molecular mechanisms of labour Flashcards

1
Q

what is the muscle structure of the uterus?

A

myometrium -> 3 major layers of smooth muscle = inner circular layer, interlocking middle layer, outer longitudinal layer

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2
Q

what are the 3 gross regions of the uterus?

A

fundal region = super segment, to part, contractions emanate here
lower segment = develops during pregnancy, little contraction
cervix = closed during pregnancy, softens for labour

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3
Q

what are the spatial expression patterns of proteins in the myometrium?

A

different levels of protein expression between each region - high levels seen in the fundal region than lower segment
lower expression during labour than pregnancy

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4
Q

how does spatial protein expression regulate myometrial function/quiescence?

A

a balanced between contraction and relaxation

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5
Q

what are some pro-quiescent molecules?

A
progesterone 
GalphaS
CRH 
cAMP
PGE2 
PKA
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6
Q

what are some contractile-associated molecules?

A
oestrogen
CRH
oxytocin 
PGE2
PGF2alpha 
calcium
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7
Q

what is the timeline to birth?

A

0wks/conception ->24wks = non-viable
24wks ->32wks = extremely premature
32wks->37wks = preterm
37wks -> 42 wks = term

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8
Q

what is the threshold of viability?

A

23-25 wks (maybe 22wks)

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9
Q

what are the parts of G-protein coupled receptors (GPCRs)?

A

receptor
3 G proteins = alpha, beta and gamma
enzyme to make second messenger (cAMP)

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10
Q

what are the G alpha subunits and what do they determine?

A

G alpha s
G alpha i
G alpha q
they determine what second messenger is made

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11
Q

what does Galpha s do?

A

positive messenger = makes cAMP

ß2 agonist, PGE2 via EP receptor = uterine relaxation

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12
Q

what does Galpha i do?

A

negative messenger = prevents cAMP
alpha adrenergic agonists- ergometrine
alpha µ, opioid receptors
PGE2 via EP1 & 3 receptors = uterine contraction - misoprostol

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13
Q

what does Galpha q do?

A

positive messenger = makes IP3 and DAG
oxytocin receptor, PGF2 via FP2alpha receptor
= uterine contraction, severe PPH - carboprost

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14
Q

how is quiescence maintained?

A

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)

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15
Q

what are some agonist drugs and how do they work?

A

ritodrine and salbutamol
increase cAMP = promotes smooth muscle relaxation
promote myocyte hyperpolarisation (open K channels)
tocolytic activity

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16
Q

why do women go into labour when they do?

A

still unknown
binary switch? placental clock concept CRH/ACTH/HPA axis
fetal derived signal - surfactant proteins
infection = abnormal

17
Q

how could infection induce labour?

A

induces inflammatory response in affected tissue - cervix, amnion, placenta, cord, myometrium
premature labour can then be initiated

18
Q

what pro-inflammatory chemicals are needed in labour?

A

prostaglandins
cytokines
chemo-attractant cytokine (chemokine)

19
Q

what is functional progesterone withdrawal?

A

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

20
Q

what are the 3 stages of parturition?

A

cervical dilation - remodelling
fetal expulsion - myometrial contraction
placental delivery - rapid

21
Q

what pro-inflammatory factors are associated with parturition?

A

COX-2
IL1ß
IL8
TNF

22
Q

what happens during cervical ripening?

A

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

23
Q

how is expression of inflammatory genes controlled?

A

signal cascade from TNFalpha -> NF-kappaB pathway -> COX-2

24
Q

what drugs can inhibit the pathways of parturition?

A
NSAIDS = indomethacin (COX-1) celecoxib (COX-2) 
corticosteroids = dexamethasone
25
Q

how does myometrial contractility occur?

A

inflammation
differential gene expression
elevated calcium - extracellular sources voltage-gated calcium channels
intracellular sources - store-operated channels on sarcoplasmic reticulum
activation of auto-myosin ATPase -> myocyte contraction

26
Q

what drug inhibits myometrial contraction?

A

Nifedipine - calcium channel blocker

inhibits premature myometrial contractions

27
Q

how does oxytocin contribute to parturition?

A

cervical stimulation/myometrial stretch induces oxytocin secretion (from hypothalamus) -> increased oxytocin receptor numbers seen at term on fundal myometrium
initiates positive feedback mechanism = Ferguson reflex
oxytocin receptors cause signally pathway IP3 -> calcium release from sarcoplasmic reticulum -> intracellular calcium. binding proteins (calmodulin) -> activation of auto-myosin ATPase -> myocyte contraction

28
Q

what analogues are used to induce labour?

A

oxytocin = syntocinon

29
Q

what drugs are used to inhibit oxytocin signalling pathway?

A

atosiban = oxytocin receptor antagonist, an inhibit premature mymetrial contractions

30
Q

what other drugs are used to induce myocyte contraction via FPR?

A

carboprost = prostaglandin analogue

used to treat PPH unresponsive to oxytocin and ergometrine

31
Q

how does the placental delivery occur?

A

significant increase in plasma fibrinogen levels and other clotting factors - blood becomes hypercoagulable
at term placental blood flow is 500ml/min and must rapidly block this as exsanguination when placenta separates

32
Q

when mechanisms are in place to stop rapid blood loss from placental delivery?

A

rapid myometrial contraction to compress blood vessels

immediate fibrin deposition over placental site

33
Q

when can depletion of fibrinogen reserve occur?

A

inadequate myometrial contraction (more common if placenta near lower segment)
incomplete placental separation

34
Q

how does ergometrine and PGE2 (misoprostol) work?

A

binds to GPCR with Galphai causing inhibition of cAMP production -> auto-myosin ATPase can contract -> promotes smooth muscle uterine contraction

35
Q

what enzymes are activated which phosphorylate other cellular proteins to cause myometria quiescence?

A

protein kinase A and C = PKA, PKC