Retinoid potentiation of chemically-induced hepatic damage: The involvement of tumor necrosis factor and endotoxin.

Persistent Link:
http://hdl.handle.net/10150/187019
Title:
Retinoid potentiation of chemically-induced hepatic damage: The involvement of tumor necrosis factor and endotoxin.
Author:
Hill, Dwayne A.
Issue Date:
1994
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:
Administration of large doses of retinol (75 mg/kg/day) results in potentiation of carbon tetrachloride-induced hepatic damage in rats. Further studies from our laboratory suggest that one of the primary mechanisms responsible for potentiation may involve the increased release of tumor necrosis factor (TNF) from activated Kupffer cells (KC). The exact mechanism of KC activation in this model is unknown. However, recent studies suggest that retinol pretreatment elevates plasma endotoxin levels and increases the proliferation of gram negative bacteria in the small intestine (SI). Therefore this dissertation project was designed to investigate the ability of other retinoids to potentiate chemically-induced hepatic damage and to investigate the involvement of TNF and endotoxin in retinol potentiation of CCl₄-induced hepatic damage. In order to conduct these studies, male Sprague Dawley rats (250 g) received retinol for 7 days by oral gavage. On day 8, either CCl₄ (200 ul/kg) or BrCCl₃ (20 ul/kg) was administered i.p. On day 9, the animals were killed via CO₂ asphyxiation. Plasma samples were collected for analysis of TNF levels (ELISA), endotoxin levels (Limulus Ameobocyte Assay) and alanine aminotransferase (ALT) activity. Inhibition of KC activity was achieved by the administration of GdCl₃ (10 mg/kg). Neutralization of TNF was achieved through the administration of a monoclona/polyclonal TNF antibody (250 ul/275 gram rat). Neomycin/polymyxin B (250 mg/20 mg) were used for endotoxin inhibition (EI). Retinol, retinoic acid or retinyl palmitate pretreatment potentiated significantly (p < 0.05) CCl₄ or BrCCl₃-induced hepatic damage. Retinol pretreatment elevated significantly (p < 0.05) plasma levels of TNF and endotoxin. Retinol pretreatment also increased the growth of SI gram negative bacteria. Administration of KC inhibitors, TNF antibody or EI reduced significantly (p < 0.05) the degree of potentiation (98%, 58%, 55% reductions, respectively). These studies suggest that retinol-induced proliferation of SI-derived gram negative bacteria and subsequent elevation of plasma endotoxin may activate Kupffer cells to release high levels of TNF. These high levels of TNF play an important role in retinol potentiation of CCl₄-induced hepatic damage.
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.titleRetinoid potentiation of chemically-induced hepatic damage: The involvement of tumor necrosis factor and endotoxin.en_US
dc.creatorHill, Dwayne A.en_US
dc.contributor.authorHill, Dwayne A.en_US
dc.date.issued1994en_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.abstractAdministration of large doses of retinol (75 mg/kg/day) results in potentiation of carbon tetrachloride-induced hepatic damage in rats. Further studies from our laboratory suggest that one of the primary mechanisms responsible for potentiation may involve the increased release of tumor necrosis factor (TNF) from activated Kupffer cells (KC). The exact mechanism of KC activation in this model is unknown. However, recent studies suggest that retinol pretreatment elevates plasma endotoxin levels and increases the proliferation of gram negative bacteria in the small intestine (SI). Therefore this dissertation project was designed to investigate the ability of other retinoids to potentiate chemically-induced hepatic damage and to investigate the involvement of TNF and endotoxin in retinol potentiation of CCl₄-induced hepatic damage. In order to conduct these studies, male Sprague Dawley rats (250 g) received retinol for 7 days by oral gavage. On day 8, either CCl₄ (200 ul/kg) or BrCCl₃ (20 ul/kg) was administered i.p. On day 9, the animals were killed via CO₂ asphyxiation. Plasma samples were collected for analysis of TNF levels (ELISA), endotoxin levels (Limulus Ameobocyte Assay) and alanine aminotransferase (ALT) activity. Inhibition of KC activity was achieved by the administration of GdCl₃ (10 mg/kg). Neutralization of TNF was achieved through the administration of a monoclona/polyclonal TNF antibody (250 ul/275 gram rat). Neomycin/polymyxin B (250 mg/20 mg) were used for endotoxin inhibition (EI). Retinol, retinoic acid or retinyl palmitate pretreatment potentiated significantly (p < 0.05) CCl₄ or BrCCl₃-induced hepatic damage. Retinol pretreatment elevated significantly (p < 0.05) plasma levels of TNF and endotoxin. Retinol pretreatment also increased the growth of SI gram negative bacteria. Administration of KC inhibitors, TNF antibody or EI reduced significantly (p < 0.05) the degree of potentiation (98%, 58%, 55% reductions, respectively). These studies suggest that retinol-induced proliferation of SI-derived gram negative bacteria and subsequent elevation of plasma endotoxin may activate Kupffer cells to release high levels of TNF. These high levels of TNF play an important role in retinol potentiation of CCl₄-induced hepatic damage.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, Charleneen_US
dc.contributor.committeememberLaird, Hughen_US
dc.contributor.committeememberLiebler, Danielen_US
dc.contributor.committeememberLantz, Clarken_US
dc.contributor.committeememberEarnest, Daviden_US
dc.identifier.proquest9527982en_US
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