Expression of human cationic trypsinogen (PRSS1) in murine acinar cells promotes pancreatitis and apoptotic cell death View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-04-10

AUTHORS

T Athwal, W Huang, R Mukherjee, D Latawiec, M Chvanov, R Clarke, K Smith, F Campbell, C Merriman, D Criddle, R Sutton, J Neoptolemos, N Vlatković

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. More... »

PAGES

e1165-e1165

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/cddis.2014.120

DOI

http://dx.doi.org/10.1038/cddis.2014.120

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1031555931

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24722290


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30 schema:description 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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37 absence
38 acinar
39 acinar cell vacuolisation
40 acinar cells
41 animals
42 apoptosis
43 apoptotic cell death
44 autosomal dominant disease
45 cationic trypsinogen
46 cell death
47 cell vacuolisation
48 cells
49 cellular insults
50 cerulein
51 chronic pancreatitis
52 control
53 death
54 development
55 disease
56 disease development
57 dominant disease
58 edema
59 elastase promoter
60 experimental system
61 expression
62 expression of WT
63 features
64 fibrosis
65 functional studies
66 hereditary pancreatitis
67 higher scores
68 histopathology
69 human cationic trypsinogen
70 infiltrates
71 inflammation
72 inflammatory infiltrate
73 initiation
74 initiation of pancreatitis
75 initiation process
76 insights
77 insult
78 major role
79 mechanism
80 mice
81 model system
82 murine acinar cells
83 murine model system
84 mutants
85 mutations
86 necrosis
87 overall histopathology
88 pancreatic acinar cells
89 pancreatic tissue
90 pancreatitis
91 pathogenesis
92 pathogenesis of pancreatitis
93 pathway
94 process
95 promoter
96 protein
97 rat elastase promoter
98 response
99 role
100 role of apoptosis
101 scores
102 secretory pathway
103 severe pancreatitis
104 spontaneous pancreatitis
105 strains
106 study
107 system
108 tissue
109 transgene expression
110 transgenic animals
111 transgenic strains
112 treatment
113 trypsinogen
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115 wt
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