Metalloproteinases and Preterm Labor
Sandra E. Reznik, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences
Preterm delivery, defined as delivery before 37 weeks’ gestation, occurs in 7 to 12% of pregnancies, and is associated with 85% of perinatal morbidity and mortality. Unfortunately, the existing therapeutic approaches for preterm delivery have not decreased the incidence of prematurity and can be associated with risks to both the mother and fetus. Previous in vitro investigations have shown that endothelin-1 increases myometrial smooth muscle tone. Infection and inflammatory cytokines, which have been associated with preterm delivery, can stimulate ET-1 production. ET-1, in turn, stimulates prostaglandin synthesis. Inflammatory cytokines may therefore trigger prostaglandin synthesis and, ultimately, contractions and delivery, indirectly, by increasing ET-1 synthesis. We have recently shown (Koscica et al. 2003) that blockade of ET-1 synthesis controls infection mediated preterm labor in an animal model, using the endothelin-converting enzyme inhibitor phosphoramidon. In a separate line of investigation, we have studied differential gene expression in labor in the human placenta, using cDNA microarray technology. Through the microarray studies, we have identified several novel potential therapeutic targets for the control of preterm labor, including matrix metalloproteinase-1 (MMP-1). Using the same animal models of preterm labor, we have now shown that inhibition of MMP-1 also results in prevention of premature delivery. These studies will hopefully lead to the development of future clinical trials addressing a very important, yet little investigated clinical problem.