title: 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.
authors.affiliation: Department of Medicine, 2 Cardiovascular Institute, and 3 Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Jakus
authors.forename: Jason P
authors.initials: JP
authors.lastname: Gleghorn
authors.forename: David R
authors.initials: DR
authors.lastname: Enis
authors.forename: Aslihan
authors.initials: A
authors.lastname: Sen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chia
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.forename: David R
authors.initials: DR
authors.lastname: Rawnsley
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Yang
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hess
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Zou
authors.forename: Jisheng
authors.initials: J
authors.lastname: Yang
authors.forename: Susan H
authors.initials: SH
authors.lastname: Guttentag
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Nelson
authors.forename: Mark L
authors.initials: ML
authors.lastname: Kahn
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000172:deficiency; D017931:DNA Primers / Q000235:genetics; D004452:Echocardiography; D004622:Embryo, Mammalian / Q000502:physiology*; D005333:Fetus / Q000502:physiology*; D007150:Immunohistochemistry; D008168:Lung / Q000502:physiology* / Q000648:ultrastructure; D008170:Lung Compliance / Q000502:physiology; D008208:Lymphatic System / Q000196:embryology / Q000502:physiology*; D008220:Lymphography; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D011654:Pulmonary Edema / Q000503:physiopathology*; D060888:Real-Time Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000172:deficiency; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C572375:Ccbe1 protein, mouse; D017931:DNA Primers; D025521:Tumor Suppressor Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3
references.citation: Cell. 1999 Sep 17;98(6):769-78
references.pmid: 10499794
references.citation: Cell Res. 2010 Dec;20(12):1319-31
references.pmid: 20697430
references.citation: Mech Dev. 2011 Jan-Feb;128(1-2):29-40
references.pmid: 20932899
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12677-82
references.pmid: 11592985
references.citation: Dev Cell. 2006 Dec;11(6):845-57
references.pmid: 17141159
references.citation: Am J Respir Crit Care Med. 2006 Aug 1;174(3):326-30
references.pmid: 16690974
references.citation: Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3566-70
references.pmid: 7724599
references.citation: J Clin Invest. 2013 Apr;123(4):1571-9
references.pmid: 23524964
references.citation: Semin Perinatol. 1980 Oct;4(4):275-86
references.pmid: 7001636
references.citation: J Cell Biol. 1981 Aug;90(2):435-47
references.pmid: 7026573
references.citation: Genes Dev. 2010 Oct 1;24(19):2115-26
references.pmid: 20889712
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1982 Oct;53(4):992-1004
references.pmid: 7153132
references.citation: J Appl Physiol (1985). 2001 Jul;91(1):316-20
references.pmid: 11408446
references.citation: Biochim Biophys Acta. 1982 Aug 18;712(2):382-9
references.pmid: 7126612
references.citation: Am J Respir Cell Mol Biol. 1997 Jan;16(1):46-52
references.pmid: 8998078
references.citation: Am J Dis Child. 1970 Oct;120(4):314-9
references.pmid: 5493829
references.citation: Am J Pathol. 2002 Mar;160(3):985-1000
references.pmid: 11891196
references.citation: J Pathol Bacteriol. 1955 Oct;70(2):325-33
references.pmid: 13295907
references.citation: Nat Genet. 1996 Mar;12(3):325-8
references.pmid: 8589728
references.citation: Pediatrics. 1964 Jan;33:55-62
references.pmid: 14115228
references.citation: Nat Genet. 2009 Dec;41(12):1272-4
references.pmid: 19935664
references.citation: Cell. 2010 Feb 19;140(4):460-76
references.pmid: 20178740
references.citation: AMA J Dis Child. 1959 May;97(5, Part 1):517-23
references.pmid: 13649082
references.citation: Nat Med. 2002 Jul;8(7):702-10
references.pmid: 12053176
references.citation: J Clin Invest. 1958 Jan;37(1):111-7
references.pmid: 13491718
references.citation: J Perinatol. 2005 May;25 Suppl 2:S40-4
references.pmid: 15861172
references.citation: Blood. 2013 Apr 18;121(16):3228-36
references.pmid: 23426945
references.citation: J Pediatr. 1990 Jan;116(1):119-24
references.pmid: 2404097
references.citation: Arch Dis Child Fetal Neonatal Ed. 2005 Mar;90(2):F128-33
references.pmid: 15724036
references.citation: Nat Immunol. 2004 Jan;5(1):74-80
references.pmid: 14634646
references.citation: J Clin Invest. 1990 Oct;86(4):1270-7
references.pmid: 2212011
references.citation: J Pediatr. 1965 Feb;66:357-64
references.pmid: 14258925
references.citation: Arch Dis Child. 1977 Dec;52(12):918-24
references.pmid: 606168
references.citation: J Clin Invest. 1994 Apr;93(4):1860-3
references.pmid: 8163685
references.citation: N Engl J Med. 1971 May 27;284(21):1185-93
references.pmid: 4929384
references.citation: Am J Med Genet A. 2003 Jul 1;120A(1):92-6
references.pmid: 12794699
references.citation: EMBO J. 2001 Sep 3;20(17):4762-73
references.pmid: 11532940
references.citation: Am J Respir Crit Care Med. 2011 Aug 15;184(4):449-58
references.pmid: 21616998