Persistent Link:
http://hdl.handle.net/10150/186991
Title:
TOXICOLOGY OF THE PULMONARY ENDOTHELIUM.
Author:
LAFRANCONI, WALTER MARK.
Issue Date:
1983
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:
To study the pulmonary responses to toxic insult, the biochemical and physiological effects of a known pulmonary toxicant (monocrotaline) were investigated. Monocrotaline is a pyrrolizidine alkaloid obtained from the seeds of Crotalaria spectabilis. When this alkaloid is administered to rats in their drinking water (20 mg/1) for 3 weeks, the lung is damaged, resulting in pulmonary hypertension, inhibition of serotonin transport by the pulmonary endothelium, and right heart hypertrophy. Preceeding the hypertrophy is a doubling of the mass of the lung and right ventricle. The change in mass of the lung preceeds that of the right ventricle. The increases in both organs is characterized by elevated RNA but not DNA. The lung mass increase is not accompanied by changes in collagenous proteins but is accompanied by an 86% increase in total lipids. The right ventricle however, responds to monocrotaline with a 400% increase in collagen protein and no change in lipid content, thereby indicating the lung and right ventricle respond differently to monocrotaline. Time course experiments established that the earliest observable event in monocrotaline induced lung damage is pulmonary edema which develops by day 5 and is resolved by day 10. Monocrotaline metabolites generated by an isolated liver and perfused through an isolated lung do not cause pulmonary edema even at concentrations of monocrotaline metabolites near 1 mM. These metabolites do however, alter the pulmonary endothelial transport of serotonin while other endothelial functions such as norepinephrine transport, angiotensin convertining enzyme and 5'-nucleotidase activities are unchanged. The effect of monocrotaline metabolites on pulmonary endothelial cell transport of serotonin is attenuated when the isolated livers are perfused under conditions which inhibit the formation of metabolites. Therefore, one of the pulmonary effects of monocrotaline that takes weeks to develop in vivo, inhibition of pulmonary endothelial transport of serotonin, can be observed under in vitro conditions. These results also directly demonstrate that the pulmonary damage caused by monocrotaline is a result of hepatic metabolism of monocrotaline to a pneumotoxic form.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Lungs -- Diseases.; Endothelium -- Diseases.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology and Toxicology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Huxtable, Ryan

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleTOXICOLOGY OF THE PULMONARY ENDOTHELIUM.en_US
dc.creatorLAFRANCONI, WALTER MARK.en_US
dc.contributor.authorLAFRANCONI, WALTER MARK.en_US
dc.date.issued1983en_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.abstractTo study the pulmonary responses to toxic insult, the biochemical and physiological effects of a known pulmonary toxicant (monocrotaline) were investigated. Monocrotaline is a pyrrolizidine alkaloid obtained from the seeds of Crotalaria spectabilis. When this alkaloid is administered to rats in their drinking water (20 mg/1) for 3 weeks, the lung is damaged, resulting in pulmonary hypertension, inhibition of serotonin transport by the pulmonary endothelium, and right heart hypertrophy. Preceeding the hypertrophy is a doubling of the mass of the lung and right ventricle. The change in mass of the lung preceeds that of the right ventricle. The increases in both organs is characterized by elevated RNA but not DNA. The lung mass increase is not accompanied by changes in collagenous proteins but is accompanied by an 86% increase in total lipids. The right ventricle however, responds to monocrotaline with a 400% increase in collagen protein and no change in lipid content, thereby indicating the lung and right ventricle respond differently to monocrotaline. Time course experiments established that the earliest observable event in monocrotaline induced lung damage is pulmonary edema which develops by day 5 and is resolved by day 10. Monocrotaline metabolites generated by an isolated liver and perfused through an isolated lung do not cause pulmonary edema even at concentrations of monocrotaline metabolites near 1 mM. These metabolites do however, alter the pulmonary endothelial transport of serotonin while other endothelial functions such as norepinephrine transport, angiotensin convertining enzyme and 5'-nucleotidase activities are unchanged. The effect of monocrotaline metabolites on pulmonary endothelial cell transport of serotonin is attenuated when the isolated livers are perfused under conditions which inhibit the formation of metabolites. Therefore, one of the pulmonary effects of monocrotaline that takes weeks to develop in vivo, inhibition of pulmonary endothelial transport of serotonin, can be observed under in vitro conditions. These results also directly demonstrate that the pulmonary damage caused by monocrotaline is a result of hepatic metabolism of monocrotaline to a pneumotoxic form.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectLungs -- Diseases.en_US
dc.subjectEndothelium -- Diseases.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.advisorHuxtable, Ryanen_US
dc.contributor.committeememberDuckles, Sueen_US
dc.contributor.committeememberSipes, Glennen_US
dc.contributor.committeememberBrendel, Klausen_US
dc.contributor.committeememberGandolfi, Jayen_US
dc.identifier.proquest8323744en_US
dc.identifier.oclc690029073en_US
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