of birth, indicating that this molecule is required for the normal
timing of the birth cascade.
Now the search is on for the naturally occurring molecules
that trigger TLR4 to control labour at the end of healthy preg-
nancy. Several candidate molecules, released from the placenta
and maturing fetus in late gestation, are being explored.
These TLR ligands appear to interact with various hormones
to trigger the downstream inflammatory cascade. The stress
hormone corticotrophin-releasing hormone is induced by, and
then amplifies, TLR-mediated responses in placental cells. The
sex hormone progesterone, which sustains pregnancy and may
protect from preterm birth, also attenuates the TLR-induced
inflammatory cascade. Human studies show that the gesta-
tional tissues become more responsive to inflammatory trig-
gers with advancing gestation as responsiveness to progesterone
declines.
Together, these emerging observations are explaining how
the same downstream pathways can be activated by a wide range
of different events, and why several inflammatory mediators
are commonly regulated in gestational tissues and the maternal
blood prior to both term and preterm birth.In vitroexperi-
ments with uterine muscle cells show how these inflammatory
cells and cytokines can elevate the synthesis of contraction-
inducing prostaglandins and matrix-softening enzymes that in
turn cause the changes in uterine and cervical tissues that allow
the child to be born.
These new insights raise the prospect of new drugs that
target the upstream events of labour, and the possibility of more
efficacious therapies for preterm labour. We have recently
discovered that a novel small molecule inhibitor of
TLR4, (+)-naloxone, can prevent infection-induced preterm
labour in mice. (+)-naloxone is the positive isomer of
(–)-naloxone, an opioid antagonist with blood–brain perme-
ability that is used to treat an opioid overdose. Both of these
isomers block TLR4 signalling, but (+)-naloxone does not bind
opioid receptors.
Our studies in mice show that the administration of
(+)-naloxone can abrogate premature birth and increase the
number of viable pups born. This result indicates the utility of
(+)-naloxone as a powerful tool to define the causal pathways
through which TLR4 controls inflammatory pathways that
lead to preterm delivery. Importantly, (+)-naloxone and related
drugs may also have value as new therapeutic drugs for delaying
preterm delivery in humans.
Sarah Robertson is Director of The University of Adelaide’s Robinson Research Institute.
Mark R. Hutchinson is the Director of the ARC Centre of Excellence for Nanoscale
Biophotonics at The University of Adelaide.JAN/FEB 2016|| 31