Login Register Cart 0
Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Fenbufen Alleviates Severe Acute Pancreatitis by Suppressing Caspase-1/Caspase-11-mediated Pyroptosis in Mice

Author(s): Shien Shen, Wenqin Xiao, Weiliang Jiang, Kai Li, Xingya Guo, Guanzhao Zong, Chuanyang Wang, Jingpiao Bao, Jiahui Chen, Zhiyuan Cheng, Jie Shen and Rong Wan*

Volume 17, 2024

Published on: 13 July, 2023

Article ID: e110523216783 Pages: 9

DOI: 10.2174/1874467217666230511095540

open_access

Abstract

Aim: In the present study, we aimed to investigate the effects of Fenbufen treatment on the SAP model induced by caerulein and lipopolysaccharide.

Background: Severe acute pancreatitis (SAP) is an extremely dangerous disease with high mortality, which is associated with inflammatory response and acinar cell death. The caspase family plays an important role in cell death, such as caspase-1 and caspase-11 in pyroptosis. In recent years, caspases have been shown to be a novel pharmacological target of Fenbufen.

Objective: Effects of Fenbufen on pancreatic tissue damage and serum levels of lipase and amylase in SAP in mice; Effect of Fenbufen on caspase-1 pathway in SAP in mice; Effect of Fenbufen on caspase-1/caspase-11-mediated pyroptosis of PACs in SAP in mice; Effect of Fenbufen on isolated PACs and caspase-1/caspase-11-mediated pyroptosis in vitro.

Methods: In vivo, eighteen female C57BL/6 mice were randomly divided into 3 groups: the NC group, the SAP group, and the Fenbufen +SAP group with 6 mice in each group. The SAP model was induced by intraperitoneal injection of caerulein and lipopolysaccharide. The pathological changes in pancreatic and the serum levels of lipase and amylase and the relative gene and protein expressions in each group were compared. In vitro, pancreatic acinar cells were assigned to 5 groups: medium group, SAP group, Fenbufen 100μM group, Fenbufen 200μM group, and Fenbufen 400μM group. The cell damage and the relative gene and protein expressions in each group were evaluated.

Results: Our results showed that Fenbufen ameliorated the severity of SAP and decreased the serum levels of lipase and amylase. Meanwhile, the in vivo and in vitro data demonstrated that Fenbufen inhibited the activation of caspase-1 and caspase-11, decreasing the levels of IL-1β, IL-18, and GSDMD. In in vitro experiments, we found that by inhibiting the activation of caspase-1 and caspase-11, Fenbufen significantly reduced lactate dehydrogenase (LDH) excretion by acinar cells.

Conclusion: In general, our data showed that Fenbufen could protect the pancreatic acinar cell from injury by inhibiting pyroptosis.

Keywords: Severe acute pancreatitis, Fenbufen, Pyroptosis, Caspase-1, Caspase-11, Acinar cell.

