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Wang B, Ge JY, Wu JN, Xu JH, Cao XH, Chang N, Zhou X, Jing PB, Liu XJ, Wu Y. Endothelin A receptor in nociceptors is essential for persistent mechanical pain in a chronic pancreatitis of mouse model. World J Gastroenterol 2025; 31:103848. [DOI: 10.3748/wjg.v31.i23.103848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 03/30/2025] [Accepted: 05/30/2025] [Indexed: 06/20/2025] Open
Abstract
BACKGROUND Chronic pancreatitis (CP) accompanied with persistent abdominal pain represents a major clinical challenge for the symptom management in patients. Although with clear involvement of neuropathy, the detailed mechanisms underlying pain hypersensitivity associated with CP are not totally clear. The endothelin system has been reported to contribute to chronic pain and chronic inflammatory settings, and is a potential therapeutic target for the treatment of chronic pain.
AIM To evaluate the role of nociceptor-specific endothelin A receptor (ETAR) in pain hypersensitivity in a CP mouse model and its potential contributing mechanisms.
METHODS Oral gavage delivery of dibutyltin dichloride (DBTC) was used to induce CP in mice. A conditional knockout (CKO) strain which specifically delete ETAR in dorsal root ganglion (DRG) nociceptive neurons was generated. Abdominal pain hypersensitivity associated with CP and other behaviors were evaluated. The size of mouse gallbladder was measured and pancreatic histopathology was examined to validate the CP model. Calcitonin gene-related peptide expression and immune cells in the innervated DRGs and spinal cord were also examined. Calcium imaging in dissociated DRG neurons was performed to investigate the excitability of affected nociceptive neurons.
RESULTS Specific deletion of endothelin receptor type A gene in nociceptive DRG neurons did not affect basal abdominal thermal and mechanical pain threshold in mice. Abdominal mechanical pain hypersensitivity was persistent in DBTC-treated WT mice but was significantly reduced in DBTC-treated CKO mice. DBTC treatment did not affect mouse nociceptive responses to heat and cold stimuli, as well as motor functions and anxiety-like behaviors of mice. DBTC treatment induced severe pancreatic inflammation and obvious gallbladder enlargement in wild type (WT) mice, but less in CKO mice. DBTC-induced increase of calcitonin gene-related peptide- and induction of brown adipocytes 1-positive signals in the DRG and spinal cord in WT mice were remarkably attenuated in CKO mice. DRG neurons from CKO mice exhibited less excitability and sensitivity in response to endothelin-1 exposure than those from WT mice.
CONCLUSION DBTC intragastric administration in mice produced a convenient and reliable animal model for studying abdominal pain associated with CP. ETAR-dependent endothelin signaling in nociceptors is important for the development of persistent abdominal mechanical hypersensitivity in mice.
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Affiliation(s)
- Bing Wang
- Department of Anesthesiology, The First People’s Hospital of Lianyungang, Lianyungang 222000, Jiangsu Province, China
| | - Jia-Yi Ge
- School of Pharmacy, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Jia-Ni Wu
- School of Pharmacy, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Jia-Huan Xu
- School of Pharmacy, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Xiao-Hua Cao
- School of Pharmacy, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Na Chang
- School of Pharmacy, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Xiang Zhou
- School of Pharmacy, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Peng-Bo Jing
- School of Pharmacy, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Xing-Jun Liu
- School of Pharmacy, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Yong Wu
- Department of Anesthesiology, The First People’s Hospital of Lianyungang, Lianyungang 222000, Jiangsu Province, China
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Rosales-Muñoz GJ, Souza-Arroyo V, Bucio-Ortiz L, Miranda-Labra RU, Gomez-Quiroz LE, Gutiérrez-Ruiz MC. Acute pancreatitis experimental models, advantages and disadvantages. J Physiol Biochem 2025:10.1007/s13105-025-01091-w. [PMID: 40380027 DOI: 10.1007/s13105-025-01091-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 05/05/2025] [Indexed: 05/19/2025]
Abstract
Acute pancreatitis represents a severe health problem, not only because of the number of people affected but also because of the severity of its clinical presentation that can eventually lead to the death of patients. The study of the disease is complex, and we lack optimized models that can approach the clinical presentation in patients, in addition to the significant vulnerability of the organ itself. In the present work, we undertook the task of reviewing and analyzing the experimental methods most currently used for the induction of acute pancreatitis, emphasizing the advantages and disadvantages of each model and their delimitation based on experimental objectives. We aimed to provide an actual and quick-access guide for researchers interested in experimental acute pancreatitis.
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Affiliation(s)
- Genaro J Rosales-Muñoz
- Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
- Departamento de Ciencias de La Salud, Área de Medicina Experimental y Traslacional, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
| | - Verónica Souza-Arroyo
- Departamento de Ciencias de La Salud, Área de Medicina Experimental y Traslacional, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
- Laboratorio de Medicina Experimental, Unidad de Medicina Traslacional IIB/UNAM, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Leticia Bucio-Ortiz
- Departamento de Ciencias de La Salud, Área de Medicina Experimental y Traslacional, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
- Laboratorio de Medicina Experimental, Unidad de Medicina Traslacional IIB/UNAM, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Roxana U Miranda-Labra
- Departamento de Ciencias de La Salud, Área de Medicina Experimental y Traslacional, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
- Laboratorio de Medicina Experimental, Unidad de Medicina Traslacional IIB/UNAM, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Luis E Gomez-Quiroz
- Departamento de Ciencias de La Salud, Área de Medicina Experimental y Traslacional, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
- Laboratorio de Medicina Experimental, Unidad de Medicina Traslacional IIB/UNAM, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - María Concepción Gutiérrez-Ruiz
- Departamento de Ciencias de La Salud, Área de Medicina Experimental y Traslacional, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.
- Laboratorio de Medicina Experimental, Unidad de Medicina Traslacional IIB/UNAM, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico.
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Swetha K, Indumathi MC, Siddappa S, Chen CH, Marathe GK. Comparative Study of Non-invasive Mouse Models of Pancreatitis. Dig Dis Sci 2025; 70:233-244. [PMID: 39604666 DOI: 10.1007/s10620-024-08771-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 11/19/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND AND AIMS Although a relevant animal model is essential for studying human diseases, one has yet to be established for mouse pancreatitis. Early non-invasive models of mouse pancreatitis have serious limitations. METHODS In this study, we compared the efficiency, consistency, and reproducibility of inducing pancreatitis in 3 non-invasive mouse models of pancreatitis in Wistar albino mice: (1) L-arginine-induced model (2 intraperitoneal injections of 4 g/kg body weight of L-arginine spaced 1 h apart), (2) caerulein-induced model (6 intraperitoneal injections of 50 µg/kg body weight of caerulein at hourly intervals), and (3) caerulein + LPS (lipopolysaccharide)-induced model (6 intraperitoneal doses of 50 µg/kg body weight of caerulein at hourly intervals, along with an LPS [10 mg/kg body weight] injection immediately after the last caerulein injection). RESULTS Our findings showed that the L-arginine-induced model was inconsistent. The levels of the pancreatic enzymes, amylase and lipase, were higher in the caerulein and caerulein + LPS groups. Histological examination showed tissue destruction in the induced groups, with varying degrees of fibrosis in the caerulein + LPS group. CONCLUSIONS The caerulein + LPS model was the most reliable model in Wistar albino mice. Our findings may be useful in helping investigators choose the most appropriate animal model for pancreatitis research.
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Affiliation(s)
- Kamatam Swetha
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore-06, India
| | | | - Shiva Siddappa
- Division of Biochemistry, School of Life Sciences, JSS Academy of Higher Education and Research, Mysore-15, India
| | - Chu-Huang Chen
- Vascular and Medicinal Research, The Texas Heart Institute, Houston, TX, 77030, USA
| | - Gopal K Marathe
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore-06, India.
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore-06, India.
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Falcão KVG, Azevedo RDSD, Lima LRAD, Bezerra RDS. A rapid protocol for inducing acute pancreatitis in zebrafish models. Comp Biochem Physiol C Toxicol Pharmacol 2024; 283:109958. [PMID: 38857668 DOI: 10.1016/j.cbpc.2024.109958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 05/19/2024] [Accepted: 06/06/2024] [Indexed: 06/12/2024]
Abstract
Acute pancreatitis (AP) is an inflammatory disorder that occurs in the exocrine pancreas associated with tissue injury and necrosis. Experimental models of AP typically involve rodents, such as rats or mice. However, rodents exhibit divergent pathophysiological responses after the establishment of AP between themselves and in comparison, with human. The experiments conducted for this manuscript aimed to standardize a new AP model in zebrafish and validate it. Here, we provide a protocol for inducing AP in zebrafish through intraperitoneal injections of synthetic caerulein. Details are provided for solution preparation, pre-injection procedures, injection technique, and monitoring animal survival. Subsequently, validation was performed through biochemical and histological analyses of pancreatic tissue. The administered dose of caerulein for AP induction was 10 μg/kg applied four times in the intraperitoneal region. The histological validation study demonstrated the presence of necrosis within the first 12 h post-injection, accompanied by an excess of zymogen granules in the extracellular milieu. These observations align with those reported in conventional rodent models. We have standardized and validated the AP model in zebrafish. This model can contribute to preclinical and clinical studies of new drugs for AP treatment. Therefore, this novel model expands the toolkit for exploring faster and more effective preventive and therapeutic strategies for AP.
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Affiliation(s)
| | | | - Luiza Rayanna Amorim de Lima
- Programa de Pós-Graduação em Saúde e Desenvolvimento Socioambiental, Universidade de Pernambuco - UPE, Campus Garanhuns, Brazil
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Dressel TD, Custer CM. A closed-loop negative feedback model for the pancreas: A new paradigm and pathway to a cure. Medicine (Baltimore) 2024; 103:e38802. [PMID: 38996137 PMCID: PMC11245245 DOI: 10.1097/md.0000000000038802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 06/12/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND AND AIMS To develop a model that describes how the pancreas functions, how the rate of synthesis of digestive enzymes is regulated, and finally what puts the pancreas to rest between meals. METHODS We applied the principals of control theory to previously published canine data to develop a model for how the canine pancreas functions. Using this model, we then describe the steps needed to apply this model to the human pancreas. RESULTS This new closed-loop negative feedback model describes what regulates digestive enzyme synthesis. This model is based on basolateral exocytosis of butyrylcholinesterase (BCHE) into the interstitial space. It is this level of BCHE * BCHE activity that controls the rate of canine pancreas digestive enzyme synthesis, and in the absence of stimulation from the vagus nerve, puts the pancreas to rest between meals. CONCLUSIONS Finding secretagogue-specific inhibitory enzymes in the human pancreas that are analogous to BCHE in the canine, and blocking its associated receptors, may lead to a cure for human pancreatitis.
