Effects and tissue penetration of anti-inflammatory drugs and peptides in an ex vivo fetal membrane perfusion model

Preterm birth (PTB) is a significant and increasing obstetric challenge in Australia and abroad. Intra-uterine infection (IUI), and associated inflammation, has been estimated to cause 30–40% of PTB. Inflammation plays a significant role in normal term parturition and is responsible for PTB by IUI. Pharmaceutical targets within biochemical inflammatory pathways may be blocked, suppressing inflammatory mediators, and possibly preventing preterm labour. The two inflammatory pathways targeted in this thesis are the nuclear factor κB (NF-κB) pathway, and the p38 MAP kinase pathway. This thesis has evaluated five inhibitors of these two pathways: the antioxidant NAC; the IKK inhibitor TPCA-1; the p38 MAPK inhibitor SB239063; a NEMO binding domain blocking peptide; and a TAK1 inhibitor, C292. Using a Transwell fetal membrane perfusion model, this thesis has evaluated the ability of these pharmaceutical agents to suppress inflammation when administered intra-amniotically. Initially four drugs where investigated in full term, Caesarean delivered human fetal membranes (n=5): NAC, TPCA-1, SB239063, and the NBD-blocking peptide. TPCA-1 was able to suppress the expression of IL-6, IL-10, and TNF-α within the amniotic compartment of the Transwell model (P