Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation
Peter Baluk, … , Kari Alitalo, Donald M. McDonald
Peter Baluk, … , Kari Alitalo, Donald M. McDonald
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):247-257. https://doi.org/10.1172/JCI22037.
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Article Angiogenesis

Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation

Abstract

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.

Authors

Peter Baluk, Tuomas Tammela, Erin Ator, Natalya Lyubynska, Marc G. Achen, Daniel J. Hicklin, Michael Jeltsch, Tatiana V. Petrova, Bronislaw Pytowski, Steven A. Stacker, Seppo Ylä-Herttuala, David G. Jackson, Kari Alitalo, Donald M. McDonald

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Figure 7

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Role of lymphangiogenesis in airway inflammation. The diagram shows rela...
Role of lymphangiogenesis in airway inflammation. The diagram shows relationships of changes in lymphatic vessels (red), blood vessels (green), inflammatory cells (blue), and plasma leakage (short arrows) in inflamed airway mucosa. Cross-sections of bronchi and vessel schematics compare 4 conditions. (I) In normal airways, blood vessels have little or no leukocyte traffic; baseline leakage drains via lymphatic vessels. (II) After infection, activated antigen-presenting cells traffic from airways to local lymph nodes, evoking an immune response. Mucosal capillaries remodel into activated venules that mediate leukocyte influx. These cells release VEGF-C and VEGF-D, which drive lymphangiogenesis via VEGFR-3 signaling in lymphatic endothelial cells. The lymphatic network expands by sprouting from existing lymphatic vessels to accommodate the increased leakage from venules and increased trafficking of immune cells to lymph nodes. (III) If lymphangiogenesis does not occur, leakage exceeds drainage, bronchial lymphedema develops, trafficking of immune cells to lymph nodes decreases, and the immune response is reduced. (IV) Treatment decreases the inflammatory stimulus, allowing blood vessels to return to the baseline state. Leukocyte influx decreases, and the stimulus for lymphangiogenesis diminishes, but lymphatic vessels that formed during the infection persist – ready for the next infection.