Iron Deficiency Amplifies Helicobacter pylori Virulence and Accelerates Gastric Carcinogenesis

the innate immunity related molecule, is playing an important role in gastric epithelial trans-differentiation.

754 Pancreatic Secretory Trypsin Inhibitor 1 Reduces the Severity of Chronic Pancreatitis in Mice Over-Expressing Interleukin-1β in the Pancreas Joelle Romac, Rafiq A. Shahid, Christoph B. Westphalen, Timothy C. Wang, Rodger A. Liddle

AGA Abstracts

752 Treatment With 17 Beta-Estradiol Prevents the Development of Cancer in Chronically H. pylori Infected INS-GAS Mice by Shifting the Inflammatory Pathways From That of Males to One Resembling Females Alexander Sheh, Nicola M. Parry, Melissa W. Mobley, Amanda F. McCabe, Julia Rager, Arek R. Racynski, Rebecca C. Fry, Timothy C. Wang, James G. Fox

A major factor in the development of acute pancreatitis is activation of digestive enzymes within the pancreas. By virtue of its ability to activate all pancreatic zymogens, trypsinogen activation is believed to be a key initiating event in pancreatic autodigestion that accompanies pancreatitis. However, the role of trypsin in chronic pancreatitis has come into question. Recently, a novel model of chronic pancreatitis has been produced by expression of human interleukin-1β (IL-1β) in pancreatic acinar cells in transgenic mice [Tg(Cela1-IL1B)L123Tcw] known here after as Tg(IL1β). Mice develop chronic pancreatitis characterized by extensive intrapancreatic inflammation, atrophy and fibrosis. We have previously created a transgenic mouse expressing rat pancreatic secretory trypsin inhibitor-I in pancreatic acinar cells [B6.Cgg(Cela1-Spink3)#Rali] known hereafter as Tg(Psti1). PSTI-I overexpression increases pancreatic trypsin inhibitor activity by 190% and confers protection against caerulein-induced pancreatitis. In order to determine if active trypsin is important in the pathogenesis of chronic pancreatitis in an inflammatory model, we crossed Tg(IL1β) mice with Tg(Psti1) mice to generate dual transgenic Tg(IL1β)−Tg(Psti1) mice. Tg(IL1β) mice were found to have marked pancreatic inflammation manifest by histologic changes including acinar cell loss, inflammatory cell infiltration, elevated myeloperoxidase (MPO) levels, and fibrosis as early as six weeks of age. In contrast to Tg(IL1β) mice, dual transgenic Tg(IL1β)-Tg(Psti1) mice expressing both IL-1β and PSTI-I in pancreatic acinar cells had markedly less severe pancreatitis as indicated by significant reductions in all pancreatitis parameters (less histological pancreatic damage, reduced levels of MPO, and less Sirius red staining indicative of less collagen deposition and fibrosis). These findings indicate that over-expression of PSTI-I reduces the severity of pancreatitis and suggest that pancreatic trypsin activity contributes to the pathogenesis of an inflammatory model of chronic pancreatitis.

Gastric cancer (GC) is a male-predominant cancer associated with Helicobacter pylori (HP). Epidemiological studies suggest that female hormones reduce GC risk and our previous work demonstrated that ovariectomized female mice have increased GC risk. We examined the effect of 17 beta-estradiol (E2) on HP-induced gastric cancer in hypergastrinemic 8 week-old male and female INS-GAS mice inoculated with HP SS1 or vehicle-only. At 16 weeks post-infection (WPI), mice were treated with E2, Tamoxifen, E2 and Tamoxifen or placebo pellets for 12 weeks. Gastric histopathology was evaluated before and after treatment. At 28 WPI, stomachs were evaluated by HP quantitative culture, promoter CpG methylation of 24 tumor suppressors/oncogenes, and gene expression, and serum inflammatory cytokines measured by Luminex. At 16 WPI, HP infection induced robust gastric pathology in mice of both genders (P