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Affiliation(s)
- Thomas D. Dressel
- Correspondence: Thomas D. Dressel, 8725 Walton Oaks Dr., Bloomington, MN 55438 (e-mail: )
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Zheng P, Li XY, Yang XY, Wang H, Ding L, He C, Wan JH, Ke HJ, Lu NH, Li NS, Zhu Y. Comparative transcriptomic analysis reveals the molecular changes of acute pancreatitis in experimental models. World J Gastroenterol 2024; 30:2038-2058. [PMID: 38681131 PMCID: PMC11045495 DOI: 10.3748/wjg.v30.i14.2038] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/19/2024] [Accepted: 03/01/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND Acute pancreatitis (AP) encompasses a spectrum of pancreatic inflammatory conditions, ranging from mild inflammation to severe pancreatic necrosis and multisystem organ failure. Given the challenges associated with obtaining human pancreatic samples, research on AP predominantly relies on animal models. In this study, we aimed to elucidate the fundamental molecular mechanisms underlying AP using various AP models. AIM To investigate the shared molecular changes underlying the development of AP across varying severity levels. METHODS AP was induced in animal models through treatment with caerulein alone or in combination with lipopolysaccharide (LPS). Additionally, using Ptf1α to drive the specific expression of the hM3 promoter in pancreatic acinar cells transgenic C57BL/6J- hM3/Ptf1α(cre) mice were administered Clozapine N-oxide to induce AP. Subsequently, we conducted RNA sequencing of pancreatic tissues and validated the expression of significantly different genes using the Gene Expression Omnibus (GEO) database. RESULTS Caerulein-induced AP showed severe inflammation and edema, which were exacerbated when combined with LPS and accompanied by partial pancreatic tissue necrosis. Compared with the control group, RNA sequencing analysis revealed 880 significantly differentially expressed genes in the caerulein model and 885 in the caerulein combined with the LPS model. Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis indicated substantial enrichment of the TLR and NOD-like receptor signaling pathway, TLR signaling pathway, and NF-κB signaling pathway, alongside elevated levels of apoptosis-related pathways, such as apoptosis, P53 pathway, and phagosome pathway. The significantly elevated genes in the TLR and NOD-like receptor signaling pathways, as well as in the apoptosis pathway, were validated through quantitative real-time PCR experiments in animal models. Validation from the GEO database revealed that only MYD88 concurred in both mouse pancreatic tissue and human AP peripheral blood, while TLR1, TLR7, RIPK3, and OAS2 genes exhibited marked elevation in human AP. The genes TUBA1A and GADD45A played significant roles in apoptosis within human AP. The transgenic mouse model hM3/Ptf1α(cre) successfully validated significant differential genes in the TLR and NOD-like receptor signaling pathways as well as the apoptosis pathway, indicating that these pathways represent shared pathological processes in AP across different models. CONCLUSION The TLR and NOD receptor signaling pathways play crucial roles in the inflammatory progression of AP, notably the MYD88 gene. Apoptosis holds a central position in the necrotic processes of AP, with TUBA1A and GADD45A genes exhibiting prominence in human AP.
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Affiliation(s)
- Pan Zheng
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xue-Yang Li
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xiao-Yu Yang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Huan Wang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Ling Ding
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Cong He
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jian-Hua Wan
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Hua-Jing Ke
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Nong-Hua Lu
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Nian-Shuang Li
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yin Zhu
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
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Fan XR, Huang Y, Su Y, Chen SJ, Zhang YL, Huang WK, Wang H. Exploring the regulatory mechanism of tRNA-derived fragments 36 in acute pancreatitis based on small RNA sequencing and experiments. World J Gastroenterol 2023; 29:4642-4656. [PMID: 37662862 PMCID: PMC10472903 DOI: 10.3748/wjg.v29.i30.4642] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/26/2023] [Accepted: 07/17/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is a disease featuring acute inflammation of the pancreas and histological destruction of acinar cells. Approximately 20% of AP patients progress to moderately severe or severe pancreatitis, with a case fatality rate of up to 30%. However, a single indicator that can serve as the gold standard for prognostic prediction has not been discovered. Therefore, gaining deeper insights into the underlying mechanism of AP progression and the evolution of the disease and exploring effective biomarkers are important for early diagnosis, progression evaluation, and precise treatment of AP. AIM To determine the regulatory mechanisms of tRNA-derived fragments (tRFs) in AP based on small RNA sequencing and experiments. METHODS Small RNA sequencing and functional enrichment analyses were performed to identify key tRFs and the potential mechanisms in AP. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was conducted to determine tRF expression. AP cell and mouse models were created to investigate the role of tRF36 in AP progression. Lipase, amylase, and cytokine levels were assayed to examine AP progression. Ferritin expression, reactive oxygen species, malondialdehyde, and ferric ion levels were assayed to evaluate cellular ferroptosis. RNA pull down assays and methylated RNA immunoprecipitation were performed to explore the molecular mechanisms. RESULTS RT-qPCR results showed that tRF36 was significantly upregulated in the serum of AP patients, compared to healthy controls. Functional enrichment analysis indicated that target genes of tRF36 were involved in ferroptosis-related pathways, including the Hippo signaling pathway and ion transport. Moreover, the occurrence of pancreatic cell ferroptosis was detected in AP cells and mouse models. The results of interference experiments and AP cell models suggested that tRF-36 could promote AP progression through the regulation of ferroptosis. Furthermore, ferroptosis gene microarray, database prediction, and immunoprecipitation suggested that tRF-36 accelerated the progression of AP by recruiting insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) to the p53 mRNA m6A modification site by binding to IGF2BP3, which enhanced p53 mRNA stability and promoted the ferroptosis of pancreatic follicle cells. CONCLUSION In conclusion, regulation of nuclear pre-mRNA domain-containing protein 1B promoted AP development by regulating the ferroptosis of pancreatic cells, thereby acting as a prospective therapeutic target for AP. In addition, this study provided a basis for understanding the regulatory mechanisms of tRFs in AP.
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Affiliation(s)
- Xi-Rui Fan
- Department of Gastroenterology, The Affiliated Yan’an Hospital of Kunming Medical University, Kunming 650051, Yunnan Province, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Yan’an Hospital of Kunming, Kunming 650051, Yunnan Province, China
| | - Yun Huang
- Department of Gastroenterology, The Affiliated Yan’an Hospital of Kunming Medical University, Kunming 650051, Yunnan Province, China
| | - Yu Su
- Department of Gastroenterology, The Affiliated Yan’an Hospital of Kunming Medical University, Kunming 650051, Yunnan Province, China
| | - Si-Jin Chen
- Department of Gastroenterology, The Affiliated Yan’an Hospital of Kunming Medical University, Kunming 650051, Yunnan Province, China
| | - Yu-Lu Zhang
- Department of Gastroenterology, The Affiliated Yan’an Hospital of Kunming Medical University, Kunming 650051, Yunnan Province, China
| | - Wei-Kang Huang
- Department of Gastroenterology, The Affiliated Yan’an Hospital of Kunming Medical University, Kunming 650051, Yunnan Province, China
| | - Hui Wang
- Department of Gastroenterology, The Affiliated Yan’an Hospital of Kunming Medical University, Kunming 650051, Yunnan Province, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Yan’an Hospital of Kunming, Kunming 650051, Yunnan Province, China
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Han C, Dong ZQ, Li ZS, Hu LH. Historical Review of Acute Pancreatitis Research Over the Last 80 Years. Pancreas 2023; 52:e263-e274. [PMID: 37855819 DOI: 10.1097/mpa.0000000000002249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2023]
Abstract
OBJECTIVES Research on acute pancreatitis (AP) has been ongoing for a long time. It is necessary to summarize and investigate the history of AP research. METHODS Publications related to AP research were retrieved from PubMed. Medical Subject Headings (MeSH) terms, countries, journals, and publication dates were analyzed. Co-occurrence analysis was conducted to illustrate the holistic trend in AP research. A dynamic bar graph, heat maps, and line charts were created to illustrate change trends of MeSH terms. RESULTS In total, 28,222 publications with 8558 MeSH terms were retrieved from 1941 to 2020. Among these, 16,575 publications with 7228 MeSH terms were from 2001 to 2020. The top 10 MeSH terms showed a considerable change from 1941 to 1970 but remained stable since the 1970s. Four clusters obtained from the co-occurrence analysis were "experiments on animals," "diagnosis and treatment," "prognosis and expectation," and "protein and enzyme." From 1941 to 2020, 33 MeSH terms with increasing trends (MH-I) and 15 MeSH terms with decreasing trends (MH-D) were selected to create a heat map (every decade). Meanwhile, 16 MH-I and 41 MH-D were selected to create the heat map from 2001 to 2020 (every 2 years). CONCLUSION Over the past 80 years, the pathogenesis, treatment, risk management, and experimental model were the main research highlights. Optimal supportive management, minimally invasive treatment, and prediction of prognosis are subjects of interest for clinical practitioners; signal transduction to identify a target for precise treatment is the focus of experimental research in AP.
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Affiliation(s)
| | - Zhi-Qi Dong
- Department of Gastroenterology, Shanghai Fourth People's Hospital, Tongji University School of Medicine
| | - Zhao-Shen Li
- From the Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai
| | - Liang-Hao Hu
- From the Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai
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9
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Tomaszewska E, Świątkiewicz M, Muszyński S, Donaldson J, Ropka-Molik K, Arciszewski MB, Murawski M, Schwarz T, Dobrowolski P, Szymańczyk S, Dresler S, Bonior J. Repetitive Cerulein-Induced Chronic Pancreatitis in Growing Pigs-A Pilot Study. Int J Mol Sci 2023; 24:ijms24097715. [PMID: 37175426 PMCID: PMC10177971 DOI: 10.3390/ijms24097715] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Chronic pancreatitis (CP) is an irreversible and progressive inflammatory disease. Knowledge on the development and progression of CP is limited. The goal of the study was to define the serum profile of pro-inflammatory cytokines and the cell antioxidant defense system (superoxidase dismutase-SOD, and reduced glutathione-GSH) over time in a cerulein-induced CP model and explore the impact of these changes on selected cytokines in the intestinal mucosa and pancreatic tissue, as well as on selected serum biochemical parameters. The mRNA expression of CLDN1 and CDH1 genes, and levels of Claudin-1 and E-cadherin, proteins of gut barrier, in the intestinal mucosa were determined via western blot analysis. The study showed moderate pathomorphological changes in the pigs' pancreas 43 days after the last cerulein injection. Blood serum levels of interleukin (IL)-1-beta, IL-6, tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGTP), SOD and GSH were increased following cerulein injections. IL-1-beta, IL-6, TNF-alpha and GSH were also increased in jejunal mucosa and pancreatic tissue. In duodenum, decreased mRNA expression of CDH1 and level of E-cadherin and increased D-lactate, an indicator of leaky gut, indicating an inflammatory state, were observed. Based on the current results, we can conclude that repetitive cerulein injections in growing pigs not only led to CP over time, but also induced inflammation in the intestine. As a result of the inflammation, the intestinal barrier was impaired.
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Affiliation(s)
- Ewa Tomaszewska
- Department of Animal Physiology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Małgorzata Świątkiewicz
- Department of Animal Nutrition and Feed Science, National Research Institute of Animal Production, 32-083 Balice, Poland
| | - Siemowit Muszyński
- Department of Biophysics, Faculty of Environmental Biology, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Janine Donaldson
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg 2193, South Africa
| | - Katarzyna Ropka-Molik
- Department of Animal Molecular Biology, National Research Institute of Animal Production, 32-083 Balice, Poland
| | - Marcin B Arciszewski
- Department of Animal Anatomy and Histology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Maciej Murawski
- Department of Animal Nutrition, Biotechnology and Fisheries, Faculty of Animal Science, University of Agriculture in Kraków, 30-059 Kraków, Poland
| | - Tomasz Schwarz
- Department of Animal Genetics, Breeding and Ethology, Faculty of Animal Science, University of Agriculture in Kraków, 30-059 Kraków, Poland
| | - Piotr Dobrowolski
- Department of Functional Anatomy and Cytobiology, Faculty of Biology and Biotechnology, Maria Curie-Sklodowska University, 20-033 Lublin, Poland
| | - Sylwia Szymańczyk
- Department of Animal Physiology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Sławomir Dresler
- Department of Analytical Chemistry, Medical University of Lublin, 20-059 Lublin, Poland
- Department of Plant Physiology and Biophysics, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, 20-033 Lublin, Poland
| | - Joanna Bonior
- Department of Medical Physiology, Chair of Biomedical Sciences, Institute of Physiotherapy, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland
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Abstract
Pancreatic ductal adenocarcinomas are distinguished by their robust desmoplasia, or fibroinflammatory response. Dominated by non-malignant cells, the mutated epithelium must therefore combat, cooperate with or co-opt the surrounding cells and signalling processes in its microenvironment. It is proposed that an invasive pancreatic ductal adenocarcinoma represents the coordinated evolution of malignant and non-malignant cells and mechanisms that subvert and repurpose normal tissue composition, architecture and physiology to foster tumorigenesis. The complex kinetics and stepwise development of pancreatic cancer suggests that it is governed by a discrete set of organizing rules and principles, and repeated attempts to target specific components within the microenvironment reveal self-regulating mechanisms of resistance. The histopathological and genetic progression models of the transforming ductal epithelium must therefore be considered together with a programme of stromal progression to create a comprehensive picture of pancreatic cancer evolution. Understanding the underlying organizational logic of the tumour to anticipate and pre-empt the almost inevitable compensatory mechanisms will be essential to eradicate the disease.
