Background: Preterm birth (PTB), defined as birth before 37 completed weeks of gestation, occurs in
up to 18 percent of births worldwide and accounts for the majority of perinatal morbidity and mortality. While the
single most common cause of PTB has been identified as inflammation, safe and effective pharmacotherapy to
prevent PTB has yet to be developed.
Methods: Our group has used an in vivo model of inflammation-driven PTB, biochemical methods, pharmacological
approaches, a novel endothelin receptor antagonist that we synthesized and RNA knockdown to help establish
the role of endothelin-1 (ET-1) in inflammation-associated PTB. Further, we have used our in vivo model to
test whether sphingosine kinase, which acts downstream of ET-1, plays a role in PTB.
Results: We have shown that levels of endothelin converting enzyme-1 (ECE-1) and ET-1 are increased when
PTB is induced in timed pregnant mice with lipopolysaccharide (LPS) and that blocking ET-1 action, pharmacologically
or using ECE-1 RNA silencing, rescues LPS-induced mice from PTB. ET-1 activates the sphingosine
kinase/sphingosine-1-phosphate (SphK/S1P) pathway. S1P, in turn, is an important signaling molecule in the proinflammatory
response. Interestingly, we have shown that SphK inhibition also prevents LPS-induced PTB in
timed pregnant mice. Further, we showed that SphK inhibition suppresses the ECE-1/ET-1 axis, implicating
positive feedback regulation of the SphK/S1P/ECE-1/ET-1 axis.
Conclusion: The ET-1/SphK/SIP pathway is a potential pharmacotherapeutic target for the prevention of PTB.