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Liu W, Du JJ, Li ZH, Zhang XY, Zuo HD. Liver injury associated with acute pancreatitis: The current status of clinical evaluation and involved mechanisms. World J Clin Cases 2021; 9:10418-10429. [PMID: 35004974 PMCID: PMC8686151 DOI: 10.12998/wjcc.v9.i34.10418] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/16/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is a very common acute disease, and the mortality rate of severe AP (SAP) is between 15% and 35%. The main causes of death are multiple organ dysfunction syndrome and infections. The mortality rate of patients with SAP related to liver failure is as high as 83%, and approximately 5% of the SAP patients have fulminant liver failure. Liver function is closely related to the progression and prognosis of AP. In this review, we aim to elaborate on the clinical manifestations and mechanism of liver injury in patients with AP.
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Affiliation(s)
- Wei Liu
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Juan-Juan Du
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Zeng-Hui Li
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xin-Yu Zhang
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Hou-Dong Zuo
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
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Gao GZ, Hao YX. Progress in research of liver injury induced by acute biliary pancreatitis. Shijie Huaren Xiaohua Zazhi 2020; 28:81-85. [DOI: 10.11569/wcjd.v28.i3.81] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Acute biliary pancreatitis (ABP) not only causes acute inflammation of the pancreas, but also leads to obstruction or infection of the biliary system. Liver injury is one of the most common complications of ABP. The pathological mechanisms mainly include infection and endotoxin, cholestasis, pancreatic enzyme damage, microcirculatory disorders, and oxidative stress, and the research conclusions are mostly derived from animal experiments. On the basis of routine medical treatment of ABP, active anti-infective treatment and rapid relief of biliary obstruction can promote the recovery of ABP-related liver injury.
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Affiliation(s)
- Guang-Zhou Gao
- Department of Gastroenterology (Division II), Baoding First Central Hospital, Baoding 071300, Hebei Province, China
| | - Ying-Xia Hao
- Department of Gastroenterology (Division II), Baoding First Central Hospital, Baoding 071300, Hebei Province, China
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Fonteh P, Smith M, Brand M. Adaptive Immune Cell Dysregulation and Role in Acute Pancreatitis Disease Progression and Treatment. Arch Immunol Ther Exp (Warsz) 2018; 66:199-209. [PMID: 29189884 DOI: 10.1007/s00005-017-0495-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 08/31/2017] [Indexed: 12/18/2022]
Abstract
Acute pancreatitis (AP) is an inflammation of the pancreas caused by various stimuli including excessive alcohol consumption, gallstone disease and certain viral infections. Managing specifically the severe form of AP is limited due to lack of an understanding of the complex immune events that occur during AP involving immune cells and inflammatory molecules such as cytokines. The relative abundance of various immune cells resulting from the immune dysregulation drives disease progression. In this review, we examine the literature on the adaptive immune cells in AP, the prognostic value of these cells in stratifying patients into appropriate care and treatment strategies based on cell frequency in different AP severities are discussed.
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Affiliation(s)
- Pascaline Fonteh
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa.
| | - Martin Smith
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa
| | - Martin Brand
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa
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Protective effects of tropisetron on cerulein-induced acute pancreatitis in mice. Biomed Pharmacother 2017; 93:589-595. [PMID: 28686973 DOI: 10.1016/j.biopha.2017.06.067] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 06/17/2017] [Accepted: 06/19/2017] [Indexed: 12/12/2022] Open
Abstract
Acute pancreatitis (AP) causes morbidity and mortality. The aim of the present study was to investigate the protective effect of tropisetron against AP induced by cerulein. Cerulein (50μg/kg, 5 doses) was used to induce AP in mice. Six hours after final cerulein injection, animals were decapitated. Hepatic/pancreatic enzymes in the serum, pancreatic content of malondialdehyde (MDA), pro-inflammatory cytokines and myeloperoxidase (MPO) activity were measured. Tropisetron significantly attenuated pancreatic injury markers and decreased the amount of elevated serum amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), MPO activities and pro-inflammatory cytokines levels caused by AP in mice. Tropisetron didn't affect the pancreatic levels of MDA. Our results suggest that tropisetron could attenuate cerulein-induced AP by combating inflammatory signaling. Further clinical studies are needed to confirm its efficacy in patients with AP.
