The Effect of Simvastatin on Infection-Induced Inflammatory Response of Human Fetal Membranes.

Abstract

Inflammatory cytokines and matrix metalloproteinases (MMPs) contribute to preterm labor pathophysiology. The objective of this study was to test anti-inflammatory properties of simvastatin in human fetal membranes exposed to lipopolysaccharide (LPS). Normal term human fetal membrane explants (n = 11) were allocated to one of the six study groups: control, LPS only (100 ng/mL), simvastatin only (125 ng/mL), simvastatin given 6 hrs prior to LPS (S-L), simvastatin given 6 hrs post-LPS (L-S), and simvastatin and LPS given simultaneously (L+S). Explants were incubated for 24 hrs. Multiplex ELISA for cytokines: IL-1β, IL-6, IL-10, and TNF-α; soluble cytokine receptors: sIL-1R2, sIL-6R, sTNFR1, and R2; MMPs (1, 2, 7, 9, and 10); and tissue inhibitor of metalloproteinase-2 (TIMP-2) was performed on tissue culture supernatants. Pairwise comparison between different groups was conducted by least square mean estimates. Compared with controls, LPS stimulation increased cytokine production and their tissue bioavailability (measured as the molar ratio of cytokine to its soluble receptor), thus confirming membrane immune reactivity (P < 0.01). Pre-treatment with simvastatin (S-L) reduced IL-6 (P = 0.02), TNF-α (P = 0.02), and MMP-9 (P = 0.01); post-treatment (L-S) reduced IL-1β (P = 0.02) and TNF-α (P = 0.04), while simultaneous treatment (L+S) did not reduce any of the cytokines tested. Simvastatin reduced the molar ratio of TNF-α/sTNFR1 or R2 and IL-1β/sIL-1R2 (P = 0.01 and 0.04 in S-L group; P = 0.01 and 0.004 in L-S group, respectively). S-L additionally reduced MMP-9/TIMP-2 molar ratio (P = 0.0007). Simvastatin downregulates LPS-induced inflammatory response and restores homeostasis between pro- and anti-inflammatory processes. Simvastatin may reduce fetal inflammatory response associated with infection-induced preterm birth.