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Thrombin induces enhanced calcium mobilization in TNF-sensitized uterine smooth muscle (USM) cells of African American patients compared to non-hispanic Caucasian patients
Abstract Number: BP-02
Abstract Type: Original Research
Objective: Racial disparity in preterm birth rates have been described for decades. Although associations with bacterial vaginosis, chronic inflammation, and TNFα levels have been reported to be higher in patients of African heritage, a biological mechanism for this observation has never been described. We questioned if myometrial cells chronically challenged with TNFα in vitro would display differential intracellular calcium [Ca2+]i mobilization between racial groups via a phospholipase-mediated pro-contractile pathway.
With IRB approval (#AAAL4005) and following consent, late gestation human USM was harvested from healthy patients undergoing elective c-section. Tissues were enzymatically dissociated and primary cultures established in vitro. To mimic a pro-inflammatory milieu, cells received chronic exposure to TNFα (0.01ng/mL x 5 days). USM cells were then loaded with the Ca2+ specific fluorophore Fura-2 AM (5 µM). To implicate the Gq/PLCβ pathway, cells were pretreated with vehicle (0.1% DMSO) or 6SH (50 μM) followed by stimulation with thrombin (1µM) or ionomycin (20µM). Evoked calcium fluorescence (340/380λ) was recorded by FlexStation 3 plate reader. Results were normalized to maximal calcium responses evoked by ionomycin, reported as mean ± SEM, and grouped by reported race. A one way ANOVA with Bonferroni's Multiple Comparison Test was used for statistical analysis.
Stimulation of TNF-sensitized USM cells with thrombin elicits significantly higher intracellular calcium release in African American patients (59.8% + 3.4%, n=12) than in non-hispanic Caucasians (35.5% + 2.4%, n=15; p<0.01). Pre-treatment with the PLC-inhibitor 6SH significantly attenuated this evoked calcium release in African American (18.7% + 2.7%, n=12; p<0.001) and Caucasian (21.5% + 3.4%; p<0.05) USM cells. Total evoked calcium response by ionomycin was not significantly different based on race.
Conclusions: Pro-inflammatory sensitization of human USM cells with TNFα induces greater reactivity to thrombin challenge in African American patients than seen in Caucasian patients. Blockade with the PLC-inhibitor 6SH illustrates this effect involves the Gq/PLCβ pathway. This is the first report of a biological mechanism related to pro-contractile pathways underlying the racial disparity observed in preterm labor.