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Published in: Digestive Diseases and Sciences 10/2018

01-10-2018 | Original Article

Regulation of Autophagy Affects the Prognosis of Mice with Severe Acute Pancreatitis

Authors: Jianhua Wan, Jie Chen, Dangyan Wu, Xiaoyu Yang, Yaobin Ouyang, Yin Zhu, Liang Xia, Nonghua Lu

Published in: Digestive Diseases and Sciences | Issue 10/2018

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Abstract

Background

Acute pancreatitis (AP) is a common inflammatory disease that may develop to severe AP (SAP), resulting in life-threatening complications. Impaired autophagic flux is a characteristic of early AP, and its accumulation could activate oxidative stress and nuclear factor κB (NF-κB) pathways, which aggravate the disease process.

Aim

To explore the therapeutic effects of regulating autophagy after the onset of AP.

Methods

In this study, intraperitoneal injections of 3-methyladenine (3-MA) and rapamycin (RAPA) in the l-arginine or cerulein plus lipopolysaccharide (LPS) Balb/C mouse model. At 24 h after the last injection, pulmonary, intestinal, renal and pancreatic tissues were analyzed.

Results

We found that 3-MA ameliorated systemic organ injury in two SAP models. 3-MA treatment impaired autophagic flux and alleviated inflammatory activation by modulating the NF-κB signaling pathway and the caspase-1-IL-1β pathway, thus decreasing the injuries to the organs and the levels of inflammatory cytokines.

