Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation

J Clin Invest. 2005 Feb;115(2):247-57. doi: 10.1172/JCI22037.


Edema occurs in asthma and other inflammatory diseases when the rate of plasma leakage from blood vessels exceeds the drainage through lymphatic vessels and other routes. It is unclear to what extent lymphatic vessels grow to compensate for increased leakage during inflammation and what drives the lymphangiogenesis that does occur. We addressed these issues in mouse models of (a) chronic respiratory tract infection with Mycoplasma pulmonis and (b) adenoviral transduction of airway epithelium with VEGF family growth factors. Blood vessel remodeling and lymphangiogenesis were both robust in infected airways. Inhibition of VEGFR-3 signaling completely prevented the growth of lymphatic vessels but not blood vessels. Lack of lymphatic growth exaggerated mucosal edema and reduced the hypertrophy of draining lymph nodes. Airway dendritic cells, macrophages, neutrophils, and epithelial cells expressed the VEGFR-3 ligands VEGF-C or VEGF-D. Adenoviral delivery of either VEGF-C or VEGF-D evoked lymphangiogenesis without angiogenesis, whereas adenoviral VEGF had the opposite effect. After antibiotic treatment of the infection, inflammation and remodeling of blood vessels quickly subsided, but lymphatic vessels persisted. Together, these findings suggest that when lymphangiogenesis is impaired, airway inflammation may lead to bronchial lymphedema and exaggerated airflow obstruction. Correction of defective lymphangiogenesis may benefit the treatment of asthma and other inflammatory airway diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae
  • Airway Obstruction
  • Animals
  • Bronchi / blood supply*
  • Bronchi / metabolism
  • Bronchi / microbiology
  • Bronchi / pathology
  • Chronic Disease
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Endothelial Growth Factors
  • Gene Expression Regulation / genetics
  • Hyperplasia / microbiology
  • Hyperplasia / pathology
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / microbiology
  • Inflammation / pathology
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymphatic Vessels / metabolism*
  • Lymphatic Vessels / pathology*
  • Macrophages, Alveolar / metabolism
  • Macrophages, Alveolar / pathology
  • Mice
  • Mice, Inbred C3H
  • Mycoplasma Infections / metabolism*
  • Mycoplasma Infections / pathology
  • Mycoplasma pulmonis*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / microbiology
  • Neovascularization, Pathologic / pathology
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Pulmonary Edema / genetics
  • Pulmonary Edema / microbiology
  • Pulmonary Edema / pathology
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / microbiology
  • Respiratory Mucosa / pathology
  • Signal Transduction / genetics
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor D / genetics
  • Vascular Endothelial Growth Factor D / metabolism


  • Endothelial Growth Factors
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor D