Objective To investigate the effect of hemodiafiltration (HDF) on the intestinal injury of severe acute pancreatitis (SAP) rats and the Keap1/Nrf2 signaling pathway. Methods Sprague-Dawley (SD) rats were randomly divided into sham operation group (n=18), SAP group (n=18) and HDF group (n=18). Open surgery without SAP manipulation was performed in sham operation group, SAP model was performed in SAP group and HDF group, and continuous HDF for 12 hours was conducted immediately after the preparation of SAP model in HDF group. The expressions of apoptotic factors Bax and Bcl-2, Keap1/Nrf2 signaling pathway-related proteins in intestinal epithelial cells, endotoxin level in plasma of portal vein, and bacterial culture were assayed after the operation. Results In SAP group, the expression of Bax in intestinal epithelial cells was higher than that in sham operation group (t=8.083, P=0.001), while the expression of Bcl-2 in intestinal epithelial cells was lower than that in sham operation group (t=4.765, P=0.008); plasma endotoxin of portal vein and positive rates of bacterial culture of pancreas and liver were higher than those in sham operation group (plasma endotoxin at 12h: t=15.110, P<0.001; at 24h: t=19.050, P<0.001; at 48h: t=18.330, P<0.001. positive bacterial culture of pancreas at 12h: t=23.712, P<0.001; at 24h: t=20.901, P<0.001; at 48h: t=36.740, P<0.001. positive bacterial culture of liver at 12h: t=23.983, P<0.001; at 24h: t=29.692, P<0.001; at 48h: t=35.694, P<0.001). In HDF group, the expression of Bcl-2 in intestinal epithelial cells was higher than that in SAP group (t=5.825, P=0.004); the expression of Bax in intestinal epithelial cells, plasma endotoxin of portal vein and positive rates of bacterial culture of pancreas and liver were lower than those in SAP group (Bax: t=6.796, P=0.002. plasma endotoxin at 12h: t=6.235, P=0.003; at 24h: t=12.251, P<0.001; at 48h: t=12.980, P<0.001. positive bacterial culture of pancreas at 12h: t=16.470, P<0.001; at 24h: t=5.950, P=0.004; at 48h: t=15.071, P<0.001. positive bacterial culture of liver at 12h: t=2.782, P=0.049; at 24h: t=9.790, P<0.001; at 48h: t=15.172, P<0.001). In SAP group, the expressions of Keap1 and Nrf2 were lower than those in sham operation group (Keap1: t=11.611, P<0.001; Nrf2: t=12.241, P<0.001). In HDF group, the expressions of Keap1 and Nrf2 were higher than those in SAP group (Keap1: t=80.658, P=0.001; Nrf2: t=12.312, P=0.000). Conclusion Continuous HDF can improve the permeability of intestinal epithelial cells and intestinal dysfunction, and inhibit endotoxin and bacterial translocation in SAP rats.
XU Hai-Ping
. Effect of hemodiafiltration on intestinal injury and Keap1/Nrf2 signaling pathway in an animal model of acute severe pancreatitis#br#[J]. Chinese Journal of Blood Purification, 2025
, 24(01)
: 44
-48
.
DOI: 10.3969/j.issn.1671-4091.2025.01.009
1. Ye S, Si C, Deng J, Chen X, Kong L, Zhou X, et al. Understanding the Effects of Metabolites on the Gut Microbiome and Severe Acute Pancreatitis. Biomed Res Int. 2021;2021:1516855.
2. Yang QY, Hu JW. Prediction of moderately severe and severe acute pancreatitis in pregnancy: Several issues. World J Gastroenterol. 2022;28(33):4926-8.
3. Zhou H, Mei X, He X, Lan T, Guo S. Severity stratification and prognostic prediction of patients with acute pancreatitis at early phase: A retrospective study. Medicine (Baltimore). 2019;98(16):e15275.
