Abstracts
2000 Digestive Disease Week

# 2292 Increased Susceptibility of Pancreatic Acinar Cells to Hyperstimulatory Stress in DF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Heterozygous Mice.
Qiang Liu, Horst Fischer, William J. Welch, Hobart W Harris, Oakland, CA, San Francisco, CA

The pathogenesis of chronic pancreatitis is poorly understood, especially in patients with the idiopathic form of the disease as they lack any identifiable risk factors for pancreatic injury. Mutations in the cystic fibrosis transmembrane regulator (CFTR), however, have recently been associated with an increased incidence of idiopathic chronic pancreatitis. These data suggest that alterations in this chloride transporter may somehow contribute to pancreatic injury. Whereas chronic pancreatitis is the presumed consequence of repetitive injury over time, we wondered whether mutations in CFTR might confer an increased susceptibility to acute pancreatic injury as well. Specifically, we hypothesized that mice heterozygous for the most common CFTR mutation (DF508), while phenotypically normal, would be more susceptible to cerulein-induced hyperstimulation and injury than wild-type controls. To address this question, transgenic mice heterozygous for the DF508 mutation (N=33) and their wild-type controls (N=12) were injected with cerulein (50 mg/kg/h x 6h) versus saline and assayed for pancreatic injury via tissue edema [% total water content = (wet weight-dry weight)/(wet weight)], Evans blue dye extravasation, and histologic evidence of acute inflammation. Both of the quantitative indicators of pancreatic injury and acute inflammation were increased in the DF508 heterozygous mice as compared to the wild-type controls. The total water content of the pancreatic tissue from the DF508 heterozygotes was 81.7±1.1% v. 79.9±2.5% in the controls (pŁ0.02). Consistent with an increase in capillary permeability within the pancreas, Evans blue extravasation was greater in the DF508 heterozygotes than the controls (300±103 v. 197±64 ng Evan blue dye/mg dry weight, pŁ0.02). Lastly, there was histologic evidence of increased pancreatic inflammation in the heterozygotes. In conclusion, the heterozygous expression of the DF508 CFTR mutation appears to confer an increased susceptibility to pancreatic injury following hyperstimulatory stress. These data may yield insight into the complex pathogenesis of acute and chronic pancreatitis.