title: Neurotrophic tyrosine kinase receptor B/neurotrophin 4 signaling axis is perturbed in clinical and experimental pulmonary fibrosis.
abstract: The neurotrophins (NTs) are emerging as exciting new participants in normal lung physiology, as well as in several pathological processes in diseased lungs. In this study, the increased expression of NT4/5 and of its cognate receptor, the neurotrophic tyrosine kinase receptor Type 2 (TrkB), was observed in human lungs explanted from patients with idiopathic pulmonary fibrosis (IPF), and in lungs from mice with bleomycin-induced pulmonary fibrosis. The expression of NT4/5 and TrkB localized to hyperplastic alveolar Type II cells (ATII) and fibroblastic foci in affected lungs. Increased concentrations of NT4/5 and TrkB were evident in ATII isolated from the lungs of bleomycin-treated mice. Primary ATII were shown to secrete NT4/5 into the cell culture medium. The profibrotic cytokine transforming growth factor-β1, stimulated TrkB, but not NT4/5 gene expression, suggesting that perturbed profibrotic growth factor signaling in affected lungs may drive the expression of TrkB. NT4/5 enhanced the proliferation of ATII through a TrkB/extracellular-regulated kinase/protein kinase B pathway, and could also drive the proliferation of primary human and murine lung fibroblasts, through TrkB-dependent and protein kinase B-dependent pathways. Taken together, these data suggest that a dysregulated TrkB/NT4/5 axis may contribute to several of the pathological lesions associated with pulmonary fibrosis, including ATII hyperplasia and the proliferation of fibroblasts, and we would add IPF to the list of disorders, such as pain and cancer, for which therapeutic targeting of the TrkB/neurotrophin axis has been proposed for further investigation.
authors.affiliation: Department of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Klinikstrasse 36, D-35392 Giessen, Germany.
authors.forename: Sibel
authors.initials: S
authors.lastname: Avcuoglu
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.forename: Leigh M
authors.initials: LM
authors.lastname: Marsh
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Ludger
authors.initials: L
authors.lastname: Fink
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
authors.forename: Grażyna
authors.initials: G
authors.lastname: Kwapiszewska
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001761:Bleomycin; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation; D020813:Receptor, trkB
chemical_list: D001761:Bleomycin; D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009414:Nerve Growth Factors; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; C071951:neurotrophin 5; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB; C073922:neurotrophin 4