4-Phenylbutyric Acid Attenuates Endoplasmic Reticulum Stress-Mediated Intestinal Epithelial Cell Apoptosis in Rats with Severe Acute Pancreatitis
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The present study aimed to determine whether intestinal epithelial cell (IECs) apoptosis could be induced by endoplasmic reticulum stress (ERS) in severe acute pancreatitis (SAP), and the role of chemical chaperone 4-phenylbutyric acid (4-PBA) in SAP-associated intestinal barrier injury.
Twenty-four male Sprague Dawley rats were randomly divided into three groups: the sham operation group, the SAP group, and the SAP model plus 4-PBA treatment group (4-PBA group). A rat model of SAP was induced by retrograde injection of 5% sodium taurocholate (STC) into the biliopancreatic duct; in the 4-PBA group, 4-PBA was injected intraperitoneally at a dose of 50 mg/kg body weight for 3 days before modeling.
The results indicated that 4-PBA attenuated the following: (1) pancreas and intestinal pathological injuries, (2) serum TNF-α, IL-1β, and IL-6, (3) serum DAO level, serum endotoxin level, (4) the apoptosis of IECs, (5) ER stress markers (caspase-12, CHOP, GRP78, PERK, IRE1α, ATF6) and caspase-3 expression in intestinal. However, the serum AMY, LIPA levels, and the expression of caspase-9, caspase-8 were just slightly decreased.
ERS may be considered a predominant pathway, which is involved in the apoptosis of IECs during SAP. Furthermore, 4-PBA protects IECs against apoptosis in STC-induced SAP by attenuating the severity of ERS.
KeywordsSevere acute pancreatitis Intestinal epithelium 4-Phenylbutyric acid Apoptosis Endoplasmic reticulum stress
This study was supported by National Natural Science Foundation of China (Nos. 81370562, 81360081), the National Natural Science Foundation Youth Project (Grant No. 81500488), and the Independent Research Project of Wuhan University (No. 2042017kf0141).
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflict of interest.
- 3.Jha RK, Yong MQ, Chen SH. The protective effect of resveratrol on the intestinal mucosal barrier in rats with severe acute pancreatitis. Med Sci Monitor Int Med J Exp Clin Res. 2008;14:BR14–BR19.Google Scholar
- 12.Kim HJ, Jeong JS, Kim SR, Park SY, Chae HJ, Lee YC. Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-kappaB/HIF-1alpha signaling pathway. Sci Rep. 2013;3:1142. https://doi.org/10.1038/srep01142.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Petrov MS, Kukosh MV, Emelyanov NV. A randomized controlled trial of enteral versus parenteral feeding in patients with predicted severe acute pancreatitis shows a significant reduction in mortality and in infected pancreatic complications with total enteral nutrition. Dig Surg. 2006;23:336–344. https://doi.org/10.1159/000097949. (discussion 344–335).CrossRefPubMedGoogle Scholar
- 20.Nakajima T, Ueda T, Takeyama Y, et al. Protective effects of vascular endothelial growth factor on intestinal epithelial apoptosis and bacterial translocation in experimental severe acute pancreatitis. Pancreas. 2007;34:410–416. https://doi.org/10.1097/mpa.0b013e3180335c64.CrossRefPubMedGoogle Scholar
- 23.Shi WY, Che CY, Liu L. Human interleukin 23 receptor induces cell apoptosis in mammalian cells by intrinsic mitochondrial pathway associated with the down-regulation of RAS/mitogen-activated protein kinase and signal transducers and activators of transcription factor 3 signaling pathways. Int J Mol Sci. 2013;14:24656–24669. https://doi.org/10.3390/ijms141224656.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Lin JH, Walter P, Yen TS. Endoplasmic reticulum stress in disease pathogenesis. Ann Rev Pathol. 2008;3:399–425. https://doi.org/10.1146/annurev.pathmechdis.3.121806.151434.CrossRefGoogle Scholar
- 34.Qi J, Chen X, Zhang C, et al. Effects of 4-phenylbutyric acid on carbon tetrachloride-induced acute liver injury in mice. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chin J Hepatol. 2015;23:286–291. https://doi.org/10.3760/cma.j.issn.1007-3418.2015.04.011.CrossRefGoogle Scholar