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1
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Villaca CBP, Mastracci TL. Pancreatic Crosstalk in the Disease Setting: Understanding the Impact of Exocrine Disease on Endocrine Function. Compr Physiol 2024; 14:5371-5387. [PMID: 39109973 PMCID: PMC11425433 DOI: 10.1002/cphy.c230008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2024]
Abstract
The exocrine and endocrine are functionally distinct compartments of the pancreas that have traditionally been studied as separate entities. However, studies of embryonic development, adult physiology, and disease pathogenesis suggest there may be critical communication between exocrine and endocrine cells. In fact, the incidence of the endocrine disease diabetes secondary to exocrine disease/dysfunction ranges from 25% to 80%, depending on the type and severity of the exocrine pathology. Therefore, it is necessary to investigate how exocrine-endocrine "crosstalk" may impact pancreatic function. In this article, we discuss common exocrine diseases, including cystic fibrosis, acute, hereditary, and chronic pancreatitis, and the impact of these exocrine diseases on endocrine function. Additionally, we review how obesity and fatty pancreas influence exocrine function and the impact on cellular communication between the exocrine and endocrine compartments. Interestingly, in all pathologies, there is evidence that signals from the exocrine disease contribute to endocrine dysfunction and the progression to diabetes. Continued research efforts to identify the mechanisms that underlie the crosstalk between various cell types in the pancreas are critical to understanding normal pancreatic physiology as well as disease states. © 2024 American Physiological Society. Compr Physiol 14:5371-5387, 2024.
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Affiliation(s)
| | - Teresa L Mastracci
- Department of Biology, Indiana University Indianapolis, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
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2
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Jancsó Z, Morales Granda NC, Demcsák A, Sahin-Tóth M. Mouse model of PRSS1 p.R122H-related hereditary pancreatitis highlights context-dependent effect of autolysis-site mutation. Pancreatology 2023; 23:131-142. [PMID: 36797199 PMCID: PMC10492521 DOI: 10.1016/j.pan.2023.02.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 01/12/2023] [Accepted: 02/06/2023] [Indexed: 02/18/2023]
Abstract
Mutation p.R122H in human cationic trypsinogen (PRSS1) is the most frequently identified cause of hereditary pancreatitis. The mutation blocks protective degradation of trypsinogen by chymotrypsin C (CTRC), which involves an obligatory trypsin-mediated cleavage at Arg122. Previously, we found that C57BL/6N mice are naturally deficient in CTRC, and trypsinogen degradation is catalyzed by chymotrypsin B1 (CTRB1). Here, we used biochemical experiments to demonstrate that the cognate p.R123H mutation in mouse cationic trypsinogen (isoform T7) only partially prevented CTRB1-mediated degradation. We generated a novel C57BL/6N mouse strain harboring the p.R123H mutation in the native T7 trypsinogen locus. T7R123H mice developed no spontaneous pancreatitis, and severity parameters of cerulein-induced pancreatitis trended only slightly higher than those of C57BL/6N mice. However, when treated with cerulein for 2 days, more edema and higher trypsin activity was seen in the pancreas of T7R123H mice compared to C57BL/6N controls. Furthermore, about 40% of T7R123H mice progressed to atrophic pancreatitis in 3 days, whereas C57BL/6N animals showed full histological recovery. Taken together, the observations indicate that mutation p.R123H inefficiently blocks chymotrypsin-mediated degradation of mouse cationic trypsinogen, and modestly increases cerulein-induced intrapancreatic trypsin activity and pancreatitis severity. The findings support the notion that the pathogenic effect of the PRSS1 p.R122H mutation in hereditary pancreatitis is dependent on its ability to defuse chymotrypsin-dependent defenses.
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Affiliation(s)
- Zsanett Jancsó
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | | | - Alexandra Demcsák
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Miklós Sahin-Tóth
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA.
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3
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Qin L, Liu N, Bao CLM, Yang DZ, Ma GX, Yi WH, Xiao GZ, Cao HL. Mesenchymal stem cells in fibrotic diseases-the two sides of the same coin. Acta Pharmacol Sin 2023; 44:268-287. [PMID: 35896695 PMCID: PMC9326421 DOI: 10.1038/s41401-022-00952-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 06/29/2022] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials.
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Affiliation(s)
- Lei Qin
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Nian Liu
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Chao-le-meng Bao
- CASTD Regengeek (Shenzhen) Medical Technology Co. Ltd, Shenzhen, 518000 China
| | - Da-zhi Yang
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Gui-xing Ma
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
| | - Wei-hong Yi
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Guo-zhi Xiao
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
| | - Hui-ling Cao
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
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Holmlund H, Yamauchi Y, Durango G, Fujii W, Ward MA. Two acquired mouse Y chromosome-linked genes, Prssly and Teyorf1, are dispensable for male fertility‡. Biol Reprod 2022; 107:752-764. [PMID: 35485405 PMCID: PMC9476217 DOI: 10.1093/biolre/ioac084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/20/2022] [Indexed: 11/13/2022] Open
Abstract
Prssly (Protease, serine-like, Chr Y) and Teyorf1 (Testis expressed, chromosome Y open reading frame 1) are two acquired single-copy genes located on the distal tip of the non-pairing short arm of the mouse Y chromosome adjacent to telomeric sequence. Both genes lack X chromosome-linked homologues and are expressed in testicular germ cells. We first performed analysis of Prssly and Teyorf1 genomic sequences and demonstrated that previously reported Prssly sequence is erroneous and the true Prssly sequence is longer and encodes a larger protein than previously estimated. We also confirmed that both genes encode pseudogenes that are not expressed in testes. Next, using CRISPR/Cas9 genome targeting, we generated Prssly and Teyorf1 knockout (KO) mice and characterized their phenotype. To create Prssly KO mice, we targeted the conserved exon 5 encoding a trypsin domain typical for serine proteases. The targeting was successful and resulted in a frame shift mutation that introduced a premature stop codon, with the Prssly KO males retaining only residual transcript expression in testes. The Teyorf1 targeting removed the entire open reading frame of the gene, which resulted in no transcript expression in KO males. Both Prssly KO and Teyorf1 KO males were fertile and had normal testis size and normal sperm number, motility, and morphology. Our findings show that Prssly and Teyorf1 transcripts with potential to encode proteins are dispensable for male fertility.
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Affiliation(s)
- Hayden Holmlund
- Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
| | - Yasuhiro Yamauchi
- Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
| | - Gerald Durango
- Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
| | - Wataru Fujii
- Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
- Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan
| | - Monika A Ward
- Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
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Li X, He J, Xie K. Molecular signaling in pancreatic ductal metaplasia: emerging biomarkers for detection and intervention of early pancreatic cancer. Cell Oncol (Dordr) 2022; 45:201-225. [PMID: 35290607 DOI: 10.1007/s13402-022-00664-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2022] [Indexed: 11/27/2022] Open
Abstract
Pancreatic ductal metaplasia (PDM) is the transformation of potentially various types of cells in the pancreas into ductal or ductal-like cells, which eventually replace the existing differentiated somatic cell type(s). PDM is usually triggered by and manifests its ability to adapt to environmental stimuli and genetic insults. The development of PDM to atypical hyperplasia or dysplasia is an important risk factor for pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDA). Recent studies using genetically engineered mouse models, cell lineage tracing, single-cell sequencing and others have unraveled novel cellular and molecular insights in PDM formation and evolution. Those novel findings help better understand the cellular origins and functional significance of PDM and its regulation at cellular and molecular levels. Given that PDM represents the earliest pathological changes in PDA initiation and development, translational studies are beginning to define PDM-associated cell and molecular biomarkers that can be used to screen and detect early PDA and to enable its effective intervention, thereby truly and significantly reducing the dreadful mortality rate of PDA. This review will describe recent advances in the understanding of PDM biology with a focus on its underlying cellular and molecular mechanisms, and in biomarker discovery with clinical implications for the management of pancreatic regeneration and tumorigenesis.
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Affiliation(s)
- Xiaojia Li
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, 510006, China
- Department of Pathology, The South China University of Technology School of Medicine, Guangzhou, China
| | - Jie He
- Institute of Digestive Diseases Research, The South China University of Technology School of Medicine, Guangzhou, China
| | - Keping Xie
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, 510006, China.
- Department of Pathology, The South China University of Technology School of Medicine, Guangzhou, China.
