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Vitamin K3 Attenuates Cerulein-Induced Acute Pancreatitis Through Inhibition of the Autophagic Pathway

Chinzei, Ryo MD*; Masuda, Atsuhiro MD, PhD*†; Nishiumi, Shin PhD*‡; Nishida, Masayuki MD*; Onoyama, Mitsuko MD*; Sanuki, Tsuyoshi MD*; Fujita, Tsuyoshi MD, PhD*; Moritoh, Satoshi MD, PhD§; Itoh, Tomoo MD, PhD§; Kutsumi, Hiromu MD, PhD*; Mizuno, Shigeto MD, PhD; Azuma, Takeshi MD, PhD*; Yoshida, Masaru MD, PhD*‡

doi: 10.1097/MPA.0b013e3181f69fc9
Original Articles

Objectives: The discovery of novel and effective treatment methods would be of great help to patients with acute pancreatitis. The aims of this study were to determine the inhibitory effects of vitamin K3 (VK3) against cerulein-induced acute pancreatitis in mice and to examine the mechanisms behind these effects.

Methods: Acute pancreatitis in mice was induced by intraperitoneal injection of cerulein 6 times at hourly intervals. Vitamin K3 was administered once before the first injection of cerulein or twice before and after the first injection of cerulein. The degrees of inflammation and autophagy in the pancreatic tissue were estimated by histological examination, measurement of enzyme activity, confocal microscopy, and Western blotting. The inhibitory effects of VK3 against rapamycin-induced autophagy were also examined using HeLa cells stably expressing green fluorescent protein LC3.

Results: Cerulein-induced acute pancreatitis was markedly attenuated by the administration of VK3. In addition, VK3 led to the inhibition of cerulein-evoked autophagic changes and colocalization of autophagosomes and lysosomes in the pancreatic tissue. Vitamin K3 also reduced rapamycin-induced autophagy in HeLa/green fluorescent protein LC3 cells.

Conclusions: Our data suggest that the administration of VK3 reduces pancreatic inflammation in acute pancreatitis through inhibition of the autophagic pathway. Vitamin K3 may be an effective therapeutic strategy against acute pancreatitis.

From the *Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University; †Department of Medical Pharmaceutics, Kobe Pharmaceutical University; ‡The Integrated Center for Mass Spectrometry, Graduate School of Medicine, Kobe University; and §Division of Diagnostic Pathology, Kobe University Hospital, Kobe, Japan.

Received for publication October 31, 2009; accepted June 4, 2010.

Reprints: Masaru Yoshida, MD, PhD, Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chu-o-ku, Kobe, 650-0017 Hyogo, Japan (e-mail: myoshida@med.kobe-u.ac.jp).

This study was supported, in part, by a grant for the Global COE Program "Global Center of Excellence for Education and Research on Signal Transduction Medicine in the Coming Generation" from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M.Y.). This study was also supported by a grant for the Education Program for Specialized Clinician in the Support Program for Improving Graduate School Education from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to R.C.).

© 2011 Lippincott Williams & Wilkins, Inc.