Autophagy and chronic inflammation in the pancreas

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Kalliope N. Diakopoulos1, Marina Lesina1, Sonja Wörmann1, Liang Song1, Michaela Aichler2, Lorenz Schild3, Anna Artati4, Werner Römisch-Margl4, Thomas Wartmann5, Robert Fischer5, Yashar Kabiri6, Hans Zischka6, Walter Halangk5, Ihsan Ekin Demir7, Claudia Pilsak8, Axel Walch2, Christos S. Mantzoros9, Jörg M. Steiner1, Mert Erkan10, Roland M. Schmid1, Heiko Witt8, Jerzy Adamski4, Hana Algül1
1 II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany, 2 Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany, 3 Institut für Klinische Chemie und Pathobiochemie, Bereich Pathologische Biochemie, Otto-von-Guericke-Universität Magdeburg Medizinische Fakultät, Magdeburg, Germany, 4 Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany, 5 Klinik für Chirurgie Bereich Experimentelle Operative Medizin, Universitätsklinikum Magdeburg, Magdeburg, Germany, 6 Institut für Molekulare Toxikologie und Pharmakologie, Helmholtz Zentrum München, Neuherberg, Germany, 7 Chirurgische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany, 8 Else Kröner-Fresenius-Zentrum, Paediatric Nutritional Medicine, Technische Universität München, Freising, Germany, 9 Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts, 10 Department of Surgery, School of Medicine, Koc University, Istanbul, Turkey
Little is known about the mechanisms of the progressive tissue destruction, inflammation, and fibrosis that occur during development of chronic pancreatitis. Autophagy is involved in multiple degenerative and inflammatory diseases, including pancreatitis, and requires the protein autophagy related 5 (ATG5). We created mice with pancreas-specific disruption of Atg5 (Ptf1aCreex1;Atg5F/F mice) and compared them to control mice. Mice with pancreas-specific disruption of Atg5 developed atrophic CP, independent of β-cell function; a greater proportion of male mice developed CP than female mice. Pancreata from ATG5-deficient mice had signs of inflammation, necrosis, acinar-to-ductal metaplasia, and acinar-cell hypertrophy; this led to tissue atrophy and degeneration. Based on transcriptome and metabolome analyses, ATG5-deficient mice produced higher levels of reactive oxygen species than control mice, and had insufficient activation of glutamate-dependent metabolism. Pancreata from these mice had reduced autophagy, increased levels of p62, and increases in endoplasmic reticulum stress and mitochondrial damage, compared with tissues from control mice; p62 signaling to Nqo1 and p53 was also activated. Dietary antioxidants, especially in combination with palm oil–derived fatty acids, blocked progression to CP and pancreatic acinar atrophy. Tissues from patients with CP had many histologic similarities to those from ATG5-deficient mice. Mice with pancreas-specific disruption of Atg5 develop a form of CP similar to that of humans. CP development appears to involve defects in autophagy, glutamate-dependent metabolism, and increased production of reactive oxygen species. These mice might be used to identify therapeutic targets for CP.

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