All- trans-retinol modulation of chemically-induced pulmonary and hepatic toxicity.

Persistent Link:
http://hdl.handle.net/10150/187501
Title:
All- trans-retinol modulation of chemically-induced pulmonary and hepatic toxicity.
Author:
Sauer, John-Michael.
Issue Date:
1996
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
It has been previously reported that acute hypervitaminosis A in rats dramatically increases the hepatotoxicity of a number of chemicals. This potentiation appears to be mediated by the enhanced release of reactive oxygen species from retinol-primed Kupffer cells. However, in the lung it has been shown that retinol can protect against many of the inflammatory effects caused by bleomycin. Whether or not retinol pretreatment can modulate chemical-induced injury of compounds that cause both liver and lung toxicity is unknown. Therefore, the studies presented here were designed to test the hypothesis that: all-trans-retinol increases hepatic injury through a pro-inflammatory mechanism, whereas in the lung injury is attenuated through an anti-inflammatory mechanism. Male Sprague-Dawley rats were administered retinol (75 mg/kg/day) or its vehicle for up to 7 days. One day after the last dose of retinol animals were given 1-nitronaphthalene (1-NN), 2-nitronaphthalene (2-NN), or paraquat (PQ). Pulmonary and hepatic toxicity was evaluated clinically, biochemically, and morphologically. The hepatotoxicity of both 1-NN and 2-NN was significantly potentiated by retinol pretreatment. The mechanism of this potentiation was, at least in part, mediated by Kupffer cells. Furthermore, as determined from monolayers of hepatocytes, the potentiation of 1-NN and 2-NN did not appear to be caused by an alteration of hepatocyte susceptibility to these chemicals. In the lung, retinol pretreatment significantly attenuated injury caused by 1-NN, 2-NN, and PQ. With each compound, retinol significantly reduced the amount of inflammatory cell infiltration following chemical insult. The mechanism of pulmonary protection by retinol was apparently not directly mediated by alveolar macrophages, but instead by a down-regulation of the pro-inflammatory response. Thus, the key observation from these studies was that retinol potentiates hepatotoxicity, while it concomitantly attenuates lung injury with respect to the same chemicals. The overall mechanism by which retinol alters chemically induced lung and liver injury appears to be by modulating the progression of injury via an alteration of the inflammatory response rather than the initial injury. In the lung inflammation is attenuated and the pulmonary tissue is protected from toxicity, while in the liver inflammation is increased and chemically induced hepatic injury is potentiated.
Type:
text; Dissertation-Reproduction (electronic)
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology and Toxicology; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Sipes, I. Glenn

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleAll- trans-retinol modulation of chemically-induced pulmonary and hepatic toxicity.en_US
dc.creatorSauer, John-Michael.en_US
dc.contributor.authorSauer, John-Michael.en_US
dc.date.issued1996en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractIt has been previously reported that acute hypervitaminosis A in rats dramatically increases the hepatotoxicity of a number of chemicals. This potentiation appears to be mediated by the enhanced release of reactive oxygen species from retinol-primed Kupffer cells. However, in the lung it has been shown that retinol can protect against many of the inflammatory effects caused by bleomycin. Whether or not retinol pretreatment can modulate chemical-induced injury of compounds that cause both liver and lung toxicity is unknown. Therefore, the studies presented here were designed to test the hypothesis that: all-trans-retinol increases hepatic injury through a pro-inflammatory mechanism, whereas in the lung injury is attenuated through an anti-inflammatory mechanism. Male Sprague-Dawley rats were administered retinol (75 mg/kg/day) or its vehicle for up to 7 days. One day after the last dose of retinol animals were given 1-nitronaphthalene (1-NN), 2-nitronaphthalene (2-NN), or paraquat (PQ). Pulmonary and hepatic toxicity was evaluated clinically, biochemically, and morphologically. The hepatotoxicity of both 1-NN and 2-NN was significantly potentiated by retinol pretreatment. The mechanism of this potentiation was, at least in part, mediated by Kupffer cells. Furthermore, as determined from monolayers of hepatocytes, the potentiation of 1-NN and 2-NN did not appear to be caused by an alteration of hepatocyte susceptibility to these chemicals. In the lung, retinol pretreatment significantly attenuated injury caused by 1-NN, 2-NN, and PQ. With each compound, retinol significantly reduced the amount of inflammatory cell infiltration following chemical insult. The mechanism of pulmonary protection by retinol was apparently not directly mediated by alveolar macrophages, but instead by a down-regulation of the pro-inflammatory response. Thus, the key observation from these studies was that retinol potentiates hepatotoxicity, while it concomitantly attenuates lung injury with respect to the same chemicals. The overall mechanism by which retinol alters chemically induced lung and liver injury appears to be by modulating the progression of injury via an alteration of the inflammatory response rather than the initial injury. In the lung inflammation is attenuated and the pulmonary tissue is protected from toxicity, while in the liver inflammation is increased and chemically induced hepatic injury is potentiated.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairSipes, I. Glennen_US
dc.contributor.committeememberMcQueen, Charlene A.en_US
dc.contributor.committeememberLiebler, Danielen_US
dc.contributor.committeememberGandolfi, A. Jayen_US
dc.contributor.committeememberLantz, R. Clarken_US
dc.identifier.proquest9626541en_US
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