Inhibition of sphingosine kinase prevents lipopolysaccharide-induced preterm birth and suppresses proinflammatory responses in a murine model

Vibhuti Vyas, Charles R. Ashby, Nicole S. Olgun, Sruthi Sundaram, Oluwabukola Salami, Swapna Munnangi, Ryan Pekson, Prathamesh Mahajan, Sandra E. Reznik

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Premature delivery occurs in 12% of all births, and accounts for nearly half of long-term neurological morbidity, and 60% to 80% of perinatal mortality. Despite advances in obstetrics and neonatology, the rate of premature delivery has increased approximately 12% since 1990. The single most common cause of spontaneous preterm birth is infection. Several lines of evidence have demonstrated the role of endothelin-1 as both a constrictor of uterine myometrial smooth muscle and a proinflammatory mediator. Endothelin-1 activates the phospholipase C pathway, leading to activation of protein kinase C and, in turn, sphingosine kinase (SphK). The inhibition of SphK has been recently shown to control the proinflammatory response associated with sepsis. We show herein, for the first time, that SphK inhibition prevents inflammation-associated preterm birth in a murine model. Rescue of pups from premature abortion with an SphK inhibitor occurs by suppression of the proinflammatory cytokines tumor necrosis factor α, Il-1β, and Il-6 and attenuation of polymorphonuclear inflammatory cells into the placental labyrinth. Moreover, we postulate that inhibition of SphK leads to suppression of endothelin-converting enzyme-1 expression, indicating the presence of an endothelin-converting enzyme 1/endothelin 1-SphK positive feedback loop. This work introduces a novel approach for the control of infection-triggered preterm labor, a condition for which there is no effective treatment.

Original languageEnglish (US)
Pages (from-to)862-869
Number of pages8
JournalAmerican Journal of Pathology
Volume185
Issue number3
DOIs
StatePublished - Mar 1 2015

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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