4. Bai J, Bai J, Yang M. Interleukin-22 Attenuates Acute Pancreatitis-Associated Intestinal Mucosa Injury in Mice via STAT3 Activation. Gut Liver. 2021;15(5):771-81.
5. You YD, Deng WH, Guo WY, Zhao L, Mei FC, Hong YP, et al. 4-Phenylbutyric Acid Attenuates Endoplasmic Reticulum Stress-Mediated Intestinal Epithelial Cell Apoptosis in Rats with Severe Acute Pancreatitis. Dig Dis Sci. 2019;64(6):1535-47.
6. Zhou Q, Xiang H, Liu H, Qi B, Shi X, Guo W, et al. Emodin Alleviates Intestinal Barrier Dysfunction by Inhibiting Apoptosis and Regulating the Immune Response in Severe Acute Pancreatitis. Pancreas. 2021;50(8):1202-11.
7. Abe R, Oda S, Shinozaki K, Hirasawa H. Continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter for severe acute pancreatitis. Contrib Nephrol. 2010;166:54-63.
8. Comstock G, Kilgallon K, Wang GS, Bourne D, Blanchette E, Stenson E. Management and Associated Toxicokinetics of Massive Valproic Acid Ingestion with High Flow Continuous Venovenous Hemodiafiltration. J Med Toxicol. 2022;18(3):239-42.
9. Liang X, Hu C, Liu C, Yu K, Zhang J, Jia Y. Dihydrokaempferol (DHK) ameliorates severe acute pancreatitis (SAP) via Keap1/Nrf2 pathway. Life Sci. 2020;261:118340.
10. Kong L, Deng J, Zhou X, Cai B, Zhang B, Chen X, et al. Sitagliptin activates the p62-Keap1-Nrf2 signalling pathway to alleviate oxidative stress and excessive autophagy in severe acute pancreatitis-related acute lung injury. Cell Death Dis. 2021;12(10):928.
11. Li J, Han J, Lv J, Wang S, Qu L, Jiang Y. Saikosaponin A-Induced Gut Microbiota Changes Attenuate Severe Acute Pancreatitis through the Activation of Keap1/Nrf2-ARE Antioxidant Signaling. Oxid Med Cell Longev. 2020;2020:9217219.
12. Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN. Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg. 1970;101(4):478-83.
13. Boxhoorn L, Voermans RP, Bouwense SA, Bruno MJ, Verdonk RC, Boermeester MA, et al. Acute pancreatitis. Lancet. 2020;396(10252):726-34.
14. Tsuji Y, Watanabe T, Kudo M, Arai H, Strober W, Chiba T. Sensing of commensal organisms by the intracellular sensor NOD1 mediates experimental pancreatitis. Immunity. 2012;37(2):326-38.
15. Zhang L, Cheng J, Shen J, Wang S, Guo C, Fan X. Ghrelin Inhibits Intestinal Epithelial Cell Apoptosis Through the Unfolded Protein Response Pathway in Ulcerative Colitis. Front Pharmacol. 2021;12:661853.
16. He C, Zhu H, Li H, Zou MH, Xie Z. Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes. 2013;62(4):1270-81.
17. Chen W, Yuan C, Lu Y, Zhu Q, Ma X, Xiao W, et al. Tanshinone IIA Protects against Acute Pancreatitis in Mice by Inhibiting Oxidative Stress via the Nrf2/ROS Pathway. Oxid Med Cell Longev. 2020;2020:5390482.
18. Wen E, Xin G, Su W, Li S, Zhang Y, Dong Y, et al. Activation of TLR4 induces severe acute pancreatitis-associated spleen injury via ROS-disrupted mitophagy pathway. Mol Immunol. 2022;142:63-75.
19. Choudhury S, Ghosh S, Gupta P, Mukherjee S, Chattopadhyay S. Inflammation-induced ROS generation causes pancreatic cell death through modulation of Nrf2/NF-kappaB and SAPK/JNK pathway. Free Radic Res. 2015;49(11):1371-83.
20. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 2004;24(16):7130-9.