008. Placental inflammation and preterm labour: studies of pathophysiology and intervention using human ex-vivo models

Abstract

Inflammatory processes and mediators are an integral aspect of the mechanics of parturition. Leukocyte infiltration/activation of the extraplacental membranes, cervix and uterus occurs prior to term labour and is accompanied by increased cytokine expression, eicosanoid production, and extracellular matrix degradation. These processes are propagated during labour to ensure progression through to delivery, and in normal parturition they occur in concert in a timely fashion. In contrast, pathological intrauterine inflammation appears to be a causative factor in a significant proportion of preterm births. While the presence of an infective organism in the amniotic cavity is confirmed in about half of pregnancies delivered with chorioamnionitis, in the remainder the cause of the excessive inflammatory response remains undetermined.

We have established and applied various models employing human placental tissues to study the processes involved in triggering intrauterine inflammatory activation and potential pharmacological approaches for intervention. Of these, an ex-vivo fetal membrane perfusion model has been the most powerful, allowing multi-aspect analysis of membrane gene expression, inflammatory mediator production, histological and structural integrity in response to maternal challenge with endotoxin (lipopolysaccharide). Using a variety of techniques including oligonucleotide and protein arrays we have determined that a robust and rapid inflammatory response is manifested in both the maternal and fetal compartments after maternal (decidual) exposure to lipopolysaccharide; this is accompanied by a marked increase in apoptosis in the chorionic membrane, but no detectable changes in membrane integrity.

We have evaluated in this model several anti-inflammatory drugs that inhibit the NF-κB pathway as potential pharmacologics for treating inflammation-induced preterm labour. Surprisingly, most were completely ineffective in suppressing lipopolysaccharide-induced cytokine production. Sulfasalazine, however, administered to the maternal face, effectively and rapidly abrogated the lipopolysaccharide response in both maternal and fetal compartments, with modest membrane transfer of drug. However, chorionic apoptosis was doubled in sulfasalazine-treated membranes, raising concerns over possible toxicity. Studies using these models are continuing to further evaluate the potential of novel and existing pharmacotherapies for the prevention of inflammation-associated preterm birth.