Inhibition of the TLR4 signalling pathway protects from LPS-induced pre-term delivery (#104)
Premature birth following preterm labour is a common and critical health issue in fetal-maternal medicine with long-term consequences especially for early preterm neonates. The pathophysiology is poorly understood and the causal factors uncertain, but inflammatory mechanisms are clearly implicated. Bacterial lipopolysaccharide (LPS) is a pathogen-associated molecular pattern (PAMP) which binds Toll-like receptor 4 (TLR4) to activate inflammation and induce preterm delivery (PTD) in mice. This project seeks to investigate (1) whether inhibition of the TLR4 signalling pathway using small molecule inhibitors of TLR4 signalling may prevent the parturition cascade caused by LPS-induced inflammation and (2) the consequences of in utero exposure to TLR4 inhibitors for the resulting progeny. The effect of administration of TLR4 inhibitors in preventing LPS-induced PTD was investigated in C57Bl/6 (B6) mice. Pregnant B6 females were treated with LPS or PBS, with or without co-administration of TLR4 inhibitor, on gestational day (GD) 16.5 and were either killed on GD18.5, or allowed to deliver pups. LPS-induced PTD was successfully alleviated using TLR4 inhibitors in B6 mice, preventing fetal loss associated with death in utero and/or early delivery, resulting in on-time birth with normal perinatal characteristics and survival rates in pups. TLR4 inhibitors did not reverse the reduced fetal weight evident in late gestation after LPS administration. However progeny born after exposure to TLR4 inhibitor in late gestation, with or without concurrent LPS administration, showed no substantial adverse effects on growth trajectory (from birth to 20 weeks), body morphometry or health in adulthood. These results indicate that TLR4 is required for the precocious activation of the inflammatory response induced by bacterial LPS and implicates TLR4 as a key trigger for infection-associated preterm labour. Early intervention with TLR4 inhibitors can inhibit progression of the LPS-induced inflammatory cascade and prevent preterm birth without adverse perinatal or postnatal consequences in mice. The TLR pathway warrants further investigation as a potential target for new prevention or treatment options in women with infection-associated, threatened PTD.