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Hydrogen-Rich Saline Attenuates Acute Hepatic Injury in Acute Necrotizing Pancreatitis by Inhibiting Inflammation and Apoptosis, Involving JNK and p38 Mitogen-Activated Protein Kinase-dependent Reactive Oxygen Species. Pancreas 2016; 45:1424-1431. [PMID: 27518466 DOI: 10.1097/mpa.0000000000000678] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES The objective of this study was to study the role of hydrogen-rich saline (HRS) on acute hepatic injury (AHI) in acute necrotizing pancreatitis (ANP). METHODS Rats were used for this study and an ANP model was induced by injecting 5% sodium taurocholate into the biliary-pancreatic duct. Experiments were performed in 3 groups: sham, ANP, and ANP + HRS (HRS). Animals were killed at 3, 12, and 24 hours after operation, and then blood and tissue samples were harvested. Various physiological, histological, and cellular and molecular parameters were analyzed. RESULTS Analyses of serum, lipase, alanine transaminase, and aspartate aminotransferase indicated that ANP-induced AHI model was established successfully and HRS attenuated hepatic dysfunction. Hepatic superoxide dismutase and malondialdehyde levels showed HRS against oxidative stress. Cellular and molecular analyses including p-p38, p-JNK, p-ERK, and caspase-3, caspase-9, NF-κB, and TNF-α in hepatic tissues revealed that HRS attenuated ANP-induced AHI by inhibiting apoptosis and phosphorylation of JNK and p38, as well as NF-κB activation. CONCLUSIONS Hydrogen-rich saline plays a protective role in ANP-induced AHI through inhibiting inflammation and apoptosis, involving JNK and p38 MAPK-dependent reactive oxygen species.
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Grabliauskaite K, Saponara E, Reding T, Bombardo M, Seleznik GM, Malagola E, Zabel A, Faso C, Sonda S, Graf R. Inactivation of TGFβ receptor II signalling in pancreatic epithelial cells promotes acinar cell proliferation, acinar-to-ductal metaplasia and fibrosis during pancreatitis. J Pathol 2015; 238:434-45. [PMID: 26510396 DOI: 10.1002/path.4666] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 09/28/2015] [Accepted: 10/20/2015] [Indexed: 12/14/2022]
Abstract
Determining signalling pathways that regulate pancreatic regeneration following pancreatitis is critical for implementing therapeutic interventions. In this study we elucidated the molecular mechanisms underlying the effects of transforming growth factor-β (TGFβ) in pancreatic epithelial cells during tissue regeneration. To this end, we conditionally inactivated TGFβ receptor II (TGFβ-RII) using a Cre-LoxP system under the control of pancreas transcription factor 1a (PTF1a) promoter, specific for the pancreatic epithelium, and evaluated the molecular and cellular changes in a mouse model of cerulein-induced pancreatitis. We show that TGFβ-RII signalling does not mediate the initial acinar cell damage observed at the onset of pancreatitis. However, TGFβ-RII signalling not only restricts acinar cell replication during the regenerative phase of the disease but also limits ADM formation in vivo and in vitro in a cell-autonomous manner. Analyses of molecular mechanisms underlying the observed phenotype revealed that TGFβ-RII signalling stimulates the expression of cyclin-dependent kinase inhibitors and intersects with the EGFR signalling axis. Finally, TGFβ-RII ablation in epithelial cells resulted in increased infiltration of inflammatory cells in the early phases of pancreatitis and increased activation of pancreatic stellate cells in the later stages of pancreatitis, thus highlighting a TGFβ-based crosstalk between epithelial and stromal cells regulating the development of pancreatic inflammation and fibrosis. Collectively, our data not only contribute to clarifying the cellular processes governing pancreatic tissue regeneration, but also emphasize the conserved role of TGFβ as a tumour suppressor, both in the regenerative process following pancreatitis and in the initial phases of pancreatic cancer.
