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Reducing Pancreatic Fibrosis Using Antioxidant Therapy Targeting Nrf2 Antioxidant Pathway: A Possible Treatment for Chronic Pancreatitis. Pancreas 2019; 48:1259-1262. [PMID: 31688588 DOI: 10.1097/mpa.0000000000001433] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic pancreatitis is the progressive inflammation of the pancreas resulting in the irreversible damage of pancreatic structure and function by means of fibrosis. Chronic pancreatitis is most commonly caused by alcohol consumption, although the direct molecular etiology is unknown. Recent studies suggest oxidative stress as a catalyst for pancreatic stellate cell activation leading to the deposition of collagenous extracellular matrix causing pancreatic fibrosis. We review the effect of oxidative stress on pancreatic fibrogenesis and indicate the molecular pathways involved in preventing oxidant-related cell damage. Likewise, we summarize existing antioxidative therapies for chronic pancreatitis and discuss a novel nuclear factor erythroid 2-related factor 2 activator, dimethyl fumarate, and its potential to reduce fibrogenesis by downregulating pancreatic stellate cell activation.
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Abstract
BACKGROUND Pancreatic stellate cells (PSCs) play a critical role in the development of pancreatic fibrosis. In this study we used a novel method to isolate and culture rat PSCs and then investigated the inhibitory effects of adipose-derived stem cells (ADSCs) on activation and proliferation of PSCs. METHODS Pancreatic tissue was obtained from Sprague-Dawley rats for PSCs isolation. Transwell cell cultures were adopted for co-culture of ADSCs and PSCs. PSCs proliferation and apoptosis were determined using CCK-8 and flow cytometry, respectively. alpha-SMA expressions were analyzed using Western blotting. The levels of cytokines [nerve growth factor (NGF), interleukin-10 (IL-10) and transforming growth factor-beta1 (TGF-beta1)] in conditioned medium were detected by ELISA. Gene expression (MMP-2, MMP-9 and TIMP-1) was analyzed using qRT-PCR. RESULTS This method produced 17.6+/-6.5X10(3) cells per gram of the body weight with a purity of 90%-95% and a viability of 92%-97%. Co-culture of PSCs with ADSCs significantly inhibited PSCs proliferation and induced PSCs apoptosis. Moreover, alpha-SMA expression was significantly reduced in PSCs+ADSCs compared with that in PSC-only cultures, while expression of fibrinolytic proteins (e.g., MMP-2 and MMP-9) was up-regulated and anti-fibrinolytic protein (TIMP-1) was down-regulated. In addition, NGF expression was up-regulated, but IL-10 and TGF-beta1 expressions were down-regulated in the co-culture conditioned medium compared with those in the PSC-only culture medium. CONCLUSIONS This study provided an easy and reliable technique to isolate PSCs. The data demonstrated the inhibitory effects of ADSCs on the activation and proliferation of PSCs in vitro.
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Abstract
OBJECTIVE Recent literature acknowledges the impact of this progressive and debilitating disease on psychological and social well-being, but the plight of those with chronic pancreatitis remains unknown and hidden. The aim of this study was to develop an understanding of what it means to live with chronic pancreatitis. DESIGN Qualitative study based on philosophical hermeneutics using multiple unstructured interviews. PARTICIPANTS Fourteen people with chronic pancreatitis and five relatives took part in 41 interviews in 2007-2008. SETTING Tertiary clinic in Ireland. RESULTS The meaning of living with chronic pancreatitis for participants in this study is 'enduring disruption'. Enduring has a two-fold meaning; it symbolises the perpetual or permanent nature of disruption that occurs at physiological, social and psychological levels (i.e., 'suffering'). Enduring also means 'to tolerate' and encompasses how the participants and their families cope and manage the overall transition from well person to a person with chronic pancreatitis. DISCUSSION This study offers an alternative perspective to previous quality of life research and presents a challenge to the emphasis on management of the pathophysiological processes and treatment of chronic pancreatitis that is decontextualised from the person's everyday living. Healthcare professionals need to understand and support people with chronic pancreatitis.
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Affiliation(s)
- Patricia Cronin
- School of Nursing and Midwifery, Trinity College Dublin, Dublin, Ireland.
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Rückert F, Brussig T, Kuhn M, Kersting S, Bunk A, Hunger M, Saeger HD, Niedergethmann M, Post S, Grützmann R. Malignancy in chronic pancreatitis: analysis of diagnostic procedures and proposal of a clinical algorithm. Pancreatology 2013; 13:243-9. [PMID: 23719595 DOI: 10.1016/j.pan.2013.03.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 03/23/2013] [Accepted: 03/24/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis, and some benign conditions and syndromes, including chronic pancreatitis (CP), are risk factors for pancreatic carcinoma. However, the differential diagnosis of CP from PDAC is difficult for clinicians because PDAC frequently causes inflammation within the pancreas. Therefore, patients with CP exhibit not only an elevated risk of cancer, but they are also in danger of underdiagnosis. METHODS The present study retrospectively analyzed 29 patients with pancreatic cancer who fulfilled our definition of "chronic pancreatitis" to identify characteristics to aid in the differential diagnosis between chronic pancreatitis with and without pancreatic cancer. All parameters were subjected to univariate analysis. RESULTS We identified several factors that differed significantly between the CP patients and patients with CP and synchronous PDAC, and these characteristics were used to develop a diagnostic algorithm. The performance of the algorithm was externally validated in a different panel of patients from the Department of Surgery, Medical Faculty Mannheim. CONCLUSION The present study succeeded in identifying characteristics that significantly differed in patients with and without PDAC in CP. These characteristics were integrated in a diagnostic algorithm that might help to improve diagnostic of PDAC in CP.
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Affiliation(s)
- Felix Rückert
- Department of Surgery, University Hospital Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.
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Li XC, Lu XL, Chen HH. α-Tocopherol treatment ameliorates chronic pancreatitis in an experimental rat model induced by trinitrobenzene sulfonic acid. Pancreatology 2011; 11:5-11. [PMID: 21311207 DOI: 10.1159/000309252] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2009] [Accepted: 03/13/2010] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the effects of α-tocopherol on pancreatic fibrosis and survival in rats with experimental chronic pancreatitis induced by trinitrobenzene sulfonic acid (TNBS). METHODS Chronic pancreatitis was induced in male Sprague-Dawley rats by infusion of TNBS into the pancreatic duct. α-Tocopherol (300, 600 or 900 mg/kg) was orally administered to rats with experimental pancreatitis (treatment group) daily for 4 weeks. The relative pancreatic weight, pancreatic pseudocyst and death rate were observed. Paraffin-embedded tissue samples were sliced, stained by hematoxylin-eosin and histopathologically examined. RESULTS α-Tocopherol administration significantly ameliorated the pancreatic weight loss induced by TNBS in chronic pancreatitis rats compared to the control group. There were pancreatic pseudocysts in 69% of the α-tocopherol group, and in 100% of the control group. α-Tocopherol administration led to a significant increase of the survival rate. The histopathologic scores were higher in the control group than in the α-tocopherol group. Subgroup analysis of histopathologic scores revealed that a high dose of α-tocopherol results in less pancreatic injuries. CONCLUSION α-Tocopherol treatment elevates survival rate, extenuates fibrosis and increases relative pancreatic weight in the chronic pancreatitis model. α-Tocopherol therapy in chronic pancreatitis is now required to confirm these findings and establish the role of this treatment in the management of this disabling condition. and IAP.
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Affiliation(s)
- X C Li
- Department of Geratology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Tajima Y, Kuroki T, Tsuneoka N, Adachi T, Isomoto I, Uetani M, Kanematsu T. Monitoring Fibrosis of the Pancreatic Remnant After a Pancreaticoduodenectomy With Dynamic MRI. J Surg Res 2010; 158:61-8. [DOI: 10.1016/j.jss.2008.07.033] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Revised: 06/24/2008] [Accepted: 07/22/2008] [Indexed: 01/18/2023]
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Internal Pancreatic Fistulae - Management Review. POLISH JOURNAL OF SURGERY 2008. [DOI: 10.2478/v10035-008-0037-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Sármán B, Tulassay Z. [Pathogenesis and treatment of pain in chronic pancreatitis]. Orv Hetil 2007; 148:397-403. [PMID: 17344167 DOI: 10.1556/oh.2007.27979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Chronic pancreatitis is an inflammatory, usually painful disease characterized by progressive fibrosis and the loss of exocrine and endocrine functions. Pain influences the quality of life of patients and may lead to inability to work and frequent hospitalisation. The pathogenesis of pain in chronic pancreatitis is still unclear. Several different mechanisms of pain have been proposed, but pain in chronic pancreatitis is most probably multifactorial. Pain management in chronic pancreatitis is difficult. This is due to the multifactorial origin, there are no standardized methods to quantify pain and patients are often addicted to alcohol in chronic pancreatitis. This review summarises the different hypotheses of pain and the possibilities of pain management in chronic pancreatitis.
