Low-Dose Carbon Monoxide Exposure in Pregnancy; a Potential Therapeutic for Pre-Eclampsia

Abstract

Preeclampsia (PE) is a maternal disorder of pregnancy, characterized by late-onset hypertension and proteinuria. It affects roughly 5-7% of all pregnancies worldwide and is a leading cause of maternal and fetal/neonatal morbidity and mortality. Cigarette smoking in pregnancy is associated with a 33% reduction in the incidence of PE, and this is dose dependent. It is hypothesized that carbon monoxide (CO), a combustion product in cigarettes, may confer cytoprotective and regulatory properties leading to the decreased incidence of PE. CO is produced endogenously by the enzyme heme oxygenase (HO), and it is thought that the manipulation of the HO/CO system in pregnancy can ameliorate or reduce the pathophysiologic signs of PE. The exposure of pregnant mice to 250 ppm CO led to an increase in each of the maternal uterine blood flow, vascularity of the placenta and vessel diameter, with a shift towards angiogenesis in the placenta tissue proteins Exposure of human placental villous explants to 250ppm CO led to a decreased production and release of the soluble vascular endothelial growth factor (VEGF) receptor -1 (sFlt-1). This molecule is increased in maternal plasma and placenta tissue of women with PE and it binds with molecules of angiogenesis, limiting their ability to interact with the endothelium. Using an AdsFlt-1 PE-like mouse model, the exposure of mice to 250ppm chronic CO prevented the hypertension, proteinuria and glomerular alterations, supporting the use of CO as a future therapeutic for women with PE. We completed a pilot study to evaluate the exposure of healthy volunteers to two, one hour inhalations of 250ppm CO. We determined the half-life of CO and we provide baseline kinetics data for males and females following CO inhalation. These data are important for future therapeutic studies in order to better establish proper dosing, concentration of CO and method of delivery. The results of this thesis contribute to the understanding of the pathophysiology of PE and provide evidence to support the use of CO as a therapeutic for this disorder.