A computer simulation of progesterone and Cox2 inhibitor treatment for preterm labor.

Abstract

BACKGROUND: Sufficient information from in vitro and in vivo studies has become available to permit computer modeling of the processes that occur in the myometrium during labor. This development allows the in silico investigation of pathological mechanisms and the trialing of potential treatments. METHODS/RESULTS: Based on the human literature, we developed a computer model of the immune-endocrine environment of the myometrial cell. The interactions between molecules are represented by differential equations. The model is designed to simulate the estrogen and progesterone receptor changes during pregnancy and particularly the changes in the progesterone receptor (PR) isoforms A and B that are thought to mediate functional progesterone withdrawal in the human at labor. Parturition is represented by an increase in the PRA to PRB ratio to levels seen in women in labor. Infection is shown by inducing inflammation in the system by increasing phospho-IkB kinase concentration (IKK) levels; which lead to increased NF-kappaB activation, causing an increase in the PRA/PRB ratio. We examined the effects of progesterone or cyclo-oxygenase 2 (Cox2) inhibitor treatments on the PRA/PRB ratio in silico. The model predicted that high doses of progesterone and Cox2 inhibition would be effective in preventing an NF-kappaB-induced PRA/PRB ratio increase to the levels found during labor. CONCLUSIONS: Our data illustrate the use of dynamic biological computer simulations to test the effectiveness of therapeutic interventions. This may allow the early rejection of ineffective therapies prior to expensive field trials.