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Affiliation(s)
- Sunil R Hingorani
- Division of Hematology and Oncology, Department of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
- Pancreatic Cancer Center of Excellence, University of Nebraska Medical Center, Omaha, NE, USA.
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11
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Song Q, Gao H, Wu W, Gao Y, Yang J, Jiao Z, Luo Y. Gabexate Mesylate-Poloxamer 407 Conjugate Alleviates Sodium Taurocholate-Induced Severe Acute Pancreatitis in an Optimized Rat Model. Dig Dis Sci 2023; 68:138-146. [PMID: 35451710 DOI: 10.1007/s10620-022-07497-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/16/2021] [Indexed: 02/01/2023]
Abstract
BACKGROUND AND AIMS We have previously shown that gabexate mesylate-poloxamer 407 conjugate (GMTI) alleviates traumatic pancreatitis in rats. In this study, we evaluated the therapeutic effect of GMTI on sodium taurocholate-induced severe acute pancreatitis (SAP) in an optimized rat model. METHODS An SAP rat model was established via microinjection of 3.5% sodium taurocholate and retention in the bile duct for 1 min. SAP rats were administered GMTI via tail vein injection (i.v.) or tail vein injection + intraperitoneal injection (i.v. + i.p.). All rats were sacrificed at 12 h after treatment. Biochemical approach and enzyme-linked immunosorbent assay were performed to measure the serum levels of amylase (AMY), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Hematoxylin and eosin staining and TUNEL assay were conducted to examine histopathology and acinar cell apoptosis in the rat pancreas. RESULTS SAP was successfully induced in all model rats, as evidenced by progressively aggravating SAP symptoms and signs, pancreatic histopathological abnormalities, as well as elevated serum levels of TNF-α, IL-6, and AMY. The mortality rates at 1 h, 6 h, and 12 h were 0%, 0%, and 25%, respectively. GMTI therapy via i.v. or i.v. + i.p. significantly reduced pancreatic wet weights, ascites amounts, pathological scores, and circulating levels of TNF-α and IL-6 while promoting acinar cell apoptosis in SAP rats. GMTI therapy via i.v. + i.p. outperformed i.v. in improving pancreatic histology and reducing TNF-α and IL-6 serum levels in SAP rats. CONCLUSIONS Our optimized SAP rat model is reliable and reproducible. GMTI therapy is a promising approach against SAP.
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Affiliation(s)
- Qing Song
- Department of Ultrasound, First Medical Center of General Hospital of Chinese PLA, Middle Street of 4th West Ring Road, Beijing, 100853, China
- Department of Ultrasound, General Hospital of Chinese PLA, Seventh medical center, Beijing, 100700, China
| | - Hanjing Gao
- Department of Ultrasound, Second Medical Center, General Hospital of Chinese PLA, Beijing, 100853, China
| | - Wen Wu
- Department of Ultrasound, General Hospital of Chinese PLA, Seventh medical center, Beijing, 100700, China
| | - Yu Gao
- Department of Ultrasound, General Hospital of Chinese PLA, Seventh medical center, Beijing, 100700, China
| | - Jihua Yang
- Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Ziyu Jiao
- Department of Ultrasound, First Medical Center of General Hospital of Chinese PLA, Middle Street of 4th West Ring Road, Beijing, 100853, China
| | - Yukun Luo
- Department of Ultrasound, First Medical Center of General Hospital of Chinese PLA, Middle Street of 4th West Ring Road, Beijing, 100853, China.
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12
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Petersen OH. Watching Living Cells in Action in the Exocrine Pancreas: The Palade Prize Lecture. FUNCTION 2022; 4:zqac061. [PMID: 36606242 PMCID: PMC9809903 DOI: 10.1093/function/zqac061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/04/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
George Palade's pioneering electron microscopical studies of the pancreatic acinar cell revealed the intracellular secretory pathway from the rough endoplasmic reticulum at the base of the cell to the zymogen granules in the apical region. Palade also described for the first time the final stage of exocytotic enzyme secretion into the acinar lumen. The contemporary studies of the mechanism by which secretion is acutely controlled, and how the pancreas is destroyed in the disease acute pancreatitis, rely on monitoring molecular events in the various identified pancreatic cell types in the living pancreas. These studies have been carried out with the help of high-resolution fluorescence recordings, often in conjunction with patch clamp current measurements. In such studies we have gained much detailed information about the regulatory events in the exocrine pancreas in health as well as disease, and new therapeutic opportunities have been revealed.
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Affiliation(s)
- Ole H Petersen
- School of Biosciences, Sir Martin Evans Building, Cardiff University, Wales, CF10 3AX, UK
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13
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Wang L, Xu T, Wang R, Wang X, Wu D. Hypertriglyceridemia Acute Pancreatitis: Animal Experiment Research. Dig Dis Sci 2022; 67:761-772. [PMID: 33939144 DOI: 10.1007/s10620-021-06928-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/26/2021] [Indexed: 12/09/2022]
Abstract
In recent years, the number of acute pancreatitis cases caused by hypertriglyceridemia has increased gradually, which has caught the attention of the medical community. However, because the exact mechanism of hypertriglyceridemic acute pancreatitis (HTG-AP) is not clear, treatment and prevention in clinical practice face enormous challenges. Animal models are useful for elucidating the pathogenesis of diseases and developing and testing novel interventions. Therefore, animal experiments have become the key research means for us to understand and treat this disease. We searched almost all HTG-AP animal models by collecting many studies and finally collated common animals such as rats, mice and included some rare animals that are not commonly used, summarizing the methods to model spontaneous pancreatitis and induce pancreatitis. We sorted them on the basis of three aspects, including the selection of different animals, analyzed the characteristics of different animals, different approaches to establish hypertriglyceridemic pancreatitis and their relative advantages and disadvantages, and introduced the applications of these models in studies of pathogenesis and drug therapy. We hope this review can provide relevant comparisons and analyses for researchers who intend to carry out animal experiments and will help researchers to select and establish more suitable animal experimental models according to their own experimental design.
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Affiliation(s)
- Lu Wang
- Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ting Xu
- Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ruifeng Wang
- Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Xiaobing Wang
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Dong Wu
- Department of Gastroenterology, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China
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14
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Li H, Wen W, Luo J. Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis. Biomedicines 2022; 10:biomedicines10010108. [PMID: 35052788 PMCID: PMC8773075 DOI: 10.3390/biomedicines10010108] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 02/04/2023] Open
Abstract
Pancreatitis and alcoholic pancreatitis are serious health concerns with an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here, we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR in developing novel therapeutic strategies for the disease.
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Affiliation(s)
- Hui Li
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
| | - Wen Wen
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
| | - Jia Luo
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
- Iowa City VA Health Care System, Iowa City, IA 52246, USA
- Correspondence: ; Tel.: +1-319-335-2256
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15
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Yi Y, Sun X, Liang B, He N, Gibson-Corley KN, Norris AW, Engelhardt JF, Uc A. Acute pancreatitis-induced islet dysfunction in ferrets. Pancreatology 2021; 21:839-847. [PMID: 33994067 PMCID: PMC8355067 DOI: 10.1016/j.pan.2021.04.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/22/2021] [Accepted: 04/24/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND /Objectives: The pathogenesis of hyperglycemia during acute pancreatitis (AP) remains unknown due to inaccessibility of human tissues and lack of animal models. We aimed to develop an animal model to study the mechanisms of hyperglycemia and impaired glucose tolerance in AP. METHODS We injected ferrets with intraperitoneal cerulein (50 μg/kg, 9 hourly injections) or saline. Blood samples were collected for glucose (0, 4, 8, 12, 24h); TNF-α, IL-6 (6h); amylase, lipase, insulin, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) (24h). Animals underwent oral glucose tolerance test (OGTT), mixed meal tolerance test (MMTT) at 24h or 3 months, followed by harvesting pancreas for histopathology and immunostaining. RESULTS Cerulein-injected ferrets exhibited mild pancreatic edema, neutrophil infiltration, and elevations in serum amylase, lipase, TNF-α, IL-6, consistent with AP. Plasma glucose was significantly higher in ferrets with AP at all time points. Plasma glucagon, GLP-1 and PP were significantly higher in cerulein-injected animals, while plasma insulin was significantly lower compared to controls. OGTT and MMTT showed abnormal glycemic responses with higher area under the curve. The hypoglycemic response to insulin injection was completely lost, suggestive of insulin resistance. OGTT showed low plasma insulin; MMTT confirmed low insulin and GIP; abnormal OGTT and MMTT responses returned to normal 3 months after cerulein injection. CONCLUSIONS Acute cerulein injection causes mild acute pancreatitis in ferrets and hyperglycemia related to transient islet cell dysfunction and insulin resistance. The ferret cerulein model may contribute to the understanding of hyperglycemia in acute pancreatitis.
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Affiliation(s)
- Yaling Yi
- Department of Anatomy and Cell Biology, Iowa City, IA, USA
| | - Xingshen Sun
- Department of Anatomy and Cell Biology, Iowa City, IA, USA
| | - Bo Liang
- Department of Anatomy and Cell Biology, Iowa City, IA, USA
| | - Nan He
- Department of Anatomy and Cell Biology, Iowa City, IA, USA
| | - Katherine N Gibson-Corley
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Andrew W Norris
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA; Department of Pediatrics, lowa City, IA, USA; Department of Biochemistry, Iowa City, IA, USA
| | - John F Engelhardt
- Department of Anatomy and Cell Biology, Iowa City, IA, USA; Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA
| | - Aliye Uc
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA; Department of Pediatrics, lowa City, IA, USA; Department of Radiation Oncology; University of Iowa, Iowa City, IA, USA.
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16
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Petersen OH, Gerasimenko JV, Gerasimenko OV, Gryshchenko O, Peng S. The roles of calcium and ATP in the physiology and pathology of the exocrine pancreas. Physiol Rev 2021; 101:1691-1744. [PMID: 33949875 DOI: 10.1152/physrev.00003.2021] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
This review deals with the roles of calcium ions and ATP in the control of the normal functions of the different cell types in the exocrine pancreas as well as the roles of these molecules in the pathophysiology of acute pancreatitis. Repetitive rises in the local cytosolic calcium ion concentration in the apical part of the acinar cells not only activate exocytosis but also, via an increase in the intramitochondrial calcium ion concentration, stimulate the ATP formation that is needed to fuel the energy-requiring secretion process. However, intracellular calcium overload, resulting in a global sustained elevation of the cytosolic calcium ion concentration, has the opposite effect of decreasing mitochondrial ATP production, and this initiates processes that lead to necrosis. In the last few years it has become possible to image calcium signaling events simultaneously in acinar, stellate, and immune cells in intact lobules of the exocrine pancreas. This has disclosed processes by which these cells interact with each other, particularly in relation to the initiation and development of acute pancreatitis. By unraveling the molecular mechanisms underlying this disease, several promising therapeutic intervention sites have been identified. This provides hope that we may soon be able to effectively treat this often fatal disease.
