Experimental study of bone morphogenetic protein-4 in promoting recovery of small intestinal mucosal barrier during recovery period of intestine ischemia-reperfusion injury_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LUO Binyu ¹ , ZHANG Qin ² , ZHANG Xiao ¹ , QIN Long ¹ , GUO Qing ¹ , REN Mingyang ¹ ,  TIAN Yunhong ¹

1. Department of Gastrointestinal Surgery, Affiliated Nanchong Central Hospital & The Second Clinical Medical College of North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
2. Department of Rehabilitation Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;

Corresponding author：

TIAN Yunhong, Email: drtianyunhong@126.com

Keywords：

small intestine; ischemia-reperfusion injury; bone morphogenetic protein-4; tight junction protein; Notch signaling protein; Smad6 signaling protein; intestinal mucosal barrier

DOI：

10.7507/1007-9424.202104080

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Objective To investigate the mechanism of bone morphogenetic protein-4 (BMP4) in promoting the recovery of small intestinal mucosal barrier function during the recovery period of small intestine ischemia-reperfusion (I/R) injury. Methods Twenty-eight C57BL/6J male mice aged 6–8 weeks were randomly selected and assigned to small intestine I/R group (n=24) and sham operation (SO) group (n=4) by random number table method. Small intestine I/R injury models of 24 mice were established, then 4 mice were randomly selected at 6, 12, 24 and 48 h after I/R established modeling and killed to observe the morphological changes of small intestinal mucosa and detect the expression of BMP4 mRNA in the jejunal epithelial cells, the other 8 mice were allocated for the experimental observation at the recovery period of small intestine I/R injury (24 h after I/R was selected as the observation time point of recovery period of small intestine I/R injury according to the pre-experimental results). Twelve mice were randomly divided into I/R-24 h-BMP4 group (recombinant human BMP4 protein was injected intraperitoneally), I/R-24 h-NS (normal saline) group (NS was injected intraperitoneally), and I/R-24 h-blank group (did nothing), 4 mice in each group. Then the small intestinal transmembrane electrical impedance (TER) was measured by Ussing chamber. The expressions of BMP4 protein and tight junction proteins (occludin and ZO-1), Notch signaling pathway proteins (Notch1 and Jagged1), and Smad6 protein were detected by Western blot. Results At 24 h after I/R injury, the injuries of villous epithelium, edema, and a small part of villi were alleviated. The BMP4 mRNA expressions at 6, 12, 24 and 48 h after I/R injury in the small intestinal epithelial cells were increased as compared with the SO group. Compared with the I/R-24 h-NS group and the I/R-24 h-blank group, the TER was increased, and the expression levels of occludin, ZO-1, p-Smad6, Notch1, Jagged1 were increased in the I/R-24 h-BMP4 group. Conclusion From the preliminary results of this study, during recovery period of small intestine I/R injury, the expression of BMP4 in small intestinal epithelial cells is increased, permeability of jejunal mucosal barrier is increased, which might promote the recovery of small intestinal mucosal barrier function by activating the Notch signaling pathway (Notch1 and Jagged1), Smad classic signaling pathway, and promoting the increase of tight junction protein expression (occludin and ZO-1).

Citation： LUO Binyu, ZHANG Qin, ZHANG Xiao, QIN Long, GUO Qing, REN Mingyang, TIAN Yunhong. Experimental study of bone morphogenetic protein-4 in promoting recovery of small intestinal mucosal barrier during recovery period of intestine ischemia-reperfusion injury. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(1): 6-11. doi: 10.7507/1007-9424.202104080 Copy