[1]
Jin, D.; Tan, J.; Jiang, J.; Philips, D.; Liu, L. The early predictive value of routine laboratory tests on the severity of acute pancreatitis patients in pregnancy: A retrospective study. Sci. Rep., 2020, 10(1), 10087.
[http://dx.doi.org/10.1038/s41598-020-66921-x] [PMID: 32572085]
[2]
Beger, H.G.; Rau, B.M. Severe acute pancreatitis: Clinical course and management. World J. Gastroenterol., 2007, 13(38), 5043-5051.
[http://dx.doi.org/10.3748/wjg.v13.i38.5043] [PMID: 17876868]
[3]
Cai, J.; Zhou, X.; Yu, H.; Xue, H.; Li, D. Effect of bone marrow mesenchymal stem cells on RhoA/ROCK signal pathway in severe acute pancreatitis. Am. J. Transl. Res., 2019, 11(8), 4809-4816.
[PMID: 31497201]
[4]
Sundar, V.; Senthil Kumar, K.A.; Manickam, V.; Ramasamy, T. Current trends in pharmacological approaches for treatment and management of acute pancreatitis-a review. J. Pharm. Pharmacol., 2020, 72(6), 761-775.
[http://dx.doi.org/10.1111/jphp.13229] [PMID: 32012276]
[5]
Fan, R.; Sui, J.; Dong, X.; Jing, B.; Gao, Z. Wedelolactone alleviates acute pancreatitis and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis. Free Radic. Biol. Med., 2021, 173, 29-40.
[http://dx.doi.org/10.1016/j.freeradbiomed.2021.07.009] [PMID: 34246777]
[6]
Zhao, S.; Li, X.; Wang; Wang, H. The role of the effects of autophagy on NLRP3 inflammasome in inflammatory nervous system diseases. Front. Cell Dev. Biol., 2021, 9, 657478.
[http://dx.doi.org/10.3389/fcell.2021.657478] [PMID: 34079796]
[7]
Wang, Z.; Gu, Z.; Hou, Q.; Chen, W.; Mu, D.; Zhang, Y.; Liu, Q.; Liu, Z.; Yang, D. Zebrafish GSDMEb cleavage-gated pyroptosis drives septic acute kidney injury in vivo. J. Immunol., 2020, 204(7), 1929-1942.
[http://dx.doi.org/10.4049/jimmunol.1901456] [PMID: 32111733]
[8]
Zasłona, Z.; Flis, E.; Wilk, M.M.; Carroll, R.G.; Palsson-McDermott, E.M.; Hughes, M.M.; Diskin, C.; Banahan, K.; Ryan, D.G.; Hooftman, A.; Misiak, A.; Kearney, J.; Lochnit, G.; Bertrams, W.; Greulich, T.; Schmeck, B.; McElvaney, O.J.; Mills, K.H.G.; Lavelle, E.C.; Wygrecka, M.; Creagh, E.M.; O’Neill, L.A.J. Caspase-11 promotes allergic airway inflammation. Nat. Commun., 2020, 11(1), 1055.
[http://dx.doi.org/10.1038/s41467-020-14945-2] [PMID: 32103022]
[9]
Yuan, B.; Zhou, X.; You, Z.; Xu, W.; Fan, J.; Chen, S.; Han, Y.; Wu, Q.; Zhang, X. Inhibition of AIM2 inflammasome activation alleviates GSDMD-induced pyroptosis in early brain injury after subarachnoid haemorrhage. Cell Death Dis., 2020, 11(1), 76.
[http://dx.doi.org/10.1038/s41419-020-2248-z] [PMID: 32001670]
[10]
Wang, J.; Wang, L.; Zhang, X.; Xu, Y.; Chen, L.; Zhang, W.; Liu, E.; Xiao, C.; Kou, Q. Cathepsin B aggravates acute pancreatitis by activating the NLRP3 inflammasome and promoting the caspase-1-induced pyroptosis. Int. Immunopharmacol., 2021, 94, 107496.
[http://dx.doi.org/10.1016/j.intimp.2021.107496] [PMID: 33639565]
[11]
Moore, R.A.; Derry, S.; McQuay, H.J. Single dose oral fenbufen for acute postoperative pain in adults. Cochrane Database Syst. Rev., 2009, 2009, CD007547.
[http://dx.doi.org/10.1002/14651858.CD007547.pub2]
[12]
Crossley, R.J. Side effect and safety data for fenbufen. Am. J. Med., 1983, 75(4), 84-90.
[http://dx.doi.org/10.1016/0002-9343(83)90334-0] [PMID: 6227235]
[13]
Husain, A.; Ahmad, A.; Alam, M.M.; Ajmal, M.; Ahuja, P. Fenbufen based 3-[5-(substituted aryl)-1,3,4-oxadiazol-2-yl]-1-(biphenyl-4-yl)propan-1-ones as safer antiinflammatory and analgesic agents. Eur. J. Med. Chem., 2009, 44(9), 3798-3804.
[http://dx.doi.org/10.1016/j.ejmech.2009.04.009] [PMID: 19457595]
[14]
Child, R.G.; Osterberg, A.C.; Sloboda, A.E.; Tomcufcik, A.S. Fenbufen, a new anti-inflammatory analgesic: synthesis and structure-activity relationships of analogs. J. Pharm. Sci., 1977, 66(4), 466-476.
[http://dx.doi.org/10.1002/jps.2600660403] [PMID: 300797]
[15]
Sloboda, A.E.; Osterberg, A.C. The pharmacology of fenbufen, 3-(4-biphenylylcarbonyl)propionic acid, and 4-biphenylacetic acid, interesting antiinflammatory-analgesic agents. Inflammation, 1976, 1(4), 415-438.
[http://dx.doi.org/10.1007/BF00920340] [PMID: 24194464]
[16]
Smith, C.E.; Soti, S.; Jones, T.A.; Nakagawa, A.; Xue, D.; Yin, H. NSAIDs are caspase inhibitors. Cell Chem. Biol., 2017, 24, 281-292.
[http://dx.doi.org/10.1016/j.chembiol.2017.02.003] [PMID: 28238723]
[17]