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Affiliation(s)
- Kamile Grabliauskaite
- Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
| | - Enrica Saponara
- Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
| | - Theresia Reding
- Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
| | - Marta Bombardo
- Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
| | - Gitta M Seleznik
- Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
| | - Ermanno Malagola
- Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
| | - Anja Zabel
- Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
| | - Carmen Faso
- Institute of Parasitology, University of Zurich, Switzerland
| | - Sabrina Sonda
- Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
| | - Rolf Graf
- Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
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Schmidt AI, Seifert GJ, Lauch R, Wolff-Vorbeck G, Chikhladze S, Hopt UT, Wittel UA. Organ-specific monocyte activation in necrotizing pancreatitis in mice. J Surg Res 2015; 197:374-81. [DOI: 10.1016/j.jss.2015.03.075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 03/04/2015] [Accepted: 03/25/2015] [Indexed: 12/11/2022]
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Overexpression of Fas and FasL is associated with infectious complications and severity of experimental severe acute pancreatitis by promoting apoptosis of lymphocytes. Inflammation 2015; 37:1202-12. [PMID: 24566874 PMCID: PMC4077252 DOI: 10.1007/s10753-014-9847-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
This study investigated the relationship of Fas and Fas ligand (FasL) expression and apoptosis of lymphocytes in relation to the pathogenic immune response and infectious complications observed in experimental severe acute pancreatitis in mice. Forty male Balb/c mice were randomly divided into control, mild (MAP), and severe acute pancreatitis (SAP) groups. Overexpression of Fas/FasL messenger ribonucleic acid (mRNA) and protein was observed in spleen-derived lymphocytes in SAP (p < 0.01). Apoptosis of these resulted in a depletion of circulating lymphocytes in this group (p < 0.05). A further significant change in the SAP group with infectious complications was observed. A positive relationship was found between the Fas/FasL expression and lymphocyte apoptosis, and negative relationships were observed between Fas/FasL expression and CD4+ and CD19+ lymphocytes and the CD4+/CD8+ ratio in SAP mice (p < 0.01). The results suggest that the overexpression of Fas/FasL is associated with infectious complications and severity of experimental severe acute pancreatitis by promoting apoptosis of lymphocytes.
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Qin Y, Pinhu L, You Y, Sooranna S, Huang Z, Zhou X, Yin Y, Song S. The role of Fas expression on the occurrence of immunosuppression in severe acute pancreatitis. Dig Dis Sci 2013; 58:3300-7. [PMID: 23861115 DOI: 10.1007/s10620-013-2793-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 07/02/2013] [Indexed: 12/21/2022]
Abstract
BACKGROUND Severe acute pancreatitis (SAP) is a dangerous illness with high mortality where most patients do not die of excessive inflammation, but die of immunosuppression and multiple infections at a later stage. The mechanism of immunosuppression in SAP is unknown. AIM The purpose of this study was to analyze the role of Fas expression on the occurrence of immunosuppression in patients with SAP. METHODS Forty-eight patients with pancreatitis were divided into two groups: 20 cases with SAP (7 cases with sepsis, 13 cases without sepsis) and 28 cases with mild acute pancreatitis (MAP). Twenty-eight healthy volunteers were selected as controls. Fas mRNA expression in peripheral blood was detected by qPCR and Fas protein of lymphocyte membranes; T lymphocyte subsets and expression of monocyte Human leukocyte antigen DR (HLA-DR) in peripheral blood were detected by flow cytometry. RESULTS Compared with MAP and control groups, expression level of Fas mRNA and lymphocyte Fas protein in peripheral blood were significantly increased in the SAP group (all P < 0.01). There was a further significant increase in the SAP group with sepsis compared to those without sepsis (all P < 0.01). The CD4(+) T cell ratio, CD4(+)/CD8(+) ratio and monocyte HLA-DR expression in the SAP group were decreased significantly compared with MAP and control groups (all P < 0.01). Significant negative relationships were observed between Fas mRNA expression and CD4(+) T-cell ratio, CD4(+)/CD8(+) ratio, and monocyte HLA-DR expression in SAP patients with sepsis (all P < 0.05). CONCLUSIONS The results suggest that expression level of Fas is related to severity and immune status of pancreatitis. Overexpression of Fas may lead to the occurrence of immunosuppression and sepsis.