1.	Wang J, Zhang W, Wu G. Intestinal ischemic reperfusion injury: recommended rats model and comprehensive review for protective strategies. Biomed Pharmacother, 2021, 138: 111482.
2.	Liu DQ, Chen SP, Sun J, et al. Berberine protects against ischemia-reperfusion injury: a review of evidence from animal models and clinical studies. Pharmacol Res, 2019, 148: 104385.
3.	罗彬予, 陈康, 冯奇, 等. 缺血再灌注条件下肠上皮细胞来源的骨形成蛋白-4 促进肠上皮间淋巴细胞凋亡的研究. 中华实验外科杂志, 2016, 33(1): 97-101.
4.	Chen G, Qiu Y, Sun L, et al. The Jagged-2/Notch-1/Hes-1 pathway is involved in intestinal epithelium regeneration after intestinal ischemia-reperfusion injury. PLoS One, 2013, 8(10): e76274.
5.	Wang S, Chen YG. BMP signaling in homeostasis, transformation and inflammatory response of intestinal epithelium. Sci China Life Sci, 2018, 61(7): 800-807.
6.	Chiu CJ, McArdle AH, Brown R, et al. Intestinal mucosal lesion in low-flow states. Ⅰ. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg, 1970, 101(4): 478-483.
7.	Soderholm JD, Hedman L, Artursson P, et al. Integrity and metabolism of human ileal mucosa in vitro in the Ussing chamber. Acta Physiol Scand, 1998, 162(1): 47-56.
8.	Vancamelbeke M, Vermeire S. The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol, 2017, 11(9): 821-834.
9.	Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol, 2009, 9(11): 799-809.
10.	牛鹏飞, 王延召, 曾庆敏, 等. 肠黏膜屏障功能及损伤机制研究进展. 中华临床医师杂志(电子版), 2020, 14(9): 735-739.
11.	Edelblum KL, Turner JR. The tight junction in inflammatory disease: communication breakdown. Curr Opin Pharmacol, 2009, 9(6): 715-720.
12.	Rose EC, Odle J, Blikslager AT, et al. Probiotics, prebiotics and epithelial tight junctions: a promising approach to modulate intestinal barrier function. Int J Mol Sci, 2021, 22(13): 6729.
13.	Slifer ZM, Blikslager AT. The integral role of tight junction proteins in the repair of injured intestinal epithelium. Int J Mol Sci, 2020, 21(3): 972.
14.	Gipson GR, Goebel EJ, Hart KN, et al. Structural perspective of BMP ligands and signaling. Bone, 2020, 140: 115549.
15.	罗彬予, 田云鸿, 张琴, 等. BMP 信号通路在肠道缺血再灌注损伤中的作用研究进展. 西部医学, 2019, 31(6): 981-984, 封3.
16.	Luo B, Chen K, Feng Q, et al. The interplay of BMP4 and IL-7 regulates the apoptosis of intestinal intraepithelial lymphocytes under conditions of ischemia/reperfusion. Int J Mol Med, 2018, 41(5): 2640-2650.
17.	Chen K, Xie W, Luo B, et al. Intestinal mucosal barrier is injured by BMP2/4 via activation of NF-κB signals after ischemic reperfusion. Mediators Inflamm, 2014, 2014: 901530.
18.	陈康, 陈应果, 王洪波, 等. 缺血再灌注条件下 BMP2/4 参与肠黏膜屏障损伤的研究. 局解手术学杂志, 2019, 28(2): 85-90.
19.	Takahashi T, Shiraishi A. Stem cell signaling pathways in the small intestine. Int J Mol Sci, 2020, 21(6): 2032.
20.	Chen G, Sun L, Yu M, et al. The Jagged-1/Notch-1/Hes-1 pathway is involved in intestinal adaptation in a massive small bowel resection rat model. Dig Dis Sci, 2013, 58(9): 2478-2486.
21.	Liang SJ, Li XG, Wang XQ. Notch signaling in mammalian intestinal stem cells: determining cell fate and maintaining homeostasis. Curr Stem Cell Res Ther, 2019, 14(7): 583-590.
22.	Mouillesseaux KP, Wiley DS, Saunders LM, et al. Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6. Nat Commun, 2016, 7: 13247.
23.	Fang H, Song P, Shen C, et al. Bone mesenchymal stem cell-conditioned medium induces the upregulation of Smad6, which inhibits the BMP-4/Smad1/5/8 signaling pathway. Neurol Res, 2016, 38(11): 965-972.
24.	Wang R, Wu G, Dai T, et al. Naringin attenuates renal interstitial fibrosis by regulating the TGF-β/Smad signaling pathway and inflammation. Exp Ther Med, 2021, 21(1): 66.