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6
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Li S, Xie K. Ductal metaplasia in pancreas. Biochim Biophys Acta Rev Cancer 2022; 1877:188698. [DOI: 10.1016/j.bbcan.2022.188698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 02/07/2023]
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Zou WB, Cooper DN, Masson E, Pu N, Liao Z, Férec C, Chen JM. Trypsinogen (PRSS1 and PRSS2) gene dosage correlates with pancreatitis risk across genetic and transgenic studies: a systematic review and re-analysis. Hum Genet 2022; 141:1327-1338. [PMID: 35089416 DOI: 10.1007/s00439-022-02436-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/15/2022] [Indexed: 12/22/2022]
Abstract
Trypsinogen (PRSS1, PRSS2) copy number gains and regulatory variants have both been proposed to elevate pancreatitis risk through a gene dosage effect (i.e., by increasing the expression of wild-type protein). However, to date, their impact on pancreatitis risk has not been thoroughly evaluated whilst the underlying pathogenic mechanisms remain to be explicitly investigated in mouse models. Genetic studies of the rare trypsinogen duplication and triplication copy number variants (CNVs), and the common rs10273639C variant, were collated from PubMed and/or ClinVar. Mouse studies that analyzed the influence of a transgenically expressed wild-type human PRSS1 or PRSS2 gene on the development of pancreatitis were identified from PubMed. The genetic effects of the different risk genotypes, in terms of odds ratios, were calculated wherever appropriate. The genetic effects of the rare trypsinogen duplication and triplication CNVs were also evaluated by reference to their associated disease subtypes. We demonstrate a positive correlation between increased trypsinogen gene dosage and pancreatitis risk in the context of the rare duplication and triplication CNVs, and between the level of trypsinogen expression and disease risk in the context of the heterozygous and homozygous rs10273639C-tagged genotypes. We retrospectively identify three mouse transgenic studies that are informative in relation to the pathogenic mechanism underlying the trypsinogen gene dosage effect in pancreatitis. Trypsinogen gene dosage correlates with pancreatitis risk across genetic and transgenic studies, highlighting the fundamental role of dysregulated expression of wild-type trypsinogen in the etiology of pancreatitis. Specifically downregulating trypsinogen expression in the pancreas may serve as a potential therapeutic and/or prevention strategy for pancreatitis.
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Affiliation(s)
- Wen-Bin Zou
- Department of Gastroenterology, Changhai Hospital, The Secondary Military Medical University, Shanghai, China
- Shanghai Institute of Pancreatic Diseases, Shanghai, China
| | - David N Cooper
- Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Emmanuelle Masson
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France
- Service de Génétique Médicale et de Biologie de la Reproduction, CHRU Brest, F-29200, Brest, France
| | - Na Pu
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France
- Department of Critical Care Medicine, Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Zhuan Liao
- Department of Gastroenterology, Changhai Hospital, The Secondary Military Medical University, Shanghai, China
- Shanghai Institute of Pancreatic Diseases, Shanghai, China
| | - Claude Férec
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France
- Service de Génétique Médicale et de Biologie de la Reproduction, CHRU Brest, F-29200, Brest, France
| | - Jian-Min Chen
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France.
- INSERM UMR1078, EFS, UBO, 22 avenue Camille Desmoulins, Brest, France.
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8
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Liu K, Liu J, Zou B, Li C, Zeh HJ, Kang R, Kroemer G, Huang J, Tang D. Trypsin-Mediated Sensitization to Ferroptosis Increases the Severity of Pancreatitis in Mice. Cell Mol Gastroenterol Hepatol 2021; 13:483-500. [PMID: 34562639 PMCID: PMC8688567 DOI: 10.1016/j.jcmgh.2021.09.008] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Pancreatitis is characterized by acinar cell death and persistent inflammation. Ferroptosis is a type of lipid peroxidation-dependent necrosis, which is negatively regulated by glutathione peroxidase 4. We studied how trypsin, a serine protease secreted by pancreatic acinar cells, affects the contribution of ferroptosis to triggering pancreatitis. METHODS In vitro, the mouse pancreatic acinar cell line 266-6 and mouse primary pancreatic acinar cells were used to investigate the effect of exogenous trypsin on ferroptosis sensitivity. Short hairpin RNAs were designed to silence gene expression, whereas a library of 1080 approved drugs was used to identify new ferroptosis inhibitors in 266-6 cells. In vivo, a Cre/LoxP system was used to generate mice with a pancreas-specific knockout of Gpx4 (Pdx1-Cre;Gpx4flox/flox mice). Acute or chronic pancreatitis was induced in these mice (Gpx4flox/flox mice served as controls) by cerulein injections or a Lieber-DeCarli alcoholic liquid diet. Pancreatic tissues, acinar cells, and serum were collected and analyzed by histology, immunoblot, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, or immunohistochemical analyses. RESULTS Supraphysiological doses of trypsin (500 or 1000 ng/mL) alone did not trigger significant cell death in 266-6 cells and mouse primary pancreatic acinar cells, but did increase the sensitivity of these cells to ferroptosis upon treatment with cerulein, L-arginine, alcohol, erastin, or RSL3. Proteasome 26S subunit, non-adenosine triphosphatase 4-dependent lipid peroxidation caused ferroptosis in pancreatic acinar cells by promoting the proteasomal degradation of glutathione peroxidase 4. The drug screening campaign identified the antipsychotic drug olanzapine as an antioxidant inhibiting ferroptosis in pancreatic acinar cells. Mice lacking pancreatic Gpx4 developed more severe pancreatitis after cerulein infection or ethanol feeding than control mice. Conversely, olanzapine administration protected against pancreatic ferroptotic damage and experimental pancreatitis in Gpx4-deficient mice. CONCLUSIONS Trypsin-mediated sensitization to ferroptotic damage increases the severity of pancreatitis in mice, and this process can be reversed by olanzapine.
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Affiliation(s)
- Ke Liu
- Department of Ophthalmology, The 2nd Xiangya Hospital, Central South University, Changsha, China
| | - Jiao Liu
- The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Borong Zou
- The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Changfeng Li
- Department of Endoscopy Center, China–Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Herbert J. Zeh
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Rui Kang
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Jun Huang
- Department of Orthopaedics, The 2nd Xiangya Hospital, Central South University, Changsha, China,Jun Huang, MD, Department of Orthopaedics, The 2nd Xiangya Hospital, Central South University, Changsha 410011, China. fax: (86) 731-85295999
| | - Daolin Tang
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas,Correspondence Address correspondence to: Daolin Tang, MD, Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390
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9
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Holcomb RJ, Oura S, Nozawa K, Kent K, Yu Z, Robertson MJ, Coarfa C, Matzuk MM, Ikawa M, Garcia TX. The testis-specific serine proteases PRSS44, PRSS46, and PRSS54 are dispensable for male mouse fertility†. Biol Reprod 2021; 102:84-91. [PMID: 31403672 PMCID: PMC7013879 DOI: 10.1093/biolre/ioz158] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 07/06/2019] [Accepted: 07/28/2019] [Indexed: 12/19/2022] Open
Abstract
High-throughput transcriptomics and proteomics approaches have recently identified a large number of germ cell-specific genes with many that remain to be studied through functional genetics approaches. Serine proteases (PRSS) constitute nearly one-third of all proteases, and, in our bioinformatics screens, we identified many that are testis specific. In this study, we chose to focus on Prss44, Prss46, and Prss54, which we confirmed as testis specific in mouse and human. Based on the analysis of developmental expression in the mouse, expression of all four genes is restricted to the late stage of spermatogenesis concomitant with a potential functional role in spermiogenesis, spermiation, or sperm function. To best understand the male reproductive requirement and functional roles of these serine proteases, each gene was individually ablated by CRISPR/Cas9-mediated ES cell or zygote approach. Homozygous deletion mutants for each gene were obtained and analyzed for phenotypic changes. Analyses of testis weights, testis and epididymis histology, sperm morphology, and fertility revealed no significant differences in Prss44, Prss46, and Prss54 knockout mice in comparison to controls. Our results thereby demonstrate that these genes are not required for normal fertility in mice, although do not preclude the possibility that these genes may function in a redundant manner. Elucidating the individual functional requirement or lack thereof of these novel genes is necessary to build a better understanding of the factors underlying spermatogenesis and sperm maturation, which has implications in understanding the etiology of male infertility and the development of male contraceptives.
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Affiliation(s)
- Richard J Holcomb
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.,Department of Biology and Biotechnology, University of Houston-Clear Lake, Houston, TX, USA.,Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA
| | - Seiya Oura
- Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
| | - Kaori Nozawa
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.,Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA
| | - Katarzyna Kent
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.,Department of Biology and Biotechnology, University of Houston-Clear Lake, Houston, TX, USA.,Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA
| | - Zhifeng Yu
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.,Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA
| | - Matthew J Robertson
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.,Advanced Technology Cores, Baylor College of Medicine, Houston, TX, USA
| | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Martin M Matzuk
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.,Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.,Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, USA
| | - Masahito Ikawa
- Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.,Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.,The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Thomas X Garcia
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.,Department of Biology and Biotechnology, University of Houston-Clear Lake, Houston, TX, USA.,Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA
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10
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Asai A, Konno M, Kawamoto K, Isotani A, Mori M, Eguchi H, Doki Y, Arai T, Ishii H. Hereditary pancreatitis model by blastocyst complementation in mouse. Oncotarget 2020; 11:2061-2073. [PMID: 32547704 PMCID: PMC7275788 DOI: 10.18632/oncotarget.27595] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 04/03/2020] [Indexed: 12/15/2022] Open
Abstract
The application of pluripotent stem cells is expected to contribute to the elucidation of unknown mechanism of human diseases. However, in vitro induction of organ-specific cells, such as pancreas and liver, is still difficult and the reproduction of their disorders in a model has been unfeasible. To study the mechanism of human hereditary pancreatitis (HP), we here performed the blastocyst complementation (BC) method. In the BC method, mouse embryonic stem (ES) cells harboring CRISPR/CAS9-mediated mutations in the Prss1 gene were injected into blastocysts with deficient Pdx1 gene, which is a critical transcription factor in the development of pancreas. The results showed that trypsin was activated extremely in Prss1-mutant mice. This implied that the mouse phenotype mimics that of human HP and that the BC method was useful for the reproduction and study of pancreatic disorders. The present study opens the possibility of investigating uncharacterized human diseases by utilizing the BC method.
