title: Inhibition of sphingosine kinase prevents lipopolysaccharide-induced preterm birth and suppresses proinflammatory responses in a murine model.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, New York.
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Vyas
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, New York.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, New York; Division of Neonatology, Winthrop University Hospital, State University of New York at Stony Brook, Mineola, New York.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Olgun
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, New York.
authors.forename: Sruthi
authors.initials: S
authors.lastname: Sundaram
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, New York.
authors.forename: Oluwabukola
authors.initials: O
authors.lastname: Salami
authors.affiliation: Emergency Department, Nassau University Medical Center, East Meadow, New York.
authors.forename: Swapna
authors.initials: S
authors.lastname: Munnangi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, New York.
authors.forename: Ryan
authors.initials: R
authors.lastname: Pekson
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, New York.
authors.forename: Prathamesh
authors.initials: P
authors.lastname: Mahajan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, New York; Departments of Pathology and Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York. Electronic address: rezniks@stjohns.edu.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Reznik
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D047928:Premature Birth / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000099157:Sphingosine Kinase
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase