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.

17-α Hydroxyprogesterone Nanoemulsifying Preconcentrate-Loaded Vaginal Tablet: A Novel Non-Invasive Approach for the Prevention of Preterm Birth

“…LPS induced preterm birth in mice is a well-established and relevant model for such investigation [20,21,22,23]. Timed pregnant Swiss Webster mice ( n = 11) were injected intraperitoneally on E15.5 ( t = 0) with LPS (serotype 026:B6, obtained from Sigma, 25 mg/kg) dissolved in PBS to induce preterm labor.…”

Recent Progress in Therapeutics for Inflammation-Associated Preterm Birth: A Review

“…44 Several studies reporting the consequences of endothelin pathway blockade are presented in Table 2. [45][46][47] Other than those mentioned previously, naturally produced compounds or alternative therapeutics have recently been drawing attention as novel therapeutics for preterm birth since these substances possess strong anti-inflammatory properties. Some of them have been commonly administered as medicines for specific diseases with an inflammation-associated etiology in nonpregnant women.…”

Involvement of calcium in 50‐Hz magnetic field‐induced activation of sphingosine kinase 1 signaling pathway

“…Various studies showed that SK1 is related to the progression of multiple tumors such as gastric cancer [Xiong et al, ], colorectal cancer [Shida et al, ], and hepatocellular carcinoma [Uranbileg et al, ]. SK1 is also relevant to inflammatory diseases [Price et al, ; Vyas et al, ; Jaigirdar et al, ]. The phosphorylation of SK1 and its subsequent translocation are critical steps for oncogenic signaling [Pitson et al, ].…”