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Affiliation(s)
- Beatrix Sármán
- Semmelweis Orvostudományi Egyetem, Altalános Orvostudományi Kar II. Belgyógyászati Klinika Budapest Szentkirályi u. 46. 1088, Hungary.
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Abstract
AIM: To establish the rats model of chronic fibrosing pancreatitis and to prove the anti-fibrotic effect of emodin in chronic pancreatitis with fibrosis.
METHODS: Fifty rats were randomly divided into five groups, 10 rats in each group. Trinitrobenzene sulfonic acid (TNBS) was infused into the pancreatic duct to induce chronic pancreatitis in rats (except for normal group). Emodin-treated rats were fed with different doses of emodin (20, 40 and 80 mg/kg body weight) for 28 d, while normal group and control group received 0.9% sodium chloride solution. Serum levels of hyaluronic acid (HA) and laminin (LN) were determined by radioimmunoassay. Histopathological alterations were studied by optical microscopy. Expression of collagen was also examined while transforming growth factor-beta-1 (TGF-β1) was localized by immunochemistry.
RESULTS: In emodin-treated rats, the serum levels of HA and LN were decreased significantly (HA, 62.2 ± 19.3 μg/L vs 112.7 ± 26.5 µg/L, P < 0.05; LN 44.3 ± 10.4 μg/L vs 86.2 ± 16.5 µg/L, P < 0.05); the degree of fibrosis was ameliorated observably; the expression of collagen in pancreatic tissue was reduced especially in high-dose emodin-treated group (36% ± 5% vs 42% ± 6%, P < 0.05); with the increased doses of emodin, the expression of TGF-β1 was declined, compared with those in control group.
CONCLUSION: Emodin has an anti-fibrotic effect on pancreatic fibrosis in rats. Because of its anti-fibrotic effect, it could be a potential herb for the treatment of chronic pancreatitis.
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Affiliation(s)
- Cai-Hua Wang
- Department of Gastroenterology, 2nd Affiliated Hosipital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China.
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Kennedy T, Preczewski L, Stocker SJ, Rao SM, Parsons WG, Wayne JD, Bell RH, Talamonti MS. Incidence of benign inflammatory disease in patients undergoing Whipple procedure for clinically suspected carcinoma: a single-institution experience. Am J Surg 2006; 191:437-41. [PMID: 16490563 DOI: 10.1016/j.amjsurg.2005.10.051] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2005] [Revised: 10/28/2005] [Accepted: 10/28/2005] [Indexed: 12/21/2022]
Abstract
BACKGROUND We evaluated the incidence of chronic pancreatitis and chronic bile duct inflammation in patients undergoing pancreaticoduodenectomy (PD) for suspected periampullary cancer. METHODS Differences between clinical presentation, surgical management, and outcomes were compared between patients with malignancy and benign inflammatory disease. RESULTS The incidence of chronic inflammatory disease was 12.9% (21/162). Patients with chronic inflammatory disease were associated with a higher incidence of smoking (75.0% versus 64.7%) and chronic alcohol use (66.7% versus 46.2%). Jaundice was significantly more frequent in patients with malignant disease (83.6% versus 42.9%, P < .05). Surgery for chronic inflammatory disease was associated with significantly more intraoperative bleeding (P < .05). CONCLUSIONS The finding of chronic inflammatory disease after PD for suspected carcinoma is justifiable because (1) none of the available diagnostic modalities are infallible, (2) early treatment of pancreatic cancer is crucial for achieving cure, and (3) PD may relieve clinical symptoms in patients with chronic pancreatitis or pancreatic cancer.