Conclusion

Our study found that the regulation of autophagy could alter the progression of AP induced by l-arginine or cerulein plus LPS in mice.
Appendix
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Literature
1.
2.
3.
go back to reference Gukovskaya AS, et al. Autophagy and pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2012;9:G993–G1003.CrossRef Gukovskaya AS, et al. Autophagy and pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2012;9:G993–G1003.CrossRef
4.
go back to reference Mareninova OA, et al. Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis. J Clin Invest. 2009;11:3340–3355. Mareninova OA, et al. Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis. J Clin Invest. 2009;11:3340–3355.
5.
go back to reference Yang S, et al. Autophagy regulation by the nuclear factor kappaB signal axis in acute pancreatitis. Pancreas. 2012;3:367–373.CrossRef Yang S, et al. Autophagy regulation by the nuclear factor kappaB signal axis in acute pancreatitis. Pancreas. 2012;3:367–373.CrossRef
6.
go back to reference Wu D, et al. Reverse-migrated neutrophils regulated by JAM-C are involved in acute pancreatitis-associated lung injury. Sci Rep. 2016;6:20545.CrossRef Wu D, et al. Reverse-migrated neutrophils regulated by JAM-C are involved in acute pancreatitis-associated lung injury. Sci Rep. 2016;6:20545.CrossRef
7.
go back to reference Kui B, et al. New insights into the methodology of l-arginine-induced acute pancreatitis. PLoS One. 2015;2:e0117588.CrossRef Kui B, et al. New insights into the methodology of l-arginine-induced acute pancreatitis. PLoS One. 2015;2:e0117588.CrossRef
8.
go back to reference Schmidt J, et al. A better model of acute pancreatitis for evaluating therapy. Ann Surg. 1992;1:44–56.CrossRef Schmidt J, et al. A better model of acute pancreatitis for evaluating therapy. Ann Surg. 1992;1:44–56.CrossRef
9.
go back to reference Wildi S, et al. Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations. Gut. 2007;5:685–692.CrossRef Wildi S, et al. Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations. Gut. 2007;5:685–692.CrossRef
10.
go back to reference He Z, et al. Intravenous hMSCs ameliorate acute pancreatitis in mice via secretion of tumor necrosis factor-alpha stimulated gene/protein. Sci Rep. 2016;6:38438.CrossRef He Z, et al. Intravenous hMSCs ameliorate acute pancreatitis in mice via secretion of tumor necrosis factor-alpha stimulated gene/protein. Sci Rep. 2016;6:38438.CrossRef
11.
go back to reference Staubli SM, et al. Laboratory markers predicting severity of acute pancreatitis. Crit Rev Clin Lab Sci. 2015;6:273–283.CrossRef Staubli SM, et al. Laboratory markers predicting severity of acute pancreatitis. Crit Rev Clin Lab Sci. 2015;6:273–283.CrossRef
12.
go back to reference Minkov GA, et al. Pathophysiological mechanisms of acute pancreatitis define inflammatory markers of clinical prognosis. Pancreas. 2015;5:713–717.CrossRef Minkov GA, et al. Pathophysiological mechanisms of acute pancreatitis define inflammatory markers of clinical prognosis. Pancreas. 2015;5:713–717.CrossRef
13.
go back to reference Dai SR, et al. Serum interleukin 17 as an early prognostic biomarker of severe acute pancreatitis receiving continuous blood purification. Int J Artif Organs. 2015;4:192–198.CrossRef Dai SR, et al. Serum interleukin 17 as an early prognostic biomarker of severe acute pancreatitis receiving continuous blood purification. Int J Artif Organs. 2015;4:192–198.CrossRef
14.
go back to reference Denham W, et al. Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis. Gastroenterology. 1997;5:1741–1746.CrossRef Denham W, et al. Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis. Gastroenterology. 1997;5:1741–1746.CrossRef
15.
go back to reference Petrov MS, et al. Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology. 2010;3:813–820.CrossRef Petrov MS, et al. Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology. 2010;3:813–820.CrossRef
16.
go back to reference Banks PA, et al. Classification of acute pancreatitis–2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;1:102–111.CrossRef Banks PA, et al. Classification of acute pancreatitis–2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;1:102–111.CrossRef
17.
go back to reference Deretic V, et al. Autophagy in infection, inflammation and immunity. Nat Rev Immunol. 2013;10:722–737.CrossRef Deretic V, et al. Autophagy in infection, inflammation and immunity. Nat Rev Immunol. 2013;10:722–737.CrossRef
18.
go back to reference Mizushima N, et al. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 2011;27:107–132.CrossRef Mizushima N, et al. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 2011;27:107–132.CrossRef
19.
go back to reference Ichimura Y, et al. Pathophysiological role of autophagy: lesson from autophagy-deficient mouse models. Exp Anim. 2011;4:329–345.CrossRef Ichimura Y, et al. Pathophysiological role of autophagy: lesson from autophagy-deficient mouse models. Exp Anim. 2011;4:329–345.CrossRef
20.
go back to reference Johansen T, et al. Selective autophagy mediated by autophagic adapter proteins. Autophagy. 2011;3:279–296.CrossRef Johansen T, et al. Selective autophagy mediated by autophagic adapter proteins. Autophagy. 2011;3:279–296.CrossRef
21.
go back to reference Zeng X, et al. Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Cancer Res. 2008;7:2384–2390.CrossRef Zeng X, et al. Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Cancer Res. 2008;7:2384–2390.CrossRef
22.
go back to reference Dai ZJ, et al. Antitumor effects of rapamycin in pancreatic cancer cells by inducing apoptosis and autophagy. Int J Mol Sci. 2012;1:273–285.CrossRef Dai ZJ, et al. Antitumor effects of rapamycin in pancreatic cancer cells by inducing apoptosis and autophagy. Int J Mol Sci. 2012;1:273–285.CrossRef
23.
go back to reference Katayama M, et al. DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ. 2007;3:548–558.CrossRef Katayama M, et al. DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ. 2007;3:548–558.CrossRef
24.
go back to reference Gukovsky I, et al. Impaired autophagy underlies key pathological responses of acute pancreatitis. Autophagy. 2010;3:428–429.CrossRef Gukovsky I, et al. Impaired autophagy underlies key pathological responses of acute pancreatitis. Autophagy. 2010;3:428–429.CrossRef
25.
go back to reference Xiao J, et al. Spautin-1 ameliorates acute pancreatitis via inhibiting impaired autophagy and alleviating calcium overload. Mol Med. 2016;22:643.CrossRef Xiao J, et al. Spautin-1 ameliorates acute pancreatitis via inhibiting impaired autophagy and alleviating calcium overload. Mol Med. 2016;22:643.CrossRef
26.
go back to reference Ji L, et al. Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway. J Cell Mol Med. 2016;12:2349–2361.CrossRef Ji L, et al. Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway. J Cell Mol Med. 2016;12:2349–2361.CrossRef
27.
go back to reference DiDonato JA, et al. NF-kappaB and the link between inflammation and cancer. Immunol Rev. 2012;1:379–400.CrossRef DiDonato JA, et al. NF-kappaB and the link between inflammation and cancer. Immunol Rev. 2012;1:379–400.CrossRef
28.
go back to reference Jakkampudi A, et al. NF-kappaB in acute pancreatitis: Mechanisms and therapeutic potential. Pancreatology. 2016;4:477–488.CrossRef Jakkampudi A, et al. NF-kappaB in acute pancreatitis: Mechanisms and therapeutic potential. Pancreatology. 2016;4:477–488.CrossRef
29.
go back to reference Rakonczay ZJ, et al. The role of NF-kappaB activation in the pathogenesis of acute pancreatitis. Gut. 2008;2:259–267.CrossRef Rakonczay ZJ, et al. The role of NF-kappaB activation in the pathogenesis of acute pancreatitis. Gut. 2008;2:259–267.CrossRef
30.
go back to reference Wang, X. et al. Acanthopanax versus 3-Methyladenine ameliorates sodium taurocholate-induced severe acute pancreatitis by inhibiting the autophagic pathway in rats. Mediators Inflamm, 8369704 (2016). Wang, X. et al. Acanthopanax versus 3-Methyladenine ameliorates sodium taurocholate-induced severe acute pancreatitis by inhibiting the autophagic pathway in rats. Mediators Inflamm, 8369704 (2016).
31.
go back to reference Zhang XH, et al. Caspase-1 inhibition alleviates acute renal injury in rats with severe acute pancreatitis. World J Gastroenterol. 2014;30:10457–10463.CrossRef Zhang XH, et al. Caspase-1 inhibition alleviates acute renal injury in rats with severe acute pancreatitis. World J Gastroenterol. 2014;30:10457–10463.CrossRef
32.
go back to reference Liu M, et al. Caspase inhibitor zVAD-fmk protects against acute pancreatitis-associated lung injury via inhibiting inflammation and apoptosis. Pancreatology. 2016;5:733–738.CrossRef Liu M, et al. Caspase inhibitor zVAD-fmk protects against acute pancreatitis-associated lung injury via inhibiting inflammation and apoptosis. Pancreatology. 2016;5:733–738.CrossRef
33.
go back to reference Liu F, et al. MiR-155 alleviates septic lung injury by inducing autophagy via inhibition of transforming growth factor-beta-activated binding protein 2. Shock. 2017;48:61.CrossRef Liu F, et al. MiR-155 alleviates septic lung injury by inducing autophagy via inhibition of transforming growth factor-beta-activated binding protein 2. Shock. 2017;48:61.CrossRef
Metadata
Title
Regulation of Autophagy Affects the Prognosis of Mice with Severe Acute Pancreatitis
Authors
Jianhua Wan
Jie Chen
Dangyan Wu
Xiaoyu Yang
Yaobin Ouyang
Yin Zhu
Liang Xia
Nonghua Lu
Publication date
01-10-2018
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 10/2018
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-018-5053-0

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