Abstract
Purpose
Many infants develop a postsurgical chylothorax after diaphragmatic hernia repair.
The pathogenesis remains elusive but may be owing to dysfunctional lymphatic development.
This study characterizes pulmonary lymphatic development in the nitrofen mouse model
of CDH.
Methods
CD1 pregnant mice were fed nitrofen/bisdiamine (N/B) or olive oil at E8.5. At E14.5
and E15.5, lung buds were categorized by phenotype: normal, N/B without CDH (N/B −
CDH), or N/B with CDH (N/B + CDH). Anti-CD31 was used to localize all endothelial cells, while anti-LYVE-1 was
used to identify lymphatic endothelial cells in lung buds using immunofluorescence.
Differential protein expression of lymphatic-specific markers was analyzed.
Results
Lymphatic endothelial cells localized to the mesenchyme surrounding the airway epithelium
at E15.5. CD31 and LYVE-1 colocalization identified lymphatic endothelial cells. LYVE-1
expression was upregulated in N/B + CDH lung buds in comparison to N/B − CDH and normal lung buds by immunofluorescence.
Western blotting shows that VEGF-D, LYVE-1, Prox-1, and VEGFR-3 expression was upregulated
in N/B + CDH lung buds in comparison to N/B − CDH or control lung buds at E14.5.
Conclusions
Lung lymphatics are hyperplastic in N/B + CDH. Upregulation of lymphatic-specific genes suggests that lymphatic hyperplasia
plays an important role in dysfunctional lung lymphatic development in the nitrofen
mouse model of CDH.
Key words
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References
- Survival of severe congenital diaphragmatic hernia has morbid consequences.J Pediatr Surg. 2005; 40 ([discussion 45–6]): 36-45
- Chylothorax after Bochadalek herniorrhaphy in a neonate. Treatment with intravenous hyperalimentation.J Thorac Cardiovasc Surg. 1973; 65: 200-206
- Chylothorax after congenital diaphragmatic hernia repair.J Pediatr Surg. 2009; 44 ([discussion 1185]): 1181-1185
- Pleural effusion requiring drainage in congenital diaphragmatic hernia: incidence, aetiology and treatment.Pediatr Surg Int. 2006; 22: 585-588
- Postoperative chylothorax in congenital diaphragmatic hernia.Eur J Pediatr Surg. 2010; 20: 391-394
- Chylothorax after repair of congenital diaphragmatic hernia–risk factors and morbidity.J Pediatr Surg. 1998; 33: 500-502
- Factors involved in chylothorax following repair of congenital posterolateral diaphragmatic hernia.J Pediatr Surg. 1986; 21: 809-811
- Chylothorax in congenital diaphragmatic hernia.Pediatr Surg Int. 2010; 26: 919-922
- Chylothorax after congenital diaphragmatic hernia repair: a population-based study.J Pediatr Surg. 2012; 47: 842-846
- The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature.Genes Dev. 2002; 16: 773-783
- Chylothorax complicating repair of congenital diaphragmatic hernia.Isr J Med Sci. 1992; 28: 891-892
- Chylothorax complicating ECMO and surgical repair of congenital diaphragmatic hernia.Isr J Med Sci. 1995; 31: 388-389
- Antenatal sildenafil treatment attenuates pulmonary hypertension in experimental congenital diaphragmatic hernia.Circulation. 2011; 123: 2120-2131
- Mesenchymal nuclear transcription factors in nitrofen-induced hypoplastic lung.J Surg Res. 2002; 108: 203-211
- Retinal dehydrogenase-2 is inhibited by compounds that induce congenital diaphragmatic hernias in rodents.Am J Pathol. 2003; 162: 673-679
- Lymphatic ontogeny and effect of hypoplasia in developing lung.Mech Dev. 2011; 128: 29-40
- Mesenchymal expression of vascular endothelial growth factors D and A defines vascular patterning in developing lung.Dev Dyn. 2002; 224: 144-153
- Proteolytic processing regulates receptor specificity and activity of VEGF-C.EMBO J. 1997; 16: 3898-3911
- Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers.J Biol Chem. 1999; 274: 32127-32136
- Lymphangiogenesis in development and disease.Novartis Found Symp. 2007; 283 ([discussion 98–105, 238–41]): 87-98
- Vascular endothelial growth factor D is dispensable for development of the lymphatic system.Mol Cell Biol. 2005; 25: 2441-2449
- Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins.Nat Immunol. 2004; 5: 74-80
- Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos.Mol Cell Biol. 2008; 28: 4843-4850
- A model for gene therapy of human hereditary lymphedema.Proc Natl Acad Sci USA. 2001; 98: 12677-12682
- Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase.Am J Hum Genet. 2000; 67: 295-301
- An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype.EMBO J. 2002; 21: 1505-1513
- Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1.Blood. 2010; 115: 418-429
- Lymphangiogenic growth factors, receptors and therapies.Thromb Haemost. 2003; 90: 167-184
- Prox1, master regulator of the lymphatic vasculature phenotype.Cell Tissue Res. 2003; 314: 85-92
- Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9.Microvasc Res. 2006; 72: 161-171
Article info
Publication history
Accepted:
March 8,
2013
Received:
February 21,
2013
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