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Affiliation(s)
- Ole H Petersen
- School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | | | | | | | - Shuang Peng
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong, People's Republic of China
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17
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Mallya K, Gautam SK, Aithal A, Batra SK, Jain M. Modeling pancreatic cancer in mice for experimental therapeutics. Biochim Biophys Acta Rev Cancer 2021; 1876:188554. [PMID: 33945847 DOI: 10.1016/j.bbcan.2021.188554] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/19/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy that is characterized by early metastasis, low resectability, high recurrence, and therapy resistance. The experimental mouse models have played a central role in understanding the pathobiology of PDAC and in the preclinical evaluation of various therapeutic modalities. Different mouse models with targetable pathological hallmarks have been developed and employed to address the unique challenges associated with PDAC progression, metastasis, and stromal heterogeneity. Over the years, mouse models have evolved from simple cell line-based heterotopic and orthotopic xenografts in immunocompromised mice to more complex and realistic genetically engineered mouse models (GEMMs) involving multi-gene manipulations. The GEMMs, mostly driven by KRAS mutation(s), have been widely accepted for therapeutic optimization due to their high penetrance and ability to recapitulate the histological, molecular, and pathological hallmarks of human PDAC, including comparable precursor lesions, extensive metastasis, desmoplasia, perineural invasion, and immunosuppressive tumor microenvironment. Advanced GEMMs modified to express fluorescent proteins have allowed cell lineage tracing to provide novel insights and a new understanding about the origin and contribution of various cell types in PDAC pathobiology. The syngeneic mouse models, GEMMs, and target-specific transgenic mice have been extensively used to evaluate immunotherapies and study therapy-induced immune modulation in PDAC yielding meaningful results to guide various clinical trials. The emerging mouse models for parabiosis, hepatic metastasis, cachexia, and image-guided implantation, are increasingly appreciated for their high translational significance. In this article, we describe the contribution of various experimental mouse models to the current understanding of PDAC pathobiology and their utility in evaluating and optimizing therapeutic modalities for this lethal malignancy.
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Affiliation(s)
- Kavita Mallya
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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18
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Yang X, Yao L, Fu X, Mukherjee R, Xia Q, Jakubowska MA, Ferdek PE, Huang W. Experimental Acute Pancreatitis Models: History, Current Status, and Role in Translational Research. Front Physiol 2020; 11:614591. [PMID: 33424638 PMCID: PMC7786374 DOI: 10.3389/fphys.2020.614591] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 11/30/2020] [Indexed: 02/05/2023] Open
Abstract
Acute pancreatitis is a potentially severe inflammatory disease that may be associated with a substantial morbidity and mortality. Currently there is no specific treatment for the disease, which indicates an ongoing demand for research into its pathogenesis and development of new therapeutic strategies. Due to the unpredictable course of acute pancreatitis and relatively concealed anatomical site in the retro-peritoneum, research on the human pancreas remains challenging. As a result, for over the last 100 years studies on the pathogenesis of this disease have heavily relied on animal models. This review aims to summarize different animal models of acute pancreatitis from the past to present and discuss their main characteristics and applications. It identifies key studies that have enhanced our current understanding of the pathogenesis of acute pancreatitis and highlights the instrumental role of animal models in translational research for developing novel therapies.
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Affiliation(s)
- Xinmin Yang
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Linbo Yao
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xianghui Fu
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Rajarshi Mukherjee
- Liverpool Pancreatitis Research Group, Liverpool University Hospitals National Health Service Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Qing Xia
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | | | - Pawel E. Ferdek
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Wei Huang
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
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19
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Khamaysi I, Hamo-Giladi DB, Abassi Z. Heparanase in Acute Pancreatitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1221:703-719. [PMID: 32274733 DOI: 10.1007/978-3-030-34521-1_29] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Acute pancreatitis (AP) is one of the most common diseases in gastroenterology, affecting 2% of all hospitalized patients. Nevertheless, neither the etiology nor the pathophysiology of the disease is fully characterized, and no specific or effective treatment has been developed. Heparanase (Hpa) is an endoglycosidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs) into shorter oligosaccharides, activity that is highly implicated in cell invasion associated with cancer metastasis and inflammation. Given that AP is a typical inflammatory disease, we investigated whether Hpa plays a role in AP. Our results provide keen evidence that Hpa expression and activity are significantly increased following cerulein-induced AP in wild type mice. In parallel to the classic manifestations of AP, namely elevation of amylase and lipase levels, pancreas edema and inflammation as well as induction of cytokines and signaling molecules, have been detected in this experimental model of the disease. Noteworthy, these features were far more profound in transgenic mice overexpressing heparanase (Hpa-Tg), suggesting that these mice can be utilized as a model system to reveal the molecular mechanism by which Hpa functions in AP. Further support for the involvement of Hpa in the pathogenesis of AP emerged from our observation that treatment of experimental AP with PG545 or SST0001(= Ronepastat), two potent Hpa inhibitors, markedly attenuated the biochemical, histological and immunological manifestations of the disease. Hpa, therefore, emerges as a potential new target in AP, and Hpa inhibitors are hoped to prove beneficial in AP along with their promising efficacy as anti-cancer compounds.
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Affiliation(s)
- Iyad Khamaysi
- Department of Gastroenterology, Advanced Endoscopy Procedures Unit, Rambam Health Care Campus, Haifa, Israel.
| | | | - Zaid Abassi
- Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel
- Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
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20
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Nadella S, Ciofoaia V, Cao H, Kallakury B, Tucker RD, Smith JP. Cholecystokinin Receptor Antagonist Therapy Decreases Inflammation and Fibrosis in Chronic Pancreatitis. Dig Dis Sci 2020; 65:1376-1384. [PMID: 31598921 PMCID: PMC8554577 DOI: 10.1007/s10620-019-05863-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 09/24/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Chronic pancreatitis is associated with recurrent inflammation, pain, fibrosis, and loss of exocrine and endocrine pancreatic function and risk of cancer. We hypothesized that activation of the CCK receptor contributes to pancreatitis and blockade of this pathway would improve chronic pancreatitis. METHODS Two murine models were used to determine whether CCK receptor blockade with proglumide could prevent and reverse histologic and biochemical features of chronic pancreatitis: the 6-week repetitive chronic cerulein injection model and the modified 75% choline-deficient ethionine (CDE) diet. In the CDE-fed model, half the mice received water supplemented with proglumide, for 18 weeks. After chronic pancreatitis was established in the cerulein model, half the mice were treated with proglumide and half with water. Histology was scored in a blinded fashion for inflammation, fibrosis and acinar ductal metaplasia (ADM) and serum lipase levels were measured. RNA was extracted and examined for differentially expressed fibrosis genes. RESULTS Proglumide therapy decreased pancreatic weight in the CDE diet study and the cerulein-induced chronic pancreatitis model. Fibrosis, inflammation, and ADM scores were significantly reduced in both models. Lipase values improved with proglumide but not in controls in both models. Proglumide decreased pancreas mRNA expression of amylase, collagen-4, and TGFβR2 gene expression by 44, 38, and 25%, respectively, compared to control mice. CONCLUSION New strategies are needed to decreased inflammation and reduce fibrosis in chronic pancreatitis. CCK receptor antagonist therapy may improve chronic pancreatitis by reversing fibrosis and inflammation. The decrease in ADM may reduce the risk of the development of pancreatic cancer.
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Affiliation(s)
- Sandeep Nadella
- Department of Medicine, Georgetown University, 4000 Reservoir Rd, NW, Building D, Room 338, Washington, DC 20007, USA
| | - Victor Ciofoaia
- Department of Medicine, Georgetown University, 4000 Reservoir Rd, NW, Building D, Room 338, Washington, DC 20007, USA,Mayo Clinic, Rochester, MN, USA
| | - Hong Cao
- Department of Medicine, Georgetown University, 4000 Reservoir Rd, NW, Building D, Room 338, Washington, DC 20007, USA
| | | | - Robin D. Tucker
- Department of Pathology, Georgetown University, Washington, DC, USA
| | - Jill P. Smith
- Department of Medicine, Georgetown University, 4000 Reservoir Rd, NW, Building D, Room 338, Washington, DC 20007, USA
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21
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Malla SR, Krueger B, Wartmann T, Sendler M, Mahajan UM, Weiss FU, Thiel FG, De Boni C, Gorelick FS, Halangk W, Aghdassi AA, Reinheckel T, Gukovskaya AS, Lerch MM, Mayerle J. Early trypsin activation develops independently of autophagy in caerulein-induced pancreatitis in mice. Cell Mol Life Sci 2020; 77:1811-1825. [PMID: 31363815 PMCID: PMC8221268 DOI: 10.1007/s00018-019-03254-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 07/16/2019] [Accepted: 07/24/2019] [Indexed: 12/18/2022]
Abstract
Premature intrapancreatic trypsinogen activation is widely regarded as an initiating event for acute pancreatitis. Previous studies have alternatively implicated secretory vesicles, endosomes, lysosomes, or autophagosomes/autophagolysosomes as the primary site of trypsinogen activation, from which a cell-damaging proteolytic cascade originates. To identify the subcellular compartment of initial trypsinogen activation we performed a time-resolution analysis of the first 12 h of caerulein-induced pancreatitis in transgenic light chain 3 (LC3)-GFP autophagy reporter mice. Intrapancreatic trypsin activity increased within 60 min and serum amylase within 2 h, but fluorescent autophagosome formation only by 4 h of pancreatitis in parallel with a shift from cytosolic LC3-I to membranous LC3-II on Western blots. At 60 min, activated trypsin in heavier subcellular fractions was co-distributed with cathepsin B, but not with the autophagy markers LC3 or autophagy protein 16 (ATG16). Supramaximal caerulein stimulation of primary pancreatic acini derived from LC3-GFP mice revealed that trypsinogen activation is independent of autophagolysosome formation already during the first 15 min of exposure to caerulein. Co-localization studies (with GFP-LC3 autophagosomes versus Ile-Pro-Arg-AMC trypsin activity and immunogold-labelling of lysosomal-associated membrane protein 2 [LAMP-2] versus trypsinogen activation peptide [TAP]) indicated active trypsin in autophagolysosomes only at the later timepoints. In conclusion, during the initiating phase of caerulein-induced pancreatitis, premature protease activation develops independently of autophagolysosome formation and in vesicles arising from the secretory pathway. However, autophagy is likely to regulate overall intracellular trypsin activity during the later stages of this disease.
