Focal lesions in toxicity studies: methods and models
This project involved the development and evaluation of techniques with regard to their potential use in the identification and investigation of toxic injury, particularly in instances of focal damage, and the development and investigation of a new model for focal renal papillary necrosis (RPN) induced by ethoxyquin. A problem in animal toxicity studies is that compounds such as those which induce RPN may only produce focal lesions, and thus these lesions may be overlooked. Much interest is focused on the development of RPN induced with analgesics and non~steroidal anti-inflammatory drugs (NSAIDS) in both humans and rodents, due to controversy about the pathogenesis of this lesion. The techniques evaluated for potential use in toxicity studies were: perfusion fixation with and without dye perfusion; histology with evaluation of step-serial sections; urinary sediment analysis; and scanning electron microscopy (SEM) with correlative histology of the same sample. Two well-known models of experimental RPN, 2-bromoethanamine (BEA) and indomethacin, were used to investigate these techniques in the kidney. Urinary sediments and Particularly SEM with correlative histology proved useful, and were used in investigating ethoxyquin as a model for RPN. Transmission electron microscopy (TEM) was performed to study the time course of lesion development with ethoxyquin and establish the initial target sites within the papilla. Haematology, clinical chemistry of blood and urine, and histological assessment of all tissues were also conducted to confirm that ethoxyquin did not induce any extra-renal effects which might preclude its use as a model for RPN. The results suggested that the development of RPN with ethoxyquin follows the same course as the two well-established models, BEA and indomethacin, and the sequence of events reponed in man. However, ethoxyquin, in contrast to the two established models but in common with analgesic-induced RPN in man, induces RPN following multiple oral dosing, and has potential as a chronic model for this lesion. Furthermore, the likely mechanism of the development of RPN induced with ethoxyquin is similar to that proposed for analgesics and NSAIDS. The use of ethoxyquin as a model for RPN may therefore help to provide important information for the identification, mechanistic basis and subsequent treatment of RPN in man.
- PhD