Noggin attenuates cerulein-induced acute pancreatitis and impaired autophagy

• Published in: Pancreas Vol. 42; no. 2; p. 301
• Main Authors: Cao, Yanna, Yang, Wenli, Tyler, Matthew A, Gao, Xuxia, Duan, Chaojun, Kim, Sung O, Aronson, Judith F, Popov, Vsevolod, Takahashi, Hitoshi, Saito, Hiroshi, Evers, Bernard Mark, Chao, Celia, Hellmich, Mark R, Ko, Tien C
• Format: Journal Article
• Language: English
• Published: United States 01.03.2013
• Subjects: Acute Disease; Animals; Apoptosis Regulatory Proteins - metabolism; Autophagy - drug effects; Beclin-1; Bone Morphogenetic Protein 2 - metabolism; Carrier Proteins - administration & dosage; Carrier Proteins - pharmacology; Cell Line; Ceruletide; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Lysosomal-Associated Membrane Protein 2 - metabolism; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins - metabolism; Pancreas - drug effects; Pancreas - metabolism; Pancreas - ultrastructure; Pancreatitis - chemically induced; Pancreatitis - metabolism; Pancreatitis - pathology; Pancreatitis - prevention & control; Phosphorylation; Rats; Recombinant Proteins - pharmacology; Signal Transduction - drug effects; Smad1 Protein - metabolism; Smad5 Protein - metabolism; Smad8 Protein - metabolism; Time Factors
• ISSN: 1536-4828
• DOI: 10.1097/MPA.0b013e31825b9f2c

To investigate the role of bone morphogenetic protein (BMP) signaling in acute pancreatitis (AP) by administration of noggin, an endogenous BMP antagonist, in a cerulein-induced AP model. Acute pancreatitis was induced by 9 hourly intraperitoneal injections of cerulein (50 μg/kg). Control mice received phosphate-buffered saline injections. In a separate group, noggin (0.5 mg/kg) was given intraperitoneally at 1 hour before and 2, 4, and 6 hours after AP induction. The mice were euthanized at 1 hour after completion of AP induction. The blood samples and the pancreas were harvested for analysis. Isolated pancreatic acini from normal mice and AR42J cells were treated with BMP2 and cerulein. AR42J cells were also treated with noggin. Phosphorylation of Smad1/5/8 was measured. Bone morphogenetic protein signaling was up-regulated in AP mouse pancreas. Bone morphogenetic protein 2 and cerulein-induced phosphorylation of Smad1/5/8 in the acinar cells in vitro, which was blocked by noggin. Noggin administration in vivo attenuated AP induction, decreased vacuole formation in acinar cells, blocked LC3-II levels, and partially restored Beclin-1 and lysosomal-associated membrane protein 2 levels. Bone morphogenetic protein signaling seems to promote AP induction and autophagy, as suggested by our study showing that noggin ameliorates AP and partially restores autophagic homeostasis.