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Affiliation(s)
- Sudarshan R Malla
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, 17475, Germany
- Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, University of California at Los Angeles, Los Angeles, CA, 90073, USA
| | - Burkhard Krueger
- Division of Medical Biology, University of Rostock, Rostock, 18051, Germany
| | - Thomas Wartmann
- Division of Experimental Surgery, University of Magdeburg, Magdeburg, 39120, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, 17475, Germany
| | - Ujjwal M Mahajan
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, 17475, Germany
- Department of Medicine II, Ludwigs-Maximilians University Munich, 80539, Munich, Germany
| | - F Ulrich Weiss
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, 17475, Germany
| | - Franziska G Thiel
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, 17475, Germany
| | - Carina De Boni
- Division of Experimental Surgery, University of Magdeburg, Magdeburg, 39120, Germany
| | | | - Walter Halangk
- Division of Experimental Surgery, University of Magdeburg, Magdeburg, 39120, Germany
| | - Ali A Aghdassi
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, 17475, Germany
| | - Thomas Reinheckel
- Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, 79104, Germany
| | - Anna S Gukovskaya
- Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, University of California at Los Angeles, Los Angeles, CA, 90073, USA
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, 17475, Germany.
| | - Julia Mayerle
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, 17475, Germany
- Department of Medicine II, Ludwigs-Maximilians University Munich, 80539, Munich, Germany
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22
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Animal models to study the role of pulmonary intravascular macrophages in spontaneous and induced acute pancreatitis. Cell Tissue Res 2020; 380:207-222. [DOI: 10.1007/s00441-020-03211-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 03/30/2020] [Indexed: 12/14/2022]
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Williams JA, Groblewski GE, Gorelick FS, Mayerle J, Apte M, Gukovskaya A. American Pancreatic Association Frank Brooks Symposium: Fifty Years of Pancreatic Cell Biology. Pancreas 2020; 49:604-611. [PMID: 32433396 PMCID: PMC7249997 DOI: 10.1097/mpa.0000000000001543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Affiliation(s)
- John A. Williams
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
- Department of Internal Medicine (Gastroenterology), University of Michigan, Ann Arbor, MI
| | - Guy E. Groblewski
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI
| | - Fred S. Gorelick
- Department of Cell Biology, Yale University School of Medicine, New Haven, CT
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Julia Mayerle
- Department of Medicine II, Liver Centre Munich, University Hospital, LMU Munich, Germany
| | - Minoti Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia
| | - Anna Gukovskaya
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, and, VA Greater Los Angeles Healthcare System, Los Angeles, CA
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24
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Roch AM, Maatman TK, Cook TG, Wu HH, Merfeld-Clauss S, Traktuev DO, March KL, Zyromski NJ. Therapeutic Use of Adipose-Derived Stromal Cells in a Murine Model of Acute Pancreatitis. J Gastrointest Surg 2020; 24:67-75. [PMID: 31745900 DOI: 10.1007/s11605-019-04411-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/11/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND No specific therapy exists for acute pancreatitis (AP), and current treatment remains entirely supportive. Adipose stem cells (ASCs) have significant immunomodulatory and regenerative activities. We hypothesized that systemic administration of ASCs would mitigate inflammation in AP. METHODS AP was induced in mice by 6 hourly intraperitoneal injections of cerulein. Twenty-four hours after AP induction, mice were randomized into four systemic treatment groups: sham group (no acute pancreatitis), vehicle, human ASCs, and human ASC-conditioned media. Mice were sacrificed at 48 h, and blood and organs were collected and analyzed. Pancreatic injury was quantified histologically using a published score (edema, inflammation, and necrosis). Pancreatic inflammation was also studied by immunohistochemistry and PCR. RESULTS When using IV infusion of Hoechst-labeled ASCs, ASCs were found to localize to inflamed tissues: lungs and pancreas. Mice treated with ASCs had less severe AP, as shown by a significantly decreased histopathology score (edema, inflammation, and necrosis) (p = 0.001). ASCs infusion polarized pancreatic macrophages toward an anti-inflammatory M2 phenotype. ASC-conditioned media reduced pancreatic inflammation similarly to ASCs only, highlighting the importance of ASCs secreted factors in modulating inflammation. CONCLUSION Intravenous delivery of human ASCs markedly reduces pancreatic inflammation in a murine model of AP ASCs which represent an effective therapy for AP.
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Affiliation(s)
- Alexandra M Roch
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA
| | - Thomas K Maatman
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA
| | - Todd G Cook
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA
| | - Howard H Wu
- Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Stephanie Merfeld-Clauss
- Department of Medicine, Division of Cardiovascular Medicine, Center for Regenerative medicine, University of Florida, Gainesville, FL, USA
| | - Dmitry O Traktuev
- Department of Medicine, Division of Cardiovascular Medicine, Center for Regenerative medicine, University of Florida, Gainesville, FL, USA
| | - Keith L March
- Department of Medicine, Division of Cardiovascular Medicine, Center for Regenerative medicine, University of Florida, Gainesville, FL, USA
| | - Nicholas J Zyromski
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA.
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25
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Dong K, Chen X, Xie L, Yu L, Shen M, Wang Y, Wu S, Wang J, Lu J, Wei G, Xu D, Yang L. Spautin-A41 Attenuates Cerulein-Induced Acute Pancreatitis through Inhibition of Dysregulated Autophagy. Biol Pharm Bull 2019; 42:1789-1798. [DOI: 10.1248/bpb.b19-00132] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Kai Dong
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
| | - Xia Chen
- Department of Endocrinology and Metabolism, Shanghai Fourth People’s Hospital, Tongji University
| | - Liping Xie
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Lanting Yu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
| | - Mengjun Shen
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
| | - Yanping Wang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Shanshan Wu
- Shandong University Affiliated Shandong Provincial Hospital Affiliated, Department of Endocrinology and Metabolism
| | - Jiajia Wang
- Department of Endocrinology, Medical College of Soochow University
| | - Junxi Lu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Gang Wei
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Dongliang Xu
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
- Department of Urology, Changzheng Hospital, Second Military Medical University
| | - Liu Yang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
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26
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Fate of Autophagic Vacuoles in Acinar Cells During Pancreatitis. Pancreas 2019; 48:e71-e75. [PMID: 31609938 PMCID: PMC6812542 DOI: 10.1097/mpa.0000000000001389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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27
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Erdos Z, Barnum JE, Wang E, DeMaula C, Dey PM, Forest T, Bailey WJ, Glaab WE. Evaluation of the Relative Performance of Pancreas-Specific MicroRNAs in Rat Plasma as Biomarkers of Pancreas Injury. Toxicol Sci 2019; 173:5-18. [PMID: 31504967 DOI: 10.1093/toxsci/kfz184] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Abstract
Drug-induced pancreatic injury (DIPI) has become linked in recent years to many commonly prescribed medications from several pharmacological classes. Diagnosis is currently most often focused on identification of acute pancreatitis and generally based on subjective clinical assessment and serum amylase and lipase enzymatic activity, which have been criticized as being insufficiently sensitive and specific. The lack of novel noninvasive biomarkers of DIPI can impede the advancement of drug candidates through nonclinical development and translation into clinical settings. Pancreas-specific microRNAs (miRNAs) are currently being evaluated as biomarkers of DIPI that may outperform and/or add value to the interpretation of amylase and lipase. To assess the relative performance of these novel miRNAs, a comprehensive evaluation was conducted to determine the sensitivity and specificity of detecting DIPI in rats. Four miRNAs were evaluated (miR-216a-5p, miR-216b-5p, miR-217-5p, and miR-375-3p) in plasma from 10 studies in which rats were treated with known pancreatic toxicants to assess sensitivity, and from 10 different studies in which toxicity was evident in tissues other than pancreas to assess specificity. The candidate miRNA biomarker performance was compared with amylase and lipase, and receiver operator characteristics (ROC) were determined. Analysis of ROCs demonstrated that all four miRNAs outperformed amylase and lipase in monitoring acute pancreatic injury defined as acinar cell degeneration/necrosis. Specifically, miR-217-5p had the highest performance among all biomarkers assessed. The increased sensitivity and specificity of these miRNAs support their use as biomarkers of DIPI, thereby adding value to the interpretation of amylase and lipase measurements in nonclinical studies. The potential for miRNAs to serve as translational biomarkers in the clinic for the monitoring of DIPI is also supported by this investigation.
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Affiliation(s)
- Zoltan Erdos
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - John E Barnum
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Erjia Wang
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Christopher DeMaula
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Paritosh Markus Dey
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Thomas Forest
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Wendy J Bailey
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Warren E Glaab
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
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28
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Abstract
OBJECTIVE The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis. METHODS LSL-Kras; P48-Cre (KC) mutant KRAS transgenic mice were crossed with gastrin-KO (GKO) mice to develop GKO/KC mice. Pancreata were examined for 8 months for stage of pancreatic intraepithelial neoplasia lesions, inflammation, fibrosis, gastrin peptide, and microRNA expression. Pancreatic intraepithelial neoplasias from mice were collected by laser capture microdissection and subjected to reverse-phase protein microarray, for gastrin and protein kinases associated with signal transduction. Gastrin mRNA was measured by RNAseq in human pancreatic cancer tissues and compared to that in normal pancreas. RESULTS In the absence of gastrin, PanIN progression, inflammation, and fibrosis were significantly decreased and signal transduction was reversed to the canonical pathway with decreased KRAS. Gastrin re-expression in the PanINs was mediated by miR-27a. Gastrin mRNA expression was significantly increased in human pancreatic cancer samples compared to normal human pancreas controls. CONCLUSIONS This study supports the mitogenic role of gastrin in activation of KRAS during pancreatic carcinogenesis.
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29
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Abstract
The incidence of acute pancreatitis continues to increase worldwide, and it is one of the most common gastrointestinal causes for hospital admission in the USA. In the past decade, substantial advancements have been made in our understanding of the pathophysiological mechanisms of acute pancreatitis. Studies have elucidated mechanisms of calcium-mediated acinar cell injury and death and the importance of store-operated calcium entry channels and mitochondrial permeability transition pores. The cytoprotective role of the unfolded protein response and autophagy in preventing sustained endoplasmic reticulum stress, apoptosis and necrosis has also been characterized, as has the central role of unsaturated fatty acids in causing pancreatic organ failure. Characterization of these pathways has led to the identification of potential molecular targets for future therapeutic trials. At the patient level, two classification systems have been developed to classify the severity of acute pancreatitis into prognostically meaningful groups, and several landmark clinical trials have informed management strategies in areas of nutritional support and interventions for infected pancreatic necrosis that have resulted in important changes to acute pancreatitis management paradigms. In this Review, we provide a summary of recent advances in acute pancreatitis with a special emphasis on pathophysiological mechanisms and clinical management of the disorder.
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30
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Saloman JL, Albers KM, Cruz-Monserrate Z, Davis BM, Edderkaoui M, Eibl G, Epouhe AY, Gedeon JY, Gorelick FS, Grippo PJ, Groblewski GE, Husain SZ, Lai KK, Pandol SJ, Uc A, Wen L, Whitcomb DC. Animal Models: Challenges and Opportunities to Determine Optimal Experimental Models of Pancreatitis and Pancreatic Cancer. Pancreas 2019; 48:759-779. [PMID: 31206467 PMCID: PMC6581211 DOI: 10.1097/mpa.0000000000001335] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
At the 2018 PancreasFest meeting, experts participating in basic research met to discuss the plethora of available animal models for studying exocrine pancreatic disease. In particular, the discussion focused on the challenges currently facing the field and potential solutions. That meeting culminated in this review, which describes the advantages and limitations of both common and infrequently used models of exocrine pancreatic disease, namely, pancreatitis and exocrine pancreatic cancer. The objective is to provide a comprehensive description of the available models but also to provide investigators with guidance in the application of these models to investigate both environmental and genetic contributions to exocrine pancreatic disease. The content covers both nongenic and genetically engineered models across multiple species (large and small). Recommendations for choosing the appropriate model as well as how to conduct and present results are provided.
