title: Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, acinar cell damage, and systemic inflammation in acute pancreatitis.
abstract: In acute pancreatitis, endoplasmic reticulum (ER) stress prompts an accumulation of malfolded proteins inside the ER, initiating the unfolded protein response (UPR). Because the ER chaperone tauroursodeoxycholic acid (TUDCA) is known to inhibit the UPR in vitro, this study examined the in vivo effects of TUDCA in an acute experimental pancreatitis model. Acute pancreatitis was induced in Wistar rats using caerulein, with or without prior TUDCA treatment. UPR components were analyzed, including chaperone binding protein (BiP), phosphorylated protein kinase-like ER kinase (pPERK), X-box binding protein (XBP)-1, phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CCAAT/enhancer binding protein homologues protein, and caspase 12 and 3 activation. In addition, pancreatitis biomarkers were measured, such as serum amylase, trypsin activation, edema formation, histology, and the inflammatory reaction in pancreatic and lung tissue. TUDCA treatment reduced intracellular trypsin activation, edema formation, and cell damage, while leaving amylase levels unaltered. The activation of myeloperoxidase was clearly reduced in pancreas and lung. Furthermore, TUDCA prevented caerulein-induced BiP upregulation, reduced XBP-1 splicing, and caspase 12 and 3 activation. It accelerated the downregulation of pJNK. In controls without pancreatitis, TUDCA showed cytoprotective effects including pPERK signaling and activation of downstream targets. We concluded that ER stress responses activated in acute pancreatitis are grossly attenuated by TUDCA. The chaperone reduced the UPR and inhibited ER stress-associated proapoptotic pathways. TUDCA has a cytoprotective potential in the exocrine pancreas. These data hint at new perspectives for an employment of chemical chaperones, such as TUDCA, in prevention of acute pancreatitis.
authors.affiliation: Department of Internal Medicine II, Campus Grobhadern, University of Munich, Germany.
authors.forename: Ersin
authors.initials: E
authors.lastname: Seyhun
authors.forename: Antje
authors.initials: A
authors.lastname: Malo
authors.forename: Claus
authors.initials: C
authors.lastname: Schäfer
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Moskaluk
authors.forename: Ralf-Thorsten
authors.initials: RT
authors.lastname: Hoffmann
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Constanze H
authors.initials: CH
authors.lastname: Kubisch
mesh_terms: D061354:Acinar Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002108:Ceruletide; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D002108:Ceruletide