title: Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis.
abstract: Pulmonary fibrosis is a progressive disease with unknown etiology that is characterized by extensive remodeling of the lung parenchyma, ultimately resulting in respiratory failure. Lymphatic vessels have been implicated with the development of pulmonary fibrosis, but the role of the lymphatic vasculature in the pathogenesis of pulmonary fibrosis remains enigmatic. Here we show in a murine model of pulmonary fibrosis that lymphatic vessels exhibit ectopic mural coverage and that this occurs early during the disease. The abnormal lymphatic vascular patterning in fibrotic lungs was driven by expression of platelet-derived growth factor B (PDGF-B) in lymphatic endothelial cells and signaling through platelet-derived growth factor receptor (PDGFR)-β in associated mural cells. Because of impaired lymphatic drainage, aberrant mural cell coverage fostered the accumulation of fibrogenic molecules and the attraction of fibroblasts to the perilymphatic space. Pharmacologic inhibition of the PDGF-B/PDGFR-β signaling axis disrupted the association of mural cells and lymphatic vessels, improved lymphatic drainage of the lung, and prevented the attraction of fibroblasts to the perilymphatic space. Our results implicate aberrant mural cell recruitment to lymphatic vessels in the pathogenesis of pulmonary fibrosis and that the drainage capacity of pulmonary lymphatics is a critical mediator of fibroproliferative changes.
authors.affiliation: Institut für Physiologie, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Anna-Katharina
authors.initials: AK
authors.lastname: Meinecke
authors.forename: Nadine
authors.initials: N
authors.lastname: Nagy
authors.forename: Gabriela D'Amico
authors.initials: GD
authors.lastname: Lago
authors.forename: Santina
authors.initials: S
authors.lastname: Kirmse
authors.forename: Ralph
authors.initials: R
authors.lastname: Klose
authors.forename: Katrin
authors.initials: K
authors.lastname: Schrödter
authors.forename: Annika
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Iris
authors.initials: I
authors.lastname: Helfrich
authors.forename: Helene
authors.initials: H
authors.lastname: Rundqvist
authors.forename: Dirk
authors.initials: D
authors.lastname: Theegarten
authors.forename: Olaf
authors.initials: O
authors.lastname: Anhenn
authors.forename: Véronique
authors.initials: V
authors.lastname: Orian-Rousseau
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.forename: Christian
authors.initials: C
authors.lastname: Stockmann
mesh_terms: D000818:Animals; D002465:Cell Movement; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010498:Perilymph / Q000378:metabolism; D010766:Phosphorylation; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D006820:Hyaluronic Acid; D020797:Receptor, Platelet-Derived Growth Factor beta