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Affiliation(s)
- Ayumu Asai
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan.,Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan.,Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan.,Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan.,Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan
| | - Ayako Isotani
- Organ Developmental Engineering, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma 630-0192 Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan.,Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582 Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan
| | | | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan.,Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita 565-0871 Japan
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11
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Huang H, Swidnicka-Siergiejko AK, Daniluk J, Gaiser S, Yao Y, Peng L, Zhang Y, Liu Y, Dong M, Zhan X, Wang H, Bi Y, Li Z, Ji B, Logsdon CD. Transgenic Expression of PRSS1 R122H Sensitizes Mice to Pancreatitis. Gastroenterology 2020; 158:1072-1082.e7. [PMID: 31419436 PMCID: PMC7580257 DOI: 10.1053/j.gastro.2019.08.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 07/19/2019] [Accepted: 08/05/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Mutations in the trypsinogen gene (PRSS1) cause human hereditary pancreatitis. However, it is not clear how mutant forms of PRSS1 contribute to disease development. We studied the effects of expressing mutant forms of human PRSS1 in mice. METHODS We expressed forms of PRSS1 with and without the mutation encoding R122H (PRSS1R122H) specifically in pancreatic acinar cells under control of a full-length pancreatic elastase gene promoter. Mice that did not express these transgenes were used as controls. Mice were given injections of caerulein to induce acute pancreatitis or injections of lipopolysaccharide to induce chronic pancreatitis. Other groups of mice were fed ethanol or placed on a high-fat diet to induce pancreatitis. Pancreata were collected and analyzed by histology, immunoblots, real-time polymerase chain reaction, and immunohistochemistry. Trypsin enzymatic activity and chymotrypsin enzymatic activity were measured in pancreatic homogenates. Blood was collected and serum amylase activity was measured. RESULTS Pancreata from mice expressing transgenes encoding PRSS1 or PRSS1R122H had focal areas of inflammation; these lesions were more prominent in mice that express PRSS1R122H. Pancreata from mice that express PRSS1 or PRSS1R122H had increased levels of heat shock protein 70 and nuclear factor (erythroid-derived 2)-like 2, and reduced levels of chymotrypsin C compared with control mice. Increased expression of PRSS1 or PRSS1R122H increased focal damage in pancreatic tissues and increased the severity of acute pancreatitis after caerulein injection. Administration of lipopolysaccharide exacerbated inflammation in mice that express PRSS1R122H compared to mice that express PRSS1 or control mice. Mice that express PRSS1R122H developed more severe pancreatitis after ethanol feeding or a high-fat diet than mice that express PRSS1 or control mice. Pancreata from mice that express PRSS1R122H had more DNA damage, apoptosis, and collagen deposition and increased trypsin activity and infiltration by inflammatory cells than mice that express PRSS1 or control mice. CONCLUSIONS Expression of a transgene encoding PRSS1R122H in mice promoted inflammation and increased the severity of pancreatitis compared with mice that express PRSS1 or control mice. These mice might be used as a model for human hereditary pancreatitis and can be studied to determine mechanisms of induction of pancreatitis by lipopolysaccharide, ethanol, or a high-fat diet.
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Affiliation(s)
- Haojie Huang
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX,Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China
| | - Agnieszka Katarzyna Swidnicka-Siergiejko
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX,Department of Gastroenterology, Medical University of Bialystok, Bialystok, Poland
| | - Jaroslaw Daniluk
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX,Department of Gastroenterology, Medical University of Bialystok, Bialystok, Poland
| | - Sebastian Gaiser
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Yao Yao
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China
| | - Lisi Peng
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China
| | - Yang Zhang
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX,Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China
| | - Yan Liu
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Minyu Dong
- Department of Gastroenterology, Guangzhou Medical University, Guangzhou, China,Department of Cancer Biology, Mayo Clinic, Jacksonville, FL
| | - Xianbao Zhan
- Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China,Department of Cancer Biology, Mayo Clinic, Jacksonville, FL
| | - Huamin Wang
- Department of Pathology, the University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Yan Bi
- Department of Gastroenterology, Mayo Clinic, Jacksonville, FL
| | - Zhaoshen Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
| | - Craig D. Logsdon
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX
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12
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Moore PC, Cortez JT, Chamberlain CE, Alba D, Berger AC, Quandt Z, Chan A, Cheng MH, Bautista JL, Peng J, German MS, Anderson MS, Oakes SA. Elastase 3B mutation links to familial pancreatitis with diabetes and pancreatic adenocarcinoma. J Clin Invest 2019; 129:4676-4681. [PMID: 31369399 PMCID: PMC6819098 DOI: 10.1172/jci129961] [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] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/25/2019] [Indexed: 01/02/2023] Open
Abstract
While improvements in genetic analysis have greatly enhanced our understanding of the mechanisms behind pancreatitis, it continues to afflict many families for whom the hereditary factors remain unknown. Recent evaluation of a patient with a strong family history of pancreatitis sparked us to reexamine a large kindred originally reported over 50 years ago with an autosomal dominant inheritance pattern of chronic pancreatitis, diabetes and pancreatic adenocarcinoma. Whole exome sequencing analysis identified a rare missense mutation in the gene encoding pancreas-specific protease Elastase 3B (CELA3B) that cosegregates with disease. Studies of the mutant protein in vitro, in cell lines and in CRISPR-Cas9 engineered mice indicate that this mutation causes translational upregulation of CELA3B, which upon secretion and activation by trypsin leads to uncontrolled proteolysis and recurrent pancreatitis. Although lesions in several other pancreatitic proteases have been previously linked to hereditary pancreatitis, this is the first known instance of a mutation in CELA3B and a defect in translational control contributing to this disease.
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Affiliation(s)
- Paul C. Moore
- Department of Pathology
- Helen Diller Family Comprehensive Cancer Center
- Diabetes Center
| | | | | | - Diana Alba
- Diabetes Center
- Department of Medicine, and
| | | | - Zoe Quandt
- Diabetes Center
- Department of Medicine, and
| | - Alice Chan
- Diabetes Center
- Department of Medicine, and
| | | | | | | | - Michael S. German
- Diabetes Center
- Department of Medicine, and
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA
| | | | - Scott A. Oakes
- Department of Pathology
- Helen Diller Family Comprehensive Cancer Center
- Diabetes Center
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
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13
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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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14
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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: 209] [Impact Index Per Article: 34.8] [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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15
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Saluja A, Dudeja V, Dawra R, Sah RP. Early Intra-Acinar Events in Pathogenesis of Pancreatitis. Gastroenterology 2019; 156:1979-1993. [PMID: 30776339 DOI: 10.1053/j.gastro.2019.01.268] [Citation(s) in RCA: 156] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 01/09/2019] [Accepted: 01/21/2019] [Indexed: 12/11/2022]
Abstract
Premature activation of digestive enzymes in the pancreas has been linked to development of pancreatitis for more than a century. Recent development of novel models to study the role of pathologic enzyme activation has led to advances in our understanding of the mechanisms of pancreatic injury. Colocalization of zymogen and lysosomal fraction occurs early after pancreatitis-causing stimulus. Cathepsin B activates trypsinogen in these colocalized organelles. Active trypsin increases permeability of these organelles resulting in leakage of cathepsin B into the cytosol leading to acinar cell death. Although trypsin-mediated cell death leads to pancreatic injury in early stages of pancreatitis, multiple parallel mechanisms, including activation of inflammatory cascades, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction in the acinar cells are now recognized to be important in driving the profound systemic inflammatory response and extensive pancreatic injury seen in acute pancreatitis. Chymotrypsin, another acinar protease, has recently been shown be play critical role in clearance of pathologically activated trypsin protecting against pancreatic injury. Mutations in trypsin and other genes thought to be associated with pathologic enzyme activation (such as serine protease inhibitor 1) have been found in familial forms of pancreatitis. Sustained intra-acinar activation of nuclear factor κB pathway seems to be key pathogenic mechanism in chronic pancreatitis. Better understanding of these mechanisms will hopefully allow us to improve treatment strategies in acute and chronic pancreatitis.
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16
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Geisz A, Sahin-Tóth M. A preclinical model of chronic pancreatitis driven by trypsinogen autoactivation. Nat Commun 2018; 9:5033. [PMID: 30487519 PMCID: PMC6261995 DOI: 10.1038/s41467-018-07347-y] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 10/30/2018] [Indexed: 02/07/2023] Open
Abstract
Inflammatory diseases of the pancreas have no specific therapy. Discovery of the genetic basis of chronic pancreatitis identified the digestive enzyme trypsin as a therapeutic target. Preclinical testing of trypsin inhibition has been hampered by the lack of animal models. Here we report the T7D23A knock-in mouse, which carries a heterozygous p.D23A mutation in mouse cationic trypsinogen (isoform T7). This trypsinogen mutant autoactivates to trypsin 50-fold faster than wild type. T7D23A mice develop spontaneous acute pancreatitis with edema, necrosis and serum amylase elevation at an early age followed by progressive atrophic chronic pancreatitis with acinar cell loss, fibrosis, dilated ducts and adipose replacement. Markedly elevated trypsin activity is apparent at first signs of pancreatitis and persists into later stages of the disease. This remarkable model provides in vivo proof of concept that trypsinogen autoactivation can drive onset and progression of chronic pancreatitis and therapy should be directed against intra-pancreatic trypsin.
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Affiliation(s)
- Andrea Geisz
- Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, 02118, USA
| | - 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, USA.
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17
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Merry TL, Petrov MS. The rise of genetically engineered mouse models of pancreatitis: A review of literature. Biomol Concepts 2018; 9:103-114. [DOI: 10.1515/bmc-2018-0011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/19/2018] [Indexed: 12/15/2022] Open
Abstract
AbstractPancreatitis is increasingly recognized as not merely a local inflammation of the pancreas but also a disease with high frequency of systemic sequelae. Current understanding of the cellular mechanisms that trigger it and affect the development of sequelae are limited. Genetically engineered mouse models can be a useful tool to study the pathophysiology of pancreatitis. This article gives an overview of the genetically engineered mouse models that spontaneously develop pancreatitis and discusses those that most closely replicate different pancreatitis hallmarks observed in humans.
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Affiliation(s)
- Troy L. Merry
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
- Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
| | - Maxim S. Petrov
- Department of Surgery, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
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18
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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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19
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Martinelli P, Real FX. Animal Modeling of Pancreatitis-to-Cancer Progression. PANCREATIC CANCER 2018:313-347. [DOI: 10.1007/978-1-4939-7193-0_66] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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20
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The Differential Role of Human Cationic Trypsinogen ( PRSS1) p.R122H Mutation in Hereditary and Nonhereditary Chronic Pancreatitis: A Systematic Review and Meta-Analysis. Gastroenterol Res Pract 2017; 2017:9505460. [PMID: 29118810 PMCID: PMC5651130 DOI: 10.1155/2017/9505460] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 08/22/2017] [Accepted: 09/07/2017] [Indexed: 02/05/2023] Open
Abstract
Background Environmental factors and genetic mutations have been increasingly recognized as risk factors for chronic pancreatitis (CP). The PRSS1 p.R122H mutation was the first discovered to affect hereditary CP, with 80% penetrance. We performed here a systematic review and meta-analysis to evaluate the associations of PRSS1 p.R122H mutation with CP of diverse etiology. Methods The PubMed, EMBASE, and MEDLINE database were reviewed. The pooled odds ratio (OR) with 95% confidence intervals was used to evaluate the association of p.R122H mutation with CP. Initial analysis was conducted with all etiologies of CP, followed by a subgroup analysis for hereditary and nonhereditary CP, including alcoholic or idiopathic CP. Results A total of eight case-control studies (1733 cases and 2415 controls) were identified and included. Overall, PRSS1 p.R122H mutation was significantly associated with an increased risk of CP (OR = 4.78[1.13-20.20]). Further analysis showed p.R122H mutation strongly associated with the increased risk of hereditary CP (OR = 65.52[9.09-472.48]) but not with nonhereditary CP, both alcoholic and idiopathic CP. Conclusions Our study showing the differential role of p.R122H mutation in various etiologies of CP indicates that this complex disorder is likely influenced by multiple genetic factors as well as environmental factors.
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Abstract
Genetic investigations have provided unique insight into the mechanism of chronic pancreatitis in humans and firmly established that uncontrolled trypsin activity is a central pathogenic factor. Mutations in the PRSS1, SPINK1, and CTRC genes promote increased activation of trypsinogen to trypsin by stimulation of autoactivation or by impairing protective trypsinogen degradation and/or trypsin inhibition. Here we review key genetic and biochemical features of the trypsin-dependent pathological pathway in chronic pancreatitis.
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Affiliation(s)
- Eszter Hegyi
- Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, 72 East Concord Street, Evans-433, Boston, MA, 02118, USA
| | - Miklós Sahin-Tóth
- Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, 72 East Concord Street, Evans-433, Boston, MA, 02118, USA.
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22
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Anchi P, Khurana A, Bale S, Godugu C. The Role of Plant-derived Products in Pancreatitis: Experimental and Clinical Evidence. Phytother Res 2017; 31:591-623. [DOI: 10.1002/ptr.5792] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 02/03/2017] [Accepted: 02/06/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Pratibha Anchi
- Department of Regulatory Toxicology; National Institute of Pharmaceutical Education and Research (NIPER), Balanagar; Hyderabad Telangana India
| | - Amit Khurana
- Department of Regulatory Toxicology; National Institute of Pharmaceutical Education and Research (NIPER), Balanagar; Hyderabad Telangana India
| | - Swarna Bale
- Department of Regulatory Toxicology; National Institute of Pharmaceutical Education and Research (NIPER), Balanagar; Hyderabad Telangana India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology; National Institute of Pharmaceutical Education and Research (NIPER), Balanagar; Hyderabad Telangana India
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23
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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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24
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Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 2016; 45:1365-1375. [PMID: 27748719 PMCID: PMC5117429 DOI: 10.1097/mpa.0000000000000713] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities in chronic pancreatitis (CP) and its sequelae. This conference marked the 20th year anniversary of the discovery of the cationic trypsinogen (PRSS1) gene mutation for hereditary pancreatitis. The event was held on July 27, 2016, and structured into 4 sessions: (1) pathophysiology, (2) exocrine complications, (3) endocrine complications, and (4) pain. The current state of knowledge was reviewed; many knowledge gaps and research needs were identified that require further investigation. Common themes included the need to design better tools to diagnose CP and its sequelae early and reliably, identify predisposing risk factors for disease progression, develop standardized protocols to distinguish type 3c diabetes mellitus from other types of diabetes, and design effective therapeutic strategies through novel cell culture technologies, animal models mimicking human disease, and pain management tools. Gene therapy and cystic fibrosis conductance regulator potentiators as possible treatments of CP were discussed. Importantly, the need for CP end points and intermediate targets for future drug trials was emphasized.
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25
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Liou GY, Storz P. Strategies to Target Pancreatic Cancer. MOLECULAR TARGETS AND STRATEGIES IN CANCER PREVENTION 2016:1-20. [DOI: 10.1007/978-3-319-31254-5_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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26
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Esposito I, Segler A, Steiger K, Klöppel G. Pathology, genetics and precursors of human and experimental pancreatic neoplasms: An update. Pancreatology 2015; 15:598-610. [PMID: 26365060 DOI: 10.1016/j.pan.2015.08.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 08/02/2015] [Accepted: 08/12/2015] [Indexed: 12/11/2022]
Abstract
Over the past decade, there have been substantial improvements in our knowledge of pancreatic neoplasms and their precursor lesions. Extensive genetic analyses, recently using high-throughput molecular techniques and next-generation sequencing methodologies, and the development of sophisticated genetically engineered mouse models closely recapitulating human disease, have improved our understanding of the genetic basis of pancreatic neoplasms. These advances are paving the way for refined, molecular-based classifications of pancreatic neoplasms with the potential to better predict prognosis and, possibly, response to therapy. Another major development resides in the identification of subsets of pancreatic exocrine and endocrine neoplasms which occur in the context of hereditary syndromes and whose genetic basis and tumor development have been at least partially defined. However, despite all molecular progress, correct and careful morphological characterization of tissue specimens both in the context of experimental and routine diagnostic pathology represents the basis for any further genetic investigation or clinical decision. This review focuses on the current and new concepts of classification and on the current models of tumor development, both in the field of exocrine and endocrine neoplasms, and underscores the importance of applying standardized terminology to allow adequate data interpretation and promote scientific exchange in the field of pancreas research.
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Affiliation(s)
- Irene Esposito
- Institute of Pathology, Heinrich-Heine-University of Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
| | - Angela Segler
- Institute of Pathology, Technische Universität München, Ismaningerstr. 22, 81675, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technische Universität München, Ismaningerstr. 22, 81675, Munich, Germany
| | - Günter Klöppel
- Institute of Pathology, Technische Universität München, Ismaningerstr. 22, 81675, Munich, Germany
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Sah RP, Garg SK, Dixit AK, Dudeja V, Dawra RK, Saluja AK. Endoplasmic reticulum stress is chronically activated in chronic pancreatitis. J Biol Chem 2014; 289:27551-61. [PMID: 25077966 DOI: 10.1074/jbc.m113.528174] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The pathogenesis of chronic pancreatitis (CP) is poorly understood. Endoplasmic reticulum (ER) stress has now been recognized as a pathogenic event in many chronic diseases. However, ER stress has not been studied in CP, although pancreatic acinar cells seem to be especially vulnerable to ER dysfunction because of their dependence on high ER volume and functionality. Here, we aim to investigate ER stress in CP, study its pathogenesis in relation to trypsinogen activation (widely regarded as the key event of pancreatitis), and explore its mechanism, time course, and downstream consequences during pancreatic injury. CP was induced in mice by repeated episodes of acute pancreatitis (AP) based on caerulein hyperstimulation. ER stress leads to activation of unfolded protein response components that were measured in CP and AP. We show sustained up-regulation of unfolded protein response components ATF4, CHOP, GRP78, and XBP1 in CP. Overexpression of GRP78 and ATF4 in human CP confirmed the experimental findings. We used novel trypsinogen-7 knock-out mice (T(-/-)), which lack intra-acinar trypsinogen activation, to clarify the relationship of ER stress to intra-acinar trypsinogen activation in pancreatic injury. Comparable activation of ER stress was seen in wild type and T(-/-) mice. Induction of ER stress occurred through pathologic calcium signaling very early in the course of pancreatic injury. Our results establish that ER stress is chronically activated in CP and is induced early in pancreatic injury through pathologic calcium signaling independent of trypsinogen activation. ER stress may be an important pathogenic mechanism in pancreatitis that needs to be explored in future studies.
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Affiliation(s)
- Raghuwansh P Sah
- From the Division of Basic and Translational Research, Department of Surgery, University of Minnesota Medical School, Minneapolis, Minnesota 55455
| | - Sushil K Garg
- From the Division of Basic and Translational Research, Department of Surgery, University of Minnesota Medical School, Minneapolis, Minnesota 55455
| | - Ajay K Dixit
- From the Division of Basic and Translational Research, Department of Surgery, University of Minnesota Medical School, Minneapolis, Minnesota 55455
| | - Vikas Dudeja
- From the Division of Basic and Translational Research, Department of Surgery, University of Minnesota Medical School, Minneapolis, Minnesota 55455
| | - Rajinder K Dawra
- From the Division of Basic and Translational Research, Department of Surgery, University of Minnesota Medical School, Minneapolis, Minnesota 55455
| | - Ashok K Saluja
- From the Division of Basic and Translational Research, Department of Surgery, University of Minnesota Medical School, Minneapolis, Minnesota 55455
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Athwal T, Huang W, Mukherjee R, Latawiec D, Chvanov M, Clarke R, Smith K, Campbell F, Merriman C, Criddle D, Sutton R, Neoptolemos J, Vlatković N. Expression of human cationic trypsinogen (PRSS1) in murine acinar cells promotes pancreatitis and apoptotic cell death. Cell Death Dis 2014; 5:e1165. [PMID: 24722290 PMCID: PMC5424103 DOI: 10.1038/cddis.2014.120] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 12/17/2013] [Accepted: 12/19/2013] [Indexed: 02/05/2023]
Abstract
Hereditary pancreatitis (HP) is an autosomal dominant disease that displays the features of both acute and chronic pancreatitis. Mutations in human cationic trypsinogen (PRSS1) are associated with HP and have provided some insight into the pathogenesis of pancreatitis, but mechanisms responsible for the initiation of pancreatitis have not been elucidated and the role of apoptosis and necrosis has been much debated. However, it has been generally accepted that trypsinogen, prematurely activated within the pancreatic acinar cell, has a major role in the initiation process. Functional studies of HP have been limited by the absence of an experimental system that authentically mimics disease development. We therefore developed a novel transgenic murine model system using wild-type (WT) human PRSS1 or two HP-associated mutants (R122H and N29I) to determine whether expression of human cationic trypsinogen in murine acinar cells promotes pancreatitis. The rat elastase promoter was used to target transgene expression to pancreatic acinar cells in three transgenic strains that were generated: Tg(Ela-PRSS1)NV, Tg(Ela-PRSS1*R122H)NV and Tg(Ela-PRSS1*N29I)NV. Mice were analysed histologically, immunohistochemically and biochemically. We found that transgene expression is restricted to pancreatic acinar cells and transgenic PRSS1 proteins are targeted to the pancreatic secretory pathway. Animals from all transgenic strains developed pancreatitis characterised by acinar cell vacuolisation, inflammatory infiltrates and fibrosis. Transgenic animals also developed more severe pancreatitis upon treatment with low-dose cerulein than controls, displaying significantly higher scores for oedema, inflammation and overall histopathology. Expression of PRSS1, WT or mutant, in acinar cells increased apoptosis in pancreatic tissues and isolated acinar cells. Moreover, studies of isolated acinar cells demonstrated that transgene expression promotes apoptosis rather than necrosis. We therefore conclude that expression of WT or mutant human PRSS1 in murine acinar cells induces apoptosis and is sufficient to promote spontaneous pancreatitis, which is enhanced in response to cellular insult.
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Affiliation(s)
- T Athwal
- Department of Molecular and Clinical Cancer Medicine, Institute for Translational Medicine, University of Liverpool, Cancer Research Centre, Liverpool, UK
| | - W Huang
- Liverpool NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK
- Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, China
| | - R Mukherjee
- Liverpool NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK
| | - D Latawiec
- Liverpool NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK
| | - M Chvanov
- Department of Cellular and Molecular Physiology, Institute for Translational Medicine, University of Liverpool, Liverpool, UK
| | - R Clarke
- Department of Molecular and Clinical Cancer Medicine, Institute for Translational Medicine, University of Liverpool, Cancer Research Centre, Liverpool, UK
| | - K Smith
- Department of Molecular and Clinical Cancer Medicine, Institute for Translational Medicine, University of Liverpool, Cancer Research Centre, Liverpool, UK
| | - F Campbell
- Department of Pathology, Royal Liverpool University Hospital, Liverpool, UK
| | - C Merriman
- Department of Molecular and Clinical Cancer Medicine, Institute for Translational Medicine, University of Liverpool, Cancer Research Centre, Liverpool, UK
| | - D Criddle
- Department of Cellular and Molecular Physiology, Institute for Translational Medicine, University of Liverpool, Liverpool, UK
| | - R Sutton
- Department of Molecular and Clinical Cancer Medicine, Institute for Translational Medicine, University of Liverpool, Cancer Research Centre, Liverpool, UK
- Liverpool NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK
| | - J Neoptolemos
- Department of Molecular and Clinical Cancer Medicine, Institute for Translational Medicine, University of Liverpool, Cancer Research Centre, Liverpool, UK
- Liverpool NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK
| | - N Vlatković
- Department of Molecular and Clinical Cancer Medicine, Institute for Translational Medicine, University of Liverpool, Cancer Research Centre, Liverpool, UK
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Abstract
Hereditary pancreatitis is an autosomal dominant disorder with 80% penetrance and variable expressivity. The vast majority of cases have been linked to mutations within the cationic trypsinogen gene, also referred to as serine protease 1 (PRSS1). Other than inheritance, PRSS1 pancreatitis has been considered clinically and pathologically indistinguishable from other etiologies of chronic pancreatitis. However, to date, the histologic findings of PRSS1 pancreatitis have not been well described. We, therefore, collected pancreatic specimens from 10 PRSS1 patients of various ages and examined their clinicopathologic features. Patients at the time of resection ranged in age from 9 to 66 years (median, 29 y), with a slight female predominance (60%). All patients reported a history of intermittent abdominal pain, with an age of onset ranging from infancy to 21 years of age. Examination of the gross and microscopic findings suggested a sequential pattern of changes with increasing patient age. In pediatric patients (n=4), although in most cases the pancreas was grossly normal, there was microscopic variation in lobular size and shape. Although the central portions of the pancreas displayed parenchymal loss accompanied by loose perilobular and interlobular fibrosis, the periphery was remarkable for replacement by mature adipose tissue. These changes were more developed in younger adults (n=2), in whom fatty replacement seemed to extend from the periphery to the central portions of the pancreas. With older patients (n=4), the pancreas showed marked atrophy and extensive replacement by mature adipose tissue with scattered islets of Langerhans and rare acinar epithelium concentrated near the main pancreatic duct. In summary, PRSS1 hereditary pancreatitis is characterized by progressive lipomatous atrophy of the pancreas.
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Németh BC, Sahin-Tóth M. Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2014; 306:G466-73. [PMID: 24458023 PMCID: PMC3949028 DOI: 10.1152/ajpgi.00419.2013] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Variations in the serine protease 1 (PRSS1) gene encoding human cationic trypsinogen have been conclusively associated with autosomal dominant hereditary pancreatitis and sporadic nonalcoholic chronic pancreatitis. Most high-penetrance PRSS1 variants increase intrapancreatic trypsin activity by stimulating trypsinogen autoactivation and/or by inhibiting chymotrypsin C-dependent trypsinogen degradation. Alternatively, some PRSS1 variants can cause trypsinogen misfolding, which results in intracellular retention and degradation with consequent endoplasmic reticulum stress. However, not all PRSS1 variants are pathogenic, and clinical relevance of rare variants is often difficult to ascertain. Here we review the PRSS1 variants published since 1996 and discuss their functional properties and role in chronic pancreatitis.
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Affiliation(s)
- Balázs Csaba Németh
- Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, Boston, Massachusetts
| | - Miklós Sahin-Tóth
- Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, Boston, Massachusetts
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31
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Abstract
Beset by poor prognosis, pancreatic ductal adenocarcinoma is classified as familial or sporadic. This review elaborates on the known genetic syndromes that underlie familial pancreatic cancer, where there are opportunities for genetic counseling and testing as well as clinical monitoring of at-risk patients. Such subsets of familial pancreatic cancer involve germline cationic trypsinogen or PRSS1 mutations (hereditary pancreatitis), BRCA2 mutations (usually in association with hereditary breast-ovarian cancer syndrome), CDKN2 mutations (familial atypical mole and multiple melanoma), or DNA repair gene mutations (e.g., ATM and PALB2, apart from those in BRCA2). However, the vast majority of familial pancreatic cancer cases have yet to have their genetic underpinnings elucidated, waiting in part for the results of deep sequencing efforts.
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Affiliation(s)
- Anil K. Rustgi
- Division of Gastroenterology, Department of Medicine and Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Zhao JB, Liao DH, Nissen TD. Animal models of pancreatitis: Can it be translated to human pain study? World J Gastroenterol 2013; 19:7222-7230. [PMID: 24259952 PMCID: PMC3831203 DOI: 10.3748/wjg.v19.i42.7222] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 08/12/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis affects many individuals around the world, and the study of the underlying mechanisms leading to better treatment possibilities are important tasks. Therefore, animal models are needed to illustrate the basic study of pancreatitis. Recently, animal models of acute and chronic pancreatitis have been thoroughly reviewed, but few reviews address the important aspect on the translation of animal studies to human studies. It is well known that pancreatitis is associated with epigastric pain, but the understanding regarding to mechanisms and appropriate treatment of this pain is still unclear. Using animal models to study pancreatitis associated visceral pain is difficult, however, these types of models are a unique way to reveal the mechanisms behind pancreatitis associated visceral pain. In this review, the animal models of acute, chronic and un-common pancreatitis are briefly outlined and animal models related to pancreatitis associated visceral pain are also addressed.
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Abstract
The nonneoplastic diseases of the human pancreas generally comprise the inflammatory and degenerative conditions that include acute and chronic pancreatitis, with cystic fibrosis being arguably one of the most important diseases that induce the condition. Both acute and chronic conditions vary in severity, but both can be life threatening; and because of this fact, the study of their progression, and their responsiveness to therapy, is largely conducted by indirect means using serum markers of damage and repair such as amylase and lipase activities that normally occur at very low levels in the circulation but can be significantly increased during inflammatory episodes. Progress in the understanding the pathogenesis of both conditions has therefore been largely due to time course studies in animal models of pancreatitis, and it is in this context that animal model development has been so significant. In general terms, the animal models can be divided into the invasive, surgical procedures, and those induced by the administration of chemical secretagogues that induce hypersecretion of the pancreatic enzymes. The former include ligation and/or cannulation of the biliopancreatic ducts with infusion of solutions of various kinds, or the formation of closed duodenal loops. Secretagogue administration includes administration of caerulein or l-arginine in various protocols. An additional model involves administration of dibutyltin dichloride, which induces a partial blockage of the pancreatic ducts to induce pancreatic disease through enzymic reflux into the gland. The models have been invaluable in generating testable hypotheses for the human diseases. These hypotheses for the production of cellular damage as the initiating events in the disease include (1) intracellular chemical activation, (2) pancreatic secretion reflux, (3) intracellular production of reactive oxygen species, and (4) intracellular production of free radicals.
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Affiliation(s)
- John R Foster
- 1AstraZeneca Pharmaceuticals, Cheshire, United Kingdom
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Abstract
PURPOSE OF REVIEW In this article, we review important advances in our understanding of the mechanisms of pancreatitis. RECENT FINDINGS The relative contributions of intrapancreatic trypsinogen activation and nuclear factor kappa B (NFκB) activation, the two major early independent cellular events in pancreatitis, have been investigated using novel genetic models. Trypsinogen activation has traditionally held the spotlight for many decades as the central pathogenic event of pancreatitis. However, recent experimental evidence points to the role of trypsin activation in early acinar cell damage but not in the inflammatory response of acute pancreatitis, which was shown to be induced by NFκB activation. Further, chronic pancreatitis developed independently of trypsinogen activation in the caerulein model. Sustained NFκB activation, but not persistent intra-acinar expression of active trypsin, was shown to result in chronic pancreatitis. Calcineurin-NFAT (nuclear factor of activated T-cells) signaling was shown to mediate downstream effects of pathologic rise in intracellular calcium. Interleukin-6 was identified as a key cytokine mediating pancreatitis-associated lung injury. SUMMARY Recent advances challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis.
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Németh BC, Wartmann T, Halangk W, Sahin-Tóth M. Autoactivation of mouse trypsinogens is regulated by chymotrypsin C via cleavage of the autolysis loop. J Biol Chem 2013; 288:24049-62. [PMID: 23814066 DOI: 10.1074/jbc.m113.478800] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Chymotrypsin C (CTRC) is a proteolytic regulator of trypsinogen autoactivation in humans. CTRC cleavage of the trypsinogen activation peptide stimulates autoactivation, whereas cleavage of the calcium binding loop promotes trypsinogen degradation. Trypsinogen mutations that alter these regulatory cleavages lead to increased intrapancreatic trypsinogen activation and cause hereditary pancreatitis. The aim of this study was to characterize the regulation of autoactivation of mouse trypsinogens by mouse Ctrc. We found that the mouse pancreas expresses four trypsinogen isoforms to high levels, T7, T8, T9, and T20. Only the T7 activation peptide was cleaved by mouse Ctrc, causing negligible stimulation of autoactivation. Surprisingly, mouse Ctrc poorly cleaved the calcium binding loop in all mouse trypsinogens. In contrast, mouse Ctrc readily cleaved the Phe-150-Gly-151 peptide bond in the autolysis loop of T8 and T9 and inhibited autoactivation. Mouse chymotrypsin B also cleaved the same peptide bond but was 7-fold slower. T7 was less sensitive to chymotryptic regulation, which involved slow cleavage of the Leu-149-Ser-150 peptide bond in the autolysis loop. Modeling indicated steric proximity of the autolysis loop and the activation peptide in trypsinogen, suggesting the cleaved autolysis loop may directly interfere with activation. We conclude that autoactivation of mouse trypsinogens is under the control of mouse Ctrc with some notable differences from the human situation. Thus, cleavage of the trypsinogen activation peptide or the calcium binding loop by Ctrc is unimportant. Instead, inhibition of autoactivation via cleavage of the autolysis loop is the dominant mechanism that can mitigate intrapancreatic trypsinogen activation.
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Affiliation(s)
- Balázs Csaba Németh
- Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts 02118, USA
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36
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Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology 2013; 144:1180-93. [PMID: 23622127 DOI: 10.1053/j.gastro.2012.12.043] [Citation(s) in RCA: 308] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 12/06/2012] [Accepted: 12/13/2012] [Indexed: 12/16/2022]
Abstract
Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer. In vitro models can be used to study early stage, short-term processes that involve acinar cell responses. Rodent models reproducibly develop mild or severe disease. One of the most commonly used pancreatitis models is created by administration of supraphysiologic concentrations of caerulein, an ortholog of cholecystokinin. Induction of chronic pancreatitis with factors thought to have a role in human disease, such as combinations of lipopolysaccharide and chronic ethanol feeding, might be relevant to human disease. Models of autoimmune chronic pancreatitis have also been developed. Most models, particularly of chronic pancreatitis, require further characterization to determine which features of human disease they include.
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Affiliation(s)
- Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, Greifswald, Germany.
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Sah RP, Dudeja V, Dawra RK, Saluja AK. Cerulein-induced chronic pancreatitis does not require intra-acinar activation of trypsinogen in mice. Gastroenterology 2013; 144:1076-1085.e2. [PMID: 23354015 PMCID: PMC3928043 DOI: 10.1053/j.gastro.2013.01.041] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 01/02/2013] [Accepted: 01/07/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Premature activation of trypsinogen activation can cause pancreatic injury and has been associated with chronic pancreatitis (CP). Mice that lack intra-acinar activation of trypsinogen, such as trypsinogen-7-null (T(-/-)) and cathepsin B-null (CB(-/-)) mice, have been used to study trypsin-independent processes of CP development. We compared histologic features and inflammatory responses of pancreatic tissues from these mice with those from wild-type mice after the development of CP. METHODS CP was induced in wild-type, T(-/-), and CB(-/-) mice by twice-weekly induction of acute pancreatitis for 10 weeks; acute pancreatitis was induced by hourly intraperitoneal injections of cerulein (50 μg/kg × 6). Pancreatic samples were collected and evaluated by histologic and immunohistochemical analyses. Normal human pancreas samples, obtained from the islet transplant program at the University of Minnesota, were used as controls and CP samples were obtained from surgical resections. RESULTS Compared with pancreatic tissues from wild-type mice, those from T(-/-) and CB(-/-) mice had similar levels of atrophy, histomorphologic features of CP, and chronic inflammation. All samples had comparable intra-acinar activation of nuclear factor (NF)-κB, a transcription factor that regulates the inflammatory response, immediately after injection of cerulein. Pancreatic tissue samples from patients with CP had increased activation of NF-κB (based on nuclear translocation of p65 in acinar cells) compared with controls. CONCLUSIONS Induction of CP in mice by cerulein injection does not require intra-acinar activation of trypsinogen. Pancreatic acinar cells of patients with CP have increased levels of NF-κB activation compared with controls; regulation of the inflammatory response by this transcription factor might be involved in the pathogenesis of CP.
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Ohmuraya M, Sugano A, Hirota M, Takaoka Y, Yamamura KI. Role of Intrapancreatic SPINK1/Spink3 Expression in the Development of Pancreatitis. Front Physiol 2012; 3:126. [PMID: 22586407 PMCID: PMC3345944 DOI: 10.3389/fphys.2012.00126] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Accepted: 04/16/2012] [Indexed: 12/17/2022] Open
Abstract
Studies on hereditary pancreatitis have provided evidence in favor of central role for trypsin activity in the disease. Identification of genetic variants of trypsinogen linked the protease to the onset of pancreatitis, and biochemical characterization proposed an enzymatic gain of function as the initiating mechanism. Mutations of serine protease inhibitor Kazal type 1 gene (SPINK1) are shown to be associated with hereditary pancreatitis. We previously reported that Spink3 (a mouse homolog gene of human SPINK1) deficient mice showed excessive autophagy, followed by inappropriate trypsinogen activation in the exocrine pancreas. These data indicate that the role of SPINK1/Spink3 is not only trypsin inhibitor, but also negative regulator of autophagy. On the other hand, recent studies showed that high levels of SPINK1 protein detected in a serum or urine were associated with adverse outcome in various cancer types. It has been suggested that expression of SPINK1 and trypsin is balanced in normal tissue, but this balance could be disrupted during tumor progression. Based on the structural similarity between SPINK1 and epidermal growth factor (EGF), we showed that SPINK1 protein binds and activates EGF receptor, thus acting as a growth factor on tumor cell lines. In this review, we summarize the old and new roles of SPINK1/Spink3 in trypsin inhibition, autophagy, and cancer cell growth. These new functions of SPINK1/Spink3 may be related to the development of chronic pancreatitis.
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Affiliation(s)
- Masaki Ohmuraya
- Institute of Resource Development and Analysis, Kumamoto University Kumamoto, Japan
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Aghdassi AA, Mayerle J, Christochowitz S, Weiss FU, Sendler M, Lerch MM. Animal models for investigating chronic pancreatitis. FIBROGENESIS & TISSUE REPAIR 2011; 4:26. [PMID: 22133269 PMCID: PMC3274456 DOI: 10.1186/1755-1536-4-26] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 12/01/2011] [Indexed: 02/06/2023]
Abstract
Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed.
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Affiliation(s)
- Alexander A Aghdassi
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
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40
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Abstract
Chronic pancreatitis (CP) is irregularly distributed around the world, and the pathogenic factors and incidence rates of CP vary greatly among different countries and regions. The main pathogenic factor for CP is alcohol in Western countries and biliary tract disease in China. Changes in the lifestyle also change the main pathogenic factors for CP. In recent years, alcohol has gradually replaced biliary tract disease to become the main etiological factor for CP in China. A deeper understanding of the etiology of CP provides new insights into the treatment of the disease.
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41
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Abstract
It is now generally believed that pancreatitis results from pancreatic autodigestion. An inappropriate conversion of pancreatic zymogens to active enzymes within the pancreatic parenchyma is thought to initiate the inflammatory process. A key role has been attributed to the activation of trypsinogen to trypsin, converting all proteolytic proenzymes to their active form. Several gain-of-function mutations in the cationic trypsinogen gene (PRSS1) have been identified in patients with chronic pancreatitis (CP). These mutations lead to enhanced intrapancreatic trypsinogen activation. In contrast, a variant in the anionic trypsinogen (PRSS2) gene, p.G191R, has been described that mitigates intrapancreatic trypsin activity and thereby plays a protective role. Beside trypsinogen mutations, loss-of-function variants in SPINK1, encoding a pancreatic trypsin inhibitor, are strongly associated with idiopathic CP. Approximately 15-40% of patients with so-called idiopathic CP carry p.N34S on one allele or on both alleles. Chymotrypsin C (CTRC) degrades all human trypsin isoforms with high specificity. Two CTRC alterations, p.R254W and p.K247_R254del, are significantly associated with idiopathic as well as alcohol-related CP. Functional analysis of the variants revealed impaired activity and/or reduced secretion. Thus, loss-of-function mutations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. Albeit the association between CFTR, the gene mutated in cystic fibrosis, and idiopathic CP is now well established, the pathogenic mechanisms are poorly understood. Nearly 25-30% of patients carry at least one CFTR mutation, but few patients only were compound-heterozygous. Several patients, however, are trans-heterozygous for a CFTR alteration and a PRSS1, SPINK1, or CTRC variant, respectively.
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Affiliation(s)
- Heiko Witt
- Department of Pediatrics, Technische Universität München (TUM), Munich, Germany.
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42
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Fukuda A, Wang SC, Morris JP, Folias AE, Liou A, Kim GE, Akira S, Boucher KM, Firpo MA, Mulvihill SJ, Hebrok M. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 2011; 19:441-55. [PMID: 21481787 PMCID: PMC3075548 DOI: 10.1016/j.ccr.2011.03.002] [Citation(s) in RCA: 422] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2010] [Revised: 12/10/2010] [Accepted: 03/01/2011] [Indexed: 12/17/2022]
Abstract
Chronic pancreatitis is a well-known risk factor for pancreatic ductal adenocarcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models of the disease. However, the mechanistic link between inflammatory damage and PDA initiation is unclear. Using a Kras-driven mouse model of PDA, we establish that the inflammatory mediator Stat3 is a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supports cell proliferation, metaplasia-associated inflammation, and MMP7 expression during neoplastic development. Furthermore, we show that Stat3 signaling enforces MMP7 expression in PDA cells and that MMP7 deletion limits tumor size and metastasis in mice. Finally, we demonstrate that serum MMP7 level in human patients with PDA correlated with metastatic disease and survival.
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Affiliation(s)
- Akihisa Fukuda
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Sam C. Wang
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - John P. Morris
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Alexandra E. Folias
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Angela Liou
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Grace E. Kim
- Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Shizuo Akira
- Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Kenneth M. Boucher
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84115, USA
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84115, USA
| | - Matthew A. Firpo
- Department of Surgery, University of Utah, Salt Lake City, UT 84115, USA
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84115, USA
| | - Sean J. Mulvihill
- Department of Surgery, University of Utah, Salt Lake City, UT 84115, USA
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84115, USA
| | - Matthias Hebrok
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
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43
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Abstract
Chronic pancreatitis is a progressive fibroinflammatory disease that exists in large-duct (often with intraductal calculi) or small-duct form. In many patients this disease results from a complex mix of environmental (eg, alcohol, cigarettes, and occupational chemicals) and genetic factors (eg, mutation in a trypsin-controlling gene or the cystic fibrosis transmembrane conductance regulator); a few patients have hereditary or autoimmune disease. Pain in the form of recurrent attacks of pancreatitis (representing paralysis of apical exocytosis in acinar cells) or constant and disabling pain is usually the main symptom. Management of the pain is mainly empirical, involving potent analgesics, duct drainage by endoscopic or surgical means, and partial or total pancreatectomy. However, steroids rapidly reduce symptoms in patients with autoimmune pancreatitis, and micronutrient therapy to correct electrophilic stress is emerging as a promising treatment in the other patients. Steatorrhoea, diabetes, local complications, and psychosocial issues associated with the disease are additional therapeutic challenges.
