Metalloproteinases and Preterm
Labor
Sandra E. Reznik, Department of Pharmaceutical
Sciences, College of Pharmacy and Allied Health Professions
Abstract
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.