acute and chronic stress in rabbits. Bull Exp Biol Med, 2021, 171(5): 582-587.
25. Rogler G, Andus T. Cytokines in inflammatory bowel disease. World J Surg, 1998, 22(4): 382-389.
26. Rieder F, Biancani P, Harnett K, et al. Inflammatory mediators in gastroesophageal reflux disease: impact on esophageal motility, fibrosis, and carcinogenesis. Am J Physiol Gastrointest Liver Physiol, 2010, 298(5): G571-G581.
27. Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliott M, et al. Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants. Gut, 2002, 50(4): 451-459.
28. Zhao L, Xie P, Geng B, et al. Destruction of the dorsal motor nucleus of the vagus aggravates inflammation and injury from acid-induced acute esophagitis in a rat model. Anal Cell Pathol (Amst), 2019, 2019: 8243813.
29. 李兆申, 宛新建, 许国铭. 食管支架术后再狭窄的病理学分析. 中华消化内镜杂志, 2000, 17(4): 217.

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