Mechanistic Investigations of Test Article–Induced Pancreatic Toxicity at the Endocrine–Exocrine Interface in the Rat
| Autor: | Srinivasa R. Mantena, Cynthia M. Rohde, Dean Messing, Sharon A. Sokolowski, John W. Davis, Michael I. Jesson, Karrie A. Brenneman, Shawn P. O'Neil, Lindsay Tomlinson, Christopher G. Leonard, Laurence O. Whiteley, Steven Bailey, Deborah C. Carraher, Walter F. Bobrowski, Zachary S. Stewart, Yutian Zhan, W. Mark Vogel, Kimberly M. Shevlin, Dale L. Morris, Hungyun Lin, Shashi K. Ramaiah, Lauren M. Gauthier |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
Pathology medicine.medical_specialty Necrosis Hemorrhage Inflammation Biology Toxicology Risk Assessment Pathology and Forensic Medicine Rats Sprague-Dawley Lesion Islets of Langerhans Fibrosis Toxicity Tests Acute medicine Animals Endocrine system Rats Wistar Pancreas Molecular Biology geography geography.geographical_feature_category Hemodynamics Endothelial Cells Cell Biology medicine.disease Islet Pancreas Exocrine Capillaries Rats Disease Models Animal Portal System medicine.anatomical_structure Lead Pancreatitis Female medicine.symptom |
| Zdroj: | Toxicologic Pathology. 42:229-242 |
| ISSN: | 1533-1601 0192-6233 |
| Popis: | Pancreatic toxicity commonly affects the endocrine or exocrine pancreas. However, it can also occur at the endocrine–exocrine interface (EEI), where the capillary network of the islet merges with the capillaries of the surrounding acinar tissue, that is, the insulo-acinar portal system. The goal of this article is to describe a novel, test article–induced pancreatic toxicity that originated at the EEI and to summarize investigations into the mechanistic basis of the injury. This injury was initially characterized by light microscopy in 7/14 day-toxicity studies in Sprague-Dawley (Crl: CD®[SD]) rats with undisclosed test articles. Microvascular injury at the interface resulted in peri-islet serum exudation, fibrin deposition, hemorrhage, inflammation, and secondary degeneration/necrosis of surrounding exocrine tissue. More chronic injury presented as islet fibrosis and lobular atrophy. Direct cytotoxicity affecting the capillary endothelium at the EEI was confirmed ultrastructurally on day 4. Endothelial microparticle and blood flow studies further confirmed endothelial involvement. Similar lesions occurred less frequently in 2 other rat strains and not in the mouse, dog, or cynomolgus macaque. In summary, in vivo and investigative study data confirmed primary endothelial cytotoxicity in the pathogenesis of this lesion and suggested that the lesion may be rat/rat strain–specific and of uncertain relevance for human safety risk assessment. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|