Biochemical changes associated with BCNU-induced pulmonary toxicity Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/zs25xc22d

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  • Male Sprague Dawley rats received a single intraperitoneal dose of BCNU in experiments designed to measure biochemical changes associated with the pulmonary toxicity described for this agent. Changes in serum and lung lavage angiotensin converting enzyme (ACE) activity were measured to detect changes in pulmonary endothelial cell integrity. Alpha-1-proteinase inhibitor (PI) concentration and activity was monitored as well as changes in lavage elastase activity. Lung malondialdehyde and hydroxyproline concentrations were followed to detect peroxidative damage and collagen deposition. Lung catalase, glutathione concentration and glutathione shuttle enzyme activity was also monitored. Biochemical changes in response to BCNU was also followed in Fischer 344 rats. Serum ACE activity was elevated 7 to 21 days postdosing. Significant inhibition of lavage ACE activity was evident at 1 and 3 days. No significant increases in lavage ACE activity were detected. Lavage PI concentration increased 484% by 21 days, and lavage PI activity was decreased at 1 and 3 days. Serum PI activity decreased 80% by 28 days postdosing. Increases in lavage PI concentration paralleled increases in lavage elastase activity. Lung malondialdehyde concentration in creased in a biphasic manner and lung collagen content increased in a time dependent manner. Lung catalase activity was elevated at 3 days and depressed from 7 to 21 days. Glutathione peroxidase activity was elevated at 7 days and glutathione reductase activity was significant ly decreased at 1 and 3 days. Oxidized glutathione concentration in the lungs of treated animals was increased at 72 hours. Treated Fischer 344 rats showed no changes in lavage elastase activity or serum PI concentration and activity. The pulmonary biochemical changes induced by BCNU treatment indicate a biphasic response pattern. The early response is probably the direct result of BCNU while the delayed effects are consistant with the possible involvement of an inflammatory component in the development of BCNU-induced pulmonary fibrosis. The Sprague Dawley rats appear to be more sensitive than the Fischer 344 rats to the toxic effects of BCNU.
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