Lu, G.; Pan, Y.; Kayoumu, A.; Zhang, L.; Yin, T.; Tong, Z.; Li, B.; Xiao, W.; Ding, Y.; Li, W. Indomethacin inhabits the NLRP3 inflammasome pathway and protects severe acute pancreatitis in mice. Biochem. Biophys. Res. Commun., 2017, 493(1), 827-832.
[http://dx.doi.org/10.1016/j.bbrc.2017.08.060] [PMID: 28867183]
[18]
De Sarro, G.; Renne, S.; Nava, F.; De Sarro, A. Fenbufen pretreatment potentiates the anticonvulsant activity of CPPene and NBQX in DBA/2 mice. J. Pharm. Pharmacol., 2011, 46(12), 1017-1022.
[http://dx.doi.org/10.1111/j.2042-7158.1994.tb03259.x]
[19]
Chiccarelli, F.S.; Eisner, H.J.; Van Lear, G.E. Disposition and metabolism of fenbufen in several laboratory animals. Arzneimittelforschung, 1980, 30(4A), 707-715.
[PMID: 6776965]
[20]
Naora, K.; Katagiri, Y.; Ichikawa, N.; Hayashibara, M.; Iwamoto, K. A minor possibility of pharmacokinetic interaction between enoxacin and fenbufen in rats. J. Pharmacobiodyn., 1990, 13(2), 90-96.
[http://dx.doi.org/10.1248/bpb1978.13.90]
[21]
Vrolyk, V.; Schneberger, D.; Le, K.; Wobeser, B.K.; Singh, B. Mouse model to study pulmonary intravascular macrophage recruitment and lung inflammation in acute necrotizing pancreatitis. Cell Tissue Res., 2019, 378(1), 97-111.
[http://dx.doi.org/10.1007/s00441-019-03023-9]
[22]
Hu, G.; Shen, J.; Cheng, L.; Guo, C.; Xu, X.; Wang, F.; Huang, L.; Yang, L.; He, M.; Xiang, D.; Zhu, S.; Wu, M.; Yu, Y.; Han, W.; Wang, X. Reg4 protects against acinar cell necrosis in experimental pancreatitis. Gut, 2011, 60(6), 820-828.
[http://dx.doi.org/10.1136/gut.2010.215178] [PMID: 21193457]
[23]
Kang, R.; Zhang, Q.; Hou, W.; Yan, Z.; Chen, R.; Bonaroti, J.; Bansal, P.; Billiar, T.R.; Tsung, A.; Wang, Q.; Bartlett, D.L.; Whitcomb, D.C.; Chang, E.B.; Zhu, X.; Wang, H.; Lu, B.; Tracey, K.J.; Cao, L.; Fan, X.G.; Lotze, M.T.; Zeh, H.J., III; Tang, D. Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice. Gastroenterology, 2014, 146(4), 1097-1107.e8.
[http://dx.doi.org/10.1053/j.gastro.2013.12.015] [PMID: 24361123]
[24]
Tang, D.; Kang, R.; Berghe, T.V.; Vandenabeele, P.; Kroemer, G. The molecular machinery of regulated cell death. Cell Res., 2019, 29(5), 347-364.
[http://dx.doi.org/10.1038/s41422-019-0164-5] [PMID: 30948788]
[25]
Portelli, M.; Jones, C.D. Severe acute pancreatitis: Pathogenesis, diagnosis and surgical management. Hepatobiliary Pancreat. Dis. Int., 2017, 16(2), 155-159.
[http://dx.doi.org/10.1016/S1499-3872(16)60163-7] [PMID: 28381378]
[26]
Minkov, G.A.; Halacheva, K.S.; Yovtchev, Y.P.; Gulubova, M.V. Pathophysiological mechanisms of acute pancreatitis define inflammatory markers of clinical prognosis. Pancreas, 2015, 44(5), 713-717.
[http://dx.doi.org/10.1097/MPA.0000000000000329] [PMID: 26061557]
[27]
Gao, L.; Dong, X.; Gong, W.; Huang, W.; Xue, J.; Zhu, Q.; Ma, N.; Chen, W.; Fu, X.; Gao, X.; Lin, Z.; Ding, Y.; Shi, J.; Tong, Z.; Liu, T.; Mukherjee, R.; Sutton, R.; Lu, G.; Li, W. Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in acute pancreatitis. Br. J. Pharmacol., 2021, 178(17), 3533-3552.
[http://dx.doi.org/10.1111/bph.15499] [PMID: 33871879]
[28]
Lv, J.; Shen, X.; Shen, X.; Li, X.; Jin, Z.; Ouyang, X.; Lu, J.; Zhu, D.; Wang, J.; Shen, X. Miltefosine as a PPM1A activator improves AD-like pathology in mice by alleviating tauopathy via microglia/neurons crosstalk. Brain, Behavior, & Immunity - Health, 2022, 26, 100546.
[http://dx.doi.org/10.1016/j.bbih.2022.100546] [PMID: 36388134]
[29]
Fang, M.; Zhang, A.; Du, Y.; Lu, W.; Wang, J.; Minze, L.J.; Cox, T.C.; Li, X.C.; Xing, J.; Zhang, Z. TRIM18 is a critical regulator of viral myocarditis and organ inflammation. J. Biomed. Sci., 2022, 29(1), 55.
[http://dx.doi.org/10.1186/s12929-022-00840-z]
[30]
Xing, J.; Zhou, X.; Fang, M.; Zhang, E.; Minze, L.J.; Zhang, Z. DHX15 is required to control RNA virus-induced intestinal inflammation. Cell Rep., 2021, 35(12), 109205.
[http://dx.doi.org/10.1016/j.celrep.2021.109205] [PMID: 34161762]
[31]
Mareninova, O.A.; Sung, K.F.; Hong, P.; Lugea, A.; Pandol, S.J.; Gukovsky, I.; Gukovskaya, A.S. Cell death in pancreatitis: Caspases protect from necrotizing pancreatitis. J. Biol. Chem., 2006, 281(6), 3370-3381.
[http://dx.doi.org/10.1074/jbc.M511276200] [PMID: 16339139]

Rights & Permissions Print Cite
Article Metrics
44
3
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy