Pancreatitis severity in mice with impaired CFTR function but pancreatic sufficiency is mediated via ductal and inflammatory cells-Not acinar cells.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101083777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1582-4934 (Electronic) Linking ISSN: 15821838 NLM ISO Abbreviation: J Cell Mol Med Subsets: MEDLINE

Publication: Oxford, England : Wiley-Blackwell
Original Publication: Bucharest : "Carol Davila" University Press, 2000-

Mutation*; Acinar Cells/*cytology ; Cystic Fibrosis/*complications ; Cystic Fibrosis Transmembrane Conductance Regulator/*genetics ; Inflammation/*pathology ; Pancreatic Ducts/*pathology ; Pancreatitis/*pathology; Acinar Cells/metabolism ; Animals ; Chlorides/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Humans ; Inflammation/etiology ; Inflammation/metabolism ; Male ; Mice ; Mice, Transgenic ; Pancreatic Ducts/metabolism ; Pancreatitis/etiology ; Pancreatitis/metabolism ; Severity of Illness Index

Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) are an established risk factor for cystic fibrosis (CF) and chronic pancreatitis. Whereas patients with CF usually develop complete exocrine pancreatic insufficiency, pancreatitis patients with CFTR mutations have mostly preserved exocrine pancreatic function. We therefore used a strain of transgenic mice with significant residual CFTR function (CFTR ^tm1HGU ) to induce pancreatitis experimentally by serial caerulein injections. Protease activation and necrosis were investigated in isolated acini, disease severity over 24h, pancreatic function by MRI, isolated duct stimulation and faecal chymotrypsin, and leucocyte function by ex vivo lipopolysaccharide (LPS) stimulation. Pancreatic and lung injury were more severe in CFTR ^tm1HGU but intrapancreatic trypsin and serum enzyme activities higher than in wild-type controls only at 8h, a time interval previously attributed to leucocyte infiltration. CCK-induced trypsin activation and necrosis in acini from CFTR ^tm1HGU did not differ from controls. Fluid and bicarbonate secretion were greatly impaired, whereas faecal chymotrypsin remained unchanged. LPS stimulation of splenocytes from CFTR ^tm1HGU resulted in increased INF-γ and IL-6, but decreased IL-10 secretion. CFTR mutations that preserve residual pancreatic function significantly increase the severity of experimental pancreatitis-mostly via impairing duct cell function and a shift towards a pro-inflammatory phenotype, not by rendering acinar cells more susceptible to pathological stimuli.
(© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

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AG 203/2-1/4-1 Deutsche Forschungsgemeinschaft; MA 4115/1-2/3 Deutsche Forschungsgemeinschaft; SE 2702/2-1 Deutsche Forschungsgemeinschaft; GRK 1947;A3 Deutsche Forschungsgemeinschaft; 03IS2061A Federal Ministry of Education and Research; 0314107 Federal Ministry of Education and Research; 01ZZ9603 Federal Ministry of Education and Research; 01ZZ0103 Federal Ministry of Education and Research; 01ZZ0403 Federal Ministry of Education and Research; 03ZIK012 Federal Ministry of Education and Research; 03zz0921E Federal Ministry of Education and Research; 03ZZ0921E Federal Ministry of Education and Research; V-630-S-150-2012/132/133 European Union; ESF/14-BM-A55-0045/16 PePPP centre of excellence MV; ESF/14-BM-A55-0008/18 EnErGie/P2 Project

Keywords: CFTR; acute pancreatitis; ductal cells; inflammatory cells

0 (CFTR protein, human)
0 (Chlorides)
126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)

Date Created: 20210308 Date Completed: 20211004 Latest Revision: 20211004

20221213

PMC8107082

10.1111/jcmm.16404

33682322