Inflammation turns off gene that stops early labor
U. SHEFFIELD (UK) — Inflammation in the uterus can switch off a key gene that stops labor from occurring too early, research shows. The discovery may lead to new treatments to prevent premature births.
The process behind how women go into normal term labor is still poorly understood, but it is vital that it happens at the right time when the baby is ready to be born and can survive. Currently there are few reliable drugs that can be used to stop labor if it starts too early.
Babies that survive going into labor too soon are at an increased risk of developing long-term medical and developmental problems including cerebral palsy, breathing difficulties, deafness, and blindness.
Published in the Journal of Biological Chemistry, the new study focuses on how inflammation in the uterus affects an experimental class of drugs called histone deacetylase inhibitors (HDACi), which aim to delay labor when it starts prematurely.
In laboratory studies using tissue samples taken from pregnant women, these experimental drugs have been shown to stop the womb contracting. However when the research team analyzed a chemical released during uterine inflammation called TNF, they found that this actually caused muscle contraction to start again even when the HDACi drug had successfully stopped womb-muscle contraction.
“Premature birth remains the biggest cause of neonatal mortality, primarily because we still do not know enough about the biochemistry and physiology of how the uterus goes into labor in normal term pregnancies,” says Neil Chapman from the University of Sheffield’s Medical School.
“Our work demonstrates that while this experimental drug can stop the womb contracting, it cannot stop the inflammation associated with normal labor from switching off the genes which ensure the uterus does not start to contract too early. This means this class of drug may not be a suitable medication to give a pregnant woman when her labor starts prematurely because it cannot override the inflammation already present.
“Our research is a major step forward in unlocking the mysteries behind the processes of normal labor. We have shown that the inflammation of the uterus switches off the genes which stops labor occurring too early.
“Understanding how to prevent this inflammation or how to stop it blocking those key genes needed to stop contraction of the womb would lead to new treatments to prevent premature births.”
Although the details of the process through which TNF reverses uterine relaxation remain to be worked out, the finding illustrates a potential target of action for this molecule, says Raheela Khan from the University of Nottingham.
The histone deacetylase inhibitor used by Chapman’s team works by stimulating the muscle cells of the womb to activate one of the genes needed to ensure the womb does not contract too early. The inflammation caused by TNF then switches off that gene leading to contractions of the uterus. Importantly, while the experimental drug causes the womb to stop contracting, it cannot prevent the inflammation from still switching off the key gene meaning the uterus will still continue to contract.
The Medical Research Council and Jessop Wing Ellen Webster Legacy funded the research.
Source: University of Sheffield
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