title: The mtDNA nt7778 G/T polymorphism augments formation of lymphocytic foci but does not aggravate cerulein-induced acute pancreatitis in mice.
abstract: A polymorphism in the ATP synthase 8 (ATP8) gene of the murine mitochondrial genome, G-to-T transversion at position 7778, has been suggested to increase susceptibility to multiple autoimmune diseases, including autoimmune pancreatitis (AIP). The polymorphism also induces mitochondrial reactive oxygen species generation, secretory dysfunction and β-cell mass adaptation. Here, we have used two conplastic mouse strains, C57BL/6N-mtAKR/J (B6-mtAKR; nt7778 G; control) and C57BL/6N-mtFVB/N (B6-mtFVB; nt7778 T), to address the question if the polymorphism also affects the course of cerulein-induced acute pancreatitis in mice. Therefore, two age groups of mice (3 and 12-month-old, respectively) were subjected to up to 7 injections of the secretagogue cerulein (50 µg/kg body weight) at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of α-amylase and activities of myeloperoxidase (MPO) in lung tissue. A comparison of cerulein-induced pancreatic tissue damage and increases of α-amylase and MPO activities showed no differences between the age-matched groups of both strains. Interestingly, histological evaluation of pancreatic tissue of both untreated and cerulein-treated B6-mtAKR and B6-mtFVB mice also revealed the presence of infiltrates of immune cells surrounding ducts and vessels; a finding that is compatible with an early stage of AIP. After recovery from cerulein-induced pancreatitis (day 7 after the injections), 12-month-old B6-mtFVB mice but not B6-mtAKR mice displayed aggravated lymphocytic lesions. A comparison of 12-month-old mice with other age groups of both strains revealed that lymphocytic foci were largely absent in 3-month-old mice, while 24-month-old mice were more affected. Together, our data suggest that the mtDNA nt7778 G/T polymorphism does not aggravate cerulein-induced acute pancreatitis. Autoimmune-like lesions, however, may progress faster if additional tissue damage occurs.
authors.affiliation: Department of Medicine II, Division of Gastroenterology, University Medicine Rostock, Rostock, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Müller
authors.affiliation: Division of Medical Biology, University Medicine Rostock, Rostock, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Krüger
authors.affiliation: Department of Medicine II, Division of Gastroenterology, University Medicine Rostock, Rostock, Germany; Oscar-Langendorff-Institute of Physiology, University Medicine Rostock, Rostock, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Lange
authors.affiliation: Department of Medicine II, Division of Gastroenterology, University Medicine Rostock, Rostock, Germany.
authors.forename: Cristin N
authors.initials: CN
authors.lastname: Bock
authors.affiliation: Institute of Pathology, University Medicine Rostock, Rostock, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Nizze
authors.affiliation: Institute for Biostatistics and Informatics in Medicine and Ageing Research, University Medicine Rostock, Rostock, Germany.
authors.forename: Änne
authors.initials: Ä
authors.lastname: Glass
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
authors.affiliation: Department of Medicine II, Division of Gastroenterology, University Medicine Rostock, Rostock, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Jaster
mesh_terms: D000818:Animals; D002108:Ceruletide / Q000633:toxicity; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D000516:alpha-Amylases / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D002108:Ceruletide; D009195:Peroxidase; D000516:alpha-Amylases