OBJECTIVE: Amniochorion matrix metalloproteinase (MMP)-9 levels increase during labor, reaching a maximum in patients with preterm premature rupture of membranes (PPROM). Bleeding is a major risk factor for PPROM. Since such hemorrhage into the tissue factor-enriched decidua induces intense thrombin formation, we determined whether thrombin stimulates MMP levels in amniochorionic membranes. STUDY DESIGN: Fetal membrane (amniochorion) cultures were maintained in media with and without thrombin, lipopolysaccharide (LPS), thrombin receptor agonist peptide (TRAP)-14, and the anti-inflammatory steroid, dexamethasone (DEX). Concentrations of MMP-9, MMP-1, and tissue inhibitor of metalloproteinase (TIMP)-1 in culture media were measured by ELISA and normalized to total cell protein. RESULTS: The presence of thrombin induced MMP-9 levels. TRAP-14, a thrombin receptor agonist, also significantly increased MMP-9 levels, suggesting that thrombin-induced changes in MMP-9 expression were mediated through the thrombin receptor. Conversely, levels of MMP-1 and TIMP-1 were not affected by thrombin treatment, indicative of specificity of its action. The presence of LPS increased the concentration of MMP-9 and MMP-1. In contrast, DEX treatment significantly reduced MMP-9 levels. CONCLUSION: Our findings clearly demonstrated that thrombin treatment selectively increased the concentration of MMP-9 in culture media of amniochorionic membranes. Our results provide a potential mechanism through which alterations in hemostasis promote PPROM through thrombin-dependent stimulation of MMP-9.
OBJECTIVE: Amniochorion matrix metalloproteinase (MMP)-9 levels increase during labor, reaching a maximum in patients with preterm premature rupture of membranes (PPROM). Bleeding is a major risk factor for PPROM. Since such hemorrhage into the tissue factor-enriched decidua induces intense thrombin formation, we determined whether thrombin stimulates MMP levels in amniochorionic membranes. STUDY DESIGN: Fetal membrane (amniochorion) cultures were maintained in media with and without thrombin, lipopolysaccharide (LPS), thrombin receptor agonist peptide (TRAP)-14, and the anti-inflammatory steroid, dexamethasone (DEX). Concentrations of MMP-9, MMP-1, and tissue inhibitor of metalloproteinase (TIMP)-1 in culture media were measured by ELISA and normalized to total cell protein. RESULTS: The presence of thrombin induced MMP-9 levels. TRAP-14, a thrombin receptor agonist, also significantly increased MMP-9 levels, suggesting that thrombin-induced changes in MMP-9 expression were mediated through the thrombin receptor. Conversely, levels of MMP-1 and TIMP-1 were not affected by thrombin treatment, indicative of specificity of its action. The presence of LPS increased the concentration of MMP-9 and MMP-1. In contrast, DEX treatment significantly reduced MMP-9 levels. CONCLUSION: Our findings clearly demonstrated that thrombin treatment selectively increased the concentration of MMP-9 in culture media of amniochorionic membranes. Our results provide a potential mechanism through which alterations in hemostasis promote PPROM through thrombin-dependent stimulation of MMP-9.
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