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Neurotrophic tyrosine kinase receptor B/neurotrophin 4 signaling axis is perturbed in clinical and experimental pulmonary fibrosis.
- Source :
-
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2011 Oct; Vol. 45 (4), pp. 768-80. Date of Electronic Publication: 2011 Feb 17. - Publication Year :
- 2011
-
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.
- Subjects :
- Alveolar Epithelial Cells drug effects
Alveolar Epithelial Cells pathology
Animals
Bleomycin
Brain-Derived Neurotrophic Factor metabolism
Cell Proliferation
Cells, Cultured
Disease Models, Animal
Female
Fibroblasts drug effects
Fibroblasts pathology
Humans
Hyperplasia
Lung drug effects
Lung pathology
Male
Membrane Glycoproteins antagonists & inhibitors
Mice
Mice, Inbred C57BL
Middle Aged
Mitogen-Activated Protein Kinase 1 antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 metabolism
Phosphorylation
Protein Kinase Inhibitors pharmacology
Protein-Tyrosine Kinases antagonists & inhibitors
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Proto-Oncogene Proteins c-akt metabolism
Pulmonary Fibrosis chemically induced
Pulmonary Fibrosis pathology
Time Factors
Up-Regulation
Alveolar Epithelial Cells metabolism
Fibroblasts metabolism
Lung metabolism
Membrane Glycoproteins metabolism
Nerve Growth Factors metabolism
Protein-Tyrosine Kinases metabolism
Pulmonary Fibrosis metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4989
- Volume :
- 45
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of respiratory cell and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 21330466
- Full Text :
- https://doi.org/10.1165/rcmb.2010-0195OC