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Netrin-1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin-Induced Pulmonary Fibrosis.
- Source :
-
Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2016 May; Vol. 68 (5), pp. 1251-61. - Publication Year :
- 2016
-
Abstract
- Objective: Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells.<br />Methods: We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc-related ILD were cultured on these scaffolds, and CD45+pro-ColIα1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin-1(+/-) mice.<br />Results: Compared with control lung scaffolds, lung scaffolds from patients with SSc-related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc-related ILD increased production of pro-ColIα1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc-related ILD demonstrated increased pro-ColIα1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin-1-expressing CD14(low) cells in patients with SSc-related ILD was observed, and antibody-mediated netrin-1 neutralization attenuated detection of CD45+pro-ColIα1+ cells in all settings. Netrin-1(+/-) mice were protected against bleomycin-induced lung fibrosis and fibrocyte accumulation.<br />Conclusion: Factors present in the lung matrices of patients with scleroderma regulate fibrocyte accumulation via a netrin-1-dependent pathway. Netrin-1 regulates bleomycin-induced pulmonary fibrosis in mice. Netrin-1 might be a novel therapeutic target in SSc-related ILD.<br /> (© 2016, American College of Rheumatology.)
- Subjects :
- Animals
Antibiotics, Antineoplastic toxicity
Antibodies, Neutralizing pharmacology
Biomechanical Phenomena
Bleomycin toxicity
Case-Control Studies
Cell Differentiation
Collagen metabolism
Collagen Type I metabolism
Collagen Type I, alpha 1 Chain
Fibrosis
Flow Cytometry
Fluorescent Antibody Technique
Heterozygote
Humans
Leukocyte Common Antigens metabolism
Leukocytes, Mononuclear
Lung drug effects
Lung pathology
Lung Diseases, Interstitial etiology
Lung Diseases, Interstitial pathology
Mice
Mice, Knockout
Microscopy, Electron, Scanning
Nerve Growth Factors antagonists & inhibitors
Nerve Growth Factors genetics
Netrin-1
Proteomics
Pulmonary Fibrosis chemically induced
Pulmonary Fibrosis pathology
Reverse Transcriptase Polymerase Chain Reaction
Scleroderma, Systemic complications
Tissue Scaffolds
Tumor Suppressor Proteins antagonists & inhibitors
Tumor Suppressor Proteins genetics
Lung metabolism
Lung Diseases, Interstitial metabolism
Nerve Growth Factors metabolism
Pulmonary Fibrosis metabolism
Scleroderma, Systemic metabolism
Tumor Suppressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2326-5205
- Volume :
- 68
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Arthritis & rheumatology (Hoboken, N.J.)
- Publication Type :
- Academic Journal
- Accession number :
- 26749424
- Full Text :
- https://doi.org/10.1002/art.39575