Using mutant mice that lack lymph vessels, Jakus et al. show that prenatal lymphatic function is required for neonatal lung inflation and respiration.

In the womb, a baby’s lungs are filled with fluid that must be cleared close to birth to allow neonatal lung inflation and respiration. The bulk of the fluid is cleared by active transepithelial absorption from the airways into the lung interstitial spaces, a process that starts before birth in response to hormonal changes.

Jakus et al. observed that in mice that lack the gene encoding CCBE1 or that express a dysfunctional VEGFR3 receptor, molecules involved in lymph vessel formation, the majority of the newborn pups are bluish in color and do not start to breathe. Although the lungs develop and mature normally, they fail to inflate and the mice die shortly after birth.

In healthy wild-type late-gestation embryos, the authors found that pulmonary lymphatics are already functioning. But in the mutant embryos, the absence of lymphatic function was associated with accumulation of fluid in the lung tissue and with reduced ability of the prenatal lung to expand (a feature known as lung compliance). Based on these observations, Jakus et al. propose a model in which pulmonary lymphatic function in preterm mice is required for drainage of absorbed fluid in the lungs, thus preventing tissue edema and securing intrinsic lung compliance prior to birth. In this way, prenatal lymphatic function helps prepare the lungs for inflation and gas exchange after birth.

It was reported previously that lymphatics contribute to the clearance of remaining lung fluid in newborns and that lymphatic hypoplasia compromises neonatal survival. Jakus et al. extend these findings by revealing the importance of functional pulmonary lymphatics prior to birth. Besides other crucial mechanisms, such as surfactant production, prenatal lymphatic function appears to be an additional mechanism required to prepare the lung for inflation, which is a previously unrecognized role of the lymphatic system.

The authors observed differences in phenotype severity depending on the genetic background of the mutant mice, suggesting the influence of as yet unidentified modifying factors. Nevertheless, further investigation into temporal aspects of prenatal lymphatic drainage may elucidate whether inadequate prenatal lymphatic function contributes to respiratory distress syndrome in premature infants, and may explain respiratory failure in infants with congenital pulmonary lymphangiectasia, a rare disorder of lung lymphatic development.

et al
J. Exp. Med.