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Affiliation(s)
- Jami L. Saloman
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Kathryn M. Albers
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Brian M. Davis
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Mouad Edderkaoui
- Basic and Translational Pancreas Research, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA
| | - Ariel Y. Epouhe
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Jeremy Y. Gedeon
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Fred S. Gorelick
- Department of Internal Medicine, Section of Digestive Diseases & Department of Cell Biology Yale University School of Medicine; Veterans Affairs Connecticut Healthcare, West Haven, CT
| | - Paul J. Grippo
- Department of Medicine, Division of Gastroenterology and Hepatology, UI Cancer Center, University of Illinois at Chicago, Chicago, IL
| | - Guy E. Groblewski
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI
| | | | - Keane K.Y. Lai
- Department of Pathology (National Medical Center), Department of Molecular Medicine (Beckman Research Institute), and Comprehensive Cancer Center, City of Hope, Duarte, CA
| | - Stephen J. Pandol
- Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA
| | - Aliye Uc
- Stead Family Department of Pediatrics, University of Iowa, Stead Family Children’s Hospital, Iowa City, IA
| | - Li Wen
- Department of Pediatrics, Stanford University, Palo Alto, CA
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31
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Silva-Vaz P, Abrantes AM, Castelo-Branco M, Gouveia A, Botelho MF, Tralhão JG. Murine Models of Acute Pancreatitis: A Critical Appraisal of Clinical Relevance. Int J Mol Sci 2019; 20:E2794. [PMID: 31181644 PMCID: PMC6600324 DOI: 10.3390/ijms20112794] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 06/04/2019] [Accepted: 06/05/2019] [Indexed: 12/15/2022] Open
Abstract
Acute pancreatitis (AP) is a severe disease associated with high morbidity and mortality. Clinical studies can provide some data concerning the etiology, pathophysiology, and outcomes of this disease. However, the study of early events and new targeted therapies cannot be performed on humans due to ethical reasons. Experimental murine models can be used in the understanding of the pancreatic inflammation, because they are able to closely mimic the main features of human AP, namely their histologic glandular changes and distant organ failure. These models continue to be important research tools for the reproduction of the etiological, environmental, and genetic factors associated with the pathogenesis of this inflammatory pathology and the exploration of novel therapeutic options. This review provides an overview of several murine models of AP. Furthermore, special focus is made on the most frequently carried out models, the protocols used, and their advantages and limitations. Finally, examples are provided of the use of these models to improve knowledge of the mechanisms involved in the pathogenesis, identify new biomarkers of severity, and develop new targeted therapies.
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Affiliation(s)
- Pedro Silva-Vaz
- Health Sciences Research Centre, University of Beira Interior (CICS-UBI), 6200-506 Covilhã, Portugal.
- General Surgery Department, Unidade Local de Saúde de Castelo Branco, 6000-085 Castelo Branco, Portugal.
- Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal.
| | - Ana Margarida Abrantes
- Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
- Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine of University of Coimbra, 3000-548 Coimbra, Portugal.
| | - Miguel Castelo-Branco
- Health Sciences Research Centre, University of Beira Interior (CICS-UBI), 6200-506 Covilhã, Portugal.
- Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal.
| | - António Gouveia
- General Surgery Department, Unidade Local de Saúde de Castelo Branco, 6000-085 Castelo Branco, Portugal.
- Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal.
| | - Maria Filomena Botelho
- Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
- Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine of University of Coimbra, 3000-548 Coimbra, Portugal.
| | - José Guilherme Tralhão
- Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
- Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine of University of Coimbra, 3000-548 Coimbra, Portugal.
- Surgery Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal.
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32
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Abstract
Pancreatitis is a major risk factor for the development of pancreatic cancer. In genetically engineered mouse models, induction of pancreatic inflammation dramatically accelerates oncogenic KRas-induced fibrosis, precancerous PanIN formation, and tumorigenesis. Here we describe simple methods of secretagogue-induced experimental acute and chronic pancreatitis, the most commonly used pancreatitis models, and their applications in pancreatic cancer research. Additionally, the preparation of primary pancreatic acinar cells is introduced. Primary acinar cells can be used to study the early events of pancreatic inflammation and pancreatic acinar-to-ductal (ADM) metaplasia.
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33
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Mayerle J, Sendler M, Hegyi E, Beyer G, Lerch MM, Sahin-Tóth M. Genetics, Cell Biology, and Pathophysiology of Pancreatitis. Gastroenterology 2019; 156:1951-1968.e1. [PMID: 30660731 PMCID: PMC6903413 DOI: 10.1053/j.gastro.2018.11.081] [Citation(s) in RCA: 226] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/14/2018] [Accepted: 11/16/2018] [Indexed: 02/07/2023]
Abstract
Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.
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Affiliation(s)
- Julia Mayerle
- Medical Department II, University Hospital, LMU, Munich, Germany,Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Eszter Hegyi
- Institute for Translational Medicine, University of Pécs, Hungary
| | - Georg Beyer
- Medical Department II, University Hospital, LMU, Munich, Germany
| | - Markus M. Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Miklós Sahin-Tóth
- Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118
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Yan H, Jiang L, Zou H, Chen T, Liang H, Tang L. PTEN suppresses the inflammation, viability, and motility of AP-AR42J cells by activating the Wnt/β-catenin pathway. RSC Adv 2019; 9:5460-5469. [PMID: 35515912 PMCID: PMC9060792 DOI: 10.1039/c8ra08998a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 01/14/2019] [Indexed: 11/23/2022] Open
Abstract
Acute pancreatitis (AP), a kind of common acute abdominal disease and typical chemical inflammation, is commonly caused by pancreatin digestion of the pancreas and surrounding tissues. The gene for phosphate and tension homology deleted on chromosome ten (PTEN) is a tumor suppressor that regulates numerous cellular processes. In the present study, we have elaborately investigated the effect of PTEN on the alleviating of AP and its underlying mechanisms. Firstly, we demonstrated an up-regulation of PTEN in the pancreatic tissues from AP rats by immunochemistry, qRT-PCR and western-blot assays. Subsequently, cellular experiments exhibited that PTEN has a significant inhibition effect on the proliferation, invasion and migration of AP cells. Further underlying mechanism studies showed that the growth of AP cells was mainly restrained by PTEN in the G1 phase through activation of the Wnt/β-catenin pathway, which can be demonstrated by the down-regulation of various pro-inflammatory cytokines such as IL-6, IL-10, TNF and IL-1β. Taking these results together, we can draw the conclusion that PTEN plays a significant role in suppressing the inflammation, viability and motility of acute pancreatitis and could be a potential target for AP therapies. Acute pancreatitis (AP), a kind of common acute abdominal disease and typical chemical inflammation, is commonly caused by pancreatin digestion of the pancreas and surrounding tissues.![]()
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Affiliation(s)
- Hongtao Yan
- General Surgery Center of PLA, General Hospital of Western Theater Command No. 270 Rong Du Road, Jinniu District Chengdu Sichuan Province 610083 P. R. China +86-028-86570326
| | - Li Jiang
- Cardiac Care Unit of Cardiothoracic Surgery, General Hospital of Western Theater Command Chengdu Sichuan 610083 P. R. China
| | - Hong Zou
- General Surgery Center of PLA, General Hospital of Western Theater Command No. 270 Rong Du Road, Jinniu District Chengdu Sichuan Province 610083 P. R. China +86-028-86570326
| | - Tao Chen
- General Surgery Center of PLA, General Hospital of Western Theater Command No. 270 Rong Du Road, Jinniu District Chengdu Sichuan Province 610083 P. R. China +86-028-86570326
| | - Hongyin Liang
- General Surgery Center of PLA, General Hospital of Western Theater Command No. 270 Rong Du Road, Jinniu District Chengdu Sichuan Province 610083 P. R. China +86-028-86570326
| | - Lijun Tang
- General Surgery Center of PLA, General Hospital of Western Theater Command No. 270 Rong Du Road, Jinniu District Chengdu Sichuan Province 610083 P. R. China +86-028-86570326
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35
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Quan S, Principe DR, Dean AE, Park SH, Grippo PJ, Gius D, Horikoshi N. Loss of Sirt2 increases and prolongs a caerulein-induced pancreatitis permissive phenotype and induces spontaneous oncogenic Kras mutations in mice. Sci Rep 2018; 8:16501. [PMID: 30405152 PMCID: PMC6220268 DOI: 10.1038/s41598-018-34792-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/14/2018] [Indexed: 02/06/2023] Open
Abstract
Mice lacking Sirt2 spontaneously develop tumors in multiple organs, as well as when expressed in combination with oncogenic KrasG12D, leading to pancreatic tumors. Here, we report that after caerulein-induced pancreatitis, Sirt2-deficient mice exhibited an increased inflammatory phenotype and delayed pancreatic tissue recovery. Seven days post injury, the pancreas of Sirt2-/- mice display active inflammation, whereas wild-type mice had mostly recovered. In addition, the pancreas from the Sirt2-/- mice exhibited extensive tissue fibrosis, which was still present at six weeks after exposure. The mice lacking Sirt2 also demonstrated an enhanced whole body pro-inflammatory phenotype that was most obvious with increasing age. Importantly, an accumulation of a cell population with spontaneous cancerous KrasG12D mutations was observed in the Sirt2-/- mice that is enhanced in the recovering pancreas after exposure to caerulein. Finally, transcriptome analysis of the pancreas of the Sirt2-/- mice exhibited a pro-inflammatory genomic signature. These results suggest that loss of Sirt2, as well as increased age, enhanced the immune response to pancreatic injury and induced an inflammatory phenotype permissive for the accumulation of cells carrying oncogenic Kras mutations.
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Affiliation(s)
- Songhua Quan
- Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Daniel R Principe
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Angela E Dean
- Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Seong-Hoon Park
- Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of General and Applied Toxicology, Genetic Toxicology Research Group, Korea Institute of Toxicology (KIT), Daejeon, South Korea
| | - Paul J Grippo
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - David Gius
- Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
- Department of Pharmacology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Nobuo Horikoshi
- Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Nadella S, Burks J, Al-Sabban A, Inyang G, Wang J, Tucker RD, Zamanis ME, Bukowski W, Shivapurkar N, Smith JP. Dietary fat stimulates pancreatic cancer growth and promotes fibrosis of the tumor microenvironment through the cholecystokinin receptor. Am J Physiol Gastrointest Liver Physiol 2018; 315:G699-G712. [PMID: 29927319 PMCID: PMC6293257 DOI: 10.1152/ajpgi.00123.2018] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The gastrointestinal peptide cholecystokinin (CCK) is released from the duodenum in response to dietary fat to aid in digestion, and plasma CCK levels are elevated with the consumption of high-fat diets. CCK is also a trophic peptide for the pancreas and has also been shown to stimulate growth of pancreatic cancer. In the current investigation, we studied the influence of a diet high in saturated fat on the growth of pancreatic cancer in syngeneic murine models before the mice became obese to exclude the confounding factors associated with obesity. The high-fat diet significantly increased growth and metastasis of pancreatic cancer compared with the control diet, and the stimulatory effect was blocked by the CCK-receptor antagonist proglumide. We then selectively knocked out the CCK receptor on the pancreatic cancer cells using clustered regularly interspaced short palindromic repeats technology and showed that without CCK-receptors, dietary fat was unable to stimulate cancer growth. We next demonstrated that dietary fat failed to influence pancreatic cancer xenograft growth in genetically engineered CCK peptide knockout mice. The tumor-associated fibrosis that is so prevalent in the pancreatic cancer microenvironment was significantly decreased with CCK-receptor antagonist therapy because fibroblasts also have CCK receptors. The CCK-receptor antagonist proglumide also altered tumor metalloprotease expression and increased tumor suppressor genes by a PCR array. Our studies confirm that a diet high in saturated fat promotes growth of pancreatic cancer and the action is mediated by the CCK-receptor pathway. NEW & NOTEWORTHY Diets high in long-chain saturated fats promote growth of pancreatic cancer independent of obesity. The mechanism through which dietary fat promotes cancer is mediated through the cholecystokinin (CCK) receptor pathway. Therapy with a CCK-receptor antagonist altered the tumor microenvironment by reducing fibrosis, increasing cluster of differentiation 8+ lymphocytes, increasing tumor suppressor genes, and thus decreasing metastases. Use of CCK-receptor antagonist therapy with standard chemotherapy for pancreatic cancer may improve response by altering the tumor microenvironment.
