title: Preferential lymphatic growth in bronchus-associated lymphoid tissue in sustained lung inflammation.
abstract: Lymphatics proliferate, become enlarged, or regress in multiple inflammatory lung diseases in humans. Lymphatic growth and remodeling is known to occur in the mouse trachea in sustained inflammation, but whether intrapulmonary lymphatics exhibit similar plasticity is unknown. We examined the time course, distribution, and dependence on vascular endothelial growth factor receptor (VEGFR)-2/VEGFR-3 signaling of lung lymphatics in sustained inflammation. Lymphatics in mouse lungs were examined under baseline conditions and 3 to 28 days after Mycoplasma pulmonis infection, using prospero heomeobox 1-enhanced green fluorescence protein and VEGFR-3 as markers. Sprouting lymphangiogenesis was evident at 7 days. Lymphatic growth was restricted to regions of bronchus-associated lymphoid tissue (BALT), where VEGF-C-producing cells were scattered in T-cell zones. Expansion of lung lymphatics after infection was reduced 68% by blocking VEGFR-2, 83% by blocking VEGFR-3, and 99% by blocking both receptors. Inhibition of VEGFR-2/VEGFR-3 did not prevent the formation of BALT. Treatment of established infection with oxytetracycline caused BALT, but not the lymphatics, to regress. We conclude that robust lymphangiogenesis occurs in mouse lungs after M. pulmonis infection through a mechanism involving signaling of both VEGFR-2 and VEGFR-3. Expansion of the lymphatic network is restricted to regions of BALT, but lymphatics do not regress when BALT regresses after antibiotic treatment. The lung lymphatic network can thus expand in sustained inflammation, but the expansion is not as reversible as the accompanying inflammation.
authors.affiliation: Department of Anatomy, the Cardiovascular Research Institute, and the Comprehensive Cancer Center, University of California, San Francisco, California. Electronic address: peter.baluk@ucsf.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Baluk
authors.affiliation: Department of Anatomy, the Cardiovascular Research Institute, and the Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Alicia
authors.initials: A
authors.lastname: Adams
authors.affiliation: Department of Anatomy, the Cardiovascular Research Institute, and the Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Keeley
authors.initials: K
authors.lastname: Phillips
authors.affiliation: Department of Anatomy, the Cardiovascular Research Institute, and the Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Feng
authors.affiliation: Departments of Surgery, Biochemistry, and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Young-Kwon
authors.initials: YK
authors.lastname: Hong
authors.affiliation: Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, Florida.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Brown
authors.affiliation: Department of Anatomy, the Cardiovascular Research Institute, and the Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000382:microbiology / Q000473:pathology*; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000187:drug effects / Q000382:microbiology / Q000473:pathology*; D008221:Lymphoid Tissue / Q000187:drug effects / Q000382:microbiology / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009175:Mycoplasma Infections / Q000150:complications / Q000382:microbiology / Q000473:pathology; D045803:Mycoplasma pulmonis / Q000187:drug effects / Q000502:physiology; D011014:Pneumonia / Q000150:complications / Q000382:microbiology / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3