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Affiliation(s)
- Timothy Kennedy
- Department of Surgery, 201 E Huron, Galter 10-105, Chicago, IL 60611, USA
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Yoo BM, Oh TY, Kim YB, Yeo M, Lee JS, Surh YJ, Ahn BO, Kim WH, Sohn S, Kim JH, Hahm KB. Novel antioxidant ameliorates the fibrosis and inflammation of cerulein-induced chronic pancreatitis in a mouse model. Pancreatology 2005; 5:165-76. [PMID: 15849487 DOI: 10.1159/000085268] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2003] [Accepted: 06/01/2004] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIM Oxygen free radicals (OFRs) mediate an important step in the initiation of experimental acute pancreatitis and several clinical findings suggested the possible contribution of OFRs to the pathogenesis of pancreatic fibrosis. So far, there are no studies which reporting potential role of OFRs in development of chronic pancreatitis with the prevention with antioxidants. This study was aimed to establish the mice model of chronic fibrosing pancreatitis and to prove the involvement of OFRs in chronic pancreatitis with fibrosis. METHODS Repeated intraperitoneal cerulein injection was performed to induce chronic pancreatitis in mice. Histological changes in the pancreas were examined, and markers for oxidative stress were measured in the pancreatic tissue and serum of the mice. DA-9601, a phytochemical possessing anti-inflammatory and antioxidative action, was given together with cerulein to the mice. RESULTS Repeated intraperitoneal injection of cerulein provoked significant severity of chronic fibrosing pancreatitis after 5 weeks. After treatment of DA-9601, the extents of pancreatic fibrosis were statistically significantly decreased in accordance with lessened pancreatic inflammations. The NF-kappaB binding activities were increased in chronic pancreatitis, which were significantly attenuated after DA-9601 treatment. The levels of myeloperoxidase and iNOS activities were also significantly decreased in DA-9601-treated group compared to the pancreatitis only group. Cytoprotective proteins such as heat shock protein-70 (HSP) and metallothionein were significantly increased in the DA-9601-treated group. DA-9601 decreased the expressions of alpha-SMA and type I collagen in cultured pancreatic stellate cells. CONCLUSIONS Oxidative stress was principally involved in the pathogenesis of chronic pancreatitis with fibrosis.
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Affiliation(s)
- Byung-Moo Yoo
- Genome Research Center for Gastroenterology, Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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Yoo BM, Yeo M, Oh TY, Choi JH, Kim WW, Kim JH, Cho SW, Kim SJ, Hahm KB. Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling. Pancreas 2005; 30:e71-9. [PMID: 15782092 DOI: 10.1097/01.mpa.0000157388.54016.0a] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
OBJECTIVES Pancreatic fibrosis is a characteristic feature of chronic pancreatic injury, which is a result of the imbalance between synthesis and degradation of extracellular matrix (ECM) proteins. Transforming growth factor-beta (TGF-beta) plays a central role in biosynthesis and turnover of the ECM. In this study, we evaluated the role of TGF-beta signaling in pancreatic fibrosis induced by repetitive acute pancreatic injuries with mice of dominant-negative mutant of TGF-beta receptor II selectively in pancreas. METHODS TGF-beta signaling was inactivated by overexpressing a dominant-negative mutant form of TGF-beta type II receptor (pS2-dnR II) only in the pancreas under control of pS2/TFF1 promoter. Pancreatic fibrosis was induced by repeated intraperitoneal injections of 40 microg/kg cerulein for 5 or 10 weeks. RESULTS Repeated administration of cerulein induced significant pancreatic fibrosis, but of which fibrosis was remarkably attenuated in pS2-dnR II mice compared with wild-type littermates (P < 0.01). The ameliorated fibrosis was due to the reduction of synthesis of ECM proteins such as collagen type I, fibronectin, and ICAM-1. DNA binding activity of transcriptional factors including nuclear factor (NF)-kappaB and AP-1, responsible for the induction of immediate early genes of inflammatory responses, were significantly decreased in pS2-dnR II mice. While TGF-beta1 treatment in isolated pancreatic stellate cells (PSCs) stimulated the expression of alpha-SMA and fibronectin, PSCs transfected with TGF-beta dnRII showed attenuation of the ECM components. CONCLUSION Conditional loss of TGF-beta signaling selectively in the pancreas led to a failure in fibrogenic responses of repeated injections of cerulein, signifying that the modulation of TGF-beta signaling could be the therapeutic target for the prevention of chronic fibrosing pancreatitis.
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MESH Headings
- Animals
- Cells, Cultured
- Ceruletide/toxicity
- Extracellular Matrix Proteins/metabolism
- Fibrosis
- Male
- Mice
- Mice, Inbred Strains
- Mice, Transgenic
- NF-kappa B/metabolism
- Pancreas/pathology
- Pancreas/physiology
- Pancreatitis, Chronic/chemically induced
- Pancreatitis, Chronic/metabolism
- Pancreatitis, Chronic/pathology
- Protein Serine-Threonine Kinases
- Receptor, Transforming Growth Factor-beta Type II
- Receptors, Transforming Growth Factor beta/genetics
- Receptors, Transforming Growth Factor beta/metabolism
- Signal Transduction/physiology
- Transcription Factor AP-1/metabolism
- Transcription, Genetic/drug effects
- Transcription, Genetic/physiology
- Transfection
- Transforming Growth Factor beta/metabolism
- Transforming Growth Factor beta1
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Affiliation(s)
- Byung Moo Yoo
- Genome Research Center for Gastroenterology, Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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