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Affiliation(s)
- Sandeep Nadella
- 1Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Julian Burks
- 2Department of Oncology, Georgetown University, Washington, District of Columbia
| | | | - Gloria Inyang
- 3Department of Biochemistry, Georgetown University, Washington, District of Columbia
| | - Juan Wang
- 1Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Robin D. Tucker
- 4Department of Comparative Medicine, Georgetown University, Washington, District of Columbia
| | - Marie E. Zamanis
- 2Department of Oncology, Georgetown University, Washington, District of Columbia
| | - William Bukowski
- 1Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Narayan Shivapurkar
- 1Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Jill P. Smith
- 1Department of Medicine, Georgetown University, Washington, District of Columbia,2Department of Oncology, Georgetown University, Washington, District of Columbia
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Klauss S, Schorn S, Teller S, Steenfadt H, Friess H, Ceyhan GO, Demir IE. Genetically induced vs. classical animal models of chronic pancreatitis: a critical comparison. FASEB J 2018; 32:fj201800241RR. [PMID: 29863911 DOI: 10.1096/fj.201800241rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Chronic pancreatitis (CP) is an utmost complex disease that is pathogenetically linked to pancreas-intrinsic ( e.g., duct obstruction), environmental-toxic ( e.g., alcohol, smoking), and genetic factors. Studying such a complex disease naturally requires validated experimental models. In the past 2 decades, the various animal models of CP usually addressed either the pancreas-intrinsic ( e.g., the caerulein model), the environmental-toxic ( e.g., diet-induced models), or the genetic component of CP. As such, these models were far from mirroring CP in its full spectrum, and the correct choice of models was vital for valid scientific conclusions on CP. The quest for mechanistic, genetic models gave rise to models based on gene modification and transgene insertion, such as the PRSS1 and the IL-1β/IL-1β models. Recently, we witnessed the development of highly exciting models that rely on the importance of autophagy in CP, that is, the murine pancreas-specific Atg5 and LAMP2 knockout models. Today, critical comparison of these several models is more important than ever for guiding research on CP in an efficient direction. The present review outlines the characteristics of the new genetic models in comparison with the well-known classic models for CP, notes the caveats in the choice of models, and also indicates novel directions for model development.-Klauss, S., Schorn, S., Teller, S., Steenfadt, H., Friess, H., Ceyhan, G. O., Demir, I. K. Genetically induced vs. classical animal models of chronic pancreatitis: a critical comparison.
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Affiliation(s)
- Sarah Klauss
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Stephan Schorn
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Steffen Teller
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Hendrik Steenfadt
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Güralp O Ceyhan
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
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Williams JA, Yule DI. Can pancreatitis be treated by inhibiting Ca 2+ signaling? ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:124. [PMID: 29955584 DOI: 10.21037/atm.2017.06.07] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- John A Williams
- Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - David I Yule
- Department of Pharmacology and Physiology, University of Rochester, Rochester, NY, USA
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Peng W, Furuuchi N, Aslanukova L, Huang YH, Brown SZ, Jiang W, Addya S, Vishwakarma V, Peters E, Brody JR, Dixon DA, Sawicki JA. Elevated HuR in Pancreas Promotes a Pancreatitis-Like Inflammatory Microenvironment That Facilitates Tumor Development. Mol Cell Biol 2018; 38:e00427-17. [PMID: 29133460 PMCID: PMC5770537 DOI: 10.1128/mcb.00427-17] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 09/07/2017] [Accepted: 11/07/2017] [Indexed: 12/30/2022] Open
Abstract
Human antigen R (ELAVL1; HuR) is perhaps the best-characterized RNA-binding protein. Through its overexpression in various tumor types, HuR promotes posttranscriptional regulation of target genes in multiple core signaling pathways associated with tumor progression. The role of HuR overexpression in pancreatic tumorigenesis is unknown and led us to explore the consequences of HuR overexpression using a novel transgenic mouse model that has a >2-fold elevation of pancreatic HuR expression. Histologically, HuR-overexpressing pancreas displays a fibroinflammatory response and other pathological features characteristic of chronic pancreatitis. This pathology is reflected in changes in the pancreatic gene expression profile due, in part, to genes whose expression changes as a consequence of direct binding of their respective mRNAs to HuR. Older mice develop pancreatic steatosis and severe glucose intolerance. Elevated HuR cooperated with mutant K-rasG12D to result in a 3.4-fold increase in pancreatic ductal adenocarcinoma (PDAC) incidence compared to PDAC presence in K-rasG12D alone. These findings implicate HuR as a facilitator of pancreatic tumorigenesis, especially in the setting of inflammation, and a novel therapeutic target for pancreatitis treatment.
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Affiliation(s)
- Weidan Peng
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
| | - Narumi Furuuchi
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
| | | | - Yu-Hung Huang
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
| | - Samantha Z Brown
- Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Wei Jiang
- Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Sankar Addya
- Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | | | - Erika Peters
- University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Jonathan R Brody
- Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Dan A Dixon
- University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Janet A Sawicki
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
- Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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Boggs K, Wang T, Orabi AI, Mukherjee A, Eisses JF, Sun T, Wen L, Javed TA, Esni F, Chen W, Husain SZ. Pancreatic gene expression during recovery after pancreatitis reveals unique transcriptome profiles. Sci Rep 2018; 8:1406. [PMID: 29362419 PMCID: PMC5780441 DOI: 10.1038/s41598-018-19392-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 12/29/2017] [Indexed: 02/07/2023] Open
Abstract
It is well known that pancreatic recovery after a single episode of injury such as an isolated bout of pancreatitis occurs rapidly. It is unclear, however, what changes are inflicted in such conditions to the molecular landscape of the pancreas. In the caerulein hyperstimulation model of pancreatitis, the murine pancreas has the ability to recover within one week based on histological appearance. In this study, we sought to characterize by RNA-sequencing (RNA-seq) the transcriptional profile of the recovering pancreas up to two weeks post-injury. We found that one week after injury there were 319 differentially expressed genes (DEGs) compared with baseline and that after two weeks there were 53 DEGs. Forty (12.5%) of the DEGs persisted from week one to week two, and another 13 DEGs newly emerged in the second week. Amongst the top up-regulated DEGs were several trypsinogen genes (trypsinogen 4, 5, 12, 15, and 16). To our knowledge, this is the first characterization of the transcriptome during pancreatic recovery by deep sequencing, and it reveals on a molecular basis that there is an ongoing recovery of the pancreas even after apparent histological resolution. The findings also raise the possibility of an emerging novel transcriptome upon pancreatic recovery.
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Affiliation(s)
- Kristy Boggs
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Ting Wang
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA
- Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Abrahim I Orabi
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Amitava Mukherjee
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - John F Eisses
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Tao Sun
- Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Li Wen
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Tanveer A Javed
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Farzad Esni
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Wei Chen
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA
- Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Sohail Z Husain
- Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA.
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Abu-El-Haija M, Gukovskaya AS, Andersen DK, Gardner TB, Hegyi P, Pandol SJ, Papachristou GI, Saluja AK, Singh VK, Uc A, Wu BU. Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis: Summary of the Working Group on Drug Development and Trials in Acute Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 2018; 47:1185-1192. [PMID: 30325856 PMCID: PMC6692135 DOI: 10.1097/mpa.0000000000001175] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities on drug development for pancreatitis. This conference was held on July 25, 2018, and structured into 3 working groups (WG): acute pancreatitis (AP) WG, recurrent AP WG, and chronic pancreatitis WG. This article reports the outcome of the work accomplished by the AP WG to provide the natural history, epidemiology, and current management of AP; inform about the role of preclinical models in therapy selection; and discuss clinical trial designs with clinical and patient-reported outcomes to test new therapies.
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Affiliation(s)
- Maisam Abu-El-Haija
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Anna S. Gukovskaya
- Department of Medicine, University of California, Los Angeles
- Pancreatic Research Group, UCLA/VA Greater Los Angeles Healthcare System, Los Angeles, CA
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Timothy B. Gardner
- Department of Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine, Darmouth University, Hanover, NH
| | - Peter Hegyi
- MTA-SZTE Translational Gastroenterology Research Group, University of Szeged, Szeged
- Institute for Translational Medicine and First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Stephen J. Pandol
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Georgios I. Papachristou
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center
- Division of Gastroenterology and Hepatology, Veterans Affairs Pittsburgh Health System, Pittsburgh, PA
| | - Ashok K. Saluja
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL
| | - Vikesh K. Singh
- Division of Gastroenterology, Department of Medicine, University of John’s Hopkins, Baltimore, MD
| | - Aliye Uc
- Stead Family Department of Pediatrics, University of Iowa, Stead Family Children’s Hospital, Iowa City, IA
| | - Bechien U. Wu
- Center for Pancreatic Care, Department of Gastroenterology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA
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Xie Q, Fei M, Fa Z, Wang L, Wang J, Zhang Y, Wang J, Deng X. Methane-rich saline alleviates cerulein-induced acute pancreatitis by inhibiting inflammatory response, oxidative stress and pancreatic apoptosis in mice. Int Immunopharmacol 2017; 51:17-24. [PMID: 28759809 DOI: 10.1016/j.intimp.2017.07.022] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 06/26/2017] [Accepted: 07/21/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Acute pancreatitis (AP) is a potentially life-threatening gastrointestinal disease involving intracellular activation of digestive enzymes and pancreatic acinar cell injury. The present study was performed to investigate whether methane-rich saline (MS) was involved in the regulation of AP. METHODS MS (16ml/kg) was administered at different dosing frequencies on mice with cerulein-induced AP. Serum amylase, lipase and histopathological changes in the pancreas tissue were measured. Serum cytokine TNFα, IL-6, IFNγ and IL-10 were detected by ELISA. The mRNA levels of these inflammatory cytokines in the pancreas were detected by real time-PCR. Myeloperoxidase (MPO) and superoxide dismutase (SOD) were determined using commercial kits. Apoptosis was assessed by immunohistochemistry and Western blot. RESULTS MS treatment reversed the increased serum level of amylase and lipase, alleviated the pathological damage in the pancreas, and decreased the expression of TNFα, IL-6, IFNγ and IL-10 in cerulean-induced AP mice. In addition, MPO was down-regulated and SOD was up-regulated in the MS treated pancreas, indicating that MS had an anti-oxidant effect against AP. Furthermore, MS protected pancreatic cells against cerulean-induced apoptosis and abolished cleaved caspase-3. CONCLUSION MS exerted anti-inflammatory, anti-oxidant and anti-apoptotic effects on cerulein-induced AP in mice and may proved to be a promising therapeutic agent for the clinical treatment of pancreatitis.
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Affiliation(s)
- Qun Xie
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Miaomiao Fei
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Zhenzong Fa
- Shanghai Key Laboratory of Molecular Mycology, Department of Dermatology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Liping Wang
- Department of Anesthesiology, Fuzhou General Hospital of Nanjing Military Region, Fuzhou 350025, Fujian Province, China
| | - Jun Wang
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Yan Zhang
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Jiafeng Wang
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
| | - Xiaoming Deng
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
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Gorelick FS, Lerch MM. Do Animal Models of Acute Pancreatitis Reproduce Human Disease? Cell Mol Gastroenterol Hepatol 2017; 4:251-262. [PMID: 28752114 PMCID: PMC5518169 DOI: 10.1016/j.jcmgh.2017.05.007] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 05/26/2017] [Indexed: 12/10/2022]
Abstract
Acute pancreatitis is currently the most common cause of hospital admission among all nonmalignant gastrointestinal diseases. To understand the pathophysiology of the disease and as a potential step toward developing targeted therapies, attempts to induce the disease experimentally began more than 100 years ago. Recent decades have seen progress in developing new experimental pancreatitis models as well as elucidating many underlying cell biological and pathophysiological disease mechanisms. Some models have been developed to reflect specific causes of acute pancreatitis in human beings. However, the paucity of data relating to the molecular mechanisms of human disease, the likelihood that multiple genetic and environmental factors affect the risk of disease development and its severity, and the limited information regarding the natural history of disease in human beings make it difficult to evaluate the value of disease models. Here, we provide an overview of key models and discuss our views on their strengths for characterizing cell biological disease mechanisms or for identifying potential therapeutic targets. We also acknowledge their limitations.
