FETAL LUNG LIQUID: A MAJOR DETERMINANT OF THE GROWTH AND FUNCTIONAL DEVELOPMENT OF THE FETAL LUNG

Abstract

SUMMARY: 1. During fetal life the lung develops as a liquid‐filled organ. This liquid is produced by the fetal lung and leaves via the trachea from where it is either swallowed or enters the amniotic sac. Fetal lung liquid plays a crucial role in the growth and development of the lungs by maintaining them in a distended state. It is now recognized that the retention of liquid within the future airways is required to maintain the lungs at an appropriate level of expansion in order to stimulate their growth. Indeed, it is likely that most, if not all, of the conditions and malformations that lead to inadequate growth of the fetal lung do so by reducing the volume of lung liquid and hence the degree of lung expansion. 2. The volume of fetal lung liquid is principally regulated by the resistance to lung liquid efflux through the fetal upper airway and by the presence of diaphragmatic activity associated with fetal breathing movements (FBM). During non‐breathing periods, the relatively high resistance offered by the upper airway to the efflux of lung liquid opposes the loss of liquid from the lung, thereby maintaining fetal lung expansion. During episodes of FBM, when the larynx is actively dilated and the resistance to lung liquid efflux is reduced, lung liquid leaves the lungs at an increased rate. However, selective inhibition of diaphragmatic muscle activity in the foetus leads to a reduction in lung liquid volume, rather than an increase. This finding indicates that during periods of FBM, rhythmical contractions of the diaphragm retard the loss of lung liquid and help to maintain lung expansion when the upper airway resistance is reduced. It is now apparent that the maintenance of lung expansion by FBM is the basis for their role in promoting fetal lung growth. 3. Successful transition from intra‐uterine to extra‐uterine life is dependent upon the clearance of liquid from the fetal lungs at the time of birth so that the lungs may effectively function as an organ of gas exchange. It is generally considered that, at the time of birth, increased circulating levels of the stress‐related hormones, adrenaline and arginine vasopressin (AVP), play an important role in suppressing fetal lung liquid secretion and stimulating its reabsorption. The ability of adrenaline and AVP to perform this role, however, is dependent upon the exposure of the lung to increasing levels of gluco‐corticoids late in gestation. Thus, the maturation of the fetal lung, induced by the preparturient increase in circulating cortisol levels, not only includes changes in lung compliance and surfactant synthesis, but also includes an increased ability of the lung to reabsorb liquid. 4. Although it is well recognized that fetal lung growth is critically determined by the degree to which the lungs are expanded with lung liquid, the mechanisms underlying this relationship are poorly understood and are likely to be complex. The increase in fetal lung growth induced by experimentally increasing the degree of fetal lung expansion is very rapid and most probably results from an acceleration of the processes involved in normal fetal lung growth. The accelerated growth response is most likely mediated by a multitude of growth factors which act on different processes within individual cells and on different cell types within the lung to produce a coordinated growth response. Because increased fetal lung expansion rapidly increases the growth of hypoplastic fetal lungs, treatments leading to increased lung expansion in utem have the potential to be used to treat lung hypoplasia in human foetuses before the lungs are required to function as the sole organ of gas exchange. Further experimentation is required to determine whether such lungs have the ability to function effectively after birth.