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Affiliation(s)
- Yueqiu Qin
- The First Clinical Medical College of Jinan University, Guangzhou, 510630, Guangdong Province, China
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Wei S, Huang Q, Li J, Liu Z, You H, Chen Y, Gong J. Taurine attenuates liver injury by downregulating phosphorylated p38 MAPK of Kupffer cells in rats with severe acute pancreatitis. Inflammation 2012; 35:690-701. [PMID: 21833764 DOI: 10.1007/s10753-011-9362-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This study was undertaken to clarify the effects of taurine on liver injury in rats with severe acute pancreatitis (SAP). Rats were randomly assigned to three groups: a sham operation (SO), a SAP (established by infusion of 5% taurocholate), and a SAP given taurine (Taur). At 12 and 24 h post-operation, taurine pretreatment significantly attenuated hepatic tissue injury induced by SAP, and concurrently, serum alanine aminotransferase, aspartate transaminase, and amylase levels were significantly reduced by taurine pretreatment. Compared with the SO group, the total and phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) expression and nuclear factor-κB (NF-κB) activity of Kupffer cells (KCs) were significantly higher in the SAP group, but taurine pretreatment inhibited the total and phosphorylated p38 MAPK expression and NF-κB activity of KCs in the SAP group. The increase of tumor necrosis factor-α and interleukin-lβ in cultured supernate of the SAP rat-derived KCs was also significantly inhibited by taurine pretreatment. These results suggest that taurine pretreatment ameliorated liver injury in rats with SAP mainly by inhibiting phosphorylated p38 MAPK and NF-κB activity in KCs, which may play an important role in liver injury.
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Affiliation(s)
- Sidong Wei
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, 74 Linjiang Road, Chongqing 400010, China
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Mossmann DDF, Edelweiss MIA, Kulczynski JM, Marroni NAP, Kretzmann NA, Antunes C, Birkhan OA, Osvaldt AB. [Effects of gadolinium chloride on sodium taurocholate-induced pancreatitis in rats]. Rev Col Bras Cir 2010; 37:288-94. [PMID: 21085847 DOI: 10.1590/s0100-69912010000400010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2009] [Accepted: 08/20/2009] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE To evaluate the effects of the use of gadolinium chloride before and after induction of acute pancreatitis with sodium taurocholate 3% in rats. METHODS Wistar rats were divided into five groups: SF--control with saline intra-ductal and IV; GD control with saline intra-ductal and gadolinium chloride IV; TS--with AP control induced by sodium taurocholate 3% and saline IV; GDTS--pre-treatment with GD (24 hours before the induction of AP) and TSGD--treatment with GD (1 hour after the induction of AP). Analysis was made in serum amylase, transaminases and TNF-α; determination of the MPO activity in lung tissue, lung and pancreatic histology. RESULTS The number of dead animals before the end of the experiment was significantly higher in TSGD (P = 0.046). The scores of pancreatitis and lung damage were higher in the groups that used sodium taurocholate compared to groups with intra-ductal infusion of saline solution. There were no differences in other variables studied when comparing TS, GDTS and TSGD groups. CONCLUSION The benefits with the use of gadolinium chloride as a prophylactic and therapeutic drug were not demonstrated.
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Peng Y, Sigua CA, Murr MM. Protein kinase C-zeta mediates apoptosis of mouse Kupffer cells via ERK-1/2: a novel mechanism. Surgery 2010; 149:135-42. [PMID: 20570304 DOI: 10.1016/j.surg.2010.04.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2009] [Accepted: 04/16/2010] [Indexed: 10/19/2022]
Abstract
BACKGROUND We have demonstrated that activated Kupffer cells undergo accelerated apoptosis via Toll-like receptor (TLR)-4 and protein kinase C (PKC)-ζ-dependent nuclear factor (NF)-κB activation. Because PKC-ζ plays a pivotal role in cell signaling, we sought to determine the signaling pathway of PKC-ζ in Kupffer cell apoptosis. METHODS Mouse Kupffer cell line (MKCL3-2) were transfected with PKC-ζ small interfering RNA (siRNA) and then treated with elastase alone or elastase along with the extracellular signal-regulated kinase (ERK) inhibitor U0126. Cell extracts were assayed for PKC-ζ (protein and activity), TLR-4, NF-κB nuclear translocation, phosphorylated ERK-1/2, activated caspase-3, and DNA fragmentation. All n ≥3; data are expressed as mean values ± standard deviations; means were compared using the t test; P < .05 was considered significant. RESULTS Elastase upregulated TLR-4, PKC-ζ, NF-κB, ERK-1/2, caspase-3, and DNA fragmentation (all P < .01 versus control). Transfection with PKC-ζ siRNA attenuated the elastase-induced upregulation of PKC-ζ activity, NF-κB, ERK-1/2, caspase-3, and DNA fragmentation (all P < .01 versus control). The interaction of PKC-ζ with ERK-1/2 was increased by elastase and was attenuated by PKC-ζ siRNA as confirmed by co-immunoprecipitation and immunofluorescent staining. CONCLUSION Activation of Kupffer cells upregulates PKC-ζ activity, increases apoptosis, and induces nuclear translocation of NF-κB via ERK-1/2-dependent pathways. Inhibiting the activity of PKC-ζ significantly attenuates Kupffer cell apoptosis, NF-κB, and ERK-1/2 activation. The interaction of PKC-ζ and ERK-1/2 warrants further investigation.
