Date of Award
Open Access Thesis
Medical Doctor (MD)
Placental vessels and the umbilical circulatory network function to carry oxygen and nutrients to the fetus. It is at this level that placental lesions such as villitis, obliterative vasculopathy, and thrombotic vasculopathy have been observed in association with fetal inflammatory response syndrome (FIRS) and cerebral palsy. We used human umbilical vein endothelial cells (HUVECs) as a model to study the regulation of inflammation and thrombosis in fetal vessels by microbial products. In this thesis we measured interleukin-8 (IL-8) and tissue factor (TF) expression by HUVECs treated with lipopolysaccharide (LPS), poly (I:C) (PIC), and peptidoglycan (PG). Our results show a profound induction of IL-8 by PIC, a TLR-3 ligand. We also show a moderate induction of tissue factor expression in PIC-treated HUVECs. These results show that HUVECs are exquisitely sensitive to PIC and suggests an important role for viral infection in umbilical vessel inflammation. We additionally treated HUVECs with dexamethasone (DEX), an anti-inflammatory steroid, and melatonin (MT), a pineal gland product with immunomodulatory and anti-oxidant properties. DEX reduced the level of both IL-8 and TF expression in PIC-treated cells. MT, however, further enhanced IL-8 expression in PIC-treated cells. Our results indicate a potential role for glucocorticoid therapy in reducing placental vessel inflammation and thrombosis. Thus, intervention with GC in pregnancies with FIRS may reduce the severity of placental lesions associated with cerebral palsy.
Davarya, Shekar Ligia, "Inflammatory and Thrombotic Responses to Microbial Products in Fetal Vessels Are Mediated through Divergent Toll-Like Receptor Signaling Pathways: Implications in Fetal Inflammatory Response Syndrome" (2008). Yale Medicine Thesis Digital Library. 319.