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Lymphatic function is required prenatally for lung inflation at birth.

ABSTRACT: Mammals must inflate their lungs and breathe within minutes of birth to survive. A key regulator of neonatal lung inflation is pulmonary surfactant, a lipoprotein complex which increases lung compliance by reducing alveolar surface tension (Morgan, 1971). Whether other developmental processes also alter lung mechanics in preparation for birth is unknown. We identify prenatal lymphatic function as an unexpected requirement for neonatal lung inflation and respiration. Mice lacking lymphatic vessels, due either to loss of the lymphangiogenic factor CCBE1 or VEGFR3 function, appear cyanotic and die shortly after birth due to failure of lung inflation. Failure of lung inflation is not due to reduced surfactant levels or altered development of the lung but is associated with an elevated wet/dry ratio consistent with edema. Embryonic studies reveal active lymphatic function in the late gestation lung, and significantly reduced total lung compliance in late gestation embryos that lack lymphatics. These findings reveal that lymphatic vascular function plays a previously unrecognized mechanical role in the developing lung that prepares it for inflation at birth. They explain respiratory failure in infants with congenital pulmonary lymphangiectasia, and suggest that inadequate late gestation lymphatic function may also contribute to respiratory failure in premature infants.

SUBMITTER: Jakus Z

PROVIDER: S-EPMC4010903 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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Lymphatic function is required prenatally for lung inflation at birth.

Jakus Zoltán Z Gleghorn Jason P JP Enis David R DR Sen Aslihan A Chia Stephanie S Liu Xi X Rawnsley David R DR Yang Yiqing Y Hess Paul R PR Zou Zhiying Z Yang Jisheng J Guttentag Susan H SH Nelson Celeste M CM Kahn Mark L ML

The Journal of experimental medicine 20140414 5

Mammals must inflate their lungs and breathe within minutes of birth to survive. A key regulator of neonatal lung inflation is pulmonary surfactant, a lipoprotein complex which increases lung compliance by reducing alveolar surface tension (Morgan, 1971). Whether other developmental processes also alter lung mechanics in preparation for birth is unknown. We identify prenatal lymphatic function as an unexpected requirement for neonatal lung inflation and respiration. Mice lacking lymphatic vessel ...[more]

PMID: 24733830

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Project description:Embryonic lungs must be inflated immediately after birth to establish respiration. In addition to pulmonary surfactant, recently, we have revealed lymphatic function as a previously unknown regulator of prenatal lung compliance that prepares the embryonic lung for inflation at birth. It is well-documented that the late gestation embryo performs episodic breathing-like movements called as fetal breathing movements (FBMs), but the physiological importance of these events is not clear. Here we aimed to study the physiological role of FBMs in preparation for air inflation at birth. Clp1 K/K late gestation embryos develop a progressive loss of spinal motor neurons associated with axonal degeneration and denervation of neuromuscular junctions serving as an ideal genetic model to test the possible role of FBMs. We demonstrated that Clp1 K/K newborns show impaired motor function resulting in fatal respiratory failure after birth. Next, we showed that the alveolar septa are thicker, and the alveolar area is reduced in Clp1 K/K late gestation embryos, while the expression of molecular markers of lung development are not affected. Importantly, pulmonary lymphatic vessels are dilated and the prenatal pulmonary lymphatic function is reduced in Clp1 K/K late gestation embryos. Our results have revealed that Clp1 K/K mice show impaired motor functions including FBMs, and late gestation Clp1 K/K embryos display reduced prenatal lymphatic function and impaired lung expansion represented as thickened alveolar septa and reduced alveolar area in preparation of the developing lung for inflation at birth. These findings suggest a possible mechanism that FBMs, similarly to breathing movements after birth, stimulate prenatal lymphatic function in pulmonary collecting lymphatics lacking smooth muscle coverage to prepare the developing lung for inflation and gas exchange at birth. Moreover, these results raise the possibility that stimulating FBMs during late gestation might be an effective way to reduce the risk of the development of neonatal respiratory failure.

Dataset Information

Lymphatic function is required prenatally for lung inflation at birth.

Publications

Lymphatic function is required prenatally for lung inflation at birth.

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