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Affiliation(s)
- Yanhua Peng
- Department of Surgery, James A. Haley Veterans Affairs Medical Center, University of South Florida Health Sciences Center, Tampa, FL, USA
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Zhao H, Zhao X, Bai C, Wang X. Potential factors of interorgan signals in the development of pancreatitis-associated acute lung injury and acute respiratory distress syndrome. ACTA ACUST UNITED AC 2009. [DOI: 10.1080/17471060500223365] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Abstract
Fas/FasL-mediated apoptosis is involved acute pancreatitis-associated liver injury. It up-regulates proapoptotic pathways in the liver and promotes hepatocytic injury as well as hepatocytic apoptosis during acute pancreatitis. The signal of the production of FasL and the expression of FasL were up-regulated in kupffer cells during acute pancreatitis. Then, FasL activates Fas-associated death domain (FADD) and unmasks its death effector domain (DED) followed by subsequent activation of the Caspase cascade and downstream effector Caspases, ultimately resulting in DNA cleavage and hepatocytic apoptosis. This review aimed to elucidate the construction, distribution and function of Fas/FasL, and to highlight mechanism of acute pancreatitis-associated liver injury mediated by Fas/FasL.
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Deletion of toll-like receptor-4 downregulates protein kinase C-zeta and attenuates liver injury in experimental pancreatitis. Surgery 2008; 143:679-85. [PMID: 18436016 DOI: 10.1016/j.surg.2008.01.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2007] [Accepted: 01/15/2008] [Indexed: 12/19/2022]
Abstract
BACKGROUND Toll-like receptor-4 (TLR4) and protein kinase C-zeta (PKC-zeta) play a role in macrophage activation. We hypothesized that deletion of TLR4 downregulates PKC-zeta and attenuates liver cell apoptosis in experimental pancreatitis. METHODS Acute pancreatitis was induced by choline-deficient ethionine diet in C57/BL6 (TLR4+/+ and TLR4-/-) mice. RESULTS During pancreatitis, staining for TLR4 and PKC-zeta, which colocalized in Kupffer cells but not in hepatocytes, increased in TLR4+/+ mice and decreased in TLR4-/- mice. In TLR4+/+ mice, pancreatitis increased TLR4 protein and mRNA and PKC-zeta protein and activity, nuclear factor (NF)-kappaB, ERK1/2, caspase-3 cleavage, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining; all P < .01 versus controls. In TLR4-/- mice with pancreatitis, PKC-zeta mRNA and activity were reduced, ERK1/2 and caspase-3 did not increase, and NF-kappaB and TUNEL (mostly in hepatocytes) increased mildly (all P < .01 vs control). PKC-zeta did not interact directly with NF-kappaB; however, during pancreatitis, coimmunoprecipitation of PKC-zeta with ERK1/2 was increased in TLR4+/+ mice and was attenuated in TLR4-/- mice (all P < .01 vs control), indicating that PKC-zeta interacts with ERK1/2. CONCLUSION Acute pancreatitis upregulates TLR4, PKC-zeta, NF-kappaB, and ERK1/2, and increases apoptosis in mice livers. PKC-zeta induces nuclear translocation of NF-kappaB via ERK1/2-dependent mechanisms. Deletion of TLR4 downregulates PKC-zeta, NF-kappaB, and ERK1/2, and attenuates pancreatitis-induced liver cell apoptosis.
