Metabolic stressors and pancreatic disease

Metabolic stressors and pancreatic disease

S24 Abstracts / Pancreatology 16 (2016) S1eS192 used as a primarily method as long as it is applicable. Peri-firing compression method (PFC), also ca...

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Abstracts / Pancreatology 16 (2016) S1eS192

used as a primarily method as long as it is applicable. Peri-firing compression method (PFC), also called as slow-flattening method, is generally used for closing pancreatic stump. The risk of pancreatic fistula depends on the thickness of the pancreatic stump, which correlate with BMI. These fact shows that closure of pancreatic stump by a stapler might be suitable for Japanese patients, who are generally lean. We, in Kyushu University, subjected pancreatic stump more than 25mm in thickness to modified DuVal anastomosis. Most of LPDs were performed as hybrid operations. The excision of pancreatic head and duodenum was performed by a laparoscopic method, the P-J anastomosis by an open method, and the reconstruction of biliary tree by a laparoscopic method. I demonstrate the current status of laparoscopic pancreatic surgery in Japan and show our current method with special reference to the points mentioned above.

S5-KL1. Relative contribution of trypsin and inflammation in pancreatitis Ashok K. Saluja

cytokines through JAK2/STAT3 signaling in pancreatic acinar cells. We also found that there are crosstalks among core inflammatory mediators including mitogen-activated protein kinases, NF-kB, AP-1, and JAK/STAT in pancreatic acinar cells upon cerulein stimulation. In addition, treatment with peroxisome proliferator activated receptor-gamma ligands such as 15d-PGJ2 and troglitazone suppress the activation of JAK2/STAT3 and the expression of pro-inflammatory cytokines in cerulein-stimulated cells. Since pancreatic stellate cells produce fibrotic proteins and facilitate cell proliferation and migration of cancer cells to the different sites by producing cytokines, growth factors and metalloproteinases, pancreatic stellate cells may be involved in the pathogenesis of chronic pancreatitis and pancreatic cancer. We found that expression of inflammatory cytokines (MCP-1, CX3CL1) and fibrotic proteins (a-SMA, desmin, COL1A1, TGF-b1) are mediated with NF-kB activation in pancreatic stellate cells exposed to TNF-a. Intracellular and mitochondrial levels of ROS increased with loss of mitochondrial membrane potential in pancreatic stellate cells exposed to TNF-a. In conclusion, the activations of NADPH oxidase and JAK2/STAT3 are important for oxidative stress-induced inflammatory and fibrotic pathways. Mitochondrial disruption may be one of the underlying mechanisms to induce oxidative stress in the pathogenesis of pancreatitis.

Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, USA During experimental initiation of pancreatitis, both trypsin and inflammatory pathway activation is observed concurrently. The relative contribution of these events to acinar cells injury and development of pancreatitis is not clear. The studies using inhibitors which block trypsin or inflammation activation were unable to yield unambiguous answers because of nonspecific effects. Mouse pancreas expresses multiple forms of trypsin of which T7, T8, T10 and T20 are expressed. In our studies, mice lacking trypsin isoform T7 do not show trypsin activation in response to supramaximal stimulation and provides an ideal tool for understanding the relative contribution of these initiating events. Deletion of T7 significantly reduced the total trypsinogen contents but did not affect physiologic function. Absence of trypsinogen activation in T7 (-/-) mice led to near complete inhibition of acinar cell death in vitro and a 50% reduction in acinar necrosis during acute pancreatitis progression. However, T7 (-/-) mice had similar degrees of local and systemic inflammation during acute pancreatitis progression and comparable levels of intra-acinar NF-kB activation. Furthermore our studies indicate that induction and severity of chronic pancreatitis is independent of trypsin activation. Compared with pancreatic tissues from wild-type mice, those from T7 (-/-) mice had similar levels of atrophy, histomorphologic features of chronic pancreatitis, and chronic inflammation. All samples had comparable intra-acinar activation of nuclear factor (NF) -kB, a transcription factor that regulates the inflammatory response, immediately after injection of caerulein. Conclusions: Activation of inflammatory pathways is not dependent on trypsin activation. Inflammatory pathways contribute to pancreatic necrosis. Absence of intra-acinar trypsin activation reduced pancreatic necrosis during acute pancreatitis progression but had no effect on chronic pancreatitis.

S5-KL3. Metabolic stressors and pancreatic disease Stephen Pandol 1, 2, 3, Mark Goodarzi 1, Guido Eibl 2, Richard Waldron 1, 2, 3, Anna Gukovskaya 2, 3, Kristine Monroe 4, V. Wendy Setiawan 4, Vay Liang Go 2, 3, Baoan Ji 6, Mouad Edderkaoui 1, 2, 3, Elham Afghani 1, Marc Goodman 1, Christie Jeon 1, Bechien Wu 5, Aurelia Lugea 1, 2, 3 1

Cedars-Sinai Medical Center, USA University of California, USA 3 Department of Veterans Affairs, USA 4 University of Southern California, USA 5 Kaiser Permanente, Los Angeles, USA 6 Mayo Clinic, Rochester, USA 2

The incidence of pancreatic diseases including pancreatitis and pancreatic adenocarcinoma is modified by both genetic and environmental factors. Further, genetic variation either germ line or acquired through mutation alters the susceptibility to environmental factors. A determination of the relative impact and mechanisms of effect of these factors alone and in combination on pancreatic diseases is essential for developing prevention, early diagnosis and treatment strategies. We describe our combined approach to assess factors regulating disease formation in human populations; utilizing the information to create animal models for investigation of mechanisms of the effects of the factors; and testing inventions that alter factors regulating disease formation in human clinical trials to determine the effects on outcome.

S5-1. S5-KL2. Signaling in pancreatic acinar and stellate cells in the pathogenesis of pancreatitis Hyeyoung Kim Department of Food and Nutrition, Yonsei University, South Korea Pancreatic acinar cells and pancreatic stellate cells are important target cells in the development of pancreatic inflammation and fibrosis. When activated by hormones such as cholecystokinin and cytokines such as tumor necrosis factor a (TNF-a), the cells induce various inflammatory cytokines and fibrotic proteins. We previously showed that cerulein, a cholecystokinin analogue, stimulated NADPH oxidase and induced expression of pro-inflammatory

The roles of cathepsin B, D, and L during acute and chronic pancreatitis in mice Masaki Ohmuraya Institute of Resource Development and Analysis, Kumamoto University, Japan Cathepsin B, D, and L (CB, CD, and CL) are the major lysosomal proteases and are widely distributed in the cells of various mammalian tissues. These cathepsins participates in various physiological events such as regulation of programmed cell death, activation of enzymatic precursors, and metabolic degradation of intracellular proteins through autophagy. Autophagy is a major pathway for degradation of cytoplasmic proteins and organelles, and has been implicated in the pathogenesis of acute and chronic pancreatitis.