Oxidative stress, hyperlipidemia, neutrophil activation and endothelial cell dysfunction are characteristic of women with preeclampsia. We used in vitro experiments to test if a combination of oxidative stress and linoleic acid favors a mechanism for neutrophil transendothelial migration. We used linoleic acid because it is one of the fatty acids elevated in preeclampsia and the precursor for arachidonic acid and its inflammatory metabolites. For these studies, we developed a methodology for isolating and Culturing human vascular smooth muscle cells from placental chorionic plate arteries. Treatment of these cells with an oxidizing solution enriched with linoleic acid, but neither component alone, led to increased production of interleukin-8 (IL-8), a potent neutrophil chemotactic agent, This treatment solution also stimulated arachidonic acid metabolites, including leukotriene B4, another potent neutrophil chemotactic agent. The same treatment solution rapidly activated neutrophils to produce superoxide, These observations suggested there might be neutrophil transendothelial migration in women with preeclampsia because increased expression of IL-8 by vascular smooth muscle would attract neutrophils to the vasculature, and activation of neutrophils would prime them for transendothelial migration. These predictions were confirmed using immunohistochemical staining of systemic vascular tissue in preeclamptic women, as compared to normal pregnant and normal non-pregnant women, by demonstrating vascular smooth muscle cell expression of lL-8 coincident with neutrophil infiltration into systemic vessels. Endothelial cells and vascular smooth muscle cells also expressed ICAM-1, a cell adhesion molecule necessary for neutrophil infiltration.
This investigation is the first to demonstrate vascular smooth muscle cell expression of IL-8 and ICAM-1 coincident with neutrophil transendothelial migration into systemic vascular tissue in women with preeclampsia. These observations provide evidence for total ‘Vascular cell dysfunction”, not only endothelial cell dysfunction, in women with preeclampsia. Together they link vascular cell dysfunction to a single mechanism, transendothelial migration of neutrophils, which could explain the clinical symptoms of hypertension, proteinuria, and pathological edema. These results bolster the use of antioxidants in preventing preeclampsia and suggest novel treatments for preeclampsia based on neutralizing antibodies to IL-8 or cell adhesion molecules.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-6221 |
| Date | 01 January 2003 |
| Creators | Leik, Courtney Elizabeth |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
Page generated in 0.0023 seconds