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Abstract
Acute pancreatitis is a frequent acute abdomen in clinic, causes damages not only to pancreas, but also to distant organs. Liver is one of the mainly involved organs. The development of liver injury may aggravate pancreatitis. The pathogenesis of acute pancreatitis with liver injury is mainly related to cytokines, pancreatic enzyme, oxidative stress, microcirculation disturbance, apoptosis and pancreatitis-associated ascitic fluid, etc. Its treatment is also to eradicate these factors. However, more methods are still under animal studies. Their clinical application requires further study.
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Su SB, Xie MJ, Sawabu N, Motoo Y. Suppressive effect of herbal medicine saikokeishito on acinar cell apoptosis in rat spontaneous chronic pancreatitis. Pancreatology 2007; 7:28-36. [PMID: 17449963 DOI: 10.1159/000101875] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2005] [Accepted: 08/14/2006] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Chronic pancreatitis is characterized by acinar destruction and fibrosis. We previously reported that apoptosis is involved in acinar destruction in chronic pancreatitis in the WBN/Kob rat. This study aimed to elucidate the antiapoptotic effect of Saikokeishito (TJ-10). METHODS Four-week-old male WBN/Kob rats were fed a special pellet diet (MB-3) with or without TJ-10 (80 mg/100 g body weight) for 20 weeks. Pancreas was histopathologically examined every 4 weeks, and the expression of apoptosis-related factors such as Fas and Fas ligand (FasL) mRNA and protein was analyzed with RT-PCR, in situ hybridization and immunohistochemistry. Apoptosis was detected with a TUNEL method. RESULTS In untreated WBN/Kob rats, chronic pancreatitis developed at 12 weeks and progressed with marked acinar cell destruction at 16 weeks. The expression of Fas and FasL peaked at 12 and 20 weeks. An apoptotic index in acinar cells correlated to the expression of Fas and FasL mRNA. However, in the TJ-10-treated rats, the rate of pancreatic acinar cell destruction, the apoptotic index at 12-20 weeks, and the expression of Fas and FasL at 12 and 20 weeks decreased significantly compared to those in untreated rats. CONCLUSION These results suggest that TJ-10 has a therapeutic effect on chronic pancreatitis by the suppression of acinar cell apoptosis via the Fas/FasL system.
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Affiliation(s)
- Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Zhang GX, Chen HL, Gong AX, Zhang L. Relationship between pancreatic acinar cell apoptosis and acute pancreatitis and the therapeutic strategy for acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2007; 15:1115-1120. [DOI: 10.11569/wcjd.v15.i10.1115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Being a kind of automatic and gene-controlled cell death, cell apoptosis involves complicated regulatory mechanism and stimulates no inflammation, which is essentially different from necrosis. Many researches proved that the apoptosis of pancreatic acinal cells, which might be a protective reaction, had been observed both in experimental and clinical acute pancreatitis, and it had shown an inverse correlation with the severity of diseases. The purpose of this article is to summarize the advances in the mechanism of pancreatic acinar cell apoptosis during acute pancreatitis in recent years, and to expound the therapeutic approaches in the treatment of acute pancreatitis.
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Gray KD, Simovic MO, Blackwell TS, Christman JW, May AK, Parman KS, Chapman WC, Stain SC. Activation of nuclear factor kappa B and severe hepatic necrosis may mediate systemic inflammation in choline-deficient/ethionine-supplemented diet-induced pancreatitis. Pancreas 2006; 33:260-7. [PMID: 17003648 DOI: 10.1097/01.mpa.0000240599.95817.34] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES We hypothesized that hepatic injury is associated with severe acute pancreatitis (SAP) and may result in lung injury through nuclear factor kappa B (NF-kappaB)-dependent inflammatory mediators. The study characterizes the timing and determines the involvement of selected cytokines and chemokines in the pathogenesis of hepatocellular injury associated with SAP. METHODS The SAP was induced in C57BL/6 mice by feeding a choline-deficient/ethionine-supplemented diet. The mice were killed at 12-hour intervals for 96 hours. Terminal deoxynucleotidyl transferase-mediated nick-end labeling staining was used to determine the extent of hepatic apoptosis. The NF-kappaB activation in nuclear protein extracts from liver tissue was measured using a sensitive RelA enzyme-linked immunoadsorbent assay. Tumor necrosis factor alpha, interleukin 6, macrophage inflammatory protein (MIP) 2, and keratinocyte-derived chemokine (KC) levels in homogenates of liver and lung tissues were measured by enzyme-linked immunoadsorbent assay. The SAP-associated neutrophil lung inflammation was measured as tissue myeloperoxidase activity. RESULTS The SAP and subsequent liver injury were confirmed by histological analysis and rises in plasma amylase and transaminase levels. Severe hepatocellular apoptosis was detected at 36 and 48 hours after the diet initiation by terminal deoxynucleotidyl transferase-mediated nick-end labeling staining (P < 0.05) and subsequently progressed to hepatic necrosis. Liver NF-kappaB activation was detected at 36 hours (P < 0.05) and followed by a sharp increase in hepatocellular levels of interleukin 6, MIP-2, and KC at 72 hours and thereafter (P < 0.05). Levels of MIP-2 and KC in lung tissue were also elevated at 72 hours (P < 0.05) and closely correlated with increased myeloperoxidase activity and increased inflammatory cell infiltrate in the lung. CONCLUSIONS Choline-deficient/ethionine-supplemented diet-induced SAP is accompanied with hepatocellular apoptosis and eventual necrosis. This injury is associated with the hepatic NF-kappaB activation leading to the production of NF-kappaB-dependent cytokines and chemokines in the liver, which may mediate the lung injury.
