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.