1. Wang J, Zhang W, Wu G. Intestinal ischemic reperfusion injury: recommended rats model and comprehensive review for protective strategies. Biomed Pharmacother, 2021, 138: 111482.
2. Liu DQ, Chen SP, Sun J, et al. Berberine protects against ischemia-reperfusion injury: a review of evidence from animal models and clinical studies. Pharmacol Res, 2019, 148: 104385.
3. 罗彬予, 陈康, 冯奇, 等. 缺血再灌注条件下肠上皮细胞来源的骨形成蛋白-4 促进肠上皮间淋巴细胞凋亡的研究. 中华实验外科杂志, 2016, 33(1): 97-101.
4. Chen G, Qiu Y, Sun L, et al. The Jagged-2/Notch-1/Hes-1 pathway is involved in intestinal epithelium regeneration after intestinal ischemia-reperfusion injury. PLoS One, 2013, 8(10): e76274.
5. Wang S, Chen YG. BMP signaling in homeostasis, transformation and inflammatory response of intestinal epithelium. Sci China Life Sci, 2018, 61(7): 800-807.
6. Chiu CJ, McArdle AH, Brown R, et al. Intestinal mucosal lesion in low-flow states. Ⅰ. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg, 1970, 101(4): 478-483.
7. Soderholm JD, Hedman L, Artursson P, et al. Integrity and metabolism of human ileal mucosa in vitro in the Ussing chamber. Acta Physiol Scand, 1998, 162(1): 47-56.
8. Vancamelbeke M, Vermeire S. The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol, 2017, 11(9): 821-834.
9. Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol, 2009, 9(11): 799-809.
10. 牛鹏飞, 王延召, 曾庆敏, 等. 肠黏膜屏障功能及损伤机制研究进展. 中华临床医师杂志(电子版), 2020, 14(9): 735-739.
11. Edelblum KL, Turner JR. The tight junction in inflammatory disease: communication breakdown. Curr Opin Pharmacol, 2009, 9(6): 715-720.
12. Rose EC, Odle J, Blikslager AT, et al. Probiotics, prebiotics and epithelial tight junctions: a promising approach to modulate intestinal barrier function. Int J Mol Sci, 2021, 22(13): 6729.
13. Slifer ZM, Blikslager AT. The integral role of tight junction proteins in the repair of injured intestinal epithelium. Int J Mol Sci, 2020, 21(3): 972.
14. Gipson GR, Goebel EJ, Hart KN, et al. Structural perspective of BMP ligands and signaling. Bone, 2020, 140: 115549.
15. 罗彬予, 田云鸿, 张琴, 等. BMP 信号通路在肠道缺血再灌注损伤中的作用研究进展. 西部医学, 2019, 31(6): 981-984, 封3.
16. Luo B, Chen K, Feng Q, et al. The interplay of BMP4 and IL-7 regulates the apoptosis of intestinal intraepithelial lymphocytes under conditions of ischemia/reperfusion. Int J Mol Med, 2018, 41(5): 2640-2650.
17. Chen K, Xie W, Luo B, et al. Intestinal mucosal barrier is injured by BMP2/4 via activation of NF-κB signals after ischemic reperfusion. Mediators Inflamm, 2014, 2014: 901530.
18. 陈康, 陈应果, 王洪波, 等. 缺血再灌注条件下 BMP2/4 参与肠黏膜屏障损伤的研究. 局解手术学杂志, 2019, 28(2): 85-90.
19. Takahashi T, Shiraishi A. Stem cell signaling pathways in the small intestine. Int J Mol Sci, 2020, 21(6): 2032.
20. Chen G, Sun L, Yu M, et al. The Jagged-1/Notch-1/Hes-1 pathway is involved in intestinal adaptation in a massive small bowel resection rat model. Dig Dis Sci, 2013, 58(9): 2478-2486.
21. Liang SJ, Li XG, Wang XQ. Notch signaling in mammalian intestinal stem cells: determining cell fate and maintaining homeostasis. Curr Stem Cell Res Ther, 2019, 14(7): 583-590.
22. Mouillesseaux KP, Wiley DS, Saunders LM, et al. Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6. Nat Commun, 2016, 7: 13247.
23. Fang H, Song P, Shen C, et al. Bone mesenchymal stem cell-conditioned medium induces the upregulation of Smad6, which inhibits the BMP-4/Smad1/5/8 signaling pathway. Neurol Res, 2016, 38(11): 965-972.
24. Wang R, Wu G, Dai T, et al. Naringin attenuates renal interstitial fibrosis by regulating the TGF-β/Smad signaling pathway and inflammation. Exp Ther Med, 2021, 21(1): 66.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Experimental study of bone morphogenetic protein-4 in promoting recovery of small intestinal mucosal barrier during recovery period of intestine ischemia-reperfusion injury

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