Evaluation of Carbon Monoxide as a Therapeutic for Preeclampsia

dc.contributor.authorMcRae, Karalynen
dc.contributor.departmentAnatomy and Cell Biologyen
dc.contributor.supervisorSmith, Graeme Nen
dc.date.accessioned2018-08-21T17:34:59Z
dc.date.available2018-08-21T17:34:59Z
dc.degree.grantorQueen's University at Kingstonen
dc.description.abstractPreeclampsia (PE), a hypertensive complication of pregnancy, is one of the leading causes of maternal and neonatal morbidity and mortality. The etiology of PE is not well-understood, however it is widely accepted to occur in two stages: poor uteroplacental perfusion and placental ischemia, which subsequently leads to a systemic maternal inflammatory response and multi-organ effects. Although cigarette smoking during pregnancy is known to cause aberrant placental development and adverse pregnancy outcomes, smoking reduces the risk of PE by 33% in a dose-dependent manner. The same risk reduction does not hold true for users of smokeless tobacco products. This has lead to the notion that carbon monoxide (CO), one of the byproducts of cigarette combustion, may confer this decrease in PE risk. Endogenously, CO is produced through the degradation of heme by heme oxygenase (HO), and it has been suggested that modulation of the HO/CO system may attenuate the development or progression of PE. The studies presented herein demonstrate that low doses of CO, delivered through gaseous CO or CO donor molecules, may exhibit physiological benefits and have therapeutic potential during complicated pregnancies. Firstly, the challenges associated with reproducing the AdsFlt-1-induced mouse model of PE for studying the effects of CO in complicated pregnancies were investigated. Clinically, inhaled CO was shown to moderately increase biological CO above endogenous levels, and increase vascular responses in the cutaneous microvasculature. In mice, it is demonstrated that the CO-releasing molecule (CORM-A1) is able to transiently increase biological CO levels. CORM-A1 delivered in mid-gestation, resulted in increased CO, without adverse maternal or fetal effects, indicating the potential for CORM-A1 as a novel method to deliver CO during pregnancy. Collectively, the data presented in this thesis verify that low dose CO may have therapeutic properties to improve endothelial dysfunction, increase placental perfusion, and reduce progression of the clinical signs of PE.en
dc.description.degreePhDen
dc.embargo.liftdate2023-08-21
dc.embargo.reasonSubmitted portions for publicationen
dc.identifier.urihttp://hdl.handle.net/1974/24456
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.rightsen
dc.rights.uri
dc.subjectPreeclampsiaen
dc.subjectPregnancyen
dc.subjectCarbon monoxideen
dc.titleEvaluation of Carbon Monoxide as a Therapeutic for Preeclampsiaen
dc.typethesisen
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