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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Investigating the Et-1/SphK/S1P Pathway as a Novel Approach for the Prevention of Inflammation-Induced Preterm Birth

Author(s): Kiersten Giusto and Charles R. Ashby*

Volume 24 , Issue 9 , 2018

Page: [983 - 988] Pages: 6

DOI: 10.2174/1381612824666180130122739

Price: $65


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.

Keywords: Endothelin-1, gestation, inflammation, preterm birth, pharmacological approaches, sphingosine kinase.

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