title: 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.affiliation: Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy, UCSF, San Francisco, California 94143, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Baluk
authors.forename: Tuomas
authors.initials: T
authors.lastname: Tammela
authors.forename: Erin
authors.initials: E
authors.lastname: Ator
authors.forename: Natalya
authors.initials: N
authors.lastname: Lyubynska
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Michael
authors.initials: M
authors.lastname: Jeltsch
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
authors.forename: Bronislaw
authors.initials: B
authors.lastname: Pytowski
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: David G
authors.initials: DG
authors.lastname: Jackson
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000256:Adenoviridae; D000402:Airway Obstruction; D000818:Animals; D001980:Bronchi / Q000098:blood supply* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D002908:Chronic Disease; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D016228:Endothelial Growth Factors; D005786:Gene Expression Regulation / Q000235:genetics; D006965:Hyperplasia / Q000382:microbiology / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D042601:Lymphatic Vessels / Q000378:metabolism* / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D009175:Mycoplasma Infections / Q000378:metabolism* / Q000473:pathology; D045803:Mycoplasma pulmonis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D011654:Pulmonary Edema / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics / Q000378:metabolism
chemical_list: D016228:Endothelial Growth Factors; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D