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Affiliation(s)
- Keith D Gray
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
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Fan ZN, Liu XL, Xiong GY, Wen W, Miao L. Change of acinar cell apoptosis in rats with acute pancreatitis induced by bile-pancreatic-duct obstruction. Shijie Huaren Xiaohua Zazhi 2006; 14:912-915. [DOI: 10.11569/wcjd.v14.i9.912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the correlations of the degrees of acute pancreatitis with the duration of bile-pancreatic duct obstruction (BPDO) and acinar cell apoptosis by observing the change of bile duct pressure.
METHODS: The model of acute pancreatitis was established by ligation of bile-pancreatic duct. Bile duct pressure was examined 4, 8, and 12 h after BPDO as well as 1 and 3 d after removal of BPDO. Flow cytometry was used to detect the acinar cell apoptosis (AnnexinV-FITC/PI assay) and the expression of Caspase-3.
RESULTS: Compared with that in control group (16.42 ± 1.03), the pressure of bile-pancreatic duct increased with the prolonging of obstruction duration (49.98 ± 3.05, 90.20 ± 8.66, 589.00 ± 60.10 for 4, 8, 12 h after obstruction, respectively). When BPDO was removed, the pressure decreased and returned to the normal level within 1 d (17.50 ± 2.84, 16.37 ± 0.46 for 1 and 3 d after removal of obstruction, respectively), and the difference was significant (P < 0.01). AnnexinV-FITC/PI assay showed that the number of apoptotic cells increased significantly 4 h after BPDO, but it decreased while the number of dead cells increased 12 h after BPDO. However, after removal of BPDO, acinar cell apoptosis increased while cell death decreased markedly with the prolonging of BPDO (P < 0.01). Caspase-3 detection confirmed that apoptosis reached the peak at 4 h, and then decreased gradually. Cell death was mostly observed at 12 h. One day after removal of BPDO, cell death still covered the most percentage, but 3 d later, apoptosis was significantly observed (P < 0.01).
CONCLUSION: Enhancement of bile duct pressure is one of the mechanisms in the pathogenesis of acute pancreatitis, which leads to a decrease of acinar cell apoptosis. It is effective to resume the enhanced pressure to normal level at the early stage in the prevention of the disease from development.
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Guzman EA, Rudnicki M. Intricacies of host response in acute pancreatitis. J Am Coll Surg 2005; 202:509-19. [PMID: 16500256 DOI: 10.1016/j.jamcollsurg.2005.10.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2005] [Revised: 10/11/2005] [Accepted: 10/11/2005] [Indexed: 12/25/2022]
Affiliation(s)
- Edgar A Guzman
- Department of Surgery, University of Illinois/Metropolitan Group Hospitals Residency Program, Chicago, IL, USA
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Peng Y, Gallagher SF, Haines K, Baksh K, Murr MM. Nuclear factor-kappaB mediates Kupffer cell apoptosis through transcriptional activation of Fas/FasL. J Surg Res 2005; 130:58-65. [PMID: 16154149 DOI: 10.1016/j.jss.2005.07.030] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2005] [Revised: 07/06/2005] [Accepted: 07/23/2005] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Nuclear factor (NF)-kappaB is a key transcriptional factor for cell survival, inflammation, and stress response. We demonstrated that Kupffer cell-derived FasL plays a central role in pancreatitis-induced hepatocyte injury. The aim of this study was to determine the role of NF-kappaB in regulating death ligand/receptor pathway in Kupffer cells during conditions that mimic acute pancreatitis. MATERIALS AND METHODS Tissue cultures of rat Kupffer cells were treated with elastase (1 U/L) to mimic pancreatitis before and after infection with AdIkappaB to block activation of NF-kappaB. Tumor necrosis factor (enzyme-linked immunoassay), Fas/FasL, and caspase-3 (Western), tumor necrosis factor and Fas/FasL mRNA (reverse-transcription polymerase chain reaction), and NF-kappaB DNA binding (electrophoretic mobility shift assay) were determined. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) and DNA fragmentation. Gels were quantified by densitometry. Data (n=3) are mean+/-SEM; student's t test was used for statistical analysis. RESULTS AdIkappaB infection up-regulated mutated IkappaBalpha that maintained its binding properties to NF-kappaB. Promoter-reporter assay demonstrated that FasL gene promoter was regulated by NF-kappaB. Infection with AdIkappaB attenuated the elastase-induced up-regulation of Fas/FasL (all P<0.01 versus elastase) and NF-kappaB DNA binding but did not affect elastase-induced up-regulation of TNF. AdIkappaB attenuated elastase-induced cleavage of caspase-3, DNA fragmentation and TUNEL staining (all P<0.01 versus elastase). CONCLUSIONS Inhibition of NF-kappaB DNA binding down-regulates Fas/FasL and attenuates elastase-induced apoptosis; however, it has no effect on TNF production, suggesting that regulation of Fas/FasL and TNF may occur via different pathways. The ability of Kupffer cells to autoregulate their stress response by up-regulating their death ligand/receptor and apoptosis warrants further investigation.
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Affiliation(s)
- Yanhua Peng
- Department of Surgery, James A. Haley Veterans Affairs Medical Center, and University of South Florida Health Sciences Center, Tampa, Florida 33601, USA
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McFadden D. Neutral Endopeptidase Determines the Severity of Pancreatitis-Associated Lung Injury. J Surg Res 2005; 128:1-2. [PMID: 16115491 DOI: 10.1016/j.jss.2005.07.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Suzuki T, Moraes TJ, Vachon E, Ginzberg HH, Huang TT, Matthay MA, Hollenberg MD, Marshall J, McCulloch CAG, Abreu MTH, Chow CW, Downey GP. Proteinase-activated receptor-1 mediates elastase-induced apoptosis of human lung epithelial cells. Am J Respir Cell Mol Biol 2005; 33:231-47. [PMID: 15891109 PMCID: PMC2715314 DOI: 10.1165/rcmb.2005-0109oc] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Apoptosis of distal lung epithelial cells plays a pivotal role in the pathogenesis of acute lung injury. In this context, proteinases, either circulating or leukocyte-derived, may contribute to epithelial apoptosis and lung injury. We hypothesized that apoptosis of lung epithelial cells induced by leukocyte elastase is mediated via the proteinase activated receptor (PAR)-1. Leukocyte elastase, thrombin, and PAR-1-activating peptide, but not the control peptide, induced apoptosis in human airway and alveolar epithelial cells as assessed by increases in cytoplasmic histone-associated DNA fragments and TUNEL staining. These effects were largely prevented by a specific PAR-1 antagonist and by short interfering RNA directed against PAR-1. To ascertain the mechanism of epithelial apoptosis, we determined that PAR-1AP, thrombin, and leukocyte elastase dissipated mitochondrial membrane potential, induced translocation of cytochrome c to the cytosol, enhanced cleavage of caspase-9 and caspase-3, and led to JNK activation and Akt inhibition. In concert, these observations provide strong evidence that leukocyte elastase mediates apoptosis of human lung epithelial cells through PAR-1-dependent modulation of the intrinsic apoptotic pathway via alterations in mitochondrial permeability and by modulation of JNK and Akt.
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Affiliation(s)
- Tomoko Suzuki
- Division of Respirology, Department of Medicine, University of Toronto and Toronto General Hospital Research Institute, 1 King's College Circle, Toronto, Ontario, M5S 1A8 Canada
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