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Affiliation(s)
- Fred S. Gorelick
- Yale University Medical School and Veterans Affairs Medical Center, West Haven, Connecticut
- Correspondence Address correspondence to: Fred S. Gorelick, MD, VA Connecticut Healthcare System/Yale University Medical School, 950 Campbell Avenue, West Haven, Connecticut 06516. fax: (203) 937-3852.VA Connecticut Healthcare System/Yale University Medical School950 Campbell AvenueWest HavenConnecticut 06516
| | - Markus M. Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
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Smad2/3 Linker Phosphorylation Is a Possible Marker of Pancreatic Stem/Progenitor Cells in the Regenerative Phase of Acute Pancreatitis. Pancreas 2017; 46:605-613. [PMID: 28099259 DOI: 10.1097/mpa.0000000000000759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES The aims of this study are to characterize cell proliferation and differentiation during regeneration after pancreatitis and pancreatic buds during development to evaluate the role of Smad2/3, phosphorylated at the specific linker threonine residues (pSmad2/3L-Thr) in positive cells. METHODS Male C57BL/6 mice received hourly intraperitoneal injections of cerulein and were analyzed after induced pancreatitis. Pancreatitis-affected tissue sections and pancreatic buds were immunostained for pSmad2/3L-Thr, with other markers thought to be stem/progenitor markers of the pancreas. RESULTS pSmad2/3L-Thr immunostaining-positive cells increased as the pancreatitis progressed. The expression of pSmad2/3L-Thr was seen in acinar cells and ductlike tubular complexes. These results suggest that pSmad2/3L-Thr is expressed during acinar-ductal metaplasia. Immunohistochemical colocalization of pSmad2/3L-Thr with Ki67 was never observed. pSmad2/3L-Thr-positive cells may remain in an undifferentiated state. During the pancreatic development process, pSmad2/3L-Thr was expressed as other markers. pSmad2/3L-Thr develops in duct structure of the undifferentiated cell population in the last part of viviparity that acinar structure is formed clearly. CONCLUSIONS pSmad2/3L-Thr expression occurs during acinar-ductal metaplasia after pancreatitis and may represent the contribution of stem cells and/or progenitor cells to the differentiation of the pancreas.
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The Role of Heparanase in the Pathogenesis of Acute Pancreatitis: A Potential Therapeutic Target. Sci Rep 2017; 7:715. [PMID: 28386074 PMCID: PMC5429646 DOI: 10.1038/s41598-017-00715-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 03/10/2017] [Indexed: 12/15/2022] Open
Abstract
Acute pancreatitis (AP) is one of the most common diseases in gastroenterology. However, neither the etiology nor the pathophysiology of the disease is fully understood and no specific or effective treatment has been developed. Heparanase is an endoglycosidase that cleaves heparan sulfate (HS) side chains of HS sulfate proteoglycans into shorter oligosaccharides, activity that is highly implicated in cellular invasion associated with cancer metastasis and inflammation. Given that AP involves a strong inflammatory aspect, we examined whether heparanase plays a role in AP. Here, we provide evidence that pancreatic heparanase expression and activity are significantly increased following cerulein treatment. Moreover, pancreas edema and inflammation, as well as the induction of cytokines and signaling molecules following cerulein treatment were attenuated markedly by heparanase inhibitors, implying that heparanase plays a significant role in AP. Notably, all the above features appear even more pronounced in transgenic mice over expressing heparanase, suggesting that these mice can be utilized as a sensitive model system to reveal the molecular mechanism by which heparanase functions in AP. Heparanase, therefore, emerges as a potential new target in AP, and heparanase inhibitors, now in phase I/II clinical trials in cancer patients, are hoped to prove beneficial also in AP.
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ULTRASTRUCTURAL CHANGES IN HEMOMICROCIRCULATION AND PANCREATIC PARENCHYMA IN THE DEVELOPMENT OF EXPERIMENTAL ACUTE PANCREATITIS IN RATS. WORLD OF MEDICINE AND BIOLOGY 2017. [DOI: 10.26724/2079-8334-2017-3-61-114-119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Yin T, Peeters R, Liu Y, Feng Y, Zhang X, Jiang Y, Yu J, Dymarkowski S, Himmelreich U, Oyen R, Ni Y. Visualization, Quantification and Characterization of Caerulein-Induced Acute Pancreatitis in Rats by 3.0T Clinical MRI, Biochemistry and Histomorphology. Theranostics 2017; 7:285-294. [PMID: 28042334 PMCID: PMC5197064 DOI: 10.7150/thno.16282] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 07/08/2016] [Indexed: 12/13/2022] Open
Abstract
Purpose: To investigate whether Caerulein-induced acute pancreatitis (AP) in rats could be noninvasively studied by clinical magnetic resonance imaging (MRI) techniques and validated by enzymatic biochemistry and histomorphology. Materials and Methods: The study was approved by the institutional animal ethical committee. The AP was induced in 26 rats by intraperitoneal injections of Caerulein, as compared to 6 normal rats. T2-weighted 3D MRI, T2 relaxation measurement and contrast enhanced T1-weighted MRI were performed at 3 Tesla. Pancreatic volume and contrast ratio of pancreas against surrounding tissues were measured by MRI. Animals were scarified at 3, 8, 24 and 48-hr respectively for analyses of serum lipase and amylase levels, and biliopancreatic perfusion-assisted histomorphology. Results: The AP could be observed on MRI 3-hr onwards after Caerulein-administration. T2 relaxation within the pancreas was prolonged due to high water content or edema. Increase of vascular permeability was indicated by T1 contrast enhancement. Both edema and vascular permeability gradually recovered afterwards (p<0.05/0.01), paralleled by declining serum enzyme levels (p<0.05). Microscopy revealed cell vacuolization and edema for early stage, and increased inflammatory cell infiltration and acinar cell loss after 24 and 48-hr. Conclusion: Multiparametric MRI techniques at 3.0T could facilitate noninvasive diagnosis and characterization of Caerulein induced AP in rats, as validated by a novel ex vivo method.
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Poulsen JL, Olesen SS, Drewes AM, Ye B, Li WQ, Aghdassi AA, Sendler M, Mayerle J, Lerch MM. The Pathogenesis of Chronic Pancreatitis. CHRONIC PANCREATITIS 2017:29-62. [DOI: 10.1007/978-981-10-4515-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Rivkin M, Simerzin A, Zorde-Khvalevsky E, Chai C, Yuval JB, Rosenberg N, Harari-Steinfeld R, Schneider R, Amir G, Condiotti R, Heikenwalder M, Weber A, Schramm C, Wege H, Kluwe J, Galun E, Giladi H. Inflammation-Induced Expression and Secretion of MicroRNA 122 Leads to Reduced Blood Levels of Kidney-Derived Erythropoietin and Anemia. Gastroenterology 2016; 151:999-1010.e3. [PMID: 27477940 DOI: 10.1053/j.gastro.2016.07.031] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 07/17/2016] [Accepted: 07/18/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Anemia is associated commonly with acute and chronic inflammation, but the mechanisms of their interaction are not clear. We investigated whether microRNA 122 (MIR122), which is generated in the liver and is secreted into the blood, is involved in the development of anemia associated with inflammation. METHODS We characterized the primary transcript of the human liver-specific MIR122 using Northern blot, quantitative real-time polymerase chain reaction, and 3' and 5' rapid amplification of cDNA ends analyses. We studied regulation of MIR122 in human hepatocellular carcinoma cell lines (Huh7 and HepG2) as well as in C57BL/6 and mice with disruption of the tumor necrosis factor (Tnf) gene. Liver tissues were collected and analyzed by bioluminescence imaging or immunofluorescence. Inflammation in mice was induced by lipopolysaccharide (LPS) or by cerulein injections. Mice were given 4 successive injections of LPS, leading to inflammation-induced anemia. Steatohepatitis was induced with a choline-deficient, high-fat diet. Hemolytic anemia was stimulated by phenylhydrazine injection. MIR122 was inhibited in mice by tail-vein injection of an oligonucleotide antagonist of MIR122. MicroRNA and messenger RNA levels were determined by quantitative real-time polymerase chain reaction. RESULTS The primary transcript of MIR122 spanned 5 kb, comprising 3 exons; the third encodes MIR122. Within the MIR122 promoter region we identified a nuclear factor-κB binding site and showed that RELA (NF-κB p65 subunit), as well as activators of NF-κB (TNF and LPS), increased promoter activity of MIR122. Administration of LPS to mice induced secretion of MIR122 into blood, which required TNF. Secreted MIR122 reached the kidney and reduced expression of erythropoietin (Epo), which we identified as a MIR122 target gene. Injection of mice with an oligonucleotide antagonist of MIR122 increased blood levels of EPO, reticulocytes, and hemoglobin. We found an inverse relationship between blood levels of MIR122 and EPO in mice with acute pancreatitis or steatohepatitis, and also in patients with acute inflammation. CONCLUSION In mice, we found that LPS-induced inflammation increases blood levels of MIR122, which reduces expression of Epo in the kidney; this is a mechanism of inflammation-induced anemia. Strategies to block MIR122 in patients with inflammation could reduce the development or progression of anemia.
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Affiliation(s)
- Mila Rivkin
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel
| | - Alina Simerzin
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel
| | - Elina Zorde-Khvalevsky
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel
| | - Chofit Chai
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel
| | - Jonathan B Yuval
- Department of Surgery, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel
| | - Nofar Rosenberg
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel
| | - Rona Harari-Steinfeld
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel
| | - Ronen Schneider
- Department of Nephrology, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel
| | - Gail Amir
- Department of Pathology, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel
| | - Reba Condiotti
- Department of Developmental Biology and Cancer Research, Hebrew University, Hadassah Medical School, Jerusalem, Israel
| | - Mathias Heikenwalder
- Institute for Virology, Technische Universität München and Helmholtz Zentrum München, Munich, Germany
| | - Achim Weber
- Institute of Surgical Pathology, University Zurich, Zurich, Switzerland
| | - Christoph Schramm
- Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Henning Wege
- Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Kluwe
- Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eithan Galun
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel.
| | - Hilla Giladi
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel
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The MET Receptor Tyrosine Kinase Confers Repair of Murine Pancreatic Acinar Cells following Acute and Chronic Injury. PLoS One 2016; 11:e0165485. [PMID: 27798657 PMCID: PMC5087859 DOI: 10.1371/journal.pone.0165485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 10/12/2016] [Indexed: 01/07/2023] Open
Abstract
Acinar cells represent the primary target in necroinflammatory diseases of the pancreas, including pancreatitis. The signaling pathways guiding acinar cell repair and regeneration following injury remain poorly understood. The purpose of this study was to determine the importance of Hepatocyte Growth Factor Receptor/MET signaling as an intrinsic repair mechanism for acinar cells following acute damage and chronic alcohol-associated injury. Here, we generated mice with targeted deletion of MET in adult acinar cells (MET-/-). Acute and repetitive pancreatic injury was induced in MET-/- and control mice with cerulein, and chronic injury by feeding mice Lieber-DeCarli diets containing alcohol with or without enhancement of repetitive pancreatic injury. We examined the exocrine pancreas of these mice histologically for acinar death, edema, inflammation and collagen deposition and changes in the transcriptional program. We show that MET expression is relatively low in normal adult pancreas. However, MET levels were elevated in ductal and acinar cells in human pancreatitis specimens, consistent with a role for MET in an adaptive repair mechanism. We report that genetic deletion of MET in adult murine acinar cells was linked to increased acinar cell death, chronic inflammation and delayed recovery (regeneration) of pancreatic exocrine tissue. Notably, increased pancreatic collagen deposition was detected in MET knockout mice following repetitive injury as well alcohol-associated injury. Finally, we identified specific alterations of the pancreatic transcriptome associated with MET signaling during injury, involved in tissue repair, inflammation and endoplasmic reticulum stress. Together, these data demonstrate the importance of MET signaling for acinar repair and regeneration, a novel finding that could attenuate the symptomology of pancreatic injury.
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