The Role of Abnormal Maternal Inflammation in the Pathogenesis of Pregnancy Complications

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Cotechini, Tiziana
Tumour Necrosis Factor , Pregnancy Complications , Pre-Eclampsia , Utero-Placental Perfusion , Spiral Artery Remodelling , Fetal Growth Restriction , Trophoblast Invasion , Nitric Oxide , Pregnancy , Nitroglycerin , Thromboelastrography , Fetal Death , Hemostasis , Rat , Placenta , Coagulopathy , Inflammation
Pre-eclampsia (PE), fetal growth restriction (FGR) and fetal death are common complications associated with human pregnancy. A hallmark of these adverse pregnancy outcomes is reduced utero-placental perfusion, which is believed to arise as a consequence of deficient trophoblast-mediated spiral artery remodelling. Other common features of PE, FGR and fetal demise include reduced nitric oxide (NO) bioavailability, alterations in maternal hemostasis and an abnormal maternal inflammatory response. Despite all that is known, the causative factors leading to the development of these adverse pregnancy outcomes remain unidentified. The results of this thesis identify aberrant maternal inflammation as key to the pathogenesis of PE, FGR and fetal loss using a rat model in which pregnant rats are injected with low-dose lipopolysaccharide (LPS). In particular, our in vivo animal studies revealed a causal role for tumour necrosis factor-alpha (TNF) in the development of FGR, features of PE and the development of maternal coagulopathies associated with fetal death. Our work also revealed a pregnancy-specific effect whereby the deleterious effects of LPS administration to pregnant rats (i.e. cytokine release, glomerular pathology, elevated white blood cell counts) did not occur to the same magnitude when LPS was administered to non-pregnant animals. Gross examination of placentas from saline and LPS-treated animals revealed that inflammation altered placental morphometrics resulting in reduced placental weight and area. Importantly, we discovered that activation of NO signalling via the administration of the NO mimetic glyceryl trinitrate (GTN) attenuated features of LPS-induced inflammation (i.e. elevated white blood cell counts) and prevented inflammation-induced FGR, features of PE, maternal coagulopathies and fetal loss. Our in vitro studies revealed that low-dose GTN exerts immunomodulatory functions given that GTN treatment prevented TNF release from LPS-stimulated THP-1 macrophage cells. Collectively, the data presented in this thesis reveal that abnormal maternal inflammation in pregnancy is casually linked to the development of FGR, features of PE and fetal loss in a rat model. Our data also provide a rationale to study the role of novel immunomodulators, including GTN, in the treatment and prevention of inflammation-induced complications of pregnancy.
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