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The inflammatory response to infections is a major factor associated with spontaneous preterm birth (PTB) and perinatal morbidity. Using an in vitro fetal membrane organ explant system we tested if simvastatin (sim), a lipophilic statin with strong anti-inflammatory properties, regulates the inflammatory response to lipopolysaccharide (LPS).
Normal term human fetal membrane (n = 11) explants were divided into 6 treatment groups: control, LPS (100ng/ml), sim (125ng/ml), sim given 6 hours prior to LPS (S-L), sim given 6 hours post LPS (L-S), and sim and LPS given simultaneously (L+S) and incubated for 24 hours. Multiplex ELISA for IL-1β, IL-1 receptor antagonist (IL-1ra), IL-6, soluble IL-6 receptor (sIL-6R), IL-10, TNF-α and soluble TNF receptors (sTNF R1 and R2) was performed in tissue culture supernatants. Differences between individual treatments and untreated controls were evaluated by comparison of least squares means estimates. Mechanistic properties of sim in (L+S) group were documented by Western blot analysis of membranes for NF-κB.
LPS stimulation increased cytokines compared to controls (p = 0.01), confirming membrane immune reactivity. Regulation of cytokine production by sim in LPS-stimulated membranes was specific and limited to pro-inflammatory cytokines. S-L reduced IL-1ra (p = 0.0005), IL-6 (p = 0.02) and TNF-α (p = 0.02); L-S reduced IL-1β (p = 0.02) and TNF-α (p = 0.04) while LS only reduced IL-1ra (p = 0.03). Compared to controls, LPS increased the TNF-α/sTNF R1 or R2 molar ratio favoring increased tissue bioavailability of TNF-α (p = 0.0001) while it was restored by L-S (p = 0.01), S-L (p = 0.01) and L+S (p = 0.05) compared to LPS (Table). Sim blocked the LPS induced phosphorylation of NF-κB/p65 subunit but did not inhibit IκB-α proteolysis.
1Cytokines and their soluble receptor concentrations (pg/ml) in various study groups
Simvastatin treatment down-regulated LPS induced inflammatory response and restored homeostasis between pro and antiinflammatory agents, by controlling NF-κB activation. Simvastatin may reduce the fetal inflammatory response in PTB.