Respiratory Embryology, Devp Flashcards
Lung and airway development
- derived/arises from…
- type of morphogenesis
- morphogenesis depends on underlying…
- depends on many factors
- resp tract derived from endoderm
- lung forms from ventral bud of esophagus (FOREGUT)
- branching morphogenesis
- branching morphogenesis depends on mesodermal MESENCHYME
Describe how lung development depends on:
- morphogens
- transcription factors
- exogenous factors
- growth factor (where is this made)
Recognize some of the factors involved in this lung development (chart)
- morphogens
- transcription factors: convert type II to I pneumocyte
- exogenous: preterm birth, infection, vent days
- growth factor: made by mesenchyme
Describe development of pulmonary vascular system
- where does it form from
- larger bronchial arteries..from..supply..
- smaller pulmonary arteries supply..are complete by…
Pulm vasculature forms from branches off 6TH AORTIC ARCH
- bronchial arteries - from aorta to conducting airways, visceral pleura, pulm arteries
- small pulm arteries
– preacinar arteries (angiogenesis) - up to nonresp bronchioles; complete at 16 weeks
– intra-acinar arteries (vasculogenesis) - supply resp bronchioles ; and alveolar ducts; growth along w. alveolar devp until 8 - 10 years
Name stages of lung development
- describe
- timing re GA
- abnormalities that can occur
Every Premie Can Suck Air
Embryonic stage
Formation of:
Lung Bud, Trachea (28d)
Separation of the trachea and esophagus is complete
Left and right primary bronchus
Major airways (all 37 d)
Pseudoglandular stage
establish bronchial tree
pre-acinar bronchi
separation of pleuroperitoneal cavity pulm lymphatics
spec epithelial cells (from primary epithelial cells)
Also congenital lobar emphysema
CPAM vs BPS
Cannalicular
Main events
*Formation of Pulmonary Acinus *Increase of Capillary Bed *Differentiation of Cuboidal Type II to squamous Type I cells (so start to secrete some surfactant)
Saccular
Main events
*Formation of Saccules
*Thinning of the Mesenchyme *Double Capillary Network in the septal walls
*Elastin deposition at secondary crests
*Fetal Lung Fluid Secretion**
Alveolar
Main events
*Formation of alveoli by epithelial outgrowth
*Double Capillary Network fuses into a single layer
*Surfactant production increases in the Type II cells
Alveoli Trivia (development)
When do most of alveoli form?
Number of alveoli at birth vs adulthood
How long do alveoli cont to develop
How long does lung surface area cont to grow
1st 6 months of life (when most alveoli form)
50 million to 300 million
2 to 8 years
18 years (squash court)
The earliest stage of lung development, which is considered viable
cannalicular
Respiratory Bronchioles are present earliest during
cannalicular
Epithelial Differentiation is
* Centrifugal
* Centripetal
* Specific
* Locus-centric
centrifugal (inside-out)
Which protein is expressed at the FREE MARGIN of the MESENCHYMAL rings?
fibroblast growth factor eg FGF 10
Mediators of Alveolarization
- Positive mediators
- Negative mediators
Positive
- Vit A, thromboxine
- fibroblast growth factor (from MESENCHYME) will direct development eg FGF10 (BIG in branching morphogenesis)
Negative
- post-natal steroids
- oxygen
- insulin
- ventilator
List some of the mediators of lung development
Origin of major vessels of the lung
- Pulmonary arteries
- Pulmonary veins
- Lymphatic vessels
PA - 6th pair of aortic arches
PV - outgrowth of LA
LV - cardinal vein
Shaped like fried egg w. tight junctions
-which cells (type I vs II pneumocytes)
- how much of alveoli does it cover?
-stage of devp
Type I pneumocyte
- role in gas exchange
- derived from type II cells
- covers 90% of alveoli surface (although less # of type I b/c flat so covers more surface with less #)
Cuboidal shaped pneumocytes
-which pneumocyte
-how much alveoli surface it covers
- role
Type II pneumocyte
- 10% of alveoli surface covered (but greater # of cells)
- role in surfactant metabolism and secretion
Composition of fetal lung fluid
- Cl high or low
- HCO3 high or low
- Protein high or low
Cl high
HCO3 and protein low
Volume of fetal lung fluid produced hourly near term (similar to FRC at birth)
4 - 5 mL/kg/hour OR 20-30 mL/kg
Describe fetal respirations and fetal lung fluid
Respiration -> larynx opens -> FLF slowly flows out of trachea -> this fluid either swallowed or mixes with amniotic fluid -> larynx closes -> helps lung maintain distended pressure (VITAL for lung growth)
How is fetal lung fluid created?
Cl secreting channels in resp epithelium -> ACTIVE transport Cl across and into future air spaces -> osmotic gradient -> flow of liquid into lungs
How does epithelial cell transition (channels) to decrease fetal lung fluid production and increase its absorption
Cl secreting TO Na absorption channels (ENaC) -> Na into interstitium -> fluid follows
Amount of:
- prenatal FLF clearance
- during active labor FLF clearance
- post-natal FLF clearance
Describe how FLF occurs
35%, 30%, 35%
Pre - less formed, Cl to Na channels, lymphatic oncotic P, low fetal alveolar protein
Labor - mech forces, catecholamine, hormones
Postnatal - lung distension, lymphatic oncotic P, low alv protein
Catecholamines and hormones that help with FLF clearance during labor
Catecholamines (increase transepithelial Na transport)
Higher cortisol, higher thyroid hormone
Primary component of surfactant
mostly lipid
50% phosphatidylcholine desaturated + 20% PC mono + 8% surf proteins + 8% lipids + 8% PG
Most common cause of surfactant deficiency (genetic cause)
ABCA3
AR inheritance
Other Items
Surf protein A,B,C,D
- which are in exogenous surfactant
- which cause disease, which most severe
B, C in exogenous
Disease - A,B,C
Involved in host defenses - A,D
Most severe disease - Surf B defn
B, C = critical esp B (tubular myelin formation)
surfactant production and secretion
- Stored as Lamellar Bodies (SPB, SP-C and lipids)
- Secreted and then interact with SP-A to form tubular myelin
- Recycled (almost 95%)
- Some cleared by alveolar macrophages
Is the half life of surfactant longer in preterm babies? Why?
Recycling and turnover of surfactant takes longer.
YES
Which surfactant proteins are hydrophilic? hydrophobic?
the hydrophobic surfactant proteins (SP-B and SP-C) play important roles in surfactant function and structure, and the hydrophilic surfactant proteins (SP-A and SP-D) in innate immunity, as well as in surfactant function (SP-A)
which surfactant protein is the most abundant?
surfactant A
*SP-B and SP-C are expressed early at the end of first semester
*SP-D is expressed last (early third trimester)
*SP-D is also present in many non-pulmonary cells
*SP-B homozygous deficiency leads to the most severe respiratory failure at birth
Other Surfactant Factrs
Which of the following surfactant proteins are important in host defense?
A and D
Animal derived natural surfactants lack…
Surf A and D proteins
What metrics indicate lung maturity
L/S > 2
+PG (phosphatidylglycerol)
When does L/S = 2
35 weeks
When does % PG within amniotic fluid increase?
phosphatidylglycerol
after 34- 35 weeks
NOTE: not present in infants with RDS; those with resolving RDS will have increasing levels in lung.
L/S ratio of 2 and appearance of PG in amniotic fluid occurs by
35 weeks
Changes in surfactant with development
Surfactant secretion is increased by
Purines
B agonists
Lung distension
Term baby with severe RDS is negative for SP-B deficiency. Which other gene defect presents similarly?
ABCA3 deficiency
After you give surfactant to a baby with RDS the time constant
Increases
What changes first after surfactant administration?
- oxygenation
- compliance
- ventilation
Consider what happens to your P-V curve after surfactant
OXYGENATION! (compliance takes time). Think about hysteresis curve.
How do antenatal CS work?
- Induction of surfactant synthesis (types II pneumocytes to mature and cause differentiation of type II to I)
- Increase surface area for gas exchange (making more surf, makes you recycle more surf!)
- Improved response to postnatal surfactant
*Also decreases: IVH, PDA, NEC and postnatal blood pressure
In experimental models, endotoxin is more effective than maternal betamethasone in inducing lung maturation
No? LPS is an endotoxin, can induce inflammatory cycle??