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MESH Headings
- Abdominal Pain/etiology
- Abdominal Pain/therapy
- Algorithms
- Animals
- Anti-Inflammatory Agents/therapeutic use
- Autoimmunity
- Biomarkers/blood
- Cholangiopancreatography, Endoscopic Retrograde
- Diabetes Mellitus/etiology
- Diabetes Mellitus/therapy
- Disease Models, Animal
- Disease Progression
- Drainage
- Endoscopy, Digestive System
- Fibrosis
- Genetic Predisposition to Disease
- Humans
- Ischemia/complications
- Magnetic Resonance Imaging
- Micronutrients/therapeutic use
- Mutation
- Pancreas/blood supply
- Pancreas/metabolism
- Pancreas/pathology
- Pancreatectomy
- Pancreaticojejunostomy
- Pancreatitis, Acute Necrotizing
- Pancreatitis, Alcoholic
- Pancreatitis, Chronic/classification
- Pancreatitis, Chronic/complications
- Pancreatitis, Chronic/diagnosis
- Pancreatitis, Chronic/etiology
- Pancreatitis, Chronic/metabolism
- Pancreatitis, Chronic/pathology
- Pancreatitis, Chronic/therapy
- Prednisolone/therapeutic use
- Risk Factors
- Smoking/adverse effects
- Steatorrhea/etiology
- Steatorrhea/therapy
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Affiliation(s)
- Joan M Braganza
- Department of Gastroenterology, Manchester Royal Infirmary, Manchester, UK.
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44
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Abstract
Hereditary chronic pancreatitis (HCP) is a rare disease in which chronic pancreatitis develops in childhood. HCP has autosomal dominant inheritance with approximately 80% penetrance. Diagnostic criteria are not universally agreed upon but the EUROPAC trial defined it as two first-degree relatives or at least 3 second-degree relatives in two or more generations, with chronic pancreatitis for which there is no other etiology. The gene for HCP was originally identified on chromosome 7 and subsequently many other genes have been reported to be associated with HCP. To date, no single genetic alteration has been found that is necessary for the development of HCP. In a recent study, 81% of patients with HCP were found to have a mutation of the PRSS1 gene. Patients with HCP are at risk for developing exocrine and endocrine insufficiency and there is a 50-fold increased risk of pancreatic cancer in HCP patients as compared with the general population.
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45
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Grippo PJ, Tuveson DA. Deploying mouse models of pancreatic cancer for chemoprevention studies. Cancer Prev Res (Phila) 2010; 3:1382-7. [PMID: 21045161 DOI: 10.1158/1940-6207.capr-10-0258] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
With the advent of mouse models that recapitulate the cellular and molecular pathology of pancreatic neoplasia and cancer, it is now feasible to recruit and deploy these models for the evaluation of various chemopreventive and/or anticancer regimens. The highly lethal nature of pancreatic ductal adenocarcinoma (PDAC) makes multiple areas of research a priority, including assessment of compounds that prevent or suppress the development of early lesions that can transform into PDAC. Currently, there are over a dozen models available, which range from homogeneous preneoplastic lesions with remarkable similarity to human pancreatic intraepithelial neoplasms to models with a more heterogeneous population of lesions including cystic papillary and mucinous lesions. The molecular features of these models may also vary in a manner comparable with the differences observed in lesion morphology, and so, navigating the route of model selection is not trivial. Yet, arming the community of cancer investigators with a repertoire of models and the guidance to select relevant models that fit their research themes promises to produce findings that will have clinical relevance.
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Affiliation(s)
- Paul J Grippo
- Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 East Superior Street, Chicago, IL 60611, USA.
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46
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Genetic factors in chronic pancreatitis; implications for diagnosis, management and prognosis. Best Pract Res Clin Gastroenterol 2010; 24:251-70. [PMID: 20510827 DOI: 10.1016/j.bpg.2010.02.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2010] [Accepted: 02/05/2010] [Indexed: 01/31/2023]
Abstract
Chronic pancreatitis (CP) is a clinical situation with persisting inflammation leading to destruction of the pancreas ensuing endocrine and exocrine failure. There are 4 subtypes: hereditary, idiopathic, alcoholic and tropical pancreatitis. Genetic factors can explain a significant proportion of CP cases. The PRSS1 gene, encoding cationic trypsinogen, was found to be correlated with hereditary CP. This signalled the extensive search for other candidate genes within the trypsin pathway. Genes like SPINK1 and CTRC are associated with CP and should be considered as important contributing factors rather than causative. The search for candidate genes not part of the trypsin pathway has been less successful and the only gene consistently associated with CP is the Cystic Fibrosis Transmembrane Regulator. In this review we will discuss the various CP subtypes in relation to the respective genetic variants. This review will also address the implications of genetic testing in daily clinical practise.
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47
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IDA S, OHMURAYA M, HIROTA M, OZAKI N, HIRAMATSU S, UEHARA H, TAKAMORI H, ARAKI K, BABA H, YAMAMURA KI. Chronic Pancreatitis in Mice by Treatment with Choline-Deficient Ethionine-Supplemented Diet. Exp Anim 2010; 59:421-9. [DOI: 10.1538/expanim.59.421] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Affiliation(s)
- Satoshi IDA
- Insitute of Resource Development and Analysis, Kumamoto University
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University
| | - Masaki OHMURAYA
- Insitute of Resource Development and Analysis, Kumamoto University
- Priority Organization for Innovation and Excellence, Kumamoto University
| | | | - Nobuyuki OZAKI
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University
| | - Sayaka HIRAMATSU
- Insitute of Resource Development and Analysis, Kumamoto University
| | - Hitoshi UEHARA
- Insitute of Resource Development and Analysis, Kumamoto University
| | - Hiroshi TAKAMORI
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University
| | - Kimi ARAKI
- Insitute of Resource Development and Analysis, Kumamoto University
| | - Hideo BABA
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University
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48
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Abstract
Chronic pancreatitis is a necroinflammatory process characterized pathologically by acinar atrophy and fibrosis and clinically by abdominal pain, diabetes and maldigestion. In this review we summarize some of the recent advances in the understanding of the pathogenesis of pancreatitis and how they have shaped our current understanding of chronic pancreatitis. We pay particular attention to advances in the genetic basis of idiopathic, hereditary and tropical pancreatitis as well as research into the relationship between alcohol and the pancreas. We have also reviewed current practices with respect to diagnosis and management of chronic pancreatitis.
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Affiliation(s)
- S J N Tattersall
- Department of Gastroenterology, Liverpool Hospital, Liverpool, Australia
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49
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Abstract
Chronic pancreatitis (CP) is a persistent inflammation of the pancreas. Over the past 12 years, genetic studies of hereditary, familial, and idiopathic forms of CP have made great progress in defining the disease pathogenesis. Identification of gain-of-function missense and copy number mutations in the cationic trypsinogen gene (PRSS1) and loss-of-function variants in both the pancreatic secretory trypsin inhibitor (SPINK1) and chymotrypsinogen C (CTRC) genes has firmly established the pivotal role of prematurely activated trypsin within the pancreas in the etiology of CP. Loss-of-function variants in the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-sensing receptor (CASR) genes also increase the risk of CP. Here, we review recent developments in this rapidly evolving field, highlight the importance of gene-gene and gene-environment interactions in causing the disease, and discuss the opportunities and challenges in identifying novel genetic factors that affect susceptibility/resistance to CP.
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Affiliation(s)
- Jian-Min Chen
- Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France.
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50
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Progressive metaplastic and dysplastic changes in mouse pancreas induced by cyclooxygenase-2 overexpression. Neoplasia 2008; 10:782-96. [PMID: 18670639 DOI: 10.1593/neo.08330] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2008] [Revised: 04/25/2008] [Accepted: 04/28/2008] [Indexed: 01/02/2023] Open
Abstract
Cyclooxygenase-2 (COX-2) overexpression is an established factor linking chronic inflammation with metaplastic and neoplastic change in various tissues. We generated transgenic mice (BK5.COX-2) in which elevation of COX-2 and its effectors trigger a metaplasia-dysplasia sequence in exocrine pancreas. Histologic evaluation revealed a chronic pancreatitis-like state characterized by acinar-to-ductal metaplasia and a well-vascularized fibroinflammatory stroma that develops by 3 months. By 6 to 8 months, strongly dysplastic features suggestive of pancreatic ductal adenocarcinoma emerge in the metaplastic ducts. Increased proliferation, cellular atypia, and loss of normal cell/tissue organization are typical features in transgenic pancreata. Alterations in biomarkers associated with human inflammatory and neoplastic pancreatic disease were detected using immunohistochemistry. The abnormal pancreatic phenotype can be completely prevented by maintaining mice on a diet containing celecoxib, a well-characterized COX-2 inhibitor. Despite the high degree of atypia, only limited evidence of invasion to adjacent tissues was observed, with no evidence of distant metastases. However, cell lines derived from spontaneous lesions are aggressively tumorigenic when injected into syngeneic or nude mice. The progressive nature of the metaplastic/dysplastic changes observed in this model make it a valuable tool for examining the transition from chronic inflammation to neoplasia.
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