Central Airway Development
To understand central airway pathology in neonates with BPD, it is first
necessary to understand the developmental changes of the airway that
occur throughout gestation. By the 3rd week of
gestation, the endoderm develops into the foregut.(1) An outpouching of
the foregut forms during the 4th week of gestation and
will ultimately give rise to the conducting airways. The trachea and
main bronchi are formed by the end of the 4th week of
gestation,(2) and by 16 weeks, what once was a single lumen has branched
into the more than 1020 conducting airways, similar to
the fully developed lung.(3)
In addition to increasing the numbers of conducting airway, the basic
structure of the trachea is developed during the first half of
gestation. The trachea is composed of 16 to 20 cartilaginous rings
anteriorly and a muscular membrane posteriorly. The first deposits of
tracheal cartilage form during the 7th week of
gestation, and the formation of new cartilage continues, following the
branching of the airways, until about 25 weeks’ gestation.(3)
While the first half of gestation is primarily devoted to developing the
structure and increasing the numbers of conducting airways, the airway
matures and remodels throughout the latter half of gestation. This
maturation results in increased dimensions of the trachea and components
of the tracheal wall, changes in the geometry of the tracheal rings, and
alterations in the chemical properties of tracheal cartilage and smooth
muscle. Throughout gestation the length and thickness of tracheal
cartilage increases, and there is a proportionate increase in the length
and thickness of airway smooth muscle. Consequently, the ratio of
cartilage to muscle is constant. The net result is a larger, more robust
airway as gestation progresses.(4) In addition to the changes in the
amount of airway cartilage and smooth muscle, the geometric
relationships of airway cartilage and smooth muscle also change during
gestation. In preterm-sheep, the free ends of airway cartilage are thin
and easy to deform; however, with increasing gestational age the
relationship changes such that the cartilage nearly abuts.(4) This
provides increased support to the posterior membrane and makes the
airway less compliant.
As structure changes throughout the second half of gestation to result
in an airway that is less susceptible to dynamic collapse, properties of
airway smooth muscle and tracheal cartilage also mature, conferring
further strength to the developing trachea. In animal models passive
stress of airway muscle increases three-fold in the term vs preterm
trachea.(5) Furthermore, myosin expression is upregulated throughout
gestation, (6, 7) which may explain the increased contractile force of
mature tracheal smooth muscle in response to chemical stimuli. (8, 9)
Maturational changes in tracheal cartilage also serve to increase
strength of the airway wall. At 24 weeks’ gestation, the airway
cartilage resembles pre-cartilage, and changes in the mucoproteins will
not result in a mature appearance until near term corrected age. (3)
With increasing age, there is also increased expression of
glycosaminoglycans in tracheal cartilage with decreased water content,
resulting in increased tracheal stiffness. (4, 10, 11)
The combination of structural and conformational changes of tracheal
cartilage and smooth muscle results in a larger, less compliant trachea
throughout development that is more resistant to damage and difficult to
deform in response to positive pressure. (12) While mechanical
ventilation has limited impact on the adult airway, there can be changes
in the dimensions and mechanical properties of the neonatal airway.
Positive pressure results in an increased radius and cross-sectional
area of the trachea and decreased thickness of the airway cartilage and
smooth muscle. Further, application of pressure to the premature airway
can cause changes in the relationship of the cartilage and smooth muscle
as well as epithelial damage.(13) Consequently, immature airways that
are exposed to mechanical ventilation have increased resistance and
collapsing compliance, making the airway more difficult to inflate.(14)
This collapsed airway results in marked increased tracheal work of
breathing in neonates.(15)
Failure of the natural developmental progression of the premature
trachea and frequent need for positive pressure ventilation predisposes
neonates with BPD to central airway pathologies. Central airway disease
can be divided into two main categories: 1) dynamic airway obstruction
and 2) fixed airway obstruction.