molecular mechanisms of labour Flashcards
what is the muscle structure of the uterus?
myometrium -> 3 major layers of smooth muscle = inner circular layer, interlocking middle layer, outer longitudinal layer
what are the 3 gross regions of the uterus?
fundal region = super segment, to part, contractions emanate here
lower segment = develops during pregnancy, little contraction
cervix = closed during pregnancy, softens for labour
what are the spatial expression patterns of proteins in the myometrium?
different levels of protein expression between each region - high levels seen in the fundal region than lower segment
lower expression during labour than pregnancy
how does spatial protein expression regulate myometrial function/quiescence?
a balanced between contraction and relaxation
what are some pro-quiescent molecules?
progesterone GalphaS CRH cAMP PGE2 PKA
what are some contractile-associated molecules?
oestrogen CRH oxytocin PGE2 PGF2alpha calcium
what is the timeline to birth?
0wks/conception ->24wks = non-viable
24wks ->32wks = extremely premature
32wks->37wks = preterm
37wks -> 42 wks = term
what is the threshold of viability?
23-25 wks (maybe 22wks)
what are the parts of G-protein coupled receptors (GPCRs)?
receptor
3 G proteins = alpha, beta and gamma
enzyme to make second messenger (cAMP)
what are the G alpha subunits and what do they determine?
G alpha s
G alpha i
G alpha q
they determine what second messenger is made
what does Galpha s do?
positive messenger = makes cAMP
ß2 agonist, PGE2 via EP receptor = uterine relaxation
what does Galpha i do?
negative messenger = prevents cAMP
alpha adrenergic agonists- ergometrine
alpha µ, opioid receptors
PGE2 via EP1 & 3 receptors = uterine contraction - misoprostol
what does Galpha q do?
positive messenger = makes IP3 and DAG
oxytocin receptor, PGF2 via FP2alpha receptor
= uterine contraction, severe PPH - carboprost
how is quiescence maintained?
ß2 agonists, CRH and PGE2 bind to GPCRs with subunit alpha s -> produces cAMP -> produces PKA -> phosphorylation of intracellular proteins -> inactivation of facto-myosin ATPase -> womb contraction blocked = myometrial quiescence
little info about expression of Galpha s is known (de novo synthesis, recycled from membrane compartments)
what are some agonist drugs and how do they work?
ritodrine and salbutamol
increase cAMP = promotes smooth muscle relaxation
promote myocyte hyperpolarisation (open K channels)
tocolytic activity
why do women go into labour when they do?
still unknown
binary switch? placental clock concept CRH/ACTH/HPA axis
fetal derived signal - surfactant proteins
infection = abnormal
how could infection induce labour?
induces inflammatory response in affected tissue - cervix, amnion, placenta, cord, myometrium
premature labour can then be initiated
what pro-inflammatory chemicals are needed in labour?
prostaglandins
cytokines
chemo-attractant cytokine (chemokine)
what is functional progesterone withdrawal?
change in myometrial responsiveness to progesterone
something is blocking pro-quiescent action of progesterone at term - different isoforms of progesterone become dominant
oestrogen activity becomes dominant
local metabolism of progesterone to inactive form
what are the 3 stages of parturition?
cervical dilation - remodelling
fetal expulsion - myometrial contraction
placental delivery - rapid
what pro-inflammatory factors are associated with parturition?
COX-2
IL1ß
IL8
TNF
what happens during cervical ripening?
growth and remodelling of cervix prior to labour
promoted by release of: PGE from cervical mucosa, relaxin, placental oestrogen
effacement and dilation due to muscular action of cervix and uterus = brachystasis -> contractions of fundal myometrium shorten muscle cell length and pull the cervix and lower segment up
how is expression of inflammatory genes controlled?
signal cascade from TNFalpha -> NF-kappaB pathway -> COX-2
what drugs can inhibit the pathways of parturition?
NSAIDS = indomethacin (COX-1) celecoxib (COX-2) corticosteroids = dexamethasone