Recognize description of RDS CXR
- what causes the described pattern
- groundglass - alveolar atelectasis
- air bronchograms - open larger airways (increased aeration of these airways, increased resistance)
Surfactant administration decreases *Mortality
* IVH
* Symptomatic PDA
* Sepsis
* BPD
MORTALITY!
but also has improved effect on all of the above
Describe La Place’s law in the alveoli (surface T, P, r)
P = 2T / r
what influences delivery of surfactant positively?
- volume of surfactant
- rate of giving surfactant
- vol of fetal lung fluid at the time of giving surfactant
- GA of infant receiving surfactant
better to give more, faster, and when there is more fetal lung fluid (eg shortly after delivery)
Memorize - Genetic Lung Diseases
Central hypoventilation syndrome (which mutation)
PHOX2B (paired like homeobox)
Memorize Genetic Lung Disease
SFTPB - presentation
severe respiratory failure + PPHN
Memorize Genetic Lung Disease
Forkhead box F1
Alveolar capillary dysplasia with misalignment pulmonary veins
NK2 Homeobox 1 (NKX2-1)
Interstitial lung disease
thyroidtranscription factor gene mutation
abnormalities of BG, thyroid gland and presents like surf deficiency
ABC3A mutation
Deficient in PG and DPPC
transport defect of lipids - so deficient DPPC, PG, lamellar bodies
Describes pathyphysiology of apnea of prematurity
DECREASE vent response to hypercarbia
(increase TV rather than RR) - central
IRRITATION of laryngeal mucosa (water, acid) -> INHIBITS breathing (mediated via superior laryngeal n)
Response to hypoxic vent depression
- centrally mediated in pons by INHIBITORY neurotransmitters lke adenosine (INHIBITS phrenic and hypoglossal nerve)
- carotid body receptors - blunted response?
How do methylxanthines work for apnea of prematurity
Competitive ANTAGONIST of adenosine – so inhibits adenosime
Caffeine preferred - wider therapeutic index
CPAP for apnea of prematurity
increase FRC so increase baseline RESERVE of oxygenation to prevent apnea
REVIEW PAGE ON PPHN
pathophysiology
increased PVR ->R to L shunt at atrial or ductal level -> decreased PBF -> hypoxemia
Factors that contribute to PPHN
Airway obstruction/atelectasis
Inflammation - increase platelet activation, leukotrienes, thromboxane
Pulm hypoplasia
Mat meds - indocin, aspirin, tylenol
Acidosis, hypoxia
PPHN - describe with ex maldevelopment vs maladaptation
Maldevp - PV bed abnormal in structure or size - SM hypertrophy with FGR, fetal ductal closure; decreased cross sectional area CDH, pulm cap dysplasia, ELBW
Maladapt - normal pulm vasc bed - pna, MSAF, sepsis, amniotic fluid aspiration, perinatal depression
PPHN clinical presentation
hypoxemia +/- hypercarbia, pre-post spot 20% (except if there is significant atrial mixing)
PPHN management
- evaluation
- medications
- optimize cardiac functioning
ECHO to rule out CHD, may see bowing of IV septum into RV, shunting R to L
O2, surf (depending on etiology), correct TEMP, correct ACIDOSIS, Euglycemic!
pRBCs
Maybe inotropes to increase SVR - may help with improving L to R shunting (even driving SBP a bit higher than usual)
iNO
- evidence FDA
- explain how it works
Selectively dilates pulm vessels that are VENTILATED
evidence that it enhances oxygenation, decreases ECMO - for term.
FDA approved for PPHN for > 34 weeks
Careful of rebound pulm vasoconstriction after discontinuing
Action of sildenafil
PDE5 inhibitor - PDE (phosphodiesterase) 5 hydrolyzes cGMP to GMP -> inhibits THIS so that there is prolonging effect of cGMP (which vasodilates in pulm arteries)
see change by about 2 weeks, titrate to try and avoid hypotension
NOTE: phosphodiesterases block the action of cGMP (cGMP increases Ca efflux for vascular SM relaxation) –> so want to inhibit these PDEs
Action of milrinone
PDE 3
inhibits PDE 3 which hydrolyzes cAMP to AMP
PPHN and BPD
vascular remodeling -> pruning vascular tree -> with decreased microvessel density and decreased blood flow area
A
Note - B is normal
what can delay alveolarization
Histopatho old vs new BPD
D
E
