ROLE OF ACTIVATED MACROPHAGES AND PRO-INFLAMMATORY CYTOKINES IN PLACENTAL TROPHOBLAST INVASION AND FETAL OUTCOME
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The invasion of trophoblast cells into the uterine wall is an essential component of normal human pregnancy. These trophoblast cells transform the uterine spiral arterioles into high-flow, low-resistance vessels that supply the placenta to support fetal growth and development. Inadequate trophoblast invasion and spiral arteriole remodelling may result in excessive placental pathology leading to pre-eclampsia and intra-uterine growth restriction (IUGR), which are major causes of maternal and fetal morbidity and mortality. These pregnancy complications have also been linked to an increased presence of pro-inflammatory cytokine-secreting (activated) macrophages at the fetal-maternal interface. In particular, increased production of tumour necrosis factor-alpha (TNF) by activated macrophages has been implicated as a causative factor mediating various pregnancy complications. Results from this thesis showed that macrophage-derived TNF decreased the invasiveness of trophoblast cells, primarily by affecting the urokinase system of plasminogen activators, a network of proteases that promotes cellular invasion. TNF also stimulated the production of macrophage chemoattractants by trophoblast cells, providing a putative mechanism for the aberrant recruitment and localization of macrophages in complicated pregnancies. Administration of lipopolysaccharide (LPS), a potent stimulator of macrophage activation and TNF production, to pregnant rats resulted in IUGR and fetal death correlating with significant placental pathology, including displaced endovascular trophoblast cells and increased fibrinoid and macrophage accumulation at the fetal-maternal interface. The immunoregulatory cytokine interleukin-10, which inhibited TNF production from macrophages after LPS-exposure, completely prevented the adverse effects of TNF in vitro and in vivo. Collectively, these findings show that the aberrant presence and localization of TNF-secreting macrophages may be involved in the etiology and pathophysiology of various pregnancy-related complications.