title: Histopathology and pathogenesis of caerulein-, duct ligation-, and arginine-induced acute pancreatitis in Sprague-Dawley rats and C57BL6 mice.
abstract: Three classical rodent models of acute pancreatitis were created in an effort to identify potential pre-clinical models of drug-induced pancreatitis (DIP) and candidate non-invasive biomarkers for improved detection of DIP. Study objectives included designing a lexicon to minimize bias by capturing normal variation and spontaneous and injury-induced changes while maintaining the ability to statistically differentiate degrees of change, defining morphologic anchors for novel pancreatic injury biomarkers, and improved understanding of mechanisms responsible for pancreatitis. Models were created in male Sprague-Dawley rats and C57BL6 mice through: 1) administration of the cholecystokinin analog, caerulein; 2) administration of arginine; 3) surgical ligation of the pancreatic duct. Nine morphologically detectable processes were used in the lexicon; acinar cell hypertrophy; acinar cell autophagy; acinar cell apoptosis; acinar cell necrosis; vascular injury; interstitial edema, inflammation and hemorrhage; fat necrosis; ductal changes; acinar cell atrophy. Criteria were defined for scoring levels (0 = absent, 1 = mild, 2 = moderate, 3 = severe) for each lexicon component. Consistent with previous studies, histopathology scores were significant greater in rats compared to mice at baseline and after treatment. The histopathology scores in caerulein and ligation-treated rats and mice were significantly greater than those of arginine-treated rats and mice. The present study supports a multifaceted pathogenesis for acute pancreatitis in which intra-acinar trypsinogen activation, damage to acinar cells, fat cells, and vascular cells as well as activation/degranulation of mast cells and activated macrophages all contribute to the initiation and/or progression of acute inflammation of the exocrine pancreas.
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, Silver Spring, MD, USA. jun.zhang@fda.hhs.gov.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Rouse
mesh_terms: D000818:Animals; D001120:Arginine / Q000633:toxicity; D002108:Ceruletide / Q000633:toxicity; D004195:Disease Models, Animal; D008026:Ligation / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010183:Pancreatic Ducts / Q000601:surgery; D010195:Pancreatitis / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002108:Ceruletide; D001120:Arginine