Sphingosine Kinase Emerges as a Potential Target in the Fight Against Preterm Birth: Study Shows

Preterm delivery may occur spontaneously or may be medically indicated when continuing the pregnancy poses risks to the mother or fetus. Clinically, preterm birth is commonly grouped into spontaneous preterm labor, premature rupture of membranes, and fetal-maternal complications. Risk factors include a previous preterm birth, abdominal or cervical surgery, multiple pregnancy, in-vitro fertilization, smoking, low socioeconomic status, diabetes before conception, chronic hypertension or preeclampsia, and asymptomatic bacterial infection.

Evidence from animal and human studies suggests that infection can trigger inflammatory pathways that lead to preterm labor. Intrauterine infection is often silent in early pregnancy, with few obvious symptoms until labor begins. Commonly implicated organisms include Ureaplasma urealyticum, Mycoplasma, and Fusobacterium. Studies of amniotic fluid have found bacterial infection more frequently in women who go into labor before 30 weeks of gestation.

Inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-8, and tumor necrosis factor-α are associated with infection-related preterm delivery. These signals can stimulate prostaglandin production, activate matrix metalloproteinases, soften the cervix, and contribute to rupture of fetal membranes. Tocolytic drugs, which suppress uterine contractions, can sometimes delay delivery for at least 48 hours. However, available therapies have not consistently reduced neonatal complications or improved maternal side-effect profiles.

Antibiotics have shown promise in some infection-related settings, but reducing infection alone has not reliably lowered preterm birth rates, neonatal sepsis, or mortality. This has encouraged researchers to investigate shared inflammatory pathways that may be targeted more precisely. Endothelin-1 (ET-1) is a potent vasoconstrictor and smooth-muscle contraction signal. Research suggests that ET-1 levels may rise in amniotic fluid during infection-associated preterm labor, linking it to the inflammatory cascade that can trigger uterine contractions. Experimental work has shown that ET-1 can produce strong myometrial contractions. ET receptor antagonists have prevented or delayed preterm delivery in animal models, but their potential use in pregnancy is complicated by safety concerns, including teratogenic risk.

Sphingosine kinase (SphK) produces sphingosine-1-phosphate (S1P), a lipid signaling molecule involved in cell survival, immune function, vascular biology, and inflammation. In pregnancy, the SphK/S1P pathway appears to participate in uterine quiescence, contraction, and apoptosis.

Studies suggest that ET-1 may activate SphK1 through protein kinase C and phospholipase C pathways. This activation can lead to Rho kinase signaling and increased uterine contractility. SphK also appears to contribute to cyclooxygenase-2 expression, which supports prostaglandin production during labor.

Because SphK sits downstream of ET-1 in this proposed pathway, it may offer a more attractive target than ET-1 itself. Blocking SphK signaling could theoretically reduce infection-triggered contractions while avoiding some concerns associated with endothelin antagonists.

The research points to a possible inflammatory chain: infection activates cytokines, cytokines promote prostaglandins and tissue-remodeling enzymes, ET-1 amplifies uterine contraction signals, and SphK/S1P helps transmit those signals inside uterine tissue.

If future studies confirm this pathway in humans, SphK inhibitors or related therapies could become candidates for preventing or delaying infection-associated preterm birth. However, the article emphasizes that more research is needed before SphK can be considered a validated clinical target.

Sphingosine kinase is not yet a treatment for preterm birth, but it is emerging as an important research target. By influencing inflammation, prostaglandin production, and uterine contraction pathways, the SphK/S1P axis may help scientists develop more targeted approaches to one of obstetrics’ most persistent challenges.

Source: Adapted from Hindawi Publishing Corporation, Obstetrics and Gynecology International, Volume 2013, Article ID 302952.