Abstract
BackgroundSufficient 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/ResultsBased 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-κB 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-κB-induced PRA/PRB ratio increase to the levels found during labor.ConclusionsOur 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.
Highlights
Preterm delivery is a common complication of pregnancy, occurring in approximately 12% of the pregnancies in the US and the rates are increasing
This may allow the early rejection of ineffective therapies prior to expensive field trials
We propose that the presence of subclinical infection/inflammation may suppress the therapeutic effect of progesterone and cyclooxygenase 2 (Cox2) inhibitors
Summary
Preterm delivery is a common complication of pregnancy, occurring in approximately 12% of the pregnancies in the US and the rates are increasing. About 45% (.$5 billion/year) of all infant health care expenditure in the US is related to prematurity [1] It is a syndrome rather than a single condition, in .80% of the preterm deliveries ,32 weeks of gestation there is intra-uterine infection that is subclinical where maternal and fetal inflammatory response-induced cyclo-oxygenase and placental prostaglandin synthesis lead to myometrial